A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer
Phase: PHASE2
Conditions: Borderline Ovarian Serous Tumor, Micropapillary Serous Carcinoma, Ovarian Serous Adenocarcinoma, Primary Peritoneal Serous Adenocarcinoma, Recurrent Ovarian Low Grade Serous Adenocarcinoma, Recurrent Primary Peritoneal Serous Adenocarcinoma
Sponsor: National Cancer Institute (NCI)

 
 
 
 
 
NCI Protocol #: GOG-0281 
NCI Version Date: July 24, 2020 
Amendment 20 
 
# 
Section 
Comments 
 
1 
Title Page 
• NCI Version date has been updated 
• Amendment 20 added 
 
2 
4.6 
• Trametinib language updated with current DSMO language 
received in RA received from Dr. Johnson on June 5, 2020 
 
3 
ICF 
• Version date has been updated. 
• No other changes were made to ICF 
 

 
 
 
 
 
PROTOCOL GOG-0281 
A RANDOMIZED PHASE II/III STUDY TO ASSESS THE EFFICACY OF TRAMETINIB (GSK 
1120212) IN PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE SEROUS 
OVARIAN CANCER OR PERITONEAL CANCER. NCT # NCT02101788 (07/28/14) 
NCI Version Date: July 24, 2020 
Includes Amendments 1-20 
POINTS: 
PER CAPITA - 
MEMBERSHIP – 
 TR PER CAPITA – Award based on specimen submission with 1.0 point for the frozen biopsy and 1.0 point for 
each FFPE and plasma (MAX = 7.0).  Note: PK plasma will be collected from approximately 12 GOG and 12 
UK patients. 
Lead Organization: NRG / NRG Oncology (07/28/14) 
 
 
 
 
 
STUDY CHAIR 
STUDY CO-CHAIR(S) 
DAVID M. GERSHENSON, MD 
JOHN FARLEY, M.D.  
THE UNIV. OF TEXAS, M.D. ANDERSON 
See GOG Website Directory 
CANCER CENTER. 
DEPARTMENT OF GYN/ONC, UNIT 1362 
 
QOL CO-CHAIR 
PO BOX 301439 
 
 
 
 
LARI B. WENZEL, PHD 
HOUSTON TX, 77230 1439 
 
 
 
See GOG Website Directory 
(713)-745-2565 
FAX: (713) 745-3510 
EMAIL: dgershen@mdanderson.org 
 
TR CO-CHAIR 
SCIENTIFIC COLLABORATORS 
ANIL SOOD, MD  
KWONG WONG, PHD
 
 
 
See GOG Website Directory  
 
 
JAMES BRENTON, MB, PHD 
 
 
 
NURSE CONTACT   
 
 
 
PATHOLOGIST 
HEESUN KIM-SUH, BSN, RN 
WILLIAM H RODGERS, MD, PHD 
See GOG Website Directory  
 
 
See GOG Website Directory 
 
STATISTICIAN 
 
 
 
 
TR SCIENTIST 
AUSTIN MILLER, PH.D. 
HEATHER A LANKES, PHD, MPH 
See GOG Website Directory  
 
 
See GOG Website Directory 
 
 
 
OPEN TO PATIENT ENTRY FEBRUARY 27, 2014: REVISED JULY 28, 2014; REVISED DECEMBER 22, 
2014; REVISED JUNE 8, 2015; REVISED AUGUST 17, 2015; REVISED NOVEMBER 30, 2015; REVISED 
DECEMBER 14, 2015, TEMPORARILY CLOSED TO ACCRUAL FEBRUARY 2, 2016; REVISED MARCH 21, 
2016; REOPENED TO PATIENT ENTRY APRIL 11, 2016; REVISED MAY 31, 2016; CLOSED TO ACCRUAL 
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be 
used only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction 
is authorized by GOG nor does GOG assume any responsibility for unauthorized use of this protocol. 
Participating Organizations (07/28/14) 
ALLIANCE / Alliance for Clinical Trials in Oncology 
ECOG-ACRIN / ECOG-ACRIN Cancer Research Group 
SWOG / SWOG

 
 
2 
 
IN THE US ONLY JUNE 29, 2016; REOPENED TO ACCRUAL IN THE US AND REVISED SEPTEMBER 19, 
2016; REVISED JANUARY 16, 2017; CLOSED TO ACCRUAL IN THE US ONLY APRIL 28, 2017: REVISED 
JUNE 26, 2017 REOPENED TO ACCRUAL IN THE US AND REVISED NOVEMBER 27, 2017; REVISED 
FEBRUARY 5, 2018: REVISED 
 
PROTOCOL GOG-0281 
A RANDOMIZED PHASE II/III STUDY TO ASSESS THE EFFICACY OF TRAMETINIB (GSK 
1120212) IN PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE SEROUS 
OVARIAN CANCER OR PERITONEAL CANCER. NCT #NCT02101788 (07/28/14) 
 
 
 
NCI Version Date: July 24, 2020 
 
CONTACT INFORMATION (07/28/14)(02-JUN-2020) 
 
For regulatory requirements: 
For patient enrollments: 
For data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the Regulatory Submission 
Portal. 
 (Sign in at www.ctsu.org, and 
select the Regulatory > 
Regulatory Submission.)  
 
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) is accessed at 
https://www.ctsu.org/OPEN_SYS
TEM/ or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk 
with any OPEN-related questions 
by phone or email : 1-888-823-
5923, or 
ctsucontact@westat.com. 
 
Data collection for this study 
will be done exclusively through 
Medidata Rave.  Please see the 
data submission section of the 
protocol for further instructions.  
 
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 in with a 
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) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
For detailed information on the regulatory and monitoring procedures for CTSU sites please 
review the CTSU Regulatory and Monitoring Procedures policy located on the CTSU members’ website   
https://www.ctsu.org  > education and resources tab > CTSU Operations Information >CTSU 
Regulatory and Monitoring Policy 

 
 
3 
 
The CTSU Website is located at https://www.ctsu.org. 
ATTENTION: UK SITES (NIHR Clinical Research Network Cancer) Please refer to the UK group specific 
appendix to protocol (Appendix VII) for important UK site specific protocol information 

 
4 
 
PROTOCOL GOG-0281 
A RANDOMIZED PHASE II/III STUDY TO ASSESS THE EFFICACY OF TRAMETINIB (GSK 
1120212) IN PATIENTS WITH RECURRENT OR PROGRESSIVE LOW-GRADE SEROUS 
OVARIAN CANCER OR PERITONEAL CANCER. NCT #NCT02101788 (07/28/14) 
NCI Version Date: July 24, 2020 
 
CRCTU / Cancer Research UK Clinical Trials Unit: (08/17/15) (11/30/15) (12/14/15) (03/21/16) 
(05/31/16) (09/19/16) (06/26/17) 
 
 
Institution Name 
Institution 
CTEP ID 
Investigator Name 
Investigator  CTEP 
ID 
Beatson West of Scotland Cancer 
Centre 
64017 
Dr Rosalind Glasspool 
55234 
Western General Hospital 
64006 
Professor Charles Gourley 
55329 
Christie Hospital 
25113 
Dr Andrew  Clamp 
55963 
Musgrove Park Hospital 
25102 
Dr Clare Barlow 
55807 
St Bartholomew’s Hospital 
25050 
Dr Melanie Powell 
56284 
University College London 
Hospital 
98013 
Dr Rebecca Kristeleit 
55929 
Hammersmith Hospital 
25067 
Professor Hani Gabra 
56215 
Addenbrookes Hospital-
Medical School 
25018 
Dr Helena Earl 
14680 
Royal Marsden Institute of 
Cancer Research 
25094 
Dr Susana Banerjee 
56316 
Bristol Haematology and 
Oncology Centre 
98015 
Dr Axel Walther 
56827 
Nottingham City Hospital 
25155 
Dr Anjana Anad 
57767 
Belfast City Hospital 
39013 
Dr Joanne Millar 
57325 
Saint James’s University 
Hospital 
25011 
Dr Geoff Hall 
57317 
Velindre Hospital 
25171 
Dr Emma Hudson 
58710 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
5 
 
 
SCHEMA
 
 
R
 
L O G S 
 
Stu d y
 
T r i al S ch em a  
 
Ar m
 
A  
 
=
 
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In ves gat o r s 
 
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• 
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mg / m 2 
 
ov e r 3 0 min
 
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1,  8
 
and 
 
15  
 
of
 
a 2 8 
 
day 
 
cycl e
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1 
 
cyc le =
 
28 
 
da ys  
A r m B = E xp eri men tal A rm 
Trame nib 
 
2 mg p o 
 
da ily
 
c on nuous 
 
t r e at m ent
 
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=
 
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S e c ondary e nd p o i n ts : 
 
•   
A dv er se e ff e c ts 
 
•   
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•   
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s u r vi v a l 
 
•   
M o le c u l a r
 
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•   
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12
 
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Scre eni ng,  th en
 
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Pr o gr es si o n 
 
Off S t u d y 

GOG-0281 
 
6 
 
TABLE OF CONTENTS 
PAGE 
1.0 
OBJECTIVES 
 
9 
1.1 
Primary objective: 
9 
1.2 
Secondary objectives: 
9 
2.0 
BACKGROUND AND RATIONALE 
 
9 
2.1 
Clinical Research Background 
9 
2.2 
Translational Research Background 
21 
2.3 
Integrated Biomarker Studies 
21 
2.4 
Inclusion of Women and Minorities 
22 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
23 
3.1 
Eligible Patients (06/08/15) 
23 
3.2 
Ineligible Patients 
25 
4.0 
STUDY MODALITIES 
 
28 
4.1 
Letrozole (Femara) (NSC #719435) 
28 
4.2 
Tamoxifen Citrate (Nolvadex®) (NSC #180973) 
28 
4.3 
Pegylated Liposomal Doxorubicin (DOXIL®, NSC #712227, Lipodox™) 
28 
4.4 
Topotecan (NSC #609699) 
30 
4.5 
Paclitaxel (NSC#673089) 
31 
4.6 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) (06/08/15) 
31 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (02-JUN-2020) 
38 
5.1 
Registration Procedures (07/28/14) 
38 
5.2 
Patient Screening (07/28/14) (06/08/15) 
41 
5.3 
Patient Entry and Registration  (07/28/14) 
42 
5.4 
Treatment Plan 
43 

GOG-0281 
 
7 
 
6.0 
TREATMENT MODIFICATIONS 
 
46 
6.1 
Control Treatments 
46 
6.2 
Trametinib 
46 
7.0 
STUDY PARAMETERS 
 
64 
7.1 
Tests and Observations (07/28/14)(06/08/15) 
64 
7.2 
Pathology Requirements 
65 
7.3 
Translational Research 
66 
7.4 
Quality of Life (12/22/14) 
68 
8.0 
EVALUATION CRITERIA 
 
71 
8.1 
Antitumor Effect – Solid Tumors 
71 
9.0 
DURATION OF STUDY 
 
79 
9.1 
Patients will receive therapy until disease progression or intolerable toxicity 
79 
9.2 
All patients will be treated (with completion of all required case report forms) 79 
9.3 
All patients will be followed for 10 years after removal from study or until death,
 
 
79 
9.4 
In the absence of treatment delays due to adverse event(s), treatment may 
79 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES 
80 
10.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT   
(CTEP IND) 
80 
10.2 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT (06/08/15)
 
83 
10.3 
Medidata Rave Data Submission and Reporting (07/28/14)(03/21/16) 
86 
10.4 
GOG DATA MANAGEMENT FORMS (06/08/15) 
87 
11.0 
STATISTICAL CONSIDERATIONS 
 
91 
11.1 
Design Summary 
91 

GOG-0281 
 
8 
 
11.2 
Principal Parameters 
91 
11.3 
Accrual Goal, Accrual Rate, and Study Duration 
92 
11.4 
Design and Analyses for the Primary Objective 
92 
11.5 
Interim Analysis (11/27/17) 
93 
11.6 
Monitoring Adverse Events and the Role of the GOG DSMB 
93 
11.7 
Analyses for Secondary Objectives 
94 
11.8 
Analyses for Integrated Biomarker Objectives 
97 
11.9 
Anticipated Gender and Minority Inclusion 
101 
12.0 
BIBLIOGRAPHY 
 
102 
APPENDIX I - CRADA/CTA LANGUAGE 
 
107 
APPENDIX II - NRG Oncology General Therapy Guidelines (06/08/15) 
109 
APPENDIX III - New York Heart Association Classifications 
110 
APPENDIX IV – Translational Research Specimen Procedures (07/28/14)(06/08/15) (11/27/17) 111 
APPENDIX V - Patient Medication Calendar (12/22/14) 
116 
APPENDIX VI – FROZEN BIOPSY PATHOLOGY VERIFICATION (12/22/14) (11/27/17) 
117 
APPENDIX VII – Translational Research Laboratory Testing Procedures 
118 
APPENDIX VIII - UK Group Specific Appendix to GOG protocol (GOG-0281) (07/28/14) 
(12/14/15) (05/31/16) (09/19/16) (01/16/17) 
  
126 
 
 

GOG-0281 
 
9 
 
1.0 
OBJECTIVES  
 
1.1 
Primary objective: 
1.11 
To estimate the progression-free survival (PFS) hazard ratio of trametinib 
compared to that of “commercially available therapies” consisting of one 
of five commercially available agents in women with recurrent low-grade 
serous carcinoma of the ovary or peritoneum previously treated with 
platinum-based chemotherapy. 
 
1.2 
Secondary objectives:  
1.21 
To determine the nature, frequency and maximum degree of toxicity as 
assessed by CTCAE v4 for each treatment arm 
1.22 
To determine the quality of life, as assessed by the FACT-O  
1.221 To compare trametinib to the control arm with regard to patients’ 
self-reported acute (up to post-cycle 6) quality of life as measured 
by the FACT-O-TOI. 
1.222 To compare trametinib to the control arm with regard to patients’ 
self-reported acute (up to post-cycle 6) neurotoxicity as measured 
by the FACT-GOG-NTX. 
1.23 
To estimate the objective response rate (RR) of patients in each treatment 
arm.  
1.24 
To test whether high expression of pERK, as quantified by 
immunohistochemistry (IHC), is associated with better prognosis (RR or 
PFS) among patients receiving the randomized treatment. 
 
1.25  To test whether genetic changes associated with MAPK pathway 
activation (KRAS, NRAS, HRAS, BRAF, MEK,ERBB2 or NF1) are 
associated with improved prognosis (RR or PFS) among patients receiving 
the randomized treatment. 
 
2.0 
BACKGROUND AND RATIONALE 
 
2.1 
Clinical Research Background 
 
 
Serous carcinoma represents the most common histologic subtype of epithelial 
ovarian cancer. Although histologic grade has been found to be a major 
prognostic factor in women with epithelial ovarian cancer, no universal grading 
system exists.1-5 After almost 20 years of analysis and refinement of the system, 
investigators at MD Anderson Cancer Center proposed a two-tier grading system 
for serous carcinoma of the ovary and subsequently found it to be highly 
reproducible, with excellent interobserver and intraobserver agreement.6, 7 
Importantly, a recent GOG study indicated that the two-tier grading system for 
serous carcinoma is superior to that of the International Federation of Gynecology 
and Obstetrics (FIGO).8 Concomitantly, several other studies provided substantial 

GOG-0281 
 
10 
 
evidence to suggest that serous ovarian tumors of low malignant potential and 
low-grade serous carcinomas exist on a continuum and have molecular signatures 
and clinical behaviors distinct from those of the high-grade variety.9-23 
 
Compared with other subtypes of ovarian cancer, advanced stage low-grade 
serous carcinoma is associated with a younger age at diagnosis and significantly 
longer overall survival but a higher rate of persistent disease at completion of 
primary platinum-based chemotherapy.20 Confirmatory evidence of the relative 
chemoresistance of low-grade serous carcinoma is found in the MD Anderson 
experience with neoadjuvant chemotherapy for this disease.22 Recurrent low-
grade serous carcinoma may occur after an original diagnosis of serous tumor of 
low malignant potential or after a diagnosis of primary low-grade serous 
carcinoma. 
 
Recurrences that are observed after a primary diagnosis of serous tumor of low 
malignant potential are low-grade serous carcinomas in 75-80% of cases.24, 25 
Whether recurrent low-grade serous carcinoma is diagnosed after an original 
diagnosis of serous tumor of low malignant potential or primary low-grade serous 
carcinoma, there is no standard therapy approach, both in terms of choice of agent 
or sequencing of agents. Because the overall survival of this patient cohort is 
prolonged, women typically receive multiple different treatments. Therapeutic 
options currently include conventional chemotherapy or hormonal therapy. 
Preliminary data suggest that recurrent low-grade serous carcinomas are relatively 
resistant to conventional chemotherapy agents, with an objective response rate of 
<5% but a stable disease rate of 60%.22 In another report from the MD Anderson 
group, a variety of hormonal agents were found to result in a response rate of 9% 
among 64 patients who received a total of 89 hormonal regimens, but with a 
stable disease rate of 62%. 26  Median progression-free survival rates in these two 
reports was 7.2 and 7.4 months, respectively. Whether the high rate of stable 
disease relates more to tumor biology or the effects of therapy remains unclear. 
Nevertheless, findings to date appear to warrant separate clinical trials for women 
with low-grade serous carcinoma of the ovary using novel targeted agents. 
 
Current therapies licensed for use in relapsed serous ovarian cancer following 
platinum-based chemotherapy are pegylated liposomal doxorubicin (Caelyx), 
weekly paclitaxel (Taxol) and topotecan (Hycamtin). Letrozole (Femara) and 
tamoxifen (Nolvadex) are often treatments of choice in this disease as well due to 
its indolent nature and poor response to cytotoxic therapeutics. However, there is 
little to no prospective evidence to assess their efficacy. High expression of ER 
and PR is seen providing a rationale for aromatase inhibitor therapy where a 
response rate of 9% is observed.19, 26 These studies are based on retrospective 
data, and therefore, prospective study of targeted biological agents compared with 
available chemotherapeutic or hormonal agents is warranted. 
Through the Gynecologic Oncology Group Rare Tumor Committee, the first 
national trial exclusively for patients with recurrent low-grade serous 
carcinoma—GOG-0239—was activated in December 2007 and closed to accrual 
in November 2009. This phase II trial studied the response rate of the MEK 

GOG-0281 
 
11 
 
inhibitor, Selumetinib, in the treatment of 52 women with recurrent low-grade 
serous carcinoma of the ovary or peritoneum.27 Fifty-eight percent of the women 
had received three or more prior chemotherapy regimens. This study 
demonstrated a response rate to Selumetinib of 15.4% and a stable disease rate of 
65%. Furthermore, the median progression-free survival time was 11 months—
almost four months better than observed with chemotherapy or hormonal 
therapies in the MD Anderson reports. There were no treatment-related deaths. 
Grade 3 toxicities that occurred in more than one patient were gastrointestinal 
(13), dermatological (9), metaboli (7), fatigue (6), anemia (4), pain (4), 
constitutional (3), and cardiac events (2). Grade 4 toxicities were cardiac (1), 
pain (1), and pulmonary events (1). Mutational analysis of formalin-fixed, 
paraffin-embedded tissue from 34 patients with sufficient DNA was conducted; 
38% had no mutation, 6% had BRAF mutation, 41% had KRAS mutation, and 
15% had NRAS mutations. This analysis failed to demonstrate a correlation 
between mutation status and response. However, only primary tumor was 
available in 28/34 patients. In the present study, recurrent tissue will be studied 
in all patients using next generation sequencing, which will exclude issues with 
spacial or temporal biomarker instability. In addition, in as yet unpublished data, 
33 of the 52 patients had pERK data available. Using a cut point of 109, there 
were statisically significant differences in the proportion of patients with 
complete or partial responses by any mutation (refer Table 1 in Appendix VII). 
Nevertheless, based on the promising response findings of this study, continuing 
to pursue the study of  novel agents that target the MAP kinase pathway using a 
superior translational research design appears to be warranted. It is quite likely 
that the MAP kinase pathway is not linear and that we do not yet fully 
understand the complex circuitry under which it functions.  
 
Singer et al. initially reported that the MAP kinase pathway may play a role in the 
pathogenesis of low-grade serous carcinoma.10 In that study, 68% of low-grade 
serous carcinomas were found to have mutations in BRAF or KRAS (33% and 
35%, respectively).10 By comparison, the incidence of activation of this pathway 
in high-grade serous ovarian cancer is low, with p53 mutations being the 
predominant molecular lesion along with mutations or epigenetic inactivation of 
BRCA1 or BRCA2. While subsequent studies have confirmed the relatively high 
frequency of KRAS mutations in low-grade serous carcinoma—19% in an MD 
Anderson report28 and 41% in the GOG-0239 trial—BRAF mutations appear to 
be much less common than originally thought—2% in the MD Anderson series28 
and 6% in GOG-0239. Clearly, elucidating the mechanisms of action of agents 
that target this pathway in serous ovarian cancer is warranted. 
 
Marked in vitro and in vivo sensitivity to a MEK inhibitor has been demonstrated 
in KRAS and BRAF mutated ovarian cancers,29 suggesting that patients with this 
tumor type may benefit. In patients with BRAF V600E/K mutated melanoma, 
40% had a complete or partial response to GSK1120212, a reversible highly 
selective allosteric inhibitor of MEK1 and MEK2, which is now in Phase III 
trials. 

GOG-0281 
 
12 
 
Further support for this type of clinical trial is provided by a Gynecologic Cancer 
Inter Group (GCIG) Ovarian Cancer Consensus Conference held in Vancouver, 
BC, in 2010, in which the consensus was to recommend separate clinical trials 
for women with low-grade serous carcinoma.30 Subsequently, a National Cancer 
Institute Clinical Trials Planning Meeting held in Philadelphia in October 2011 
agreed with this strategy [manuscript in preparation]. 
 
Upon progression of disease, patients on the standard treatment arm will be 
allowed to crossover to the experimental arm.  While this complicates the 
interpretation of the comparison of overall survival (OS) between the two arms of 
the study and may even preclude meaningful interpretation of that endpoint, OS is 
not the primary endpoint of the study.  Moreover, this patient population’s long 
overall survival prognosis could make an OS comparison largely impractical 
anyway.  And lastly, there are potentially other MEK inhibitors entering trials in 
this population, which could make crossover to a similar treatment regimen a 
likely possibility even outside this trial. 
If a positive result is observed, with the MEK inhibitor leading to superior 
outcomes compared to “standard” therapy, at the very least, another therapeutic 
option would become available to women with this tumor subtype. At the most, a 
true standard therapy for women with recurrent low-grade serous carcinoma 
could become a reality, and the integration of the MEK inhibitor into primary 
therapy would also become a future focus.  
 
The proposed study is an international collaboration between the GOG in the 
United States and National Cancer Research Network (NCRN) institutions in the 
UK. This study aims to assess the efficacy of a MEK inhibitor in the context of a 
randomized phase II/III study in a prospective manner for the first time in low-
grade serous ovarian cancer. The investigation of mutational status of members of 
the RAS/RAF/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways will be 
important to allow clinical correlation of treatment response in this rare disease. 
 
 
2.11 
Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST) (07/28/14) 
 
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 
BRAFV600E or BRAFV600K mutations as detected by an FDA-approved test (U.S. 
Food and Drug Administration, 2013).  On January 10, 2014, the Food and Drug 

GOG-0281 
 
13 
 
Administration 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 (U.S. 
Food and Drug Administration, 2014). 
 
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 
(Flaherty et al., 2012).  However, single agent activities are limited.  Extensive 
research is underway to identify the patient selection markers and develop rational 
combination strategies.  Preclinical studies have provided strong rationale and 
proof of principle for combination of MEK inhibitors with RTK inhibitors (EGFR 
or IGF-1R) (Gopal et al., 2010; Ebi et al., 2011), PI3K/AKT inhibitors (Engelman 
et al., 2008; Hoeflich et al., 2009), and mTOR inhibitors.  On the other hand, the 
optimal dose/schedule and patient selection criteria for combination regimens 
have not been defined.  Phase 1 results for a number of combinations have been 
reported, including AZD6244 + MK2206 (Tolcher et al., 2011) and GDC-0973 + 
GDC-094 (MEK + PI3K inhibitor) (Bendell et al., 2011). 
 
The most up-to-date preclinical and clinical study information for trametinib can 
be found in the GSK1120212 (trametinib) Investigator's Brochure (2013). 
 
2.111 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 

GOG-0281 
 
14 
 
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 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. 
 
2.112 Clinical Pharmacokinetics (PK) and Activity of Trametinib 
 
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
There are 3 parts in this study.  Part 1:  The dose-escalation portion involves 
administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients 
with solid tumors or lymphoma in one of three schedules - (1) QD for 21 days 
followed by 7 days without drug, (2) loading dose on Day 1 or Day 1-2, 
followed by QD with the designated dose, or (3) QD dosing without a drug 
holiday.  Part 2:  cohort expansion at the recommended phase 2 dose (RP2D) 
for pancreatic cancer, melanoma, non-small cell lung cancer (NSCLC), 
colorectal cancer (CRC), or any BRAF mutation-positive cancer.  Part 3:  
expansion to characterize the biologically active range of trametinib via 
analysis of pharmacodynamic biomarkers (biopsies or FDG-PET). 
 
The MTD of trametinib was established as 3 mg QD, but the recommended 
phase 2 dose (RP2D) was chosen at 2 mg QD based on tolerability of repeated 
cycles (Infante et al., 2010). 
 
PK and metabolism of trametinib: 
PK measurements were conducted under fasting conditions.  After a single 
dose (Day 1), AUC0-24 and Cmax values were dose-proportional up to 6 mg, 
lower than dose proportional following 8 mg, and greater than dose 
proportional following the 10 mg dose.  Median Tmax was 1.5 hours. 
 
After repeat doses (Day 15), trametinib accumulated with a mean 
accumulation ratio of 6.6 at the RP2D of 2 mg QD.  Between-subject 
variability in exposure ranged from 27-50% for Cmax and 20-41% for AUC0-24 
across all dosing regimens.  The effective t1/2 was approximately 4.5 days, and 
steady state was reached by approximately Day 15.  Trametinib had a small 
peak:trough ratio of ~2 (Infante et al., 2010).  At 2 mg QD on Day 15, mean 

GOG-0281 
 
15 
 
AUC0-24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough 
concentrations ranged from 10.0 to18.9 ng/mL.  The long half-life and small 
peak:trough ratio of trametinib allowed constant target inhibition within a 
narrow range of exposure. 
 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome 
P450 [CYP450]-mediated) with secondary oxidation or in combination with 
glucuronidation biotransformation pathways (Investigator’s Brochure, 2012a).  
The deacetylation is likely mediated by hydrolytic esterases, such as 
carboxylesterases, or amidases.  Based on in vitro studies, trametinib is not an 
inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4.  
Trametinib has an overall low potential for drug-drug interactions. 
 
Pharmacodynamic effect and biomarkers: 
The relationship between dose and tumor biomarkers such as pERK, Ki67, 
and p27, were evaluated in patients with BRAF or NRAS mutation-positive 
metastatic melanoma (Investigator's Brochure, 2012a).  In general, increasing 
exposures and/or doses provided greater pharmacodynamic effects.  The 
median change observed at a dose of 2 mg QD was 62% inhibition of pERK, 
83% inhibition of Ki67, and a 175% increase in p27. 
 
Antitumor Activity in the FTIH phase 1 trial:  
In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received 
trametinib at 2 mg QD.  The overall objective response rate (ORR) was 43% 
(6/14), including 2 complete responses (CRs) (Investigator's Brochure, 
2012a).  In 9 patients with BRAF wt melanoma, 2 patients achieved a partial 
response (PR), and 3 stable disease (SD) (Infante et al., 2010).  In 26 
evaluable pancreatic cancer patients, there were 2 PRs (1 PR was KRAS 
mutation-positive) and 11 SD (2 achieved ≥20% tumor reduction) 
(Messersmith et al., 2011).  Among the 27 CRC patients (without selection of 
RAS or RAF mutations), 8 SD were observed. 
 
Antitumor Activity in Melanoma  
 
Phase 3 trial of trametinib vs. chemotherapy in advanced V600 mutant 
melanoma: 
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous 
melanoma with a BRAF V600E or V600K mutation were randomized (2:1) to 
trametinib (2 mg, PO, QD) or chemotherapy (dacarbazine or paclitaxel) 
(Flaherty et al., 2012; MEKINIST, 2013).  There were 322 patients in the 
intention-to-treat (ITT) population, of whom 273 (85%) were in the primary 
efficacy population (patients with BRAFV600E-positive cancer who did not 
have brain metastases at baseline).  Of the patients, 214 were randomized to 
receive trametinib, and 108 were randomized to receive chemotherapy.  
Investigator-assessed efficacy data are summarized as follows: 
 
 

GOG-0281 
 
16 
 
 
Trametinib 
(n=214) 
Chemotherapy (DTIC) 
(n=108) 
PFS 
Median, months (95% CI) 
 
4.8 (4.3, 4.9) 
 
1.5 (1.4, 2.7) 
HR (95% CI) 
P value (log-rank test) 
0.47 (0.34, 0.65) 
P<0.0001 
Confirmed Tumor Responses 
Objective Response Rate (95% CI) 
CR, n (%) 
PR, n (%) 
 
22% (17, 28) 
4 (2%) 
43 (20%) 
 
8% (4, 15) 
0 
9 (8%) 
Duration of response 
Median, months (95% CI) 
5.5 (4.1, 5.9) 
NR (3.5, NR) 
CI = confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PFS = progression-free 
survival; PR = partial response 
 
The 6-month OS rate was 81% in the trametinib group and 67% in the 
chemotherapy group.  Mature data on OS are pending. 
 
Experience with Trametinib in Metastatic Melanoma Following BRAF 
Inhibitor Therapy 
 
The clinical activity of single-agent trametinib was evaluated in a single-
arm, multicenter, international trial in 40 patients with BRAF V600E or 
V600K mutation-positive, unresectable, or metastatic melanoma who had 
received prior treatment with a BRAF inhibitor.  All patients received 
trametinib at a dose of 2 mg PO QD until disease progression or 
unacceptable toxicity.  None of the patients achieved a confirmed PR or 
CR. 
 
Antitumor Activity of Trametinib in Cancer Other Than Melanoma 
 
In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or 
myelodysplastic syndrome (MDS) patients were given trametinib at dose 
levels from 1-2 mg QD.  Drug-related AEs in 45 patients were similar to 
that observed in patients with solid tumors, and 2 mg PO QD was selected 
for further investigation in this patient population.  Twelve patients (23%) 
withdrew due to an AE, including cardiac failure (2) and infection (2).  
Efficacy was reported in 39 patients (Borthakur et al., 2010).  The best 
response in 13 patients with KRAS or NRAS mutations included 3 CRs 
(23%), 7 SD (54%), and 1 PD (progressive disease) (5%).  In 26 patients 
with wild-type RAS or an unknown mutation, there were 2 PRs (8%). 
 
In a multicenter phase 2 study, NSCLC patients with KRAS mutant 
tumors were randomized 2:1 to receive trametinib (2 mg QD) or docetaxel 
(75 mg/m2 IV every 3 weeks) (Blumenschein et al., 2013).  A total of 134 
pts were randomized to trametinib (89) or docetaxel (45); 129 patients had 
KRAS-mutant NSCLC.  The hazard ratio for PFS was 1.14 (95% CI, 0.75-
1.75; P=0.5197) with a median PFS of 11.7 versus 11.4 weeks for 

GOG-0281 
 
17 
 
trametinib versus docetaxel.  The overall response rate (ORR) was 12% 
for trametinib and 12% for docetaxel. 
 
In a double-blind, phase 2 study evaluating the combination of 
gemcitabine with trametinib, untreated pancreatic cancer patients were 
randomized to receive gemcitabine (1000 mg/m2 weekly ×7 for 8 weeks, 
then weekly ×3 every 4 weeks) plus either trametinib 2mg or placebo QD 
(Infante et al., 2013).  Median OS was 8.4 months with trametinib 
compared to 6.7 months with placebo.  Median PFS was 16 weeks versus 
15 weeks, and ORRs and median duration of responses were 22% and 
23.9 weeks and 18% and 16.1 weeks on trametinib and placebo; the 
median OS and ORR in the subgroup of patients with KRAS mutations 
(143/160) was similar to OS and ORR for all randomized patients.   
 
 
2.113 Trametinib Safety Profile 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list 
using NCI Common Terminology Criteria for Adverse Events (CTCAE) 
terms is included in Section 4.6 of the protocol. 
 
Based on available AE data from clinical studies involving trametinib to 
date, the most common toxicities are rash and diarrhea.  Rash and diarrhea 
are common, class-effect toxicities for MEK inhibitors.  In addition, visual 
impairment and left ventricular ejection fraction (LVEF) reduction, 
although observed at lower frequencies, are also considered class-effect 
toxicities as they have been observed with trametinib as well as other 
MEK inhibitors. 
 
AEs of special interest: 
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, 
and pneumonitis are considered AEs of special interest because they are 
either known class effects (i.e., have been observed with other MEK 
inhibitors) or are potentially life-threatening (Investigator’s Brochure, 
2013).  The following sections provide integrated summaries for these 
AEs across different clinical trials, with emphasis on trials using 
trametinib as monotherapy, especially at the RP2D of 2 mg. 
 
Refer to dose modification guidelines for the toxicities for which they are 
addressed in Section 6. 
 
Rash:  Rash was a common AE observed across different dose levels and 
in different combinations (Investigator’s Brochure, 2013).  At the 2 mg 
dose, rash was seen in 27% to 78% of patients in different trials.  Of the 
~370 subjects with rash AEs at the 2 mg monotherapy dose (including 
crossover subjects) in five studies, the majority of rash AEs were grades 1 
or 2 (24% to 73%); 0% to 9% of patients experienced grade 3 rash AEs, 
and four patients had a grade 4 rash AE. 
 

GOG-0281 
 
18 
 
In a randomized phase 3 trial of trametinib vs. chemotherapy, the overall 
incidence of skin toxicity (including rash, dermatitis, acneiform rash, 
palmar-plantar erythrodysesthesia syndrome, and erythema) was 87% in 
patients treated with trametinib and 13% in chemotherapy-treated patients.  
Severe skin toxicity occurred in 12% of patients on the trametinib arm, 
most commonly for secondary infections of the skin.  The median time to 
onset of skin toxicity was 15 days (range:  1 to 221 days), and median time 
to resolution was 48 days (range:  1 to 282 days).  Dose reduction was 
required in 12% for skin toxicities, and permanent discontinuation of 
trametinib was required in 1% of patients.  
 
Diarrhea:  At the 2 mg monotherapy dose, 33% to 58% of patients in five 
trials had diarrhea (Investigator’s Brochure, 2013).  Of ~320 subjects 
(including crossover subjects) with diarrhea at this dose, the majority of 
diarrhea AEs were grade 1 or 2 in severity (33% to 56% of all study 
patients); 17 patients had grade 3 diarrhea, and none had grade 4 diarrhea. 
 
Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the 
patients in five trials experienced visual disorders (Investigator’s 
Brochure, 2013).  Of the 85 total subjects (including crossover subjects) 
experiencing visual disorders at this dose level, the majority of visual 
disorders were grades 1 or 2 (4% to 20% of all study patients); six patients 
experienced grade 3 visual disorders, and one patient experienced a grade 
4 visual disorder. 
− 
Retinal Pigment Epithelial Detachment (RPED):  Also known as 
chorioretinopathy, RPED is a visual impairment due to fluid 
accumulation under the retina and causes blurry vision.  There were 
five cases of RPED, previously termed central serous retinopathy, 
reported from the integrated trametinib safety population consisting of 
subjects treated with trametinib 2 mg once daily from five studies 
(Investigator’s Brochure, 2013).  As of 23 June 2013, 14 cases of 
RPED were reported across the entire trametinib program amongst 
subjects treated with trametinib either as monotherapy or in 
combination with other anti-cancer agents (including cases from a 
MEK/BRAF combination study). 
 
− 
Retinal vein occlusion (RVO):  As of 23 June 2013, a total of four 
cases of RVO were reported across the entire trametinib program 
(including one case from a MEK/BRAF combination study) 
(Investigator’s Brochure, 2013).  All cases of RVO occurred in one 
eye only.  Study drug was stopped at time of diagnosis in all cases.  
There was a decrease of visual acuity in two subjects with central 
RVO (CRVO) while the other two subjects had no meaningful 
decrease of visual acuity.  In the two subjects with CRVO, local 
treatment with intravitreal injections of anti-VEGF antibodies was 
initiated within 2 weeks after RVO diagnosis, and visual acuity 
improved in one subject and restored to baseline conditions in another 

GOG-0281 
 
19 
 
subject, at the time of the data cutoff.  Three of these four cases were 
considered related to study treatment by the investigators. 
 
Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have 
been observed with administration of trametinib (Investigator’s Brochure, 
2013).  However, assessment of these cases was often confounded by co-
morbid conditions (such as biliary obstruction), concomitant use of other 
potentially hepatotoxic drugs, and liver metastases.  At the 2 mg 
monotherapy dose, 8% to 34% of patients in five trials had LFT 
abnormalities.  Of the 96 total patients (including crossovers) with LFT 
changes, the majority were grade 1 or 2 in severity (4% to 20% of all 
study patients); 26 had grade 3 events, and 6 patients had grade 4 events. 
 
Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the 
subjects in six studies had cardiac-related AEs (Investigator’s Brochure, 
2013).  Of the 65 total subjects (including crossover subjects) 
experiencing cardiac-related AEs at the 2.0 mg monotherapy dose in five 
of the studies, the majority of cardiac-related AEs were grades 1 or 2 in 
severity (0% to 16% of all study subjects); 18 subjects had grade 3 
cardiac-related AEs, and no subjects had Grade 4 cardiac-related AEs in 
any study.  No subject in one study, which evaluated the effect of repeat 
oral dosing of trametinib 2 mg QD on cardiac repolarization in subjects 
with solid tumors, had cardiac-related AEs.  One study subject receiving 
trametinib 2 mg QD had grade 5 (fatal) acute cardiac failure, with 
evidence of massive tumor invasion of the heart; this AE was considered 
not drug-related by the investigator. 
In the phase 3 trial of trametinib vs. chemotherapy in patients with 
melanoma (MEK114267), cardiomyopathy (defined as cardiac failure, left 
ventricular dysfunction, or decreased LVEF) occurred in 7% (14/211) of 
patients treated with trametinib, and in no patients in the chemotherapy arm.  
Cardiomyopathy was identified within the first month of treatment in five of 
these 14 patients; median onset of cardiomyopathy was 63 days (range: 16 to 
156 days).  Cardiomyopathy resolved in 10 of these 14 (71%) patients.  
Cardiac monitoring should be included in trametinib protocols, to include 
LVEF assessment by echocardiogram or MUGA scan at baseline, one 
month after initiation of trametinib and then at 2- to 3-month intervals 
while on treatment.  Refer to dose modification guidelines for cardiac AEs 
in the event of LVEF decline or symptomatic cardiac AEs. 
 
Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in 
five studies had pneumonitis (Investigator’s Brochure, 2013).  Of the nine 
total subjects (including crossovers) experiencing pneumonitis AEs at this 
dose, three subjects had grade 1 or 2 pneumonitis and six subjects had 
grade 3 pneumonitis. 
 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can 
cause fetal harm when administered to a pregnant woman.  Trametinib 

GOG-0281 
 
20 
 
was embryotoxic and abortifacient in rabbits at doses greater than or equal 
to those resulting in exposures approximately 0.3 times the human 
exposure at the recommended clinical dose.  If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the 
patient should be apprised of the potential hazard to a fetus. 
 
Incidence of common AEs reported from a phase III trial of trametinib vs. 
chemotherapy in patients with advanced melanoma: 
 
Patients with abnormal LVEF, history of acute coronary syndrome within 
6 months, or current evidence of Class II or greater congestive heart 
failure (New York Heart Association) were excluded from this trial.  
Selected adverse reactions (AR) occurring in patients receiving trametinib 
as compared to patients in the chemotherapy arm are listed as below: 
 
Table:  Selected adverse reactions (ARs) occurring in ≥10% of patients receiving trametinib 
AND at a higher incidence than in the chemotherapy arm (high in the trametinib arm compared 
with chemotherapy by ≥5% in overall incidence or by ≥2% grade 3 or 4 AEs) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
 
Table:  Percent-patient incidence of laboratory abnormalities occurring at a higher incidence in 
patients treated with trametinib versus chemotherapy (between-arm difference of ≥5% [all 
grades] or ≥2% [grades 3 or 4]) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate aminotransferase 
(AST) 
60 
2 
16 
1 
Increased alanine aminotransferase (ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline phosphatase 
24 
2 
18 
3 

GOG-0281 
 
21 
 
 
Other clinically important adverse reactions observed in ≤10% of patients 
(n=329) treated with trametinib were: nervous system disorders (dizziness, 
dysgeusia), ocular disorders (blurred vision, dry eye), infections and 
infestations (folliculitis, rash pustular, cellulitis), cardiac disorders 
(bradycardia), gastrointestinal disorders (xerostomia), and musculoskeletal 
and connective tissue disorders (rhabdomyolysis). 
 
 
 
 
2.2 
Translational Research Background 
 
Mutation Analysis 
 
RAF/RAS mutations have been shown to be a strong predictor of sensitivity to 
MEK inhibitors.31 Formalin-fixed, paraffin-embedded (FFPE) primary, 
metastatic, and/or recurrent tumor will be collected from consenting patients and 
used for mutational analysis. Whole exome sequencing analysis will be performed 
on all fixed tumor submitted prior to treatment. Results from mutational analyses 
of  KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 and NF1 mutations will be 
correlated with tumor response and PFS. 
 
Immunohistochemistry 
 
FFPE tumor will be used for immunohistochemical analysis of pERK. Tumor 
response will be correlated with expression levels of pERK. 
 
Population Pharmacokinetics 
 
A population PK analysis will be completed utilizing a sparse PK sampling design 
on a subset of patients (approximately 12 GOG and 12 UK) to assess the 
pharmacokinetics of trametinib in this patient population.  Population 
pharmacokinetic parameters including but not limited to clearance (CL) and 
volume of distribution (Vd), depending on the final compartmental model 
describing trametinib concentrations will be derived.    If the data permit, a 
population PK/PD analysis may be completed to explore the trametinib exposure-
response relationship including but not limited to safety, efficacy and/or toxicity.   
 
2.3 Integrated Biomarker Studies 
 
Low-grade ovarian serous carcinomas (LGSC) account for a significant proportion 
of epithelial ovarian cancers in young women. The exact biological pathways that 
underlie this disease are incompletely understood. Because the Ras/Raf/MEK/ERK 
pathway is frequently activated in LGSC, targeting this pathway has been examined 
as a potential treatment.27 In this study, integrated biomarker studies will test 
whether (1) high expression of pERK is associated with a low hazard of progression 
among patients treated with trametinib by immunohistochemistry (IHC), and (2) 

GOG-0281 
 
22 
 
KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 and NF1 mutations are associated 
with a lower hazard of progression among patients treated with trametinib by whole 
exome sequencing. Please refer to Appendix VII for additional background 
information and assay details. 
 
2.4 
Inclusion of Women and Minorities 
 
The Gynecologic Oncology Group and GOG participating institutions will not 
exclude potential subjects from participating in this or any study solely on the 
basis of ethnic origin or socioeconomic status.  Every attempt will be made to 
enter all eligible patients into this protocol and therefore address the study 
objectives in a patient population representative of the entire serous ovarian and 
peritoneal population treated by participating institutions. 

GOG-0281 
 
 
23 
 
3.0 
PATIENT ELIGIBILITY AND EXCLUSIONS  
 
3.1 
Eligible Patients (06/08/15) 
 
3.11 
Patients age greater than 18 with the following tumors are included in the 
study: 
 
3.111  Patients initially diagnosed with low-grade serous ovarian or 
peritoneal carcinoma that recur as low-grade serous carcinoma 
(invasive micropapillary serous carcinoma or invasive grade I 
serous carcinomas as defined by GOG, FIGO WHO or Silverberg). 
 
3.112 Patients initially diagnosed with serous borderline ovarian or 
peritoneal carcinoma that recur as low-grade serous carcinoma 
(invasive micropapillary serous carcinoma or invasive grade I 
serous carcinomas as defined by GOG, FIGO WHO or Silverberg). 
 
3.12 
At least 4 weeks must have elapsed since the patient underwent any major  
Surgery (eg. MAJOR: Laparotomy, laparoscopy, thoracotomy, VATS 
(video assisted thorascopic surgery).  There is no restriction on MINOR 
procedures: (eg. central venous catheter placement, ureteral stent 
placement or exchange, tumor core or FNA biopsy). (12/22/14) 
 
3.13 
Patients must have documented low-grade serous carcinoma. 
Confirmation must occur by prospective pathology review prior to study 
entry (as specified in Section 7.1). The prospective pathology review can 
be done on tissue from the recurrent carcinoma or from original diagnostic 
specimen. (12/22/14) 
 
3.14 
All patients must have measurable disease as defined by RECIST 1.1. 
Measurable disease is defined as at least one target lesion that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded). Each lesion must be > 10 mm when measured by CT, MRI, or 
caliper measurement by clinical exam; or > 20 mm when measured by 
chest x-ray. Lymph nodes must be > 15 mm in short axis when measured 
by CT or MRI. (06/08/15) 
 
All imaging studies must be performed within 28 days prior to 
registration. 
 
3.15 
Prior therapy (12/22/14) 
 
3.151 Patients must have recurred or progressed following at least one 
platinum-based chemotherapy regimen. 
 
3.152 Patients may have received an unlimited number of prior therapy 
regimens. 

GOG-0281 
 
 
24 
 
 
3.153 Patients may not have received all of the five choices in  
the “standard therapy” arm. 
 
3.154 Any hormonal therapy directed at the malignant tumor must be  
discontinued at least one week prior to registration 
 
3.155 Any other prior therapy directed at the malignant tumor, including  
chemotherapy and radiation therapy, must be discontinued at least 
4 weeks prior to registration. Any investigational agent must be 
discontinued at least 28 days prior to registration. 
 
3.16  
Trametinib, can cause fetal harm when administered to a pregnant woman.  
Women of child-bearing potential (i.e. patients whose reproductive organs 
remain in place and who have not passed menopause) and men must agree 
to use a highly effective method of contraception (e.g. hormonal, 
intrauterine device or; abstinence1) prior to study entry, during the study 
participation, and for six months after the last dose of the drug.  Women of 
child-bearing potential must have a negative serum pregnancy test within 
14 days prior to randomization, cannot be breast-feeding, and must agree 
to use a highly effective form of contraception throughout the treatment 
period and for 6 months after the last dose of study treatment.  Should a 
woman become pregnant or suspect she is pregnant while she or her 
partner is participating in this study, she should inform her treating 
physician immediately.  
 
(1Abstinence is only acceptable when this is in line with the preferred and usual lifestyle 
of the patient.) 
 
(07/28/14) (12/22/14) 
 
3.17 
Patients must have ability to understand and sign an approved informed 
consent and authorization permitting release of personal health 
information. 
 
3.18 
Patients must have a GOG Performance Status of 0 or 1. 
 
3.19 
Able to swallow and retain orally-administered medication and does not 
have any clinically significant gastrointestinal abnormalities that may alter 
absorption, such as malabsorption syndrome, bowel obstruction, or major 
resection of the stomach or bowel. (12/22/14) 
 
3.110 All prior treatment-related toxicities must be CTCAE v4 grade <1 (except 
alopecia) at the time of randomization. (07/28/14) 
 
3.111 Patients must have a left ventricular ejection fraction > lower limit of 
normal by ECHO or MUGA. 
 

GOG-0281 
 
 
25 
 
3.112 Patients must have adequate renal, endocrine, and hepatic function and 
bone marrow reserve. (07/28/14) (12/22/14) 
 
• Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance 
(Cockroft-Gault formula) ≥50 mL/min OR 24-hour urine creatinine 
clearance ≥50 mL/min 
• Bilirubin < 1.5 times upper limit of normal 
• ALT < 2.5 times upper limit of normal 
• AST < 2.5 times upper limit of normal 
• Albumin > 2.5 g/dL 
• PT and APTT < 1.5 times upper limit of normal 
• Neutrophil count > 1.5 x 109/L Platelet count > 100 x 109/L 
• Hemoglobin > 9.0 g/dL 
Samples must be taken within 14 days prior to treatment. 
 
3.113 If letrozole is selected as the control therapy, patients must be 
postmenopausal, either following bilateral oophorectomy or at least 5 
years after spontaneous menopause. Patients within 5 years of spontaneous 
menopause or who have had a hysterectomy without bilateral 
oophorectomy must have postmenopausal LH and FSH levels. Patients on 
HRT must agree to withdrawal of hormone therapy before letrozole is 
started. 
 
3.2 
Ineligible Patients 
 
3.21 
Patients who have had chemotherapy or radiotherapy within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or 
those who have not recovered from adverse events due to agents 
administered more than 4 weeks earlier. 
 
3.22 
Use of other investigational drugs within 28 days (or five half-lives, 
whichever is shorter; with a minimum of 14 days from the last dose) 
preceding the first dose of trametinib or standard of care agent. (07/28/14)   
 
3.23 
If patients have had a potential index lesion radiated, it must have 
progressed post radiation therapy to be used as a measurable eligibility 
lesion 
 
3.24 
Patients may not have received prior MEK, KRAS, or BRAF inhibitor 
therapy 
 
3.25 
Current use of a prohibited medication. The following medications or non-
drug therapies are prohibited: 
 
 
3.251 Patients may not be receiving any other anti-cancer or 
 
investigational agents. 
 

GOG-0281 
 
 
26 
 
 
3.252 Because the composition, PK, and metabolism of many herbal  
supplements are unknown, the concurrent use of all herbal 
supplements is prohibited during the study (including, but not 
limited to St. John’s Wort, kava, ephedra [ma huang], gingko 
biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, 
or ginseng). 
 
3.26 
Patients with known leptomeningeal or brain metastases or spinal cord 
compression should be excluded from this clinical trial because of their 
poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
 
3.27 
Patients with a bowel obstruction or any other gastrointestinal condition 
that might affect absorption of the oral drug should be excluded. This 
would include patients with inability to swallow and retain orally-
administered medication, malabsorption syndrome, or those with a major 
resection of the stomach or bowels. 
 
3.28 
Patients with a history of interstitial lung disease or pneumonitis. 
 
3.29 
Patients with a previous or current malignancy at other sites should be 
excluded, with the exception of: 
 
 
a. Curatively treated local tumors such as carcinoma-in-situ of the cervix, 
basal or squamous cell carcinoma of the skin 
b. Tumors for which no relapse has been observed within 5 years  
 
3.30 
Known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection 
(patients with chronic or cleared HBV and HCV infection are eligible).  
Patients with Human Immunodeficiency Virus (HIV) are not eligible if on 
anti-retroviral medications (07/28/14) 
 
 
3.31 
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to Trametinib, or excipients, or to dimethyl 
sulfoxide (DMSO), or to Cremophor EL (polyoxyethylated castor oil). 
Please note, exclusion for Cremophor is unnecessary unless paclitaxel is 
the only agent available and the patient randomizes to the conventional 
therapy option. (07/28/14) 
 
3.32 
Patients with a history or evidence of cardiovascular risk, including any of 
the following: 
 
• LVEF<LLN 
• QTcB > 480 msec. 
• History or evidence of current clinically significant uncontrolled 
arrhythmias. 

GOG-0281 
 
 
27 
 
• Exception: Subjects with controlled atrial fibrillation for > 30 days 
prior to randomization are eligible. 
• History of (within 6 months prior to randomization) acute coronary 
syndromes (including myocardial infarction and unstable angina), 
coronary angioplasty, or stenting. 
• History or evidence of current > Class II congestive heart failure as 
defined by New York Heart Association (NYHA). 
• Treatment refractory hypertension defined as a blood pressure of 
systolic >140mmHg and/or diastolic >90mmHg which cannot be 
controlled by anti-hypertensive therapy 
• Patients with intra-cardiac defibrillators or permanent pacemakers 
• Known cardiac metastases 
 
3.33 Patients with a history or current evidence/risk of retinal vein occlusion 
(RVO) (07/28/14)  
 
3.34 Any serious and/or unstable pre-existing medical disorder (aside from 
malignancy exception above), psychiatric disorder, or other conditions that 
could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures. (07/28/14) 
 
3.35 Patients who require use of a concomitant medication that can prolong the 
QT interval. See the table in section 6.28 (07/28/14) 
 
 
3.36 Animal reproductive studies have not been conducted with trametinib.   
Therefore, the study drug must not be administered to pregnant women or 
nursing mothers.  Women of childbearing potential should be advised to 
avoid pregnancy and use effective methods of contraception. If a female 
patient or a female partner of a patient becomes pregnant while the patient 
receives trametinib, the potential hazard to the fetus should be explained to 
the patient and partner (as applicable). (07/28/14)

GOG-0281 
 
 
28 
 
  
4.0 
STUDY MODALITIES   
 
4.1 
Letrozole (Femara) (NSC #719435) 
 
 
4.11 
Formulation: Tablets of 2.5 mg of Letrozole 
 
4.12 
Storage and Stability:  Store between 59 degrees and 86 degrees F, protect 
from moisture; Very stable 
 
4.13 
Adverse Effects: Vascular disorders, flushing, cerebrovascular accident,  
hypertension, thromboembolic event, angina, skin rash, increased 
sweating, increased hepatic enzymes, arthralgia/arthritis. See package 
insert for complete list of adverse effects.  
 
4.14 
Supplier: Commercially available. 
 
4.15 
Administration: Letrozole 2.5 mg orally daily   
 
4.2 
Tamoxifen Citrate (Nolvadex®) (NSC #180973)  
 
4.21 
Formulation:  Tablets of 10 and 20 mg of tamoxifen. The 20 mg tablets 
 
are to be used for this study. 
 
4.22 
Storage:  Room temperature protected from heat and light. 
 
4.23 
Adverse Effects:  Transient thrombocytopenia and leukopenia,  
menopause-like reactions (hot flushes, nausea), skin rashes/changes, 
pruritus vulvae, dizziness, headaches, depression, lassitude, muscle pain, 
fluid retention, anorexia, menstrual irregularities, vaginal bleeding, 
vaginal discharge, food distaste and thromboembolic events.  In patients 
with breast carcinoma, a flare of symptoms related to known areas of 
disease and hypercalcemia in patients with bone metastases have been 
reported.  Of note also is a report of a few cases of severe retinopathy 
associated with decreased visual acuity in patients on high doses (>200 
mg/day) for prolonged periods over a year.  Dose modifications or 
cessation of drug because of adverse effects is seldom necessary. See 
package insert for complete list of adverse effects.  
 
4.24    Supplier:  Commercially available.  
 
4.25    Administration:  See Section 5.21.  
 
4.3 
Pegylated Liposomal Doxorubicin (DOXIL®, NSC #712227, Lipodox™) 
 
Refer to the PLD package insert (Doxil, Lipodox™) for the most complete and 
current information on the following: 
 

GOG-0281 
 
 
29 
 
4.31  Formulation:  PLD (doxorubicin HCl liposome injection) is supplied as a  
 
sterile, translucent, red liposomal dispersion in 5 mL (Lipodox only), 
 
10 mL, or 30 mL glass, single-use vials. Each vial contains doxorubicin 
 
HCl at a concentration of 2 mg/mL.  
 
4.32 
Storage: Refrigerate unopened vials of PLD at 2°–8°C (36°–46°F). Avoid  
freezing. Prolonged freezing may adversely affect liposomal drug 
products; however, short-term freezing (less than 1 month) does not 
appear to have a deleterious effect on PLD. 
 
4.33 
Preparation: PLD doses up to 90 mg must be diluted in 250 mL of 5%  
Dextrose Injection, USP prior to administration. Doses exceeding 90 mg 
should be diluted in 500 mL of 5% Dextrose Injection, USP prior to 
administration. Aseptic technique must be strictly observed since no 
preservative or bacteriostatic agent is present in PLD. Diluted PLD should 
be refrigerated at 2°C–8°C (36°F–46°F) and administered within 24 hours. 
Do not mix with other drugs. 
Do not use with any diluent other than 5% Dextrose Injection.  
Do not use any bacteriostatic agent, such as benzyl alcohol.  
Do not infuse with in-line filters. 
 
PLD is not a clear solution but a translucent, red liposomal dispersion.  
Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration, whenever solution and 
container permit. Do not use if a precipitate or foreign matter is present.  
 
4.34 
Procedure for Proper Handling and Disposal:  Caution should be exercised 
 
in the handling and preparation of PLD.  
The use of gloves is required.  
If PLD comes into contact with skin or mucosa, immediately wash 
thoroughly with soap and water.  
PLD should be considered an irritant and precautions should be taken to 
avoid extravasation. With intravenous administration of PLD, 
extravasation may occur with or without an accompanying stinging or 
burning sensation, even if blood returns well on aspiration of the infusion 
needle. If any signs or symptoms of extravasation have occurred, the 
infusion should be immediately terminated and restarted in another vein. 
PLD must not be given by the intramuscular or subcutaneous route.  
PLD should be handled and disposed of in a manner consistent with other 
anticancer drugs.  
 
4.35 
Adverse Effects:  Consult the PLD package insert for the most current and 
 
complete information. 
 

GOG-0281 
 
 
30 
 
4.36 
Supplier: Commercially available.  
 
Consult the American Hospital Formulary Service Drug Information 
guide, Facts and Comparisons, or the package insert for additional 
information. 
 
4.4 
Topotecan (NSC #609699) 
 
4.41 
Formulation:  Topotecan is a cell cycle specific inhibitor of the nuclear 
enzyme topoisomerase I.  It has a mean half-life of approximately three 
hours.  Topotecan’ s metabolism and clearance are complex but it is 
estimated that approximately 40% of the drug undergoes renal clearance.  
It is supplied as a lyophilized, light-yellow powder as the base Topotecan 
AS with 48 mg mannitol and 20 mg tartaric acid, NF. 
 
4.42 
Supplier/How Supplied:  Topotecan is commercially available. It is 
supplied in a sterile form for intravenous use only.  Topotecan is supplied 
as a lyophilized, light-yellow powder in vials containing 4 mg Topotecan 
AS (as the base) and 48 mg mannitol and 20 mg tartaric acid, NF.  It has a 
reverse magenta label for identification purposes.    
 
4.43 
Solution Preparation:  The contents of each 4 mg vial will be reconstituted 
with 4 ml Sterile Water for Injection, USP, yielding a 1 mg/ml solution of 
Topotecan AS. The ph is adjusted to 3.0. The vials reconstituted with 
Sterile Water for Injection, USP, contain no antibacterial preservative and 
must be used within 24 hours.  
 
The reconstituted solution will be further diluted in plastic bags to 
concentrations of 10 mcg/ml to 500 mcg/ml in Dextrose 5% in Water, or 
Normal Saline.  The plastic bags for infusion are stable at room 
temperature for 24 hours if reconstituted with Dextrose 5% in Water or 
Normal Saline. No incompatibilities with other drugs have been described.  
The drug is stable in IV solutions as stated above. 
 
4.44 
Storage/Stability:  Un-reconstituted vials are stored at room temperature, 
15-30°C (59- 86°F).  The reconstituted vials, when reconstituted with 
Sterile Water for Injection, USP, will contain no antibacterial preservative 
and should be used within 24 hours.   
 
4.45  
Adverse effects:  
Hematologic:  thrombocytopenia, leukopenia, anemia, neutropenia 
Gastrointestinal:  nausea and vomiting, mucositis, diarrhea 
Skin: rash 
Other:  alopecia, fever, flu-like symptoms 
 
     *Refer to Package Insert for additional information. 
 

GOG-0281 
 
 
31 
 
4.5 
Paclitaxel (NSC#673089)  
 
 
4.51   Formulation: Paclitaxel is supplied as a 6mg/mL non-aqueous solution in 
multi dose vials containing 30mg/5mL, 100mg/16.7mL, or 300mg/50mL 
of paclitaxel. In addition to 6mg of paclitaxel, each mL of sterile non-
pyrogenic solution contains 527mg of purified Cremophor® EL 
(polyoxyethylated castor oil) and 49.7% (v/v) dehydrated alcohol, USP.  
 
 
4.52   Storage: Unopened vials of paclitaxel are stable to the date indicated on  
 
 
the package when stored between 20 to 25°C (68 to 77°F). Protect from  
 
 
light.  
 
4.53   Preparation: Paclitaxel must be diluted prior to infusion. Paclitaxel should 
be diluted in 0.9% Sodium Chloride for Injection, USP; 5% Dextrose 
Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 
or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 
1.2mg/mL. The solutions are physically and chemically stable for up to 27 
hours at ambient temperature (approximately 25°C / 77°F) and room 
lighting conditions.  
 
 
NOTE: In order to minimize patient exposure to the plasticizer DEHP, 
which may be leached from PVC infusion bags or sets, diluted paclitaxel 
solutions should be stored in bottles (glass, polypropylene) or plastic 
(polypropylene, polyolefin) bags and administered through polyethylene-
lined administration sets. Paclitaxel should be administered through an 
inline filter with a microporous membrane not greater than 0.22 microns. 
Use of filter devices such as IVEX- 2® or IVEX-HP®, which incorporate 
short inlet and outlet PVC-coated tubing, has not resulted in significant 
leaching of DEHP.  
 
 
All patients should be premedicated with corticosteroids, 
diphenhydramine, and H2 antagonists prior to paclitaxel administration in 
order to prevent severe hypersensitivity reactions. Patients who experience 
severe hypersensitivity reactions to paclitaxel should not be re-challenged 
with the drug.  
 
4.54   Adverse Effects: Consult the package insert for the most current and  
 
 
complete information.  
4.55   Supplier: Commercially available. Consult the American Hospital 
Formulary Service Drug Information guide, Facts and Comparisons, or the 
package insert for additional information. 
4.6 
Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
(06/08/15)(07/24/2020) 
 
4.61     Chemical Name (IUPAC):  equimolecular combination of N-(3-{3-
cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-

GOG-0281 
 
 
32 
 
3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide with 
(methylsulfinyl)methane  
 
Other Names:  trametinib, GSK1120212B, TMT212-NXA, JTP-74057, 
JTP-78296, JTP-75303, Mekinist® 
 
CAS Registry Number:  1187431-43-1 
 
Classification:  MEK inhibitor 
 
Molecular Formula:  C26H23FIN5O4 • C2H6OS 
 
M.W.:  693.53 (DMSO solvate form) 
 
Approximate Solubility:  Trametinib dimethyl sulfoxide is almost 
insoluble in aqueous media at pH range of 2-8. 
 
 
4.62     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. 
 
    4.63   Description:  Trametinib dimethyl sulfoxide is a white to almost white  
 
 
powder. 
 
4.64  How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 
trametinib as 0.5 mg and 2 mg (as free base) tablets (05/31/16).  Each 
investigationally-labeled bottle contains 32 tablets with a desiccant. 
 
The tablet core contains mannitol, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, magnesium stearate (non-animal), 
colloidal silicon dioxide and sodium lauryl sulfate.  
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated. 
Aqueous film coating consists of hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow. 
• 2 mg tablets are pink, round, biconvex and film-coated. Aqueous film 
coating consists of hypromellose, titanium dioxide, polyethylene 
glycol, polysorbate 80, iron oxide red.  
 
4.65  Storage: Store tablets at 2°C -8°C ( 36° F to 46° F) in the original bottle and 
dispense unopened bottles. Do not open bottles or 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 

GOG-0281 
 
 
33 
 
excursion (including documentation of temperature monitoring and duration 
of the excursion) to PMBAfterHours@mail.nih.gov for determination of 
suitability. 
 
4.66  Stability:  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.   
 
4.67  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. 
 
4.68 
Adverse Effects: Please refer to section 4.612 for a full list of adverse 
effects.  
 
4.69  Potential Drug Interactions:  In vitro studies suggest that trametinib 
dimethyl sulfoxide 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 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. 
 
4.610  Patient Care Implications: 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.  

GOG-0281 
 
 
34 
 
 
 
4.611 Availability: Trametinib dimethyl sulfoxide (GSK1120212B) is an 
investigational agent supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
Trametinib dimethyl sulfoxide (GSK1120212B) is provided to the NCI 
under a Collaborative Agreement between the Pharmaceutical 
Collaborator and the DCTD, NCI. 
 
4.612 Agent Ordering and Agent Accountability 
 
NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly 
to the institution where the patient is to be treated.  PMB does not permit 
the transfer of agents between institutions (unless prior approval from 
PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible 
investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA Form 1572 (Statement of 
Investigator), Curriculum Vitae, Supplemental Investigator Data Form 
(IDF), and Financial Disclosure Form (FDF).  If there are several 
participating investigators at one institution, CTEP-supplied 
investigational agents for the study should be ordered under the name of 
one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and ordering designees can submit agent requests through the 
PMB Online Agent Order Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx).  Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, 
transfers, returns, or accountability, call (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
4.612  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 specific exceptions to expedited reporting to NCI (except as noted below). Refer to the 

GOG-0281 
 
 
35 
 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for 
further clarification. Frequency is provided based on 1111 patients. Below is the CAEPR for 
Trametinib (GSK1120212B). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER. If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the 
grades to determine if expedited reporting is required. 
 
   Version 2.6, October 10, 20191 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
 
Eye disorders - Other 
(chorioretinopathy also known 
as retinal pigment epithelial 
detachment) 
  
 
 
Eye disorders - Other (retinal 
vein occlusion) 
  
 
Eye disorders - Other (visual 
disorders)2 
 
  
 
 
Papilledema 
  
 
Periorbital edema 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
Generalized edema3 
 
 
 Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
  
INFECTIONS AND INFESTATIONS 
  

GOG-0281 
 
 
36 
 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Folliculitis 
 
 Folliculitis (Gr 2) 
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
Skin and subcutaneous tissue 
disorders - Other (rash)5 
  
 
 Skin and subcutaneous 
tissue disorders - Other 
(rash)5 (Gr 3) 
 
 
Stevens-Johnson syndrome6 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
(venous) 
  

GOG-0281 
 
 
37 
 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Vascular disorders - Other 
(hemorrhage)7 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed 
to all Principal Investigators at the time of revision.  The current version can be obtained by 
contacting PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and 
the agent should be included in the e-mail. 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, 
visual acuity reduced, visual impairment, and vitreous detachment. 
 
3Generalized edema includes edema, lymphedema, and edema limbs. 
 
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased 
liver function tests, and visual disturbances. 
 
5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin 
chapped. 
 
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
 
7The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and 
fatal intracranial hemorrhages have been reported. 
 
 
 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for 
which there is insufficient evidence to suggest that there was a reasonable possibility 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) 

GOG-0281 
 
 
38 
 
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; Pneumothorax; 
Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Purpura; Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; 
Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
 
Note: Trametinib (GSK1120212B) 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. 
 
 
5.0 
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE (02-JUN-
2020)    
 
5.1 
Investigator and Research Associate Registration with CTEP (07/28/14) 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at https://ctepcore.nci.nih.gov/rcr.    
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 

GOG-0281 
 
 
39 
 
• 
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 such as the Roster Update Management System [RUMS], OPEN, Rave, 
acting as a primary site contact, or with consenting privileges; 
• 
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 Cancer Trials Support Unit (CTSU) websites and applications. In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards 
(IRBs) covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Addition to a site roster; 
• 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN; 
• 
Act as the site-protocol Principal Investigator (PI) on the IRB approval; and 
• 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).  
 
In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the 
DTL must be rostered at the enrolling site with a participating organization.  
 
Additional information is located 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. 
 
5.11 
CTSU Registration Procedures (03/21/16) 
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 Regulatory Support System (RSS). 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
5.111 IRB Approval:   

GOG-0281 
 
 
40 
 
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 email or calling 1-
888-651-CTSU (2878). 
 
 
5.112 Downloading Site Registration Documents:   
 
Download the site registration forms from the protocol-specific 
page located on the CTSU members’ website. Permission to view 
and download this protocol and its supporting documents is 
restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff 
must be associated with the LPO or a Protocol Organization (PO) 
on the protocol. One way to search for a protocol is listed below.  
• Log in to the CTSU members’ website (https://www.ctsu.org) 
using your CTEP-IAM username and password; 
• Click on Protocols in the upper left of the screen 
o Enter the protocol number in the search field at the top 
of the protocol tree; or 
o Click on the By Lead Organization folder to expand, 
then select [Corresponding Organization], and protocol 
number [NCI Protocol #]. 
Click on Documents, select Site Registration, and download and 
complete the forms provided. (Note: For sites under the CIRB, IRB 
data will load automatically to the CTSU.)  

GOG-0281 
 
 
41 
 
 
 
5.113 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. 
 
5.114 Checking Your Site’s Registration Status: 
Site registration status may be verified on the CTSU members’ 
website.  
• Click on Regulatory at the top of the screen; 
• Click on Site Registration; and 
• Enter the sites 5-character CTEP Institution Code and click 
on Go. 
o Additional filters are available to sort by Protocol, 
Registration Status, Protocol Status, and/or IRB 
Type. 
Note: The status shown only reflects institutional compliance with 
site registration requirements as outlined within the protocol. It 
does not reflect compliance with protocol requirements for 
individuals participating on the protocol or the enrolling 
investigator’s status with NCI or their affiliated networks. 
 
5.2 
Patient Screening (07/28/14) (06/08/15) 
 
When a suitable candidate has been obtained for protocol entry, the following 
steps should be taken: 
 
Screening 
 
When a suitable candidate has been identified for protocol entry, the following 
steps should be taken: 
 
• An approved informed consent form and authorization permitting the release 
of personal health information must be signed by the patient or guardian. 

GOG-0281 
 
 
42 
 
Current FDA, NCI and institutional regulations concerning informed consent 
will be followed. 
 
• All eligibility requirements indicated in Section 3.0 must be satisfied. 
 
• Log onto the GOG website (http://www.gog.org), go to the Web Menu page 
and open the link to Screening to obtain a Screening Patient Identifier.  
 
• The patient must have histologically documented low grade serous carcinoma 
confirmed by prospective review.  An H&E stained slide from the primary 
tumor or tumor recurrence specimen may be submitted to meet histologic 
eligibility requirements (see section 7.21), label the slide with the Screening 
ID, and send the slide(s) along with a copy of the patient’s pathology report to 
the GOG Tissue Bank in Columbus, OH. 
 
GOG-0281 Pathology Review 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 
Columbus, OH 43205 
614-722-2865 
 
• Receive the results of the central pathology review on the Screening web 
application. 
 
• If the patient is eligible, proceed to patient registration in GOG-0281. 
 
5.3 
Patient Entry and Registration  (07/28/14) 
 
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 LPOs registration/randomization systems or the 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: Must be on an LPO 
roster, ETCTN corresponding roster, or participating organization roster 

GOG-0281 
 
 
43 
 
with the role of Registrar. Registrars must hold a minimum of an 
Associate Plus (AP) registration type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrars 
must hold the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the 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. If a 
DTL is required for the study, the IVR or NPIVR must be assigned the 
appropriate OPEN-related tasks on the DTL. 
Prior to accessing OPEN, site staff should verify the following: 
• Patient has met all eligibility criteria within the protocol stated 
timeframes; and  
• 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. You may 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 in the OPEN section of the CTSU 
website at https://www.ctsu.org or https://open.ctsu.org. For any additional questions, 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
5.4 
Treatment Plan 
 
For each arm, one cycle is 28 days. The first dose of study medication should be 
administered as close as possible to the time of randomization as the site allows. 
 
5.41 
Arm A 
 
Clinician’s choice of ‘control’ arm is made from the list below prior to 
randomization: 
 
• Letrozole 2.5mg orally once daily continuous treatment until 
progression or unacceptable toxicity 
• Tamoxifen 20mg orally twice daily continuous treatment until 
progression or unacceptable toxicity 
• Paclitaxel 80mg/m2 IV infusion over one hour on   days 1, 8, and 15 of 
a 28 day cycle until progression or unacceptable toxicity or until 6 
cycles have been administered* 

GOG-0281 
 
 
44 
 
• Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV infusion over 
one hour on day 1 every 28 days until progression or unacceptable 
toxicity or until 6 cycles have been administered* 
• Topotecan 4.0 mg/m2 IV infusion over 30 minutes on days 1, 8, and 15 
of a 28 day cycle until progression or unacceptable toxicity or until 6 
cycles have been administered* 
 
*more than 6 cycles of chemotherapy can be administered at investigator’s 
discretion. 
 
5.42 
Arm B  
 
 Trametinib 2 mg orally once daily continuous treatment until progression 
or unacceptable toxicity 
 
5.43 
Premedication 
For Arm A, premedication is given as per local policy. 
No premedication is required for Arm B. 
 
5.44 
Patient Monitoring 
 
For Arm A, monitoring is performed as per local policy 
 
No specific monitoring is required for Arm B. 
 
5.45 
Treatment Compliance 
Compliance with oral medications on both arms will be assessed through 
querying the subject during the site visits and documented in the source 
documents and CRF.A record of the number of tablets dispensed to and 
taken by each subject must be maintained and reconciled with study 
treatment and compliance records. Treatment start and stop dates, 
including dates for treatment delays and/or dose reductions will also be 
recorded in the CRF. 
 
 
5.46 
Crossover (03/21/16) 
If a patient develops progressive disease (as defined in Section 8.134) on 
Arm A, she will be given the opportunity to crossover to the Trametinib 
arm. No PK specimens will be collected on crossover patients. 
(12/22/14) 
 
Prior to crossover, the following must occur: 
• The patient’s progression must be documented on the CRFs, which 
must be submitted prior to starting crossover treatment and will be 

GOG-0281 
 
 
45 
 
reviewed to confirm progression (Retrospective review of the 
scans may be done to examine this.) 
All eligibility criteria in section 3 must be met (with the exception 
of 3.143, 3.151, and 3.113).  This includes the requirement 3.21 
such that 4 weeks must elapse between the end of treatment with 
Arm A and start of treatment on Arm B. These requirements will 
be documented on the CRFs. If the patient meets the above 
requirements (with appropriate documentation on the CRFs), she 
will be allowed to continue on study. 

GOG-0281 
 
 
46 
 
6.0 
TREATMENT MODIFICATIONS    
 
Doses will be reduced for hematological and other adverse events. Dose adjustments are 
to be made according to the greatest degree of toxicity. Adverse events will be graded 
using the NCI CTCAE v4.0. 
 
6.1 
Control Treatments 
 
Dose adjustments as per standard of care 
6.2 
Trametinib 
The severity of adverse events will be graded utilizing the CTCAE v 4.0.  
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment are provided in this section. 
 
The guidelines that follow outline dose adjustments for several of these toxic 
effects. If a patient experiences several adverse events and there are conflicting 
recommendations, use the recommended dose adjustment that reduces the dose to 
the lowest level. 
 
The table below outlines the dose levels to be used for any necessary trametinib 
dose modifications: 
 
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg QD 
-1 
1.5 mg QD 
-2 
1 mg QD 
 
A maximum of two trametinib dose level reductions are allowed.  If a third dose 
level reduction is required, treatment will be permanently discontinued. 
 
6.21 
Trametinib Dose Modification for Toxicities Not Specified in Subsequent 
 
Sections 
 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically indicated.  
Provide supportive care 
Continue trametinib at current dose level. 
Grade 2 
(tolerable) 
• Interrupt treatment until resolution to grade 1 or baseline.   
• Upon resolution, restart treatment at current dose level. 

GOG-0281 
 
 
47 
 
Trametinib Treatment Modification for Clinically Significant Toxicities Deemed Related to Trametinib 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, 
liver chemistry, QTc prolongation, or visual changes.  Refer to other sections for these specific AEs). 
CTCAE v4 
Grade 
Management Guideline 
Dose Modification 
Grade 2 
(intolerable)/ 
Grade 3 
according to institutional 
standards 
• Interrupt treatment until resolution to grade 1 or baseline.   
• Upon resolution to baseline or grade 1, restart with one 
level of dose reduction 
• If the Grade 3 toxicity recurs, interrupt trametinib; When 
toxicity resolves to Grade 1 or baseline, restart trametinib 
reduced by another dose level 
Grade 4 
Permanently discontinue trametinib. 
1. Trametinib should be discontinued if treatment delay is >21 days due to toxicities.  If the investigator 
concludes that continued trametinib will benefit a patient, the study chair and CTEP Medical Monitor may be 
consulted for the possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 
1. 
2. CTEP Medical Monitor: 
Helen Chen, MD 
240-276-6565 
Helen.chen@nih.gov  
 
6.22 
Trametinib Dose Modification for Rash 
 
Rash is a frequent AE observed in patients receiving trametinib 
(Investigator’s Brochure, 2012a).  Recommendations for supportive care 
and guidelines for dose modifications for rash are based on experience 
with other MEK inhibitors and EGFR inhibitors (Balagula et al., 2010; 
Lacouture et al., 2011). 
 
The institutional standards for the management of skin-related AEs can 
differ from these guidelines.  In this case, best clinical judgment should be 
applied and a consultation with the study chair or the CTEP Medical 
Monitor may be required. 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/Prophylaxisa 
 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily, 
starting on Day 1 of study treatment, to body areas such as face, chest, and 
upper back.   
• Use mild-strength topical steroid (hydrocortisone 1% cream) 
or topical antibiotic (e.g., clindamycin) or oral antibiotics 
(e.g., doxycycline 100 mg BID, minocycline 100 mg BID). 

GOG-0281 
 
 
48 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Symptomatic Careb 
 
• Pruritic lesions:  Cool compresses and oral antihistamine therapies. 
• Fissuring lesions:  Monsel’s solution, silver nitrate, or zinc oxide cream. 
• Desquamation:  Thick emollients and mild soap. 
• Paronychia:  Antiseptic bath, local potent corticosteroids in addition to 
antibiotics; if no improvement, consult dermatologist or surgeon. 
• Infected lesions:  Appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics. 
a Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
b Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management. 
 
Trametinib Dose Modification Guidelines and Management for Rash 
Rash Severity 
Management Guideline 
Dose Modification 
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue trametinib. 
• If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
trametinib by one dose level.3 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Reduce trametinib by one dose level. 
• If rash recovers to ≤ grade 1 within 2 weeks, increase 
dose to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, interrupt 
trametinib until recovery to ≤ grade 1. 
• Restart trametinib at reduced dose level.3 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib until rash recovers to ≤ grade 1. 
• Restart with trametinib reduced by one dose 
level.3,4 
• If no recovery to ≤ grade 2 within 4 weeks, 
permanently discontinue trametinib. 
1. Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
2. Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone priopionate 0.5% cream. 
3. Approval of CTEP Medical Monitor is required to restart study treatment after >4 weeks of interruption. 
4. Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study 
treatment. 
5.    CTEP Medical Monitor: 
Helen Chen, MD 
240-276-6565 
Helen.chen@nih.gov 
 
6.23 
Trametinib Dose Modifications for Visual Changes (07/28/14) 
Trametinib is known to be associated with visual adverse events.  An 
ophthalmologist should be consulted if changes in vision develop.  
However, if the visual changes are clearly unrelated to study treatment 
(e.g., allergic conjunctivitis), then monitor closely as it may be reasonable 
to defer ophthalmic examination.  Special attention should be given to 

GOG-0281 
 
 
49 
 
retinal findings (e.g., retinal pigment epithelial detachment (RPED) or 
retinovascular abnormalities (i.e., branch or central retinal vein occlusions 
[RVO]). (12/22/14) 
 
The ophthalmology exam will include best corrected visual acuity, visual 
field examination, tonometry, slit lamp biomicroscopic examination, and 
indirect fundoscopy.  Optical coherence tomography is recommended at 
scheduled visits and if retinal abnormalities are suspected.  Other types of 
ancillary testing including visual field examination, fundus photography, 
and fluorescein angiography may also be indicated as determined by 
clinical exam. 
 
Guidelines regarding event management and dose reduction for visual 
changes considered to be related to study treatment are provided in the 
table below. 
 
Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Grade 1* 
 
 
• Consult ophthalmologist 
within 7 days of onset. 
 
• If dilated fundus examination cannot be performed 
within 7 days of onset, hold trametinib until RPED and 
RVO can be excluded by retina 
specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart 
trametinib at same dose level. 
• If RPED suspected/diagnosed:  See RPED dose 
modification table below (following this table); report 
as SAE. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
Grade 2 and Grade 3 
 
• Consult ophthalmologist 
immediately. 
 
• Hold trametinib 
• If RPED or RVO excluded, restart trametinib at same 
dose level after visual AE is < grade 1.  If no recovery 
within 3 weeks, discontinue trametinib 
• If RPED diagnosed:  See RPED dose modification table 
below; report as SAE. 
• If RVO:  Permanently discontinue trametinib and 
report as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
• Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at same 
or reduced dose after discussion with the CTEP Medical 
Monitor. 
• If RVO or RPED, permanently discontinue 
trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious 
adverse event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
 
 

GOG-0281 
 
 
50 
 
Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations 
only) 
• Continue treatment with retinal evaluation monthly until resolution.  If 
RPED worsens, follow instructions below. 
Grade 2-3 RPED (Symptomatic 
with mild to moderate decrease in 
visual acuity; limiting instrumental 
ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one dose level reduction 
(reduced by 0.5 mg) or discontinue in patients taking trametinib 1 mg 
daily. 
• If no recovery within 4 weeks permanently discontinue trametinib 
 
 
6.24 
Trametinib Dose Modification for Diarrhea 
Episodes of diarrhea have occurred in patients receiving trametinib 
(Investigator’s Brochure, 2012a).  Other frequent causes of diarrhea may 
include concomitant medications (e.g., stool softeners, laxatives, antacids, 
etc.), infections by C. difficile or other pathogens, or partial bowel 
obstruction.  Those conditions should be excluded. 
 
Guidelines regarding management and dose modification for diarrhea 
considered related to trametinib are provided in the table below. 
 

GOG-0281 
 
 
51 
 
Management and Trametinib Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated Diarrhea,1 
Grade 1 or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, BRAT-
diet (banana, rice, apples, toast) 
recommended. 
• Hydration:  8-10 large glasses of 
clear liquids per day (e.g., Gatorade 
or broth). 
• Loperamide3:  Initially 4 mg, 
followed by 2 mg every 4 hours or 
after every unformed stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free for 12 hours. 
• Diarrhea >24 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Consider adding oral 
antibiotics. 
• Diarrhea >48 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Add budesonide or other 
second-line therapies (otreotide, or 
tincture of opium) and oral 
antibiotics. 
 
• Continue trametinib. 
• If diarrhea is grade 2 for > 48 h, 
interrupt trametinib until diarrhea 
resolves to grade ≤1. 
• Restart trametinib at the same dose 
level 
• If treatment delay is > 1 days, 
discontinue trametinib. 
Uncomplicated Diarrhea,1 
Grade 3 or 4 
 
Any Complicated Diarrhea2 
 
• Clinical evaluation mandatory. 
• Loperamide3:  Initially 4 mg, 
followed by 2 mg every 4 hours or 
after every unformed stool; 
maximum 16 mg/day.  Continue 
until diarrhea-free for 12 hours. 
• Oral antibiotics and second-line 
therapies if clinically indicated 
• Hydration:  Intravenous fluids if 
clinically indicated. 
• Antibiotics (oral or intravenous) if 
clinically indicated. 
• Intervention should be continued 
until the subject is diarrhea-free for 
≥24 hours. 
• Intervention may require 
hospitalization for subjects at risk 
of life-threatening complications. 
• Interrupt trametinib until diarrhea 
resolves to ≤ grade 1. 
• Restart with trametinib reduced by 
one dose level.4 
• If 3 dose reductions of study 
treatment are clinically indicated, 
permanently discontinue 
trametinib. 
• If treatment delay is >21 days, 
discontinue trametinib. 
1.  Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution. 
2.  Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution. 
3.  Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea. 
4.  Escalation of trametinib to previous dose level is allowed after consultation with the medical monitor and in the 
absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 

GOG-0281 
 
 
52 
 
 
6.25 
Trametinib Dose Modification for Liver Chemistry Changes (07/28/14) 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
• 
ALT ≥3x ULN but <5x ULN and 
TB <2x ULN, without symptoms 
considered related to liver injury 
or hypersensitivity and who can 
be monitored weekly for 4 weeks 
 
• 
May continue study drug. 
• 
Report as SAE if CTEP-AERS reporting criteria is met. 
• 
If liver chemistry stopping criteria are met any time, proceed as 
described below. 
 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) until they return to normal/baseline 
or stabilise (LFT may be every 2 weeks after 4 weeks if ALT <3x ULN and 
TB <2 ULN). 
Criteria for discontinuing study 
drug:  When any of the liver stopping  
criteria below is met, discontinue 
trametinib  
 
1. ALT ≥3xULN and bilirubin ≥2x 
ULN  or >35% direct bilirubin 1, 2 
2. ALT ≥ 3xULN and INR >1.5, if 
INR measured2  (INR threshold 
does not apply if subject is on 
anticoagulant) 
3. ALT ≥5x ULN 
4. ALT ≥3x ULN persists for ≥4 
weeks 
5. ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks 
6. ALT  ≥3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver 
injury or hypersensitivity 
 
 
• 
Immediately discontinue study treatment. 
• 
Do not restart/rechallenge unless approved by CTEP trametinib 
medical monitor.   
• 
Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) 
patients meet criteria 1-2. 
• 
Perform liver event ASSESSMENT AND WORKUP (see below). 
• 
Monitor the subject until liver chemistries resolve, stabilize, or 
return to baseline (see MONITORING below). 
 
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, indicating 
potentially more significant liver toxicities): 
• 
Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform 
liver event follow-up assessments within 24 hours. 
• 
Monitor subjects twice weekly until LFT return to normal/baseline 
or stabilize. 
• 
A specialist or hepatology consultation is recommended. 
In patients stopping for criteria 2-6: 
• 
Repeat LFT and perform liver event follow up assessments within  
24-72 hrs  
• 
Monitor subjects weekly until LFTs return to normal/baseline or 
stabilize. 
 
ASSESSMENT and WORKUP: 
• 
Viral hepatitis serology.4 
• 
If possible, obtain blood sample for PK analysis.5 

GOG-0281 
 
 
53 
 
• 
Serum CPK and LDH. 
• 
Fractionate bilirubin, if total bilirubin ≥2x ULN. 
• 
CBC with differential to assess eosinophilia. 
• 
Record clinical symptoms of liver injury, or hypersensitivity on AE 
CRF. 
• 
Record concomitant medications (including acetaminophen, herbal 
remedies, other over the counter medications). 
• 
Record alcohol use. 
Additional work up for patient stopping for criteria 1-2 (with abnormal TB 
and INR, indicating potentially more significant liver toxicities): 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-
liver kidney microsomal antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC assay (in subjects with likely 
acetaminophen use in the preceding). 
• 
If there is underlying chronic hepatitis B (e.g. positive hepatitis B 
surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody.6 
• 
Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1.  Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, which indicates direct bilirubin elevations 
and suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5 (if 
INR measured) may indicate severe liver injury (possible “Hy’s Law”).  INR measurement is not required, and the 
threshold value stated will not apply to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5.  PK sample is desired if feasible.  Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide 
the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be 
collected in the time period indicated above, do not obtain a PK sample.   
6.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) (Le Gal et al., 2005). 
7. CTEP Medical Monitor: 
Helen Chen, MD 
240-276-6565 
Helen.chen@nih.gov 
 
6.26 
Trametinib Dose Modification for Pneumonitis 

GOG-0281 
 
 
54 
 
 
Pneumonitis has been observed in patients receiving trametinib.  To 
reduce the risk of pneumonitis, patients will be monitored closely for 
symptoms and evaluated with imaging and functional tests.  Dose 
modification and supportive care guidelines for pneumonitis are described 
in the tables below. 
 
Pneumonitis Guidelines for Trametinib Monotherapy 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
• CT scan (high-resolution with lung windows) 
recommended. 
• Work-up for infection. 
• Monitoring of oxygenation via pulse-oximetry 
recommended. 
•  Consultation with pulmonologist recommended. 
Continue trametinib at current dose. 
Grade 2 
• CT scan (high-resolution with lung windows). 
• Work-up for infection. 
• Consult pulmonologist. 
• Pulmonary function tests:  If < normal, repeat every 8 
weeks until ≥ normal. 
• Bronchoscopy with biopsy and/or BAL 
recommended. 
• Symptomatic therapy including corticosteroids if 
clinically indicated. 
• Interrupt trametinib until recovery 
to grade ≤1. 
• If AE resolved to grade ≤1 and 
relationship to trametinib is 
equivocal, restarting trametinib 
with one dose reduction may be 
considered, after discussion with 
the medical monitor.   
• If treatment delay is > 4 weeks, 
permanently discontinue 
trametinib. 
Grade 3 
• CT scan (high-resolution with lung windows). 
• Work-up for infection. 
• Consult pulmonologist. 
• Pulmonary function tests-if < normal, repeat every 8 
weeks until ≥ normal. 
• Bronchoscopy with biopsy and/or BAL if possible. 
• Symptomatic therapy including corticosteroids as 
clinically indicated. 
• Interrupt trametinib until recovery 
to grade ≤1. 
• If AE resolved to grade ≤1 
and relationship to trametinib 
is equivocal, restarting 
trametinib with one dose 
reduction may be considered, 
after discussion with the 
medical monitor.   
• If treatment delay is >4 
weeks, permanently 
discontinue trametinib. 
Grade 4 
Same as grade 3. 
Permanently discontinue 
trametinib. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 
 
6.27 
Trametinib Dose Modification for Reduced Left Ventricular Ejection   
Fraction (07/28/14) (06/08/15) 
 
Decreases of the left ventricular ejection fraction (LVEF) have been 
observed in patients receiving trametinib.  Therefore, ECHO/MUGAs 

GOG-0281 
 
 
55 
 
must be performed in regular intervals outlined in the Study Calendar.  
The same procedure (either ECHO or MUGA, although ECHO is 
preferred) should be performed at baseline and at follow-up visit(s). 
 
Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of 
>10% in LVEF compared 
to baseline and ejection 
fraction below the 
institution’s LLN. 
• Interrupt trametinib and repeat ECHO/MUGA 
within 2 weeks.a 
• If the LVEF recovers within 4 weeks 
(defined as an absolute increase of 10 points, 
or a return back to baseline of greater than or 
equal to 50%, would be considered resolved): 
− Consult with the CTEP trametinib medical 
monitor and request approval for restart. 
− Restart treatment with trametinib at 
reduced dose by one dose level.b 
− Repeat ECHO/MUGA 2, 4, 8, and 12 
weeks after re-start; continue in intervals 
of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
− Consult with cardiologist. 
− Permanently discontinue trametinib. 
− Report as SAE 
− Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution. 
− Consult with the CTEP trametinib medical 
monitor.c 
Symptomaticb 
 
• Grade 3:  resting LVEF 
39-20% or >20% 
absolute reduction from 
baseline 
• Grade 4:  Resting LVEF 
≤20%. 
• Permanently discontinue trametinib. 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution. 
a If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after 
restarting of trametinib.  Approval from the CTEP trametinib medical monitor is required. 
c Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. 
 
6.28 
Trametinib Dose Modification for QTc Prolongation (07/28/14) 
(06/08/15) 

GOG-0281 
 
 
56 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTcB >530 msec for subjects with 
bundle branch block 
 
• Interrupt study treatment until QTcB prolongation resolves to grade 1 or 
baseline. 
• Test serum potassium, calcium, phosphorus, and magnesium.  If 
abnormal, correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose level.b 
• If the event does not resolve or recurs after restarting, permanently 
discontinue study treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using Bazett’s formula 
a Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued. 
b if the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and the CTEP trametinib medical monitor agree that the subject will benefit from further treatment. 
 
MEDICATIONS THAT MAY CAUSE QTc PROLONGATION (06/08/15) 
 
The following table presents a list of drugs that may prolong the QTc.  These drugs are prohibited during the 
study. Trametinib may be administered after a 5 half-life washout period elapses following the use of these 
drugs.  Washout period is based on roughly 5 half-lives and rounded to a convenient interval.  
 
 
The drug list below contains drugs from the categories: Known Risk of TdP Possible Risk of TdP 
 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Therapeutic Use 
Risk 
Category 
Route 
Alfuzosin 
Uroxatral® 
Alpha1-blocker 
Benign prostatic 
hyperplasia 
Possible 
Risk of 
TdP 
oral 
Amiodarone 
Cordarone®, Pacerone®, 
Nexterone® 
Anti-arrhythmic 
Abnormal heart 
rhythm 
Risk of 
TdP 
oral, 
injection 
Anagrelide 
Agrylin®, Xagrid® 
Phosphodiesterase 
3 inhibitor 
Thrombocythemia 
Risk of 
TdP 
oral 
Apomorphine 
Apokyn®, Ixense®, 
Spontane®, Uprima® 
Dopamine agonist 
Parkinson's disease 
Possible 
Risk of 
TdP 
injection 
Aripiprazole 
Abilify®, Aripiprex® 
Anti-psychotic, 
atypical 
Schizophrenia, 
depression (adjunct) 
Possible 
Risk of 
TdP 
oral, 
injection 
Arsenic trioxide 
Trisenox® 
Anti-cancer 
Cancer (leukemia) 
Risk of 
TdP 
injection 

GOG-0281 
 
 
57 
 
Astemizole (Removed from 
US Market) (Removed from 
US Market) 
Hismanal® 
Antihistamine 
Allergic rhinitis 
Risk of 
TdP 
oral 
Atazanavir 
Reyataz® 
Anti-viral 
Viral infection 
(HIV/AIDS) 
Possible 
Risk of 
TdP 
oral 
Atomoxetine (On US Market) Strattera® 
Norepinephrine 
reuptake inhibitor 
ADHD 
Possible 
Risk of 
TdP 
oral 
Azithromycin 
Zithromax®, Zmax® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral, 
injection 
Bedaquiline 
Sirturo® 
Antibiotic 
Bacterial infection 
(Drug resistant 
tuberculosis) 
Possible 
Risk of 
TdP 
oral 
Bepridil (Removed from US 
Market) (Removed from US 
Market) 
Vascor® 
Anti-anginal 
Angina Pectoris (heart 
pain) 
Risk of 
TdP 
oral 
Bortezomib 
Velcade®, Bortecad® 
Proteasome 
inhibitor 
Cancer (multiple 
myeloma,lymphoma) 
Possible 
Risk of 
TdP 
injection 
Bosutinib 
Bosulif® 
Tyrosine kinase 
inhibitor 
Cancer (leukemia) 
Possible 
Risk of 
TdP 
oral 
Chloroquine 
Aralen® 
Anti-malarial 
Malaria 
Risk of 
TdP 
oral 
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen® 
Anti-psychotic / Anti-
emetic 
Schizophrenia, 
nausea, many others 
Risk of 
TdP 
oral, 
injection, 
suppositor
Cilostazol (On US Market) 
Pletal® 
Phosphodiesterase 
3 inhibitor 
Intermittent 
claudication 
Risk of 
TdP 
oral 
Ciprofloxacin 
Cipro®, Cipro-XR®, 
Neofloxin® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral, 
injection 
Cisapride (Removed from US 
Market) (Removed from US 
Market)
Propulsid® 
GI stimulant 
Increase GI motility 
Risk of 
TdP 
oral 
Citalopram 
Celexa®, Cipramil® 
Anti-depressant, 
SSRI 
Depression 
Risk of 
TdP 
oral 
Clarithromycin 
Biaxin®, Prevpac® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral 
Clozapine 
Clozaril®, Fazaclo®, 
Versacloz® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP
oral 
Cocaine 
Cocaine 
Local anesthetic 
Anesthesia (topical) 
Risk of 
TdP 
topical 
Crizotinib 
Xalkori® 
Kinase inhibitor 
Cancer (Non-small cell 
lung cancer, 
metastatic)
Possible 
Risk of 
TdP
oral 
Dabrafenib 
Tafinlar® 
Kinase inhibitor 
Cancer (melanoma) 
Possible 
Risk of 
TdP
oral 

GOG-0281 
 
 
58 
 
Dasatinib 
Sprycel® 
Tyrosine kinase 
inhibitor 
Cancer (leukemia) 
Possible 
Risk of 
TdP
oral 
Dexmedetomidine 
Precedex®, Dexdor®, 
Dexdomitor® 
Sedative 
Sedation 
Possible 
Risk of 
TdP
injection 
Dihydroartemisinin+piperaqui 
ne 
Eurartesim® 
Anti-malarial 
Malaria 
Possible 
Risk of 
TdP
oral 
Disopyramide 
Norpace® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral 
Dofetilide 
Tikosyn® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral 
Dolasetron 
Anzemet® 
Anti-nausea 
Nausea, vomiting 
Possible 
Risk of 
TdP
oral, 
injection 
Domperidone (On non US 
Market) (On non US Market) 
Motilium®, Motillium®, 
Motinorm Costi®, Nomit® 
Anti-nausea 
Nausea, vomiting 
Risk of 
TdP 
oral, 
injection, 
suppositor
Donepezil 
Aricept® 
Cholinesterase 
inhibitor 
Dementia (Alzheimer's 
Disease) 
Risk of 
TdP 
oral 
Dronedarone 
Multaq® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral 
Droperidol 
Inapsine®, Droleptan®, 
Dridol®, Xomolix® 
Anti-psychotic / Anti-
emetic 
Anesthesia (adjunct), 
nausea 
Risk of 
TdP 
injection 
Eribulin 
Halaven® 
Anti-cancer 
Cancer (breast, 
metastatic) 
Possible 
Risk of 
TdP
injection 
Erythromycin 
E.E.S.®, Robimycin®, 
EMycin®, Erymax®, 
Antibiotic 
Bacterial infection, 
increase GI motility 
Risk of 
TdP 
oral, 
injection 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E® (India), 
Exodus® (Brazil) Esto®
Anti-depressant, 
SSRI 
Depression (major), 
anxiety disorders 
Risk of 
TdP 
oral 
Famotidine 
Pepcid®, Fluxid®, 
Quamatel® 
H2-receptor 
antagonist 
Gastric hyperacidity, 
GERD 
Possible 
Risk of 
TdP
oral, 
injection 
Felbamate 
Felbatol® 
Anti-convulsant 
Epilepsy 
Possible 
Risk of 
TdP
oral 
Fingolimod 
Gilenya® 
Sphingosine 
phospate receptor 
modulator
Multiple Sclerosis 
Possible 
Risk of 
TdP
oral 
Flecainide 
Tambocor®, Almarytm®, 
Apocard®, Ecrinal®, 
Flécaine®
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral 
Fluconazole 
Diflucan®, Trican® 
Anti-fungal 
Fungal infection 
Risk of 
TdP 
oral, 
injection 
Foscarnet 
Foscavir® 
Anti-viral 
Viral infection 
(HIV/AIDS) 
Possible 
Risk of 
TdP
injection 
Gatifloxacin (Removed from 
US Market) (Removed from 
US Market)
Tequin® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP
oral, 
injection 
Gemifloxacin 
Factive® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP
oral 
Granisetron 
Kytril®, Sancuso®, 
Granisol® 
Anti-nausea 
Nausea, vomiting 
Possible 
Risk of 
TdP
oral, 
injection, 
topical

GOG-0281 
 
 
59 
 
Grepafloxacin (Off market 
worldwide) (Off market 
worldwide)
Raxar® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral 
Halofantrine 
Halfan® 
Anti-malarial 
Malaria 
Risk of 
TdP 
oral 
Haloperidol 
Haldol® (US & UK), 
Aloperidin®, Bioperidolo®, 
Brotopon® Dozic®
Anti-psychotic 
Schizophrenia, 
agitation 
Risk of 
TdP 
oral, 
injection 
Ibutilide 
Corvert® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
injection 
Iloperidone 
Fanapt®, Fanapta®, 
Zomaril® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP 
oral, 
injection 
Isradipine 
Dynacirc® 
Anti-hypertensive 
Hypertension 
Possible 
Risk of 
TdP
oral 
Lapatinib 
Tykerb®, Tyverb® 
Anti-cancer 
Cancer (breast, 
metastatic) 
Possible 
Risk of 
TdP
oral 
Levofloxacin 
Levaquin®, Tavanic® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral, 
injection 
Levomethadyl (Removed from 
US Market) (Removed from 
US Market)
Orlaam® 
Opiate 
Narcotic dependence 
Risk of 
TdP 
oral 
Lithium 
Eskalith®, Lithobid® 
Anti-mania 
Bipolar disorder 
Possible 
Risk of 
TdP 
oral, 
injection 
Mesoridazine (Removed from 
US Market) (Removed from 
US Market) 
Serentil® 
Anti-psychotic 
Schizophrenia 
Risk of 
TdP 
oral 
Methadone 
Dolophine®, Symoron®, 
Amidone®, Methadose®, 
Physeptone®, Heptadon® 
Opiate 
Narcotic dependence, 
pain 
Risk of 
TdP 
oral, 
injection 
Mifepristone 
Korlym®, Mifeprex® 
Progesterone 
antagonist 
Pregnancy termination Possible 
Risk of 
TdP 
oral 
Mirabegron 
Myrbetriq® 
Beta3 adrenergic 
antagonist 
Bladder spasm 
Possible 
Risk of 
TdP 
oral 
Mirtazapine 
Remeron 
Anti-depressant, 
Tetracyclic 
Depression 
Possible 
Risk of 
TdP 
oral 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Anti-hypertensive 
Hypertension 
Possible 
Risk of 
TdP 
oral 
Moxifloxacin 
Avelox®, Avalox®, Avelon® Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral, 
injection 
Nicardipine 
Cardene® 
Anti-hypertensive 
Hypertension 
Possible 
Risk of 
TdP 
oral, 
injection 
Nilotinib 
Tasigna® 
Anti-cancer 
Cancer (leukemia) 
Possible 
Risk of 
TdP 
oral 
Norfloxacin 
Noroxin®, Ambigram® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP 
oral 
Ofloxacin 
Floxin® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP 
oral, 
injection 

GOG-0281 
 
 
60 
 
Olanzapine 
Zyprexa®, Zydis®, 
Relprevv® 
Anti-psychotic, 
atypical 
Schizophrenia, bipolar 
disorder 
Possible 
Risk of 
TdP 
oral, 
injection 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Anti-emetic 
Nausea, vomiting 
Risk of 
TdP 
oral, 
injection 
Oxytocin 
Pitocin®, Syntocinon® 
Oxytocic 
Labor stimulation 
Possible 
Risk of 
TdP 
injection 
Paliperidone 
Invega®, Xepilon® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP 
oral, 
injection 
Pasireotide 
Signifor® 
Somatostatin analog Cushings Disease 
Possible 
Risk of 
TdP 
injection, 
topical 
Pazopanib 
Votrient® 
Tyrosine kinase 
inhibitor 
Cancer (renal cell, 
sarcoma) 
Possible 
Risk of 
TdP 
oral 
Pentamidine 
Pentam® 
Antifungal 
Fungal infection 
(Pneumocystis 
pneumonia) 
Risk of 
TdP 
injection 
Perflutren lipid microspheres 
Definity® 
Imaging contrast 
agent 
Echocardiography 
Possible 
Risk of 
TdP 
injection 
Pimozide 
Orap® 
Anti-psychotic 
Tourette's Disorder 
Risk of 
TdP 
oral 
Pipamperone (On non US 
Market) (On non US Market) 
Dipiperon (E.U), Propitan 
(Japan) 
Antipsychotic 
Schizophrenia 
Possible 
Risk of 
TdP 
oral 
Probucol (Removed from US 
Market) (Removed from US 
Market) 
Lorelco® 
Antilipemic 
Hypercholesterolemia Risk of 
TdP 
oral 
Procainamide (Oral off US 
mkt) (Oral off US mkt) 
Pronestyl®, Procan® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
injection 
Promethazine 
Phenergan® 
Anti-psychotic / Anti-
emetic 
Nausea, vomiting 
Possible 
Risk of 
TdP 
oral, 
injection, 
suppositor 
Propofol 
Diprivan®, Propoven® 
Anesthetic, general 
Anesthesia 
Risk of 
TdP 
injection 
Quetiapine 
Seroquel® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP 
oral 
Quinidine 
Quinaglute®, Duraquin®, 
Quinact®, Quinidex®, 
Cin-Quin®, Quinora®
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral, 
injection 
Ranolazine 
Ranexa®, Ranozex® 
Anti-anginal 
Angina Pectoris (heart 
pain) 
Possible 
Risk of 
TdP 
oral 
Rilpivirine 
Edurant®, Complera®, 
Eviplera® 
Anti-viral 
Viral infection 
(HIV/AIDS) 
Possible 
Risk of 
TdP 
oral 
Risperidone 
Risperdal® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP 
oral, 
injection 
Roxithromycin (On non US 
Market) (On non US Market) 
Rulide®, Xthrocin®, 
Roxl-150®, Roxo®, Surlid®, 
Rulide®, Biaxsig®, Roxar®,
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP 
oral 

GOG-0281 
 
 
61 
 
Saquinavir 
Invirase®(combo) 
Anti-viral 
Viral infection 
(HIV/AIDS) 
Possible 
Risk of 
TdP 
oral 
Sertindole (On non US 
Market) (On non US Market) 
Serdolect®, Serlect® 
Anti-psychotic, 
atypical 
Schizophrenia, anxiety Possible 
Risk of 
TdP 
oral 
Sevoflurane 
Ulane®, Sojourn® 
Anesthetic, general 
Anesthesia 
Risk of 
TdP 
inhaled 
Sorafenib 
Nexavar® 
Tyrosine kinase 
inhibitor 
Cancer (liver, renal 
cell, metastatic thyroid) 
Possible 
Risk of 
TdP 
oral 
Sotalol 
Betapace®, Sotalex®, 
Sotacor® 
Anti-arrhythmic 
Abnormal heart rhythm Risk of 
TdP 
oral 
Sparfloxacin (Removed from 
US Market) (Removed from 
US Market) 
Zagam® 
Antibiotic 
Bacterial infection 
Risk of 
TdP 
oral 
Sulpiride (On non US Market) 
(On non US Market) 
Dogmatil®, Dolmatil®, 
Eglonyl®, Espiride®, 
Modal®, Sulpor® 
Anti-psychotic, 
atypical 
Schizophrenia 
Risk of 
TdP 
oral 
Sunitinib 
Sutent® 
Kinase inhibitor 
Cancer (GIST, renal 
cell, pNET) 
Possible 
Risk of 
TdP 
oral 
Tacrolimus 
Prograf®, Prograf®, 
Advagraf®, Protopic® 
Immunosuppressant Immune suppression 
Possible 
Risk of 
TdP 
oral, 
injection 
Tamoxifen 
Nolvadex®(discontinued 
6/13), Istubal®, Valodex® 
Anti-cancer 
Cancer (breast) 
Possible 
Risk of 
TdP 
oral 
Telavancin 
Vibativ® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP 
injection 
Telithromycin 
Ketek® 
Antibiotic 
Bacterial infection 
Possible 
Risk of 
TdP 
oral 
Terfenadine (Removed from 
US Market) (Removed from 
US Market) 
Seldane® 
Antihistamine 
Allergic rhinitis 
Risk of 
TdP 
oral 
Tetrabenazine (Orphan drug 
in US) (Orphan drug in US) 
Nitoman®, Xenazine® 
Monoamine 
Transporter Inhibitor 
Chorea (Huntington's 
disease) 
Possible 
Risk of 
TdP 
oral 
Thioridazine 
Mellaril®, Novoridazine®, 
Thioril® 
Anti-psychotic 
Schizophrenia 
Risk of 
TdP 
oral 
Tizanidine 
Zanaflex®, Sirdalud® 
Muscle relaxant 
Muscle spasticity 
Possible 
Risk of 
TdP 
oral 
Tolterodine 
Detrol®, Detrusitol® 
Muscle relaxant 
Bladder spasm 
Possible 
Risk of 
TdP 
oral 
Toremifene 
Fareston® 
Estrogen 
agonist/antagonist 
Cancer (breast, 
metastatic) 
Possible 
Risk of 
TdP 
oral 
Vandetanib 
Caprelsa® 
Anti-cancer 
Cancer (thyroid) 
Risk of 
TdP 
oral 
Vardenafil 
Levitra® 
Phosphodiesterase 
5 inhibitor 
Erectile dysfunction 
Possible 
Risk of 
TdP 
oral 

GOG-0281 
 
 
62 
 
Vemurafenib 
Zelboraf® 
Kinase inhibitor 
Cancer (melanoma) 
Possible 
Risk of 
TdP 
oral 
Venlafaxine 
Effexor®, Efexor® 
Anti-depressant, 
SNRI 
Depression 
Possible 
Risk of 
TdP 
oral 
Vorinostat 
Zolinza® 
Anti-cancer 
Cancer (lymphoma) 
Possible 
Risk of 
TdP 
oral 
Ziprasidone 
Geodon®, Zeldox® 
Anti-psychotic, 
atypical 
Schizophrenia 
Possible 
Risk of 
TdP 
oral, 
injection 
 
6.29 
Trametinib Dose Modification for Hypertension (07/28/14) 
Increases in blood pressure (BP) have been observed in patients receiving 
trametinib.  Recommendations for BP monitoring and management are 
provided below. 
 
Monitoring:  All BP assessments should be performed under the following 
optimal conditions: 
 
• The subject has been seated with back support, ensuring that legs 
are uncrossed and flat on the floor. 
• The subject is relaxed comfortably for at least 5 minutes. 
• Restrictive clothing has been removed from the cuff area, and the 
right cuff size has been selected. 
• The subject’s arm is supported so that the middle of the cuff is at 
heart level. 
• The subject remains quiet during the measurement. 
• In subjects with an initial BP reading within the hypertensive 
range, a second reading should be taken at least 1 minute later, 
with the two readings averaged to obtain a final BP measurement.  
The averaged value should be recorded in the eCRF. 
• Persistent hypertension is defined as an increase of systolic blood 
pressure (SBP) >140 mmHg and/or diastolic blood pressure (DBP) 
>90 mmHg in three consecutive visits with blood pressure 
assessments from two readings as described above.  Visits to 
monitor increased blood pressure can be scheduled independently 
from the per-protocol visits outlined in the study calendar.  Ideally, 
subsequent blood pressure assessments should be performed within 
1 week. 
 

GOG-0281 
 
 
63 
 
Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up to three subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in two separate 
readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension) that resolve after the blood 
pressure is controlled within the normal range. 
- Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of the above symptoms. 
(Scenario A) 
• Asymptomatic and persistent SBP 
of ≥140 and <160 mmHg, or DBP 
≥90 and <100 mmHg,  
or 
Clinically significant increase in 
DBP of 20 mmHg (but still below 
100 mmHg). 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP.  If BP is not well-controlled 
within 2 weeks, consider referral to 
a specialist and go to scenario (B). 
Continue trametinib at the current 
dose. 
(Scenario B) 
• Asymptomatic SBP ≥160 mmHg, 
or DBP ≥100 mmHg,  
or 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario C) 
• Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks 
after restarting of trametinib.  Approval from Medical Monitor is required. 
 

GOG-0281 
 
 
64 
 
7.0 
STUDY PARAMETERS   
 
7.1 
Tests and Observations (07/28/14)(06/08/15)  
 
The following observations and tests are to be performed and recorded on the 
appropriate forms: 
Study Assessments 
Prior to 
Study 
Therap
y 
During Treatment (randomized 
or crossover) 
Crossover from 
Standard Arm 
to Trametinib 
Arm 
Every 3 months for 
2 years, every 6 
months for 3 years, 
then annually‡  
Prior to 
Each 
Cycle  
Prior to Cycles 2, 5, 
8, 11 (then every 4 
cycles)† 
Confirmation of 
Eligibility 
X 
 
 
X 
 
History & Physical 
1, 7 
7 
 
7 
X 
Serum pregnancy test 
2, 3 
 
 
X 
 
Ophthalmologic 
Exam* 
1 
12 
 
X 
 
Assessment of visual 
disorders 
X 
X 
 
X 
 
Radiographic disease 
assessment 
4 
4 
 
 
 
Quality of life 
assessment 
X 
5 
 
 
 
Vital signs (including 
Height/Weight) 
2, 7 
7 
 
X 
X 
ECG 
1,7 
 
7,10 
7 
 
Echocardiogram 
(ECHO)/MUGA* 
1 
 
9,10 
 
11 
CBC/Differential/ 
Platelets 
2 
6 
 
X 
X 
Electrolytes (including 
potassium), BUN, 
creatinine, Ca, Mg, 
PO4, Albumin 
2 
6 
 
X 
11 
Bilirubin, 
SGOT(AST), 
SGPT(ALT), 
Alkaline Phosphatase 
2 
X 
 
X 
11 
PTT, PT/INR 
2 
 
 
X 
11 
CA125 
2 
X 
 
X 
X 
Toxicity Assessment 
X 
X 
 
X 
X 
Urinalysis 
X 
 
 
 
 
† Cycles are relative to randomized or crossover treatment.  For example, after crossover, cycle 2 refers to the 2nd 
cycle of crossover treatment. 
‡ Relative to end of most recent study treatment, whether randomized or crossover. 
* Not standard of care, will be paid for by from study funds, email Nicole Lamack Nlamack@gog.org (07/28/14) 
MRI = magnetic resonance imaging; ECG = electrocardiogram; ECHO = echocardiogram 
 
1. Must be obtained within 28 days prior to initiating protocol therapy. 
2. Must be obtained within 14 days prior to initiating protocol therapy. 
3. Serum pregnancy test will be required in women of child-bearing potential within 14 days prior to 
randomization.  Subsequent tests may be urine tests, and should be performed as clinically indicated. 

GOG-0281 
 
 
65 
 
4. Lesion assessment by contrast CT or MRI of chest, abdomen and pelvis every 8 weeks for the first 15 months, 
then every 3 months thereafter must be performed within 28 days prior to randomization. Assessments must be 
performed on a calendar basis (i.e., not delayed due to delays in administering study medication).  A window of 
± 7 days is allowed for scheduling. The same diagnostic method, including use of contrast when applicable, 
must be used throughout the study to evaluate each lesion.  Lesion assessment [contrast CT (preferred) or MRI 
of chest, abdomen and pelvis], should occur at times shown until disease progression (even if the patient 
withdraws from treatment) but should continue after progression in patients who crossover from the standard 
arm to the Trametinib arm and should continue in that arm until progression.    
Scans should be sent on CD* labelled with NRG Patient ID to: 
NRG Oncology Statistics and Data Management Center – Buffalo Office 
Roswell Park Cancer Institute 
Elm & Carlton Streets 
Buffalo, NY 14263 
*Note: In that event that an Institution’s policies do not permit for scans to be sent via CD, the institution staff 
should contact Amy Speaker (SpeakerA@nrgoncology.org) at the NRG Oncology SDMC – Buffalo Office to 
coordinate another Institution-provided means of electronic delivery – including, but not limited to tools such as 
Box.com. (11/27/17) 
5. QOL assessments should be done at the following time points: 
 
• 
Prior to cycle 1 
• 
Prior to cycle 4 (12 weeks after starting treatment), 
• 
4 weeks post cycle 6 (24 weeks after starting study therapy)   
• 
36 weeks after starting treatment 
• 
52 weeks after starting treatment 
6. Must be obtained within 4 days prior to next cycle.  
7. Record blood pressure, pulse rate and body weight. Height measured only at screening.  
8. Two copies of the ECG tracing should be obtained at the time of the ECG, one to be kept in the site’s study file 
for retrospective collection by the sponsor if necessary.  
9. Post baseline ECHO (preferred)/MUGA must be done for patients receiving Trametinib. Subjects who have an 
asymptomatic, absolute decrease of >10% in LVEF compared to baseline and the ejection fraction is below the 
institution’s lower limit of normal (LLN) must follow the LVEF guidelines for study drug management and 
requirements for subsequent ECHO/MUGA. The same modality (ECHO or MUGA) should be used at baseline 
and at follow-up. 
10. For those on the standard arm, it is recommended that investigators follow institutional guidelines for ECG and 
ECHO/MUGA. 
11. When clinically indicated. 
12. At each visit, patients on both arms of the study will be queried regarding visual disturbances. If visual 
disturbances are reported, they should be carefully documented, and a follow-up ophthalmologic exam is required. 
 
7.2 
Pathology Requirements 
 
7.21 
Pathology review for confirmation of eligibility (11/27/17) 
 
This protocol requires prospective digital review of pathology to confirm 
eligibility. Regardless of whether the patient’s original diagnosis was 
ovarian or peritoneal serous tumor of low malignant potential or low-grade 
serous carcinoma, eligible patients include those with recurrent low-grade 
serous carcinoma of the ovary or peritoneum. One H&E stained slide from 
the recurrent tumor (obtained at secondary surgery, prior biopsy, or the 
image-guided fine needle/core biopsy) or from the original diagnostic 
specimen documenting low-grade serous carcinoma should be obtained 
from the pathology department and sent by overnight courier at the 

GOG-0281 
 
 
66 
 
institution’s expense to the GOG Tissue Bank in Columbus, Ohio, for 
determination of eligibility by review of digital slides. Please also send the 
screening form and a copy of the patient’s pathology report that has been 
labeled with the Screening ID with the slides. Slides must also be labeled 
with the Screening ID ,the surgical pathology accession number and the 
block number. 
 
GOG-0281 Pathology Review 
Nationwide Children’s Hospital 
700 Children’s Drive, WA 1340 
Columbus, OH 43205 
614-722-2865 
 
7.22 
Protocol for digital review of pathology slides 
 
A representative H&E stained slide will be scanned at the GOG Tissue 
Bank into a GOG-0281 digital tissue review database. 
 
A panel of 5 pathologists will be notified by email that a case is ready for 
central prospective review. Confirmation of protocol eligibility requires 
agreement of at least 3 pathologists on the diagnosis of recurrent low-
grade serous carcinoma using VIPER (Virtual Imaging for Pathology 
Education and Research). The institution will be notified of patient 
eligibility by email with 3 business days of receipt of the slide at the GOG 
Tissue Bank. At that time, institution personnel can go to the GOG-0281 
Screening web site to confirm a patient’s eligibility for enrollment in 
GOG-0281. 
 
7.3 
Translational Research 
 
Note: Testing of banked samples will not occur until an amendment to this 
treatment protocol (or separate correlative science protocol) is reviewed and 
approved in accordance with National Clinical Trials Network (NCTN) policies. 
 
 
7.31 
Specimen Requirements (07/28/14) (06/08/15) (11/27/17) 
 
Note: Frozen biopsy and PK plasma specimens are no longer required 
as of October 2017, and should not be collected. 
 
If the patient gives permission for her fixed tissue and blood specimens to 
be used for translational research, then the participating institution is 
required to submit the patient’s specimens as outlined below (unless 
otherwise specified). 
 
A detailed description of the specimen requirements and procedures can 
be found in Appendix IV. 

GOG-0281 
 
 
67 
 
 
All Patients (Arms A and B) (11/27/17) 
Required Specimen (Specimen 
Code) 
Collection Time Point 
Sites Ship Specimens To 
FFPE Primary Tumor (FP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm + 10 uncharged 10 µm) 
Prior to all treatment 
 
Preferred FFPE 
GOG Tissue Bank within 8 weeks 
of registration1 
FFPE Metastatic Tumor (FM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm +  10 uncharged 10 µm) 
Prior to all treatment 
 
Optional if FP01, FRP01, or 
FRM01 is submitted 
FFPE Recurrent Primary Tumor 
(FRP01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm +  10 uncharged 10 µm) 
Prior to study treatment 
 
Optional if FP01, FM01, or 
FRM01 is submitted 
FFPE Recurrent Metastatic Tumor 
(FRM01)* 
1st Choice: block 
2nd Choice: 20 unstained slides (10 
charged, 5µm +  10 uncharged 10 µm) 
Prior to study treatment 
 
Optional if FP01, FM01, or 
FRP01 is submitted 
Pre-Treatment Plasma (PB01) 
prepared from 7-10mL of blood drawn 
into a K2 EDTA tube2 
Prior to study treatment 
GOG Tissue Bank within 1 week of 
registration1 
C3D1 Pre-Treatment Plasma (PB06) 
prepared from 7-10mL of blood drawn 
into a K2 EDTA tube2  
Cycle 3, day 1, prior to 
administering study treatment 
GOG Tissue Bank within 9 weeks 
of registration1 
* 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the GOG Tissue Bank. 
1 
GOG Tissue Bank / Protocol GOG-0281, Nationwide Children’s Hospital, 700 Children’s Drive, WA1340, Columbus, OH 
43205, Phone: (614) 722-2865, FAX: (614) 722-2897, Email: BPCBank@nationwidechildrens.org 
2 
Please note the protocol-specific plasma processing instructions described in appendix IV. 
 
 
 
7.32 
Laboratory Testing 
Please refer to Appendix VII for additional background information and 
assay details. 
 
 
Priority 
Specimen 
1 
2 
Fixed material 
WES (7.321) 
IHC (7.322) 
 
 
 
 
7.321 Next-Generation Sequencing Mutational Analysis 
 
unstained sections of tumor will be used for whole exome 
sequencing (WES). 
 
 
7.322 Immunohistochemistry 
 
Unstained sections of tumor will be used for immunohistochemical 
(IHC) analysis of pERK. IHC will be performed by Kwong Wong 
at MD Anderson using the CLIA-certified clinical 

GOG-0281 
 
 
68 
 
immunohistopathology Laboratory. All stained sections will be 
quality controlled. They will be initially be scanned by laboratory 
personnel using a low-power objective. If areas suggesting 
technical errors are observed, they will be further examined with 
higher power objectives to identify problem. Appropriate steps are 
then taken to resolve the problem. Acceptable slides are initialed 
by ASCP certified technician performing Quality Control.  
 
 
 
 
7.324 Pharmacokinetics 
 
Plasma will be used to determine trametinib pharmacokinetics in a 
subset of patients (approximately 12 GOG and 12 UK; collected 
prior to October 2017). Plasma samples collected at the following 
seven time points will be used for PK testing: 
 
1. pre-treatment (PB01), 
2. cycle 1, day 15, 4-8 hours post-trametinib (PB02), 
3. cycle 1, day 28, pre-trametinib (PB03), 
4. cycle 1, day 28, 2 hours post-trametinib (PB04), 
5. cycle 2, day 1, 30 minutes post-trametinib (PB05),  
6. cycle 3, day 1, pre-trametinib (PB06), and 
7. cycle 3, day 1, 30 minutes post-trametinib (PB07). 
 
Due to the limited number of complete serial plasma sets 
received, PK assays will not be pursued at this time. 
 
 
 
7.33 
Future Research 
 
Details regarding the banking and use of specimens for future research can 
be found in Appendix IV. 
 
7.4 
Quality of Life (12/22/14) 
 
 
To be submitted as a separate submission to DCP. 
 
7.41 
There are two quality of life issues of interest: 
7.411 To compare Trametinib to the control arm with regard to patients’ 
self-reported acute (up to post cycle 6) quality of life as measured by the 
FACT-O-TOI. 
 
7.412 To compare Trametinib to the control arm with regards to patients’ 
self-reported acute (up to post-cycle 6) neurotoxicity as measured by the 
FACT-GOG-NTX. 

GOG-0281 
 
 
69 
 
 
7.42 
The primary measure used in this study to assess the quality of life is the  
adapted self-administered FACT-GOG-NTX, available on Scantron from 
NRG.  Each patient will be asked to complete the questionnaire at the 
following time points during their participation in the study: 
1. Prior to Cycle 1 
2. Prior to Cycle 4 (12 weeks after starting study therapy) 
3. 4 weeks post cycle 6 (24 weeks after starting study therapy) 
4. 36 weeks after starting study therapy 
5. 52 weeks after starting study therapy 
*The times in parentheses indicate the assessment time for those who 
terminate treatment early.  
7.43 
Quality of Life Background  
 
Rationale:  A thorough review of the literature specific to the low-grade 
serous carcinoma of the ovary or peritoneum revealed no descriptive, 
retrospective or prospective quality of life data on this rare tumor.  As 
stated above, this population differs considerably from the high-grade 
ovarian cancer population (e.g., indolent nature of disease, lack of 
response to cytotoxic therapies, younger age of onset, longer survival).  As 
a result, one could speculate regarding the QOL similarities or 
dissimilarities between these variants of ovarian cancer, but specific QOL 
concerns or symptoms in this rare tumor population are virtually 
unknown, and the extent to which QOL concerns in this rare tumor 
population are related to disease symptoms, treatment, or their combined 
influence on QOL are also consequently unknown.   
 
The previous GOG-0239 trial did not measure QOL or other Patient 
Reported Outcomes (PROs).  However, clinical data from this trial suggest 
that a MEK inhibitor may, among responders, potentially reduce tumor 
volume as measured through traditional disease response monitoring.  This 
may, in turn, reduce abdominal symptoms often associated with recurrent 
disease, which may improve QOL.  It is also noteworthy that targeted 
therapy with a MEK inhibitor is likely to be associated with significantly 
less toxicity than that of the cytotoxic chemotherapies.  It is less apparent, 
however, whether QOL for patients in the MEK inhibitor arm will be 
substantially different from those patients in the control arm when 
letrozole or tamoxifen are selected. These heretofore unexamined 
questions are of critical importance, in this rare, unstudied patient 
population in which no optimal treatment exists.  Since most women with 
LGS ovarian cancer will survive for many months, if not years, an 
important goal in assessing QOL is essentially to help to determine the 

GOG-0281 
 
 
70 
 
optimal treatment regimen, which could indeed positively influence 
practice changes. In addition, systematic documentation of QOL among 
those enrolled onto this trial may assist in providing information to future 
non-trial patients regarding the expected effects of therapy as they make 
their treatment choices.  Quality of life information will also provide an 
important, and perhaps the first, characterization of the health-status of 
women with recurrent LGS ovarian cancer, thereby alerting patients and 
clinicians to specific areas of concern. 
 
 

GOG-0281 
 
 
71 
 
8.0 
EVALUATION CRITERIA   
 
8.1 
Antitumor Effect – Solid Tumors 
Response and progression will be evaluated in this study using the Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [Eur J Ca 
45:228-247, 2009]. Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
8.11 
Definitions (06/08/15) 
Measurable disease. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be 
recorded) as >10 mm with CT scan, as >20 mm by chest x-ray, or >10 mm 
with calipers by clinical exam. All tumor measurements must be recorded 
in decimal fractions of centimeters. 
Note: Tumor lesions that are situated in a previously irradiated area will 
not be considered measurable unless progression is documented or a 
biopsy is obtained to confirm persistence at least 90 days following 
completion of radiation therapy. 
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. 
Leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal/pelvic masses (identified by physical exam and not CT or 
MRI), are considered as non-measurable. 
Notes: Bone lesions: Lytic bone lesions or mixed lytic-blastic lesions, with 
identifiable soft tissue components, that can be evaluated by CT or MRI 
can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. Blastic bone lesions are 
non-measurable. 
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 

GOG-0281 
 
 
72 
 
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, and in 
addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the 
next largest lesion which can be measured reproducibly should be 
selected. A sum of the diameters (longest for non-nodal lesions, short axis 
for nodal lesions) for all target lesions will be calculated and reported as 
the baseline sum diameters. If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
8.12 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a 
ruler or calipers. All baseline evaluations should be performed as closely 
as possible to the beginning of treatment and never more than 4 weeks 
before the beginning of the treatment. 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during 
follow- up. Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when 
they are superficial (e.g., skin nodules and palpable lymph nodes) and 
>=10 mm diameter as assessed using calipers (e.g., skin nodules). In the 
case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended. 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung. However, 

GOG-0281 
 
 
73 
 
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), but NOT 
lung. 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, 
and temporal resolution; however, there are many image acquisition 
variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement. Furthermore, the availability of MRI is 
variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the 
modality used at follow-up should be the same as was used at baseline, 
and the lesions should be measured/assessed on the same pulse sequence. 
It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, subsequent image acquisitions should use the same type of 
scanner and follow the baseline imaging protocol as closely as possible. If 
possible, body scans should be performed with breath-hold scanning 
techniques. 
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. PET-CT scans are not always done with 
oral and IV contrast. In addition, the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or 
serially performed. For these reasons, the GOG will not allow PET-CT 
use for RECIST 1.1 response criteria. 
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 

GOG-0281 
 
 
74 
 
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.  
Note: A “positive” FDG-PET scan lesion means one that is FDG avid with 
an uptake greater than twice that of the surrounding tissue on the 
attenuation corrected image. 
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. 
CA-125 (Ovarian, fallopian tube and primary peritoneal cancer trials): 
CA-125 cannot be used to assess response or progression in this study. If 
CA-125 is initially above the upper normal limit, it must normalize for a 
patient to be considered in complete clinical response. Specific guidelines 
for CA-125 response (in recurrent ovarian cancer) have been published 
[JNCI 96:487-488, 2004]. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria that are to be integrated with 
objective tumor assessment for use only in first-line trials in ovarian 
cancer [JNCI 92:1534-1535, 2000]. 
Cytology, Histology: These techniques can be used to differentiate 
between partial responses (PR) and complete responses (CR) in rare cases, 
e.g., residual lesions in tumor types, such as germ cell tumors, where 
known residual benign tumors can remain. 
It is mandatory to obtain cytological confirmation of the neoplastic origin 
of any effusion that appears or worsens during treatment when measurable 
disease has met criteria for response or stable disease. This confirmation is 
necessary to differentiate response or stable disease versus progressive 
disease, as an effusion may be a side effect of the treatment. 
8.13 
Response Criteria 
Determination of response should take into consideration all target (See 
8.131) and non-target lesions (See 8.132) and, if appropriate, biomarkers 

GOG-0281 
 
 
75 
 
(See 8.133). 
8.131 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the 
diameters of target lesions, taking as reference the baseline sum 
diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of 
the diameters of target lesions, taking as reference the smallest sum 
on study (this includes the baseline sum if that is the smallest on 
study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the 
appearance of one or more new lesions is also considered 
progressions). 
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. 
8.132 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).  
 
Note: If CA-25 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical 
response.  
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) 
Progressive Disease (PD): Appearance of one or more new lesions 
and/or unequivocal progression of existing non-target lesions. 
Unequivocal progression should not normally trump target lesion 
status. It must be representative of overall disease status change, 
not a single lesion increase.  
 
Not evaluable (NE): When at least one non-target lesion is not 
evaluated at a particular time point.  
 
Although a clear progression of only “non-target” lesions 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).  

GOG-0281 
 
 
76 
 
 
8.133  Evaluation of Biomarkers  
 
If serum CA-125 is initially above the upper normal limit, it must 
normalize for a patient to be considered in complete clinical 
response.  
 
Progression cannot be based upon biomarkers, such as serum CA- 
125, for this study.  
 
8.134  Evaluation of Best Overall (unconfirmed) Response  
The best overall response is the best time point response recorded 
from the start of the treatment until disease progression/recurrence 
(taking as reference for progressive disease the smallest sum 
recorded since Biomarker baseline). The patient's best response 
assignment will depend on the achievement of both measurement 
and confirmation criteria in some circumstances. 
 
 
Time Point Response for Patients with Measurable Disease at baseline (i.e., Target 
Disease) 
Target 
Lesions 
Non-Target 
Lesions 
CA 125 
New 
Lesions* 
Time Point 
Response 
CR 
CR 
WNL 
No 
CR 
CR 
Non-CR/Non-
PD 
Any value 
No 
PR 
CR 
NE 
Any value 
No 
PR 
PR 
Non-PD or NE 
Any value 
No 
PR 
SD 
Non-PD or NE 
Any value 
No 
SD 
NE 
Non-PD 
Any value 
No 
NE 
PD 
Any 
Any value 
Yes or No 
PD 
Any 
PD ** 
Any value 
Yes or No 
PD 
Any 
Any 
Any value 
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. 
 
Time Point Response for Patients with only Non-Measurable Disease at baseline (i.e., 
Non-Target Disease) 
Non-Target Lesions 
Biomarker CA 125 
New Lesions* 
Time Point 
Response 
CR 
WNL 
No 
CR 

GOG-0281 
 
 
77 
 
CR 
Above normal limits 
No 
Non-CR/Non-PD* 
Non-CR/Non-PD 
Any value 
No 
Non-CR/Non-PD* 
NE 
Any value 
No 
NE 
Unequivocal PD 
Any value 
Yes or No 
PD 
Any 
Any value 
Yes 
PD 
*See RECIST 1.1 manuscript for further details on what is evidence of a new lesion 
** ‘Non-CR/Non-PD is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point at least 4 weeks later. 
 
8.14 
Frequency of Tumor Re-evaluation 
 
In the present study, tumors will be re-evaluated by CT scan of the chest, 
abdomen, and pelvis every 8 weeks during treatment and at least 4 weeks 
after the first observation of a complete or partial response. After 
discontinuation of protocol treatment, patients who have not progressed 
will still be re-evaluated every 8 weeks. 
 
8.15 
Date of progression 
 
Date of progression is defined as the first day when the RECIST (version 
1.1) criteria for PD are met. CA 125 (GCIG) progression alone is not 
sufficient for progression to be defined. 
 
8.16 
Reporting of tumor response 
 
All patients included in the study must be assessed for response to 
treatment, even if there is a major protocol deviation or if they are 
ineligible, or not followed/re-evaluated. Each patient will be assigned one 
of the following categories: complete response, partial response, stable 
disease, progressive disease, early death from malignant disease, early 
death from toxicity, early death from other cause or unknown (not 
assessable, insufficient data). 
 
Early death is defined as any death occurring before the first per protocol 
time point of tumor re-evaluation. The responsible investigator will decide 
if the cause of death is malignant disease, toxicity, or other cause. 
 

GOG-0281 
 
 
78 
 
Patients for whom response is not confirmed will be classified as 
“unknown” unless they meet the criteria for stable disease (or the criteria 
for partial response in case of an unconfirmed complete response). 
Patients’ response will also be classified as “unknown” if insufficient data 
were collected to allow evaluation per these criteria. See table above in 
section 8.13 for further detail. 
 
8.17 
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). 
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 date of 
study entry until the criteria for progression are met, taking as reference 
the smallest measurements recorded since the date of study entry, 
including the baseline measurements. 
8.18 
Progression-free survival 
 
Progression-free survival (PFS) is defined as the duration of time from 
study entry to time of progression or death, whichever occurs first. 
8.19 
Overall survival 
 
Overall survival is defined as the time from study entry to time of death or 
date of last contact. 

GOG-0281 
 
 
79 
 
9.0 
DURATION OF STUDY    
 
 
9.1 
Patients will receive therapy until disease progression or intolerable toxicity  
intervenes. Patients can refuse the study treatment at any time. 
 
9.2 
All patients will be treated (with completion of all required case report forms)  
Until disease progression or study withdrawal. All patients will then be followed 
(with physical exams and histories) every three months for the first two years, 
then every six months for the next three years and then annually for the next 5 
years. All patients will be monitored for delayed toxicity and survival for this 10 
year period with Follow-up forms submitted via Medidata Rave, unless consent is 
withdrawn. 
 
9.3 
All patients will be followed for 10 years after removal from study or until death,  
 
 
whichever occurs first.   
 
9.4 
In the absence of treatment delays due to adverse event(s), treatment may  
 
 
continue until one of the following criteria applies: 
 
• Disease progression 
 
• Intercurrent illness that prevents further administration of treatment 
 
• Unacceptable adverse event(s) 
 
• Pregnancy (12/22/14) 
 
• Patient decides to withdraw from the study  
 
• General or specific changes in the patient’s condition render the patient  
 
 
 
unacceptable for further treatment in the judgment of the investigator. 

GOG-0281 
 
 
80 
 
10.0 
STUDY MONITORING AND REPORTING PROCEDURES   
 
10.1 
ADVERSE EVENT REPORTING FOR AN INVESTIGATIONAL AGENT  
 
(CTEP IND) 
   
 
10.11 Definition of Adverse Events (AE) 
 
Adverse event (21 CFR 312.32(a)):  Any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered 
drug related. 
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
The CTCAE v4.0 Manual is also available on the GOG member web site 
(http://www.gog.org under MANUALS). 
 
 
10.12 Reporting Expedited Adverse Events (07/28/14) 
 
Depending on the phase of the study, use of investigational agents, and 
role of the pharmaceutical sponsor, an expedited AE report may need to 
reach multiple destinations.  For patients participating on a GOG trial, all 
expedited AE reports should be submitted by using the CTEP Adverse 
Event Reporting System (CTEP-AERS).  ).  All CTEP-AERS submissions 
are reviewed by GOG before final submission to CTEP.  Submitting a 
report through CTEP-AERS serves as notification to GOG, and satisfies 
the GOG requirements for expedited AE reporting. All adverse reactions  
will be immediately directed to the Study Chair for further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
 
 
10.13 Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for 
Adverse Events that Occur on Studies under a CTEP IND/IDE within 30 
Days of the Last Administration of the Investigational Agent/Intervention1, 
2 
 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that Occur 
on Studies under a CTEP IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2 

GOG-0281 
 
 
81 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) (07/28/14) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be 
considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH 
E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
7 Calendar Days 
24-Hour 3 Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
7 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 3 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 3 calendar days of the initial 24-hour 
report. 
o “7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 3 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 
Expedited 7 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
 

GOG-0281 
 
 
82 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements: 
   
 There are no additional instructions or exceptions to CTEP-AERS expedited 
reporting requirements for this protocol. 
 
 
10.14 Procedures for Expedited Adverse Event Reporting: (07/28/14) 
 
10.141 CTEP-AERS Expedited Reports: Expedited reports are to be submitted 
using CTEP-AERS available at http://ctep.cancer.gov. The CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements for expedited adverse 
event reporting requirements are also available at this site.  
 
AML/MDS events must be reported via CTEP-AERS (in addition to 
routine AE reporting mechanisms). In CTCAE v4.0, the event(s) may be 
reported as either: 1) Leukemia secondary to oncology chemotherapy, 2) 
Myelodysplastic syndrome, or 3) Treatment related secondary 
malignancy. Any malignancy possibly related to cancer treatment 
(including AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
Second Malignancy:  
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting via CDUS unless 
otherwise specified. 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) 
provides a single list of reported and/or potential adverse events (AE) 
associated with an agent using a uniform presentation of events by body 
system.  In addition to the comprehensive list, a subset of AEs, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in 
a separate column and is identified with bold and italicized text.  The 
SPEER is a list of events that are protocol-specific exceptions to expedited 
reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/default.htm#adverse_events_ 
CTEP-AERS for further clarification. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to NCI by telephone at: 301-897-7497. An 
electronic report MUST be submitted immediately upon re-establishment 
of internet connection. Please note that all paper CTEP-AERS forms have 
been removed from the CTEP website and will NO LONGER be accepted. 
 

GOG-0281 
 
 
83 
 
10.2 
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT (06/08/15) 
   
10.21 Definition of Adverse Events (AE) 
 
An adverse event (AE) is any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease that occurs in a 
patient administered a medical treatment, whether the event is considered 
related or unrelated to the medical treatment.  
 
The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 
4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov). 
The CTCAE v4.0 Manual is also available on the GOG member web site 
(http://www.gog.org under MANUALS). 
 
10.22 Reporting Expedited Adverse Events 
 
Depending on the phase of the study, use of investigational or commercial 
agents, and role of the pharmaceutical sponsor, an AE report may need to 
reach multiple destinations.  For patients participating on a GOG trial, all 
expedited AE reports should be submitted by using the CTEP automated 
system for expedited reporting (CTEP-AERS).  All CTEP-AERS 
submissions are reviewed by GOG before final submission to CTEP-
AERS.  Submitting a report through CTEP-AERS serves as notification to 
GOG, and satisfies the GOG requirements for expedited AE reporting.  
All adverse reactions will be immediately directed to the Study Chair for 
further action. 
 
The requirement for timely reporting of AEs to the study sponsor is 
specified in the Statement of Investigator, Form FDA-1572.  In signing the 
FDA-1572, the investigator assumes the responsibility for reporting AEs 
to the NCI.  In compliance with FDA regulations, as contained in 21 CFR 
312.64, AEs should be reported by the investigator. 
 
10.23 Phase 2 and 3 Trials Utilizing a Commercial Agent:  CTEP-AERS 
Expedited Reporting Requirements for Adverse Events That Occur Within 
30 Days of the Last Dose of Any Commercial Study Agent  
 

GOG-0281 
 
 
84 
 
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the Last Dose of the 
Commercial Agent on Phase 2 and 3 Trials 
 
 
Grade 1 
 
Grade 2 
 
Grade 2 
 
Grade 3 
 
Grade 3 
Grades 
4 & 52 
Grades 
4 & 52 
Unexpected  
and Expected 
 
 
Unexpected 
 
 
Expected 
Unexpected 
Expected 
Unexpected Expected 
With  
Hospitali-
zation 
Without 
Hospitali- 
zation 
With  
Hospitali- 
zation 
Without 
Hospitali- 
zation 
Unrelated 
Unlikely 
Not 
Required 
Not 
Required 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 
Calendar 
Days 
Possible 
Probable 
Definite 
Not 
Required 
7 Calendar 
Days 
Not 
Required 
7 Calendar 
Days 
7 Calendar 
Days 
7 Calendar 
Days 
Not 
Required 
24-Hrs; 
3 Calendar 
Days 
7 
Calendar 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of 
treatment with a commercial agent require reporting as follows: 
CTEP-AERS 24-hour notification followed by complete report within 3 calendar days for: 
• Grade 4 and Grade 5 unexpected events  
      CTEP-AERS 7 calendar day report: 
• Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
• Grade 5 expected events 
 
2 Although an CTEP-AERS 24-hour notification is not required for death clearly related to progressive disease, a full 
report is required as outlined in the table. 
 
 Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to CTEP-AERS 
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.”          March 2005 
 
Note:  All deaths on study require both routine and expedited reporting regardless 
of causality.   Attribution to treatment or other cause must be provided. 
 
• 
Expedited AE reporting timelines defined: 
 “24 hours; 3 calendar days” – The investigator must initially report the AE via CTEP-
AERS within 24 hours of learning of the event followed by a complete CTEP-AERS 
report within 3 calendar days of the initial 24-hour report. 
“7 calendar days” – A complete CTEP-AERS report on the AE must be submitted within 
7 calendar days of the investigator learning of the event. 
 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of 
attribution and designation as expected or unexpected with the exception of any 
events identified as protocol-specific expedited adverse event reporting exclusions. 
 
• 
Any event that results in persistent or significant disabilities/incapacities, congenital 
anomalies, or birth defects must be reported to GOG via CTEP-AERS if the event occurs 
following treatment with a commercial agent. 
 

GOG-0281 
 
 
85 
 
• 
Use the NCI protocol number and the protocol-specific patient ID provided during trial 
registration on all reports. 
 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting Requirements for 
Phase 2 and 3 Trials Utilizing a Commercial Agent: 
 
• [Include any applicable instructions or exceptions here.  For example, “All Grade 2 and 
3 myelosuppression (including neutropenia, anemia, and thrombocytopenia) that does 
not require hospitalization is exempt from expedited reporting.” 
 
•  [Include the following statement if there are no exceptions] There are no additional 
instructions or exceptions to CTEP-AERS expedited reporting requirements for this 
protocol. 
 
10.24 Procedures for Expedited Adverse Event Reporting: 
 
10.241 CTEP-AERS Expedited Reports: Expedited reports are to be 
submitted using CTEP-AERS available at http://ctep.cancer.gov. 
The CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements for expedited adverse event reporting requirements 
are also available at this site.  
 
AML/MDS events must be reported via CTEP-AERS (in addition 
to routine AE reporting mechanisms). In CTCAE v4.0, the event(s) 
may be reported as either: 1) Leukemia secondary to oncology 
chemotherapy, 2) Myelodysplastic syndrome, or 3) Treatment 
related secondary malignancy. 
 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made to GOG by telephone at: 215-854-0770. 
An electronic report MUST be submitted immediately upon re-
establishment of internet connection. Please note that all paper 
CTEP-AERS forms have been removed from the CTEP website 
and will NO LONGER be accepted. 
  
 
10.25 Automated CDUS reporting  
 
For studies using commercial agents, the GOG Statistical and Data Center 
(SDC) routinely reports adverse events electronically to the CTEP Clinical 
Data Update System (CDUS Version 3.0).  The SDC submits this data 
quarterly.  The AEs reported through CTEP-AERS will also be included 
with the quarterly CDUS data submissions. 
 

GOG-0281 
 
 
86 
 
10.3 
Medidata Rave Data Submission and Reporting (07/28/14)(03/21/16)(02-JUN-
2020) 
 
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: 
o Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
o Rave Investigator role must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
o 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. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write 
access to Rave must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System 
(RSS), all persons with Rave roles assigned on the appropriate roster will be sent 
a study invitation e-mail from iMedidata. To accept the invitation, site staff must 
log in to the Select Login (https://login.imedidata.com/selectlogin) using their 
CTEP-IAM username and password and click on the accept link in the upper 
right-corner of the iMedidata page. Site staff will not be able to access the study 
in Rave until all required Medidata and study specific trainings are 
completed. Trainings will be in the form of electronic learnings (eLearnings) and 
can be accessed by clicking on the link 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.  
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a 
separate invitation from iMedidata to activate their account. Account activation 
instructions are located on the CTSU website in the Data Management section 

GOG-0281 
 
 
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under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on 
the CTSU members’ website in the Data Management > Rave section 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.   
 
10.4 
GOG DATA MANAGEMENT FORMS (06/08/15) 
The following forms must be completed for all patients registered and submitted 
to the GOG Statistical and Data Center (SDC) according to the schedule below. 
GOG electronic case report forms must be submitted through the Medidata Rave 
Electronic Data Entry System (www.imedidata.com). All amendments to forms 
must also be submitted through Medidata Rave. The operative report, discharge 
summary and pathology reports can be sent to the GOG Statistical and Data 
Center via postal mail or uploaded in Medidata Rave. The upload option is an 
alternative method for submitting paper reports. Quality of Life questionnaires are 
to be completed on the original Scantron forms and submitted via postal mail 
 
 
 
 
 
Form 
Comments 
Baseline Folder  
(Forms due within 2 weeks of registration) 
 
Baseline/History Forms: 
- 
Visit Information – Baseline Form 
- 
Registration Form 
- 
History Information Form 
- 
Primary Surgery Form  
- 
Chemotherapy Information Form 
- 
Pre-Treatment Summary Form 
- 
Specimen Consent 
- 
Vitals Form 
- 
ECHO/MUGA Form 
 
Solid Tumor Evaluation Forms: 
- 
Target Lesions Form 
- 
Non-Target Lesions Form 
 
The appropriate forms will load in the Baseline Folder 
based on the answers reported on the corresponding 
Baseline Visit Information form. 
 

GOG-0281 
 
 
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Form 
Comments 
Visit Folder 
(Forms due within 2 weeks of the completion of each cycle) 
Cycle Information and Treatment Forms: 
- 
Visit Information Form 
- 
Cycle Patient Information Form 
- 
Cycle Drug Information Form  
- 
Labs and Chemistries Form 
- 
Vitals Form 
- 
ECHO/MUGA Form 
 
Toxicity Forms: 
- 
Section 1 Form 
- 
NADIRS Form 
- 
Adverse Event Form 
- 
Adverse Event Grades 
Solid Tumor Evaluation Forms: 
- 
 Target Lesions Form 
- 
 No Target lesion Form 
- 
 Non-Target Form 
- 
 New Target Lesions Form 
- 
 Status and Response Form 
The appropriate forms will load in the Visit Folder 
based on the answers reported on the corresponding 
Visit Information forms. 
 
Pathology Folder 
(Reports due within 6 weeks of registration) 
 
Primary disease: 
Pathology Report 
 
Recurrent or Persistent Disease: 
Pathology Report 
 
Submit one copy of the pathology report to SDC via 
postal mail or upload the pathology report online via 
RAVE. 
 
Stained pathology slides are required for prospective 
digital review See Section 7.11 for mailing 
instructions. 
 
 

GOG-0281 
 
 
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Form 
Comments 
Translational Research Folder (11/27/17) 
TR Forms: 
- 
Snap Frozen Recurrent Primary Biopsy 
(RRP01)* 
- 
Snap Frozen Recurrent Metastatic Biopsy 
(RRM01)* 
- 
FFPE Primary Tumor (FP01) 
- 
FFPE Metastatic Tumor (FM01) optional 
- 
FFPE Recurrent Primary Tumor (FRP01) 
optional 
- 
FFPE Recurrent Metastatic Tumor (FRM01) 
optional 
- 
Pre-Treatment Plasma (PB01) 
- 
C1D15 4-8 Hour Post-Treatment Plasma 
(PB02)* 
- 
C1D28 Pre-Treatment Plasma (PB03)* 
- 
C1D28 2 Hour Post-Treatment Plasma 
(PB04)* 
- 
C2D1 30 Minute Post-Treatment Plasma 
(PB05)* 
- 
C3D1 Pre-Treatment Plasma (PB06) 
- 
C3D1 30 Minute Post-Treatment Plasma 
(PB07)* 
A completed copy of Form TR must accompany 
each specimen shipped to the GOG Tissue Bank 
(or alternate laboratory). Handwritten forms will 
not be accepted. 
 
FP01, FM01, FRP01, and FRM01 are due 8 weeks 
from registration. 
 
RRP01 or RRM01 and PB01 are due 1 week from 
registration. 
 
PB02-PB07* are due 9 weeks from registration. 
 
*RRP01, RRM01, PB02-PB05, and PB07 are no 
longer required as of October 2017, and should not 
be collected. 
Quality of Life 
Scantron Form 
Submit Original Scantron Form to SDC via postal mail 
Treatment Completion Folder 
(Forms due within 2 weeks of treatment completion) 
Treatment Completion Form 
 
Follow-up Visit Folder 
(Forms due within 2 weeks of follow-up visits, disease progression or death) 
 
Visit Information Follow-Up Form 
 
Follow-Up Form 
 
Follow-Up Period Adverse Event: 
- 
Reporting Form – Part 1 
- 
Reporting Form – Part 2 
 
Follow-up visits should be scheduled quarterly for 2 
years, semi-annually for 3 more years, and annually 
thereafter. 
 
The appropriate forms will in the Follow-up Visit 
Folder based on the answers reported on the 
corresponding Follow-up Visit Information forms. 
 

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Solid Tumor Evaluation: 
- 
 Target Lesions Form 
- 
 No Target lesion Form 
- 
 Non-Target Form 
- 
 New Target Lesions Form 
- 
 Status and Response Form 
 
 
This study will be monitored by the Abbreviated Clinical Data System (CDUS) Version 3.0 
CDUS data will be submitted quarterly by the January 31, April 30, July 31 and October 31 
due dates to CTEP by electronic mean. 

GOG-0281 
 
 
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11.0 
STATISTICAL CONSIDERATIONS   
 
 
11.1 
Design Summary 
This is an unblinded, randomized phase II/III study of comparing trametinib to 
“standard therapy” (consisting of one of five commercially available agents) in 
patients with low-grade serous carcinoma of the ovary or peritoneum previously 
treated with platinum-based chemotherapy treated with in women with recurrent 
low-grade serous. 
 
Patients will be randomized in a 1:1 ratio to receive Trametinib or standard of 
care (the control arm). The randomization will be stratified—using 
minimization—by the following factors: geographic region (UK or US), 
performance status (0 or 1), number of prior treatment regimens, and planned 
treatment regimen (if in the control arm). 
 
All patients will be registered centrally via OPEN. Prior to registration, eligibility 
will be reviewed via Eligibility check list verification. All reports will include a 
complete accounting of all patients registered to this protocol. 
 
All reports will include an accounting of all patients registered onto the study, 
regardless of their eligibility status or compliance to the assigned treatment. 
 
All analyses will be done on the data combined from the US and UK.  This is one, 
international study.  The data will be collected in the GOG database but will be 
transferred to the UK for analysis. 
 
 
11.2 
Principal Parameters 
The principle parameters employed to evaluate the primary, secondary, and 
translational research objectives are: 
 
11.21 Primary efficacy endpoint: progression-free survival 
 
11.22 Secondary endpoints 
 
11.221 Adverse events assessed using CTCAE version 4 
 
11.222 Overall survival 
 
11.223 Objective tumor response rate 
 
11.224 Quality of Life as measured by FACT and FACT-NTX 
 
11.23 Translational Research Endpoints: 
 
11.231 Mutations of genes in the MAPK pathway 
 

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11.232 Protein levels of pERK 
 
11.3 
Accrual Goal, Accrual Rate, and Study Duration 
The targeted accrual for this study is 250 patients (125 per arm). The accrual rate 
for this same patient population in GOG-0239 was 3 patients per month.  We 
project an accrual rate of 5.5 patients per month, and project half the accrual to be 
from the US and half to be from the UK.  The higher rate here compared to GOG-
0239 is due to (i) the participation of NCRN institutions in the UK, and (ii) this is 
a randomized phase II/III trial, in which more institutions are likely to participate.  
Women with low-grade serous carcinoma have a significantly better prognosis 
than those with typical high-grade ovarian cancers although they recur at 
approximately the same rate. Thus, this patient cohort typically receives multiple 
sequential chemotherapy and hormonal therapy regimens. 
 
We expect to accrue 250 patients over 46 months, with a follow-up period of 10 
months to provide the requisite number of events, which is specified below. 
 
This randomized study will follow CTEP slow accrual Guidelines; for this, the 
total accrual (GOG and International) will be considered. 
 
Participation in the study by non-US, non-NCTN sites will require an official 
amendment with approval by CTEP. 
 
 
11.4 
Design and Analyses for the Primary Objective 
This is as a two-arm randomized phase II/III study. The primary endpoint is 
progression-free survival (PFS). The null and alternative hypotheses with regard 
to the relative PFS event rate for the trametinib versus standard of care arms are 
as follows: 
 
H0: Δ=λT/ λS =1.0 vs. H1: Δ=λT/ λS <1.0 
 
where λT and λS are the PFS hazards in the trametinib and standard of care arms, 
respectively. 
 
PFS is being used as the primary endpoint as opposed to survival in the study 
because of the relatively long overall survival in this patient population. 
 
The primary analyses of PFS will include all patients enrolled onto the study 
regardless of eligibility or compliance to their assigned study regimen. Patients 
will be grouped by their randomized treatment for intention-to-treat analyses 
(ITT). 
 
In order to have 80% power to detect a 50% improvement in PFS (from 8 to 12 
months) and using a one-sided 2.5% significance level at the final analysis, 213 
events are required.  A sample size of 250 patients accrued over 46 months, with a 
follow-up period of 10 months should provide this number of events. The final 

GOG-0281 
 
 
93 
 
analysis will occur when at least 112 events (deaths or progressions) are observed 
in the control arm (which is the expected number to occur with 213 events total 
and a 33% reduction in the hazard for the experimental arm). The analysis will be 
based on a log rank test stratified by geographic region (UK or US), performance 
status (0 or 1), and planned treatment regimen (in the control arm). The study 
includes an interim analysis for futility, which is described below.  (When the 
trial’s futility analysis is considered, the overall type I error of the trial is 0.022.) 
 
 
11.5 
Interim Analysis (11/27/17) 
The phase II portion of the trial corresponds to results prior to the interim, futility 
analysis, which has an aggressive stopping rule.  The futility analysis will occur 
when 58 PFS events are observed in the either arm (which is the expected number 
to occur within the control arm when there are 106 events total, i.e., 50% 
information, and a 33% reduction in the hazard for the experimental arm).  This is 
expected to occur after approximately 32 months of accrual.  A Rho family 
spending function with a parameter of 0.95 will be used 32.  If the test statistic 
from the log-rank test is <0.826, the trial will be stopped for futility. Under the 
null hypothesis, the probability of stopping for futility is 0.796, and under the 
alternative hypothesis, the probability is 0.104 (i.e., 0.104 of the 0.20 beta is spent 
at the interim analysis). 
 
The results of interim analyses will be examined by an independent data 
monitoring committee, made up of representatives from GOG and the UK. The 
decision to terminate accrual will include consideration of toxicities, treatment 
compliance, and progression-free survival and other endpoints, and results from 
external studies. 
 
The trial will not be suspended for the interim analysis. 
 
Expansion of the study from the phase 2 portion to the phase 3 portion of the 
study will require an official amendment with approval by CTEP. 
 
The results of the interim futility analysis indicated that the trial could go forward 
to the phase III portion of the study, and the NRG Data Monitoring Committee 
(DMC) recommended doing so in a meeting on July 13, 2017.  In addition, no 
new safety signals were seen during this (or previous) reviews. 
 
 
 
11.6 
Monitoring Adverse Events and the Role of the GOG DSMB 
The GOG Data Safety and Monitoring Board (DSMB) reviews accumulating 
summaries of toxicities and all serious adverse event (SAE) reports on an ongoing 
basis (not efficacy results). This committee also reviews those deaths in which 
study treatment may have been a contributing cause. The DSMB reports to the 
DMC and it may recommend study amendments pertaining to patient safety. Data 
sheets from patients on this protocol will be reviewed before each semi-annual 
meeting and will also be reviewed by the Study Chair in conjunction with the 

GOG-0281 
 
 
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Statistical and Data Center. In some instances, because of unexpectedly severe 
toxicity, the Statistical and Data Center may elect, after consultation with the 
Study Chair and the Medical Oncology Committee, to recommend early 
suspension of a study. 
 
The frequency and severity of all toxicities are tabulated from submitted case 
report forms and summarized for review by the study chair, Ovarian Committee, 
and GOG Data Safety and Monitoring Board (DSMB) in conjunction with each 
semi-annual GOG meeting. For studies sponsored by the Cancer Therapy 
Evaluation Program (CTEP) of 
The National Cancer Institute (NCI), standardized toxicity reports are also 
submitted to the drug and disease monitors at the Investigational Drug Branch 
(IDB) and Clinical Investigation Branch (CIB). 
 
 
11.7 
Analyses for Secondary Objectives 
All tests for secondary objectives will be done using one-sided tests with α=0.05. 
 
Safety Analyses 
The National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) criteria version 4.0 will be used to classify adverse events (AEs) 
observed during treatment. The severity of each AE will be assessed according to 
the NCI CTCAE 4.0 grading system. Patients will be tabulated according to their 
maximum severity for each organ system or preferred term. 
 
Safety endpoints will be summarized with descriptive statistics for the patients in 
the safety analysis dataset. The safety analysis dataset will include all patients 
enrolled to the study who receive any of their assigned study treatment, and 
patients will be grouped by their assigned treatment. Patients who do not receive 
any of their assigned study treatment will not be included in these analyses. 
 
Analyses of Overall Survival 
Secondary endpoints include overall survival (OS) and tumor response. With the 
projected accrual above, and assuming a median overall survival of 30 months in 
the control arm, the study has 80% power to detect a 33% improvement in median 
OS from 30 to 40 months at a one-sided 25% significance level.  The analysis of 
overall survival will be based on a log-rank test. 
 
Overall survival will be characterized by treatment group with Kaplan-Meier plots 
and estimates of the median time until death. The log rank test33 will be used to 
compare treatment groups with respect to overall survival. Patients will not be 
censored at the time of crossover.  We note that analyses of overall survival will 
be problematic (and biased in undetermined ways) due to the crossover allowed at 
progression. Therefore, these analyses must be considered in this light. Prior to 
the analysis, other potential analysis methods (e.g., inverse probability 
weighting37) will be considered and pre-specified. 
 

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95 
 
Response rates (Complete and Partial combined) will be compared between the 
arms using logistic regression via a model incorporating study arm and the factors 
used in the minimization algorithm.  The p-value associated with study arm will 
be obtained from this model.  An 80% confidence interval for the odds ratio will 
be provided.   
 
 
 
Analyses of Quality of Life 
The Functional Assessment of Cancer Therapy scale developed for ovarian cancer 
(FACT-O TOI) is a tool that provides a general QoL score. It consists of 3 
subscales: physical well-being (7 items), functional well-being (7 items) and the 
Ovarian Cancer subscale (12 items).  The FACT-GOG/NTX4 is a four-item 
subscale which assesses patient reported platinum/taxane-induced symptoms of 
neuropathy.   
 
 
 
Hypotheses and analyses 
QOL Objective 1: To compare the MEK inhibitor to the “cytotoxic standard 
therapy” (i.e., PLD, weekly topotecan or weekly paclitaxel) on patients’ self-
reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-
TOI. 
QOL Hypothesis 1:  Patients’ randomized to the MEK inhibitor treatment arm 
will report significantly better acute QOL compared to patients randomized to the 
cytotoxic standard therapy arm. 
 
QOL Objective 2: To compare the MEK inhibitor to the “cytotoxic standard 
therapy” (i.e., PLD, weekly topotecan or weekly paclitaxel) on patients’ self-
reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-GOG-
NTX. 
QOL Hypothesis 2: Patients’ randomized to the MEK inhibitor treatment arm will 
report significantly less acute neurotoxicity compared to patients randomized to 
the cytotoxic standard therapy arm. 
 
QOL Objective 3: To compare the MEK inhibitor to the “endocrine standard 
therapy” (i.e., letrozole, tamoxifen) with respect to patients’ self-reported acute 
quality of life and neurotoxicity, as measured by the FACT-O-TOI, and FACT-
GOG-NTX, respectively. 
QOL Hypothesis 3:  Patients’ randomized to the MEK inhibitor treatment arm 
will report significantly better acute QOL compared to patients randomized to the 
endocrine standard therapy arm. 
 
The primary QoL hypothesis will be examined with a mixed model, adjusting for 
pretreatment TOI score, age, and treatment option (PLD, weekly topotecan, or 
weekly paclitaxel) and using post-baseline scores from pre-cycle 4 and post-cycle 
6.  Patients will be included in these analyses regardless of the amount of study 
treatment they received.  For the primary analyses, patients will be categorized by 
their randomized treatment assignment rather than the treatment received.  

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96 
 
Analyses which classify patients by the actual treatment they received will be 
considered exploratory. 
 
 
 
The second QoL hypothesis will be examined as above but the FACT-NTX. 
 
The third QoL hypothesis will be examined as above but with the treatment 
options restricted to letrozole or tamoxifen. 
 
Analyses of all four post-baseline QoL assessments will be considered 
exploratory. 
 
Multiplicity of Outcomes 
The overall type I error for the two primary QoL hypotheses (1 and 2) will be 
controlled at α=0.10 by using a Bonferroni adjustment: each will be tested at 
α=0.0513.  The overall alpha for the QoL hypotheses will be controlled by testing 
the secondary hypothesis (3) only if one or both of the two primary hypotheses 
are rejected.  All tests will be two-sided. 
 
Statistical Power Considerations 
 
Based on a trial of GOG of 415 patients with advanced ovarian cancer were 
treated with platinum and paclitaxel for 6 cycles every 21 days, we estimate the 
standard deviation (SD) of the FAC-TOI scores to be approximately 15. We 
roughly project the following numbers of patients will receive each of the 
following standard of care treatments (with equal numbers to the experimental 
therapy in each strata) 
• Letrozole: 50 
• Tamoxifen:  25 
• Taxol: 
25 
• PLD: 
20 
• Topotecan: 5 
 
This would yield 25 patients per treatment arm for the primary QoL hypothesis, 
and 100 patients per treatment arm for the secondary hypothesis. 
 
 
The table below shows the between-treatment difference that is detectable with 
90% power, given the sample sizes shown per arm, and assuming a SD=15 (and 
two-sided α=0.0513). 
N 
per arm 
Detectable Difference 
With 80% power 
With 90% power 
 
25 
12.1 
14.0 
 
50 
8.5 
9.8 
 
75 
6.9 
8.0 
 
100 
5.9 
6.9 
 
 

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11.8 
Analyses for Integrated Biomarker Objectives 
 
Secondary Objectives 1.24 and 1.25 consider the prognostic and predictive abilities of 
several biomarkers relative to Objective Response Rate (ORR, section 8.16) or progression 
free survival (section 8.16, 8.18).  The biomarkers of interest are: 
1. (Objective 1.24) pERK expression, quantified using the H-Score (page 117) derived from 
IHC analysis of patient tumor tissue.  The H-Score is expected to present as a continuous  
measure. 
2. (Objective 1.25) Markers of genotype status within the MAPK pathway, quantified by 
Whole Exome Sequencing (WES).  WES output includes indicators of 
a. single nucleotide polymorphisms (SNPs) 
b. multiple nucleotide polymorphisms (MNPs) 
c. insertions (INS) 
d. deletions (DEL) 
These measures are expected to present as dichotomous factors.  When 3 or more levels 
are presented, the modeling will likely require collapsing the analysis variable down to 2 
biologically rational levels. 
Notation and Definitions 
Let λi,j denote the true odds of response or PFS hazard associated with marker expression i ϵ 
{High(H), Low (L)} receiving randomized treatment j ϵ {Trametinib(T), Control(C)}.  For 
continuous markers, λi,j represents a one-unit difference in the expression measurement. We 
assume that higher expression levels correspond to better prognosis. 
Then let δ•j= λH,j /λL,j  denote the true odds- or hazard ratio related to high (ref: low) marker 
expression among patients randomized to treatment = (j).  Similarly, let δi•= λi,T /λi,C  denote 
the true odds- or hazard- ratio related to trametinib (ref: control) among patients with marker 
expression = (i).  
Prognostic Hypothesis Testing and Statistical Power 
A prognostic marker is expected to provide information on the clinical outcome of patients 
receiving the standard therapy.34,35  The null and alternative hypotheses for a prognostic 
marker are 
H0: δ•C =λH,C /λL,C =1.0   vs   HA: δ•C ≠1.0 
The design parameters in Section 11.3-11.4 suggest the dataset supporting the prognostic 
marker analyses will include 125 patients randomized to the control arm, with 100 PFS 
events.  
The power of the proportional hazards and logistic regression models is a function of the 
proportion of patients with evaluable tumor tissue, the distribution of the marker within the 
evaluable patient set and the number of events or responses.36  The following tables 
summarize the biomarker effect that can be detected by a 2-sided, with α=0.05 test with 80% 
power, given assumptions for the size of the evaluable patient set.  These estimates assume 
no impact from the multivariable covariate adjustment. 

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Prognostic Effect Estimation  
The prognostic models will be supported by patients randomized to the control arm, 
excluding information collected after crossover to trametinib. 
The prognostic hazard ratio and odds ratio estimates related to each marker/outcome 
combination will be estimated by multivariable proportional hazards or logistic regression 
models, with covariate adjustment for the main effects of geographic region, performance 
status and number of prior regimens (the stratification factors in Section 11.2).  If the marker-
effect term from this model has p-value < 0.05, the marker will be considered prognostic, and 
interesting for future validation studies. 
Similar methods will support exploratory analyses among patients randomized to trametinib 
therapy. 
Predictive Hypothesis Testing and Statistical Power 
Predictive markers are expected to provide information on the likelihood of response to a 
particular treatment.  The predictive hypothesis considers whether the treatment effect 
depends on marker status.  As shown by Peterson,37 the null and alternative hypotheses for a 
predictive marker are 
H0: δH• = δL•   vs   HA: δH• ≠ δL• 
Gail (1985) assumes the marker effect estimates in the treatment subsets (δH• , δL•) are 
independent, suggesting these treatment effect estimates should be obtained from separate, 
marker-specific models.38  Peterson shows the z-test statistic implied by this prediction 
hypothesis simplifies to 
𝑙𝑙𝑙𝑙ቈ𝛿𝛿𝐻𝐻∙
𝛿𝛿𝐿𝐿∙
෢
቉~𝑁𝑁ቌ𝑙𝑙𝑙𝑙൤𝛿𝛿𝐻𝐻∙
𝛿𝛿𝐿𝐿∙
൨, ඨ1
𝐷𝐷𝐻𝐻𝐻𝐻
+ 1
𝐷𝐷𝐻𝐻𝐻𝐻
+ 1
𝐷𝐷𝐿𝐿𝐿𝐿
+ 1
𝐷𝐷𝐿𝐿𝐿𝐿
ቍ 
where DHT is the expected number of events among the high marker trametinib patients.37    
The power/effect size relationship shown in the table below considers the simplified scenario 
where the treatment effect is limited to the high marker patients, i.e δL•=1.0 throughout.  High 
Proportion with
Proportion with
Favorable Marker
100
80
60
Favorable Marker
120
100
80
50%
0.571
          
0.534
          
0.485
          
50%
0.647
          
0.669
          
0.697
          
35%
0.556
          
0.519
          
0.468
          
35%
0.657
          
0.679
          
0.707
          
20%
0.496
          
0.457
          
0.405
          
20%
0.698
          
0.720
          
0.749
          
(Response rate for Unfavorable Marker = 0.400)
# Evaluable Events
# Evaluable Patients
PFS HAZARD RATIOS
OBJECTIVE RESPONSE RATES
Shows the maximum detectable hazard ratio (MDHR) 
associated with favorable (vs unfavorable) biomarker 
expression.  Differences in PFS are tested using a 
logrank test with 2-sided alpha=0.05, power=0.80.  If 
all patients have sufficient tissue, the analysis is 
supported by 100 PFS events.   The MDHR decreases 
with as the number of evaluable patients decreases, 
or the prevalence of favorable expression decreases.
Shows the minumum detectable Objective Response 
Rate (MDORR) among patient with favorable 
biomarker expression.  Proportions are compared 
using a z-test with 2-sided alpha=0.05, power=0.80.  If 
all patients have sufficient tissue, the analysis is 
supported by 120 patients. The MDORR increases as 
the number of evaluable patients decreases, or the 
prevalence of favorable expression decreases.

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marker status has a small prognostic effect (δ•C = 0.83, or a 3-month improvement in PFS in 
control patients with high marker expression).  These assumptions focus the predictive effect 
into the high marker patients treated with trametinib.  The table shows the treatment effect 
estimate among marker high patients.  A 2-sided, α=0.05 z-test has 80% power to detect the 
hazard ratios shown below, assuming no impact from the multivariable covariate adjustment.   
 
 
Predictive Effect Estimation  
These models will include all evaluable patients according to the randomized treatment 
assignment.  For patients randomized to the control arm, information collected after 
crossover to trametinib will be excluded. 
The predictive hypotheses will be assessed using multivariable logistic or proportional 
hazards modeling, specified with main effects for the randomized treatment assignment, 
baseline marker status, and the interaction terms.  Covariate adjustment will include the main 
effects of geographic region, performance status and number of prior regimens (the 
stratification factors in Section 11.2).  If the interaction term from this model has p-value < 
0.05, the marker will be considered predictive and interesting for future validation studies. 
Qualitative Interaction  
The predictive modeling above considers so-called quantitative differences in the treatment 
effects within patient subsets defined by marker status. Gail (1985) defines a qualitative 
interaction as when “the direction of the true treatment differences varies among subsets of 
patients.”38 This working definition is satisfied by the combination of two scenarios: 
(𝛿𝛿𝐻𝐻∙< 1.0 and 𝛿𝛿𝐿𝐿∙> 1.0)  or  (𝛿𝛿𝐻𝐻∙> 1.0 and 𝛿𝛿𝐿𝐿∙< 1.0) 
 
These possibilities will be addressed using a forest plot of the point estimates and 
simultaneous confidence intervals for (δH∙, δL∙) obtained from the multivariable modeling 
described above. Juxtaposition of these confidence intervals will show whether the data 
support the presence of a qualitative interaction.  If the number of events and distribution of 
Evaluable
Patients
50%
35%
20%
250
                  
0.396
               
0.359
       
0.250
       
200
                  
0.347
               
0.306
       
0.182
       
150
                  
0.280
               
0.232
       
N/A
HAZARD RATIOS (Tram/Control, Marker=High)
% Marker High
Shows the maximum detectable hazard ratio (MDHR) associated with 
Trametinib (vs control) in patients with high marker expression.  The 
treatment HR in low marker patients is set to =1.  The ratio of hazard 
ratios is tested using z-test with 2-sided alpha=0.05, power=0.80.  
Assumes all Marker=Low pts have median PFS=15 months, and the 
Marker= High Control pts have median PFS=18 months (prognostic HR = 
0.83).  With 150 evaluable pts and 20% Marker=High, the event count is 
too low for analysis.

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the markers permit modeling within marker-based subsets, independent-sample modeling 
will be used instead. 
Shared Analysis Details  
All estimates will be derived using patient information collected while receiving the 
randomized treatment.  Information from control patients collected after crossing over to 
trametinib will be excluded.  
Our preference is to model the pERK H-Score as continuous variable, centered and scaled to 
reflect a clinically meaningful change. For explanatory purposes, the expected PFS 
distributions for specific pERK values may be estimated from the proportional hazards 
modeling.  For confirmation, these expected distributions will be compared to Kaplan-Meier 
estimates based on the dichotomized H-Score. 
Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest 
plots of the odds-ratio and hazard ratio estimates.  Duration of response will be depicted 
using swimmer plots, with median duration estimated using Kaplan Meier methods. 
The multivariable models will include covariate adjustment for geographic region, 
performance status and number of prior regimens, presented using effect coding.  If the data 
cannot reasonably support this many covariates, geographic region and performance status 
may be dropped.  This approach assumes the number of prior therapy lines is the strongest 
confounder for the marker/outcome associations. 
Cases with undue influence will be identified using deviance or martingale residual 
diagnostics, changes in the estimated effects (e.g. diff betas), and likelihood displacement 
measures. If a problem exists, subsequent exploratory analyses will be conducted with these 
cases removed (these cases will be explicitly stated as being dropped from the analysis). 
The adjusted hazard- and odds- ratio estimates from the multivariable models will be 
supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals 
will be interpreted as the plausible range of values for the true (unobserved) ratio that is 
supported by the data.  For the prediction analyses, point estimates and confidence intervals 
will be provided for the treatment effect within the biomarker levels. 
Multiplicity adjustments will be conducted within the prognostic and predictive testing 
families, and if at least one nominal p-value is <0.05.  Familywise type I error rates will be 
controlled to 0.05 using methods described by Hommel.39  Both nominal and adjusted p-
values will be presented.   
 
 
 
 
 
Additional information on Human Tumor Tissues: Refer to Appendix IV. 
 
 

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11.9 
Anticipated Gender and Minority Inclusion 
This study restricts entry to women by nature of the site of disease.  The table 
below lists the anticipated percentages of patients by racial and ethnic subgroups 
(based on previous studies in this patient population) for patients in the US.   
 
NOTE: approximately half of the patients are expected to come from accrual in 
the United Kingdom, in which race and ethnicity information is not collected. 
 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
18 
+ 
0 
= 
18 
Not Hispanic or Latino 
107 
+ 
0 
= 
107 
Ethnic Category: Total of all subjects 
125 
+ 
0 
= 
125 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
0 
= 
1 
Asian 
6 
+ 
0 
= 
6 
Black or African American 
6 
+ 
0 
= 
6 
Native Hawaiian or other Pacific Islander 
1 
+ 
0 
= 
1 
White 
111 
+ 
0 
= 
111 
Racial Category: Total of all subjects 
125 
+ 
0 
= 
125 

GOG-0281 
 
 
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12.0 
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Yamada SD, Mutch D, Rodgers WH, Birrer M, Gershenson DM. Selumetinib in women 
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38. Gail (1985) Testing for Qualitative Interactions between Treatment Effects and Patient 
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40. Schmeler KM, Gershenson DM. Low-grade serous ovarian cancer: a unique disease. Curr 
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41. Romero I, Sun CC, Wong KK et al. Low-grade serous carcinoma: new concepts and 
emerging therapies. Gynecol Oncol 2013; 130: 660-666. 
42. Gershenson DM, Bodurka DC, Lu KH et al. Impact of Age and Primary Disease Site on 
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47. Pohl G, Ho CL, Kurman RJ et al. Inactivation of the mitogen-activated protein kinase 
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52. Rennert H, Eng K, Zhang T et al. Development and validation of a whole-exome 
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APPENDIX I - CRADA/CTA LANGUAGE 
 
NCI/ DCTD Standard Language to Be Incorporated into All Protocols Involving Agent(s) 
Covered by a Clinical Trials Agreement (CTA) a Cooperative Research and Development 
Agreement (CRADA) or a Clinical Supply Agreement, hereinafter referred to as Collaborative 
Agreement: 
 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study:  
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study.  
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing 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. 
 

GOG-0281 
 
 
108 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative  
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164.   
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review 
and comment prior to submission for publication.  Collaborator(s) will have 30 days from 
the date of receipt for review.  Collaborator shall have the right to request that publication 
be delayed for up to an additional 30 days in order to ensure that Collaborator’s 
confidential and proprietary data, in addition to Collaborator(s)’s intellectual property 
rights, are protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings. Press releases and other media presentations must also be 
forwarded to CTEP prior to release. Copies of any manuscript, abstract and/or press 
release/ media presentation should be sent to: 
 
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 Collaborators confidential 
proprietary information. 

GOG-0281 
 
 
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APPENDIX II - NRG Oncology General Therapy Guidelines (06/08/15) 
 
• For 21 or 28 day cycles, a patient will be permitted to have a new cycle of 
therapy delayed up to 7 days (without this being considered to be a protocol 
violation) for major life events (e.g., serious illness in a family member, major 
holiday, vacation which is unable to be re-scheduled).  Documentation to justify 
this decision should be provided. 
• It will be acceptable for individual doses to be delivered within a “24-hour 
window before and after the protocol-defined date” for “Day 1” treatment of 21 
or 28 day cycles.  If the treatment due date is a Friday, and the patient cannot be 
treated on that Friday, then the window for treatment would include the Thursday 
(1 day earlier than due) through the Monday (day 3 past due). 
• For weekly regimens, it will be acceptable for individual doses to be delivered 
within a “24-hour window,” for example; “Day 8 therapy” can be delivered on 
Day 7, Day 8, or Day 9 and “Day 15 therapy” can be given on Day 14, Day 15, or 
Day 16. 
• Doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 
5% of the calculated dose). 
• Doses are required to be recalculated if the patient has a weight change of greater 
than or equal to 10%.  Patients are permitted to have chemotherapy doses 
recalculated for less than 10% weight changes. 
 

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110 
 
APPENDIX III - New York Heart Association Classifications 
 
Clinical Evaluation of Functional Capacity of Patients 
with Heart Disease in Relation to Ordinary Physical Activity 
 
 
 
Class 
 
 
Cardiac Symptoms 
 
 
Limitations 
 
Need for 
Additional Rest* 
 
Physical Ability  
      to work**__ 
 
 
 
 
 
I 
None 
None 
None 
Full time 
 
 
 
 
 
II 
Only moderate 
Slight 
Usually only slight 
or occasional 
Usually full  
time 
 
 
 
 
 
III 
Defined, with  
less than  
ordinary activity 
Marked 
Usually moderate 
Usually part  
time 
 
 
 
 
 
IV 
May be present  
even at rest,  
and any activity 
increases discomfort 
Extreme 
Marked 
Unable to work 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by the 
physician. 
** At accustomed occupation or usual tasks. 
 
 

GOG-0281 
 
 
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APPENDIX IV – Translational Research Specimen Procedures (07/28/14)(06/08/15) 
(11/27/17) 
 
I. Obtaining a Bank ID for Translational Research Specimens 
 
Only one Bank ID (# # # # - # # - G # # #) is assigned per patient. All translational research 
specimens and accompanying paperwork must be labeled with this coded patient number. 
 
A Bank ID is automatically assigned once the Specimen Consent is completed and indicates 
that a patient has agreed to participate in the translational science component. If a patient has 
previously been assigned a Bank ID, please ensure the Bank ID appearing in Rave is the 
same as the previously assigned Bank ID. 
 
Please contact User Support if you need assistance or have assigned more than one Bank ID 
to a patient (Email: support@nrgoncology.org; Phone: 716-845-7767). 
 
II. Requesting Translational Research Specimen Kits 
 
Single chamber specimen kits will be provided for the collection and shipment of the frozen 
plasma specimens. Separate kits are provided for baseline and cycle 3 specimens.  
 
Kits can be ordered online via the Kit Management system 
(http://ricapps.nationwidechildrens.org/KitManagement/). Each site may order two kits per 
protocol per day (daily max = 6 kits). 
 
Please contact the GOG Tissue Bank if you need assistance (Email: 
BPCBank@nationwidechildrens.org; Phone: 866-464-2262). 
 
Be sure to plan ahead and allow time for kits to be shipped by ground transportation. Kits 
should arrive within 3-5 business days. 
 
Note: Unused supplies and kits should be returned to the GOG Tissue Bank. A pre-paid 
shipping label for the return of unused supplies and kits may be obtained via the Kit 
Management system. Select “Empty Kit” for package contents when returning unused kits. 
 
III. Labeling Translational Research Specimens 
 
A waterproof permanent marker or printed label should be used to label each translational 
research specimen with: 
 
Bank ID (# # # # - # # - G # # #) 
protocol number (GOG 0281) 
specimen code (see protocol section 7.3) 
collection date (mm/dd/yyyy) 
surgical pathology accession number (tissue specimens only) 
block number (tissue specimens only) 

GOG-0281 
 
 
112 
 
 
Note: If labeling slides, only label on the top, front portion of the slide. Do not place a label 
on the back of the slide or over the tissue. The label must fit on the slide and should not be 
wrapped around the slide or hang over the edge. 
 
IV. Submitting Frozen Tissue 
 
Note: Frozen biopsy and PK plasma specimens are no longer required as of October 
2017, and should not be collected. 
 
VI. Submitting Formalin-Fixed, Paraffin-Embedded Tissue 
 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
tumor type (primary, metastatic, recurrent). Primary and metastatic tumor should be 
collected prior to all treatment. Recurrent tumor should be collected prior to the study 
treatment. Only one block may be submitted per tissue type. 
 
Every attempt should be made to provide a FFPE block; however, if a block cannot be 
provided on a permanent basis, then 20 unstained slides (10 charged, 5µm, and 10 
uncharged, 10µm) should be submitted. All tissue sections should be cut sequentially from 
the same block. 
 
The type of specimen (block or slides) should be specified on Form TR. If submitting 
slides, the slide type, thickness, and count should also be specified. 
 
All FFPE tissue should be submitted with the corresponding pathology report. 
 
VII. Submitting Plasma 
 
Please note the protocol-specific plasma processing instructions described below. 
 
1.  Label 2mL cryovials as described above. 
2.  Draw 7-10mL of blood into a K2 EDTA tube.  
3.  Immediately after collection, gently invert the blood collection tube 5-10 times to mix 
the blood and EDTA. 
4. Immediately after mixing the blood and EDTA, the blood collection tube must be 
placed on wet ice until centrifuged. The blood sample must be centrifuged within 
15 minutes (30 minutes maximum).* 
5.  Centrifuge the blood at approximately 1600g for 15 minutes at 4ºC* to separate the 
plasma (top, straw-colored layer) from the red blood cells (bottom, red layer).  
6. Quickly, evenly dispense (aliquot) the plasma into the pre-labeled cryovials and cap 
the tubes securely. Place a minimum of 0.25mL into each cryovial. 
7.  Immediately freeze the plasma in an upright position in a -70°C to -80°C freezer or 
by direct exposure with dry ice until ready to ship. If a -70°C to -80°C freezer is not 
available for storage, store and ship on dry ice within 24 hours of collection. 
 

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* Deviations to the plasma processing protocol must be noted in Rave. 
 
VIII. Submitting Form TR 
 
A specimen transmittal form (i.e., Form TR) for each specimen will be available in the 
Translational Research Folder in Rave, once the Specimen Consent (located in the 
Baseline Folder) has been completed. 
 
An electronically (i.e., Rave) completed copy of Form TR must accompany each specimen 
shipped to the GOG Tissue Bank. Handwritten forms will not be accepted. 
 
Note: A copy does not need to be sent to the GOG Tissue Bank if specimens are not 
collected. 
 
Form TR must be printed from the Translational Research Form screen in Rave using the 
“PDF File” link at the top of the form. Clicking this link will generate a single page PDF. 
Do not use the “Printable Version” or “View PDF” links at the bottom of the form or any 
other method to print the form, as these formats will not be accepted.  
 
Note: Specimens will not be marked as received in Rave without receipt of a corresponding 
electronically completed Form TR. Incomplete forms or those containing incorrect 
information will not be processed. 
  
Retain a printout of the completed form for your records. 
  
Please contact Support if you need assistance (Email: support@nrgoncology.org; Phone: 
716-845-7767). 
 
IX. Shipping Translational Research Specimens 
 
A completed copy of Form TR must be included for each translational research 
specimen. 
 
A. FFPE Tissue 
 
FFPE tissue and a copy of the corresponding pathology report should be shipped using 
your own container at your own expense to: 
 
GOG Tissue Bank / Protocol GOG-0281 
Nationwide Children’s Hospital 
700 Children’s Dr, WA1340 
Columbus, OH 43205 
Phone: (614) 722-2865 
FAX: (614) 722-2897 
Email: BPCBank@nationwidechildrens.org 
 

GOG-0281 
 
 
114 
 
Do not ship FFPE tissue for Saturday delivery. 
 
B. Frozen Plasma 
 
The frozen plasma should be shipped using the specimen kit provided to the GOG 
Tissue Bank (address above). 
 
Frozen specimens should be shipped Monday through Thursday for Tuesday 
through Friday delivery. Do not ship frozen specimens the day before a holiday. 
 
Frozen specimens should be stored in an ultra-cold freezing/storage space (i.e., ultra 
cold ≤-70oC freezer, liquid nitrogen, or direct exposure with dry ice) until the 
specimens can be shipped. 
 
Shipping Frozen Translational Research Specimens in a Single Chamber Kit 
 
 
1. Pre-fill the kit chamber about 1/3 full with dry ice. 
2. Place the frozen specimens  in a  zip-lock bag. If shipping specimens from more 
than one time point, place specimens for each time point in separate bags.  
3. Place the zip-lock bag(s) in the biohazard envelope containing absorbent material. If 
batch shipping more than one patient in the same shipment, do not put more than 20 
vials in a biohazard envelope.  Put the secondary envelope into a Tyvek envelope. 
Expel as much air as possible before sealing both envelopes. 
4. Place the Tyvek envelope containing the frozen specimens into the kit and fill the 
chamber to the top with dry ice. 
5. Insert a copy of Form TR for each specimen. 
6. Place the cover on top of the kit. Tape the outer box of the kit closed with filament 
or other durable sealing tape. Please do not tape the inner chamber.  
7. Print a pre-paid FedEx air bill using the Kit Management system 
(http://ricapps.nationwidechildrens.org/KitManagement/). Attach the air bill. 
8. Attach the dry ice label (UN1845) and the Exempt Human Specimen sticker. 
9. Arrange for FedEx pick-up through your usual Institutional procedure or by calling 
800-238-5355.  
 
X. 
Distributing Translational Research Specimens 
 
The GOG Statistical and Data Center and Tissue Bank (or alternate laboratory) will 
coordinate the distribution of translational research specimens to approved investigators. 
 
Investigators will not be given access to any personal identifiers. 
 
Investigators will be responsible for the direct supervision and oversight of translational 
research performed and for keeping accurate records. 
 

GOG-0281 
 
 
115 
 
Investigators will ensure the results are linked to the appropriate specimen-specific 
identifiers and are responsible for transferring relevant laboratory data to the Statistical 
and Data Center. 
 
At the discretion of the Chair of the Committee on Experimental Medicine and the 
Director of the GOG Tissue Bank, investigators may be required to ship any specimens (or 
by-products) remaining after the completion of the translational research to the GOG 
Tissue Bank. 
 
XI. Banking Translational Research Specimens for Future Research 
 
Specimens will remain banked in the GOG Tissue Bank and made available for approved 
projects if the patient has provided permission for the use of her specimens for future health 
research. The patient’s choices will be recorded on the signed informed consent document 
and electronically via the online Specimen Consent Application. At the time of specimen 
selection for project distribution, the most recent consent information will be used. 
 
GOG institutions can amend a patient’s choices regarding the future use of her 
specimens at any time if the patient changes her mind. 
 
If the patient revokes permission to use her specimens, the GOG Tissue Bank will destroy or 
return any remaining specimens. The patient’s specimens will not be used for any further 
research; however, any specimens distributed for research prior to revoking consent cannot 
be returned or destroyed. In addition, the patient cannot be removed from any research that 
has been done with her specimens prior to revoking consent. 
 
Note: If return of specimens is requested, shipping will be at the institution’s expense. 

GOG-0281 
 
 
116 
 
APPENDIX V - Patient Medication Calendar (12/22/14) 
PILL DIARY 
INSTRUCTIONS FOR THE PATIENT: 
This is a monthly calendar on which you are to record the total number of pills (study medication) you 
take each day and the time of day you take your pills (study medication).  
 
Bring the bottle(s) with any unused pills and your calendar with you each time you have an 
appointment.   
 
If you have any questions, please contact: ____________________________________ 
Telephone: ________________________ 
Your next appointment is: __________________________________________________ 
 
 
#of pills 
taken_____ 
 
Time: 
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This section is to be completed by the physician, nurse or staff: 
 
Reporting period (mm/dd/yy):  Start _______ Stop _______Total # of pills taken: ____   # pills left in 
bottle: ____  
 
Patient’s Signature: __________________________________________________ Date: _________   

 
117 
 
 
 
APPENDIX VI – FROZEN BIOPSY PATHOLOGY VERIFICATION (12/22/14) (11/27/17) 
 
Note: Frozen biopsy and PK plasma specimens are no longer required as of October 2017, 
and should not be collected. 
 
A copy of the corresponding pathology report must be shipped with all tissue specimens sent to the 
GOG Tissue Bank. 
 
If a pathology report is not available for the frozen biopsy, a copy of the radiology report or 
operative report from the biopsy procedure must be sent to the GOG Tissue Bank. A 
completed copy of this appendix (i.e., Frozen Biopsy Pathology Verification) must also be 
submitted to the GOG Tissue Bank. 
 
Note: If this information is not provided with the frozen biopsy specimen, it will not be 
accepted by the GOG Tissue Bank. 
 
 
Please have the Pathologist responsible for signing out this patient’s case complete the following: 
 
GOG Bank ID: __ __ __ __ - __ __ - G __ __ __ 
 
GOG Study ID: __ __ __ - 0 2 8 1  - __ __ __ 
 
Date of Procedure (mm/dd/yyyy): _________________________________________ 
 
Tissue Type (circle one): 
Recurrent Primary  
Recurrent Metastatic 
 
Site Tissue Taken From: ________________________________________________ 
 
Diagnosis: ___________________________________________________________ 
 
Recurrent disease documented by: ________________________________________ 
 
I agree that this tissue may be released for research purposes only and that the release of this tissue 
will not have any impact on the patient’s care. 
 
 
___________________________________  
 
_____________________ 
Pathologist’s Signature 
 
 
 
 
Date 
 
 
___________________________________ 
Pathologist’s Printed Name  

 
 
 
118
APPENDIX VII – Translational Research Laboratory Testing Procedures 
 
A. OVERVIEW: Low-grade ovarian serous carcinomas (LGSC) account for a significant 
proportion of epithelial ovarian cancers in young women. The exact biological pathways that underlie 
this disease are incompletely understood. Chemotherapy has a very poor response rate (< 4%), and 
the disease is associated with high morbidity and mortality.40,41 With a median overall survival 
exceeding 80 months, an updated analysis of 350 women with LGSC from the MD Anderson Low-
Grade Serous Tumor Database indicated that over 85% develop recurrent disease, and almost all 
ultimately die of the disease.42 This is particularly important, as LGSC is more common in young 
women. Also, the overall response rate of recurrent low-grade serous cancer to various 
chemotherapies is dismal (< 4%).23 Therefore, patients with LGSC have a 10-year overall survival 
rate (~21%) comparable to that of high-grade serous carcinoma (HGSC).43 Even though LGSC and 
HGSC develop from a different pathogenetic pathway,44,45 they do share several cancer hallmarks—
invasiveness, peritoneal implantation and angiogenesis. 
 
Because the Ras/Raf/MEK/ERK or MAP kinase (MAPK) pathway is frequently activated in LGSC, 
targeting this pathway has been examined as a potential treatment.27 In a recent phase II Gynecologic 
Oncology Group (GOG) trial for patients with recurrent LGSC, GOG-0239 (Co-PI and senior author, 
Dr. Gershenson), 52 patients were treated with the MEK inhibitor (MEKi) selumetinib. Of these, one 
had a complete response, seven had a partial response, and 34 had stable disease.27 Because of the 
encouraging overall response rate of 15% in this therapy-resistant disease, we have initiated, through 
NRG Oncology, an international phase II/III trial (NCT02101788, GOG-0281) to assess the efficacy 
of another MEKi (trametinib), with improved pharmacology, for patients with recurrent or 
progressive LGSC. 
 
SIGNIFICANCE AND PRELIMINARY DATA: 
This study using MEKi in the randomized setting provides the 
opportunity to investigate potential predictive biomarkers.46 Based 
on our preliminary data, we will interrogate MAPK pathway 
mutations as well as protein expression of pERK. The 
Ras/Raf/MEK/ERK pathway is frequently dysregulated in LGSC41  
with pERK protein expressed (Figure 1). Activation of the 
Ras/Raf/MEK/ERK 
pathway by oncogenic 
KRAS mutation is well 
established.9,47-49 
We 
recently 
also 
demonstrated that KRAS-mutated clones are selected 
during the progression of a subset of serous borderline 
tumors to LGSC.50 Preliminary data from the completed 
GOG-0239 trial of the MEKi selumetinib indicated that 
the percentage of patients with a response as measured by 
reduction in CA-125 level was significantly higher in 
patients with pERK H-score >109 than in those with 
pERK H-score ≤109: 46% versus 5% (p=0.008) (Table 
1). Higher levels of pERK in the pre-treatment specimens 
from patients enrolled in GOG-0239 may suggest the 
tumor is more addicted to the pERK pathway and thus more sensitive to MEKi. In the GOG-0281 
trial, we expect to find a similar correlation between pERK levels and response measured by reduction 
in CA-125 level. In addition, since  we will use WES to interrogate mutations in genes involved in 
the Ras/Raf/MEK/ERK pathway (KRAS, BRAF, NRAS, HRAS, MEK, ERRB2 and NF-1), we 
anticipate that, in contrast to the findings of GOG-0239 (only KRAS and BRAF mutations were 
Figure 1. pERK was detected in 
the majority of low-grade OSC 
samples; however, only sample 
00-136 had a KRAS mutation. 
Table 1. CA-125 response by pERK positivity (score 
>109) (unpublished data from GOG 239 trial) 
 
pERK (H-Score)* 
 
 
N 
≤109 
n (%) 
>109 
n (%) 
p 
value† 
Total 
33 20 
13 
 
CA-125 Response‡ 
No 
26 19 (95) 
7 (54) 
0.008 
Yes 
7 
1 (5) 
6 (46) 
 
*H-Score 
is 
derived 
from 
multiplying 
the 
immunostaining intensity (1, 2, or 3) by the 
percentage of cells stained (range: 0-300). 
† Fisher’s exact test. 
‡ ≥50% decrease from baseline confirmed ≥28 days 
later. 

 
 
 
119
checked), we will observe a more robust correlation between response to trametinib and mutation 
status.  [Although NF-1 is not an integral part of the MAPK pathway, it has long been recognized 
that loss of function mutations result in MAPK activation and this event has been detected in our pilot 
sequencing studies (see below)]. 
 
 
SUMMARY: 
If trametinib is found to be effective in this phase 2/3 clinical trial, the MAPK pathway signaling and 
gene mutations landscape investigated in this study will be critical in identifying the best candidates 
for this unique targeted therapy and guiding further studies and management strategies for LGSC. 
Alternatively, if trametinib is not found to be overall effective in the intention to treat population, we 
may be able to identify subgroups of patient who did derive benefit. 
 
Integrated Biomarker Research Objective 
 
(1) To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is 
associated with better prognosis (RR or PFS) among patients receiving the randomized treatment. 
(IHC analysis will be performed at MD Anderson Cancer Center by Kwong Wong, PhD). 
 
To quantify the expression level of pERK, we will perform IHC using formalin fixed paraffin 
embedded (FFPE) sections. The details of the pERK IHC are discussed in the laboratory procedure 
section below. 
 
(2) To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, 
HRAS, BRAF, MEK,ERBB2 or NF1) are associated with improved prognosis (RR or PFS) 
among patients receiving the randomized treatment. (Whole Exome sequencing using FFPE 
samples will be performed at the University of Edinburgh by Dr. Charlie Gourley’s group)  
 
Whole Exome Sequencing (WES) has been used to identify clinical actionable mutations from FFPE 
patient samples.51,52 As the sequencing cost of WES is now comparable to targeted sequencing using 
cancer gene panels, we will perform WES of all the available FFPE samples to identify mutations 
that are associated with trametinib treatment response in LGSC.  The details of the WES using FFPE 
samples are discussed in the laboratory procedure section. As well as providing a robust readout of 
sequence changes in the key genes of interest, the additional information provided by WES (over 
panel sequencing) will allow future exploratory analysis of mutational and copy number events across 
the genome. 
 
Expected Findings: 
We expect to be able to determine the sensitivity and specificity of each of the biomarkers individually 
or in combination to predict MEKi response. We also expect to have several exceptional responders 
with complete response as we have observed in the GOG-0239 trial. For those exceptional responders, 
the integrated WES and IHC analyses will reveal potential factors that contribute to the exceptional 
response. From previous study, Next Generation Sequencing analysis of an extreme responder with 
complete response in the GOG-0239 trial revealed a 15-nucleotide deletion in the negative regulatory 
helix of the MAP2K1 gene encoding for MEK1. This mutated MEK protein induced extracellular 
signal-regulated kinase pathway activation and promoted anchorage-independent growth and tumor 
formation in mice.53 Another extreme responder had a KRAS G12V mutation54 and is still on 
selumetinib treatment with stable disease for more than nine years.  
 
B. Laboratory Testing Procedures 
 

 
 
 
120
 
 
Immunohistochemistry: 
Using FFPE samples from patients receiving the randomized treatment , the expression level of pERK 
will be determined by immunocytochemistry and test for its prognostic significance and predictive 
value to trametinib. Two FFPE slides for each patient will be needed for reproducibility of pERK 
IHC. 
Procedures will follow the IHC standard operating procedure (SOP) at the MD Anderson clinical 
histopathology lab. Paraffin-embedded specimens will be sliced into 5-µm sections, placed on glass 
slides. The BondMax Protocol described below using the BondMax autostainer will be used for 
staining of pERK in FFPE sections. 
 
 
 
Sources of antibodies 
Anti-Phospho-p44/42 MAPK (pERK) (Thr202/Tyr204) (cat#4370s), which is a Rabbit monoclonal 
antibody (D13.14.4E), will be purchased from Cell Signaling Technology. The specificity and 
performance of the anti-pERK antibody has been confirmed using FFPE NIH/3T3 cells, treated with 
U0126 (MEK inhibitor) and FFPE section of lung carcinoma treated with λ phosphatase (Figure 3) 
 

 
 
 
121
 
Figure 3. Performance of Anti-Phospho-p44/42 MAPK (pERK) (Thr202/Tyr204) in IHC with FFPE 
samples. 
 
Analysis IHC images and scoring procedures 
All the immunostained tissue sections will be captured by Vectra 3.0 Automated Quantitative 
Pathology Imaging System. For each case, 15-20 fields at a magnification of x200 will be assessed. 
The staining intensity will be semi-quantified into four categories (0, negative; 1, low, 2, moderate; 
3, strong) and the percentage of cells stained will be categorized into three groups (1, <25% positive 
cells; 2, 25-75% positive cells; 3, >75% positive cells).  Quantification and scoring will be generated 
by InForm® software (PerkinElmer). 2000 to 10000 tumor cells will be quantified. The threshold 
Max for the selected nuclear component will be calculated automatically by the software and the 
positivity threshold value will be defined by the user based on region with negative stain and negative 
control slides. An H-score is assigned to each case using the following formula and H-score will be 
generated automatically by InForm® imaging software : 
[1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]; the final score will range from 0 to 300. An 
example of the imaging processing using the The BondMax Protocol for IHC analysis of pERK in 
LGSC FFPE section is shown in Figure 4.  

 
 
 
122
 
Figure 4. H-score analysis of a LGSC FFPE section after IHC staining of pERK. Image was captured 
by Vectra 3.0 Automated Quantitative Pathology Imaging System. Image was then analyzed by 
inForm® imaging analysis software. A, DAB pathology view. B, tissue segmentation view (red, 
tumor cell region; green, stromal cell region; blue, psammoma body; yellow, non-cellular region). C, 
cell segmentation view, individual cell was identified. D, scoring view (blue, negative=0; yellow, 
low=1; orange, moderate=2; brown, strong=3). H-score of this IHC staining was calculated as 172. 
 
To select the immunohistochemical cut-off scores for pERK as a biomarker of tumor response in 
LGSC, the receiver operating characteristic (ROC) curve analysis will be adapted as described 
previously. The score with the shortest distance from the curve to the point with both maximum 
sensitivity and specificity, i.e. the point (0.0, 1.0), will be selected as the cut‐off score leading to the 
greatest number of tumors correctly classified as having or not having the clinical outcome.  
 
Whole Exome sequencing (WES): 
For WES, we will extract DNA from FFPE tissues using the Qiagen FFPE Tissue kit (P/N 56404) 
using the Qiagen deparaffinization solution (P/N 19093) and finally eluting in 30ul EB buffer. The 
WES will require at least 100ng of input DNA and as a rule we would QC the FFPE DNA via UV 
spectroscopy (for 260/280 and 260/230 ratio) and by Qubit for DNA quantitation. In some 
circumstances if there have been issues with yield or purity at this stage, we have been able to rescue 
the DNA using the Zymo Clean and Concentrate kit. Finally, we will use a fragment analyser to 
visualise the DNA and to generate a Genomic Quality Number (GQN), for FFPE if this score is 
greater than 0.3 then the DNA is of sufficient quality to continue for sequencing library preparation. 
FFPE DNA samples with sufficient library yield generated will proceed for sequencing using Illumina 
platform with a sequencing depth of 50X. Potential mutations associated with response can be 
validated upon CLIA-certified method for confirmation of specific sequencing results. 
 

 
 
 
123
Depending on the size of the tumor tissue, four FFPE slides will be needed for microdissection of 
tumor cells. 50x exome capture will be performed using the Illumina TruSeq Exome Library Prep 
kit. Such depth has been used in a pilot study and has allowed us to robustly detect key mutations 
present in LGSOC samples (adequate sequence data obtained from 24/24 specimens, see below). 
Libraries are prepared from each DNA sample using the TruSeq Exome Library Prep kit according 
to the provided protocol using modifications for working with FFPE sourced material. 100ng of 
DNA is end-repaired to remove 3’ and 5’ overhangs, and fragment length optimised using sample 
purification beads. For a limited number of patients with no archival FFPE material or FFPE 
material is insufficient, 5 mg fresh frozen material will be needed for exome sequencing. (02-JUN-
2020) 
 
DNA sequencing is carried out on an Illumina NextSeq 550 (Illumina, Inc., San Diego, CA, USA). 
A 2x75bp sequencing run on the Nextseq 550 using a high-output flow cell is expected to generate 
up to 400M paired-end (PE) reads (50-60Gb). When multiplexing 12 samples per flow cell we would 
therefore expect to see up to ~33M reads per sample. If we opt for a 2x75bp sequencing run on the 
Nextseq 550 using a mid-output flow cell we would expected to generate up to 130M PE reads (16-
19Gb). When multiplexing 6 samples per flow cell we would therefore expect to see up to ~22M 
reads per sample. 
 
DNA sequencing data will undergo informatic based QC and then alignment to the human reference 
genome (hg38) using in house bioinformatic pipelines built on bwa-0.7.1. Further informatic 
processing will correct for sequencing artefacts such as duplication and base quality scores will be 
recalibrated with the Genome Analysis Toolkit (GATK) v4 again using in house informatic pipelines 
developed within the University of Edinburgh and Gourley lab.  
 
 
 
 
 
Figure 5. Example data following sequencing QC. Sequence quality scores > 25 indicate good 

EudraCT Number: 2013-001627-39 
 
 
124
quality data. Sequence duplication is also checked. Mapped reads can also be checked across the 
genome to ensure adequate coverage. Data is then trimmed accordingly to remove low quality 
reads.  
 
 
Detection of somatic single-nucleotide variants (SNVs) and short insertion and deletion 
(INDEL) variants.  
Somatic variant calling will be carried out using an informatics pipeline developed within the Gourley 
lab based on a majority vote from three variant caller algorithms; VarDict, Mutect2, Freebayes. 
Filtering for C>T (FFPE artifacts) and G>T (oxidation artifacts) are applied using GATK (Collect 
Sequencing Artifact Metrics and Filter By Orientation Bias). Data is then filtered to remove common 
variants 
in 
the 
population 
(1000 
genomes 
phase 
1 
snp 
and 
indel 
dataset; 
(http://www.internationalgenome.org/) and the Exome Aggregation consortium (EXAC) reference 
datasets (ExAC.0.3.GRCh38 : http://exac.broadinstitute.org/ ). Variants reported as “silent” or those 
which are not predicted to result in causal mutations were filtered using the Polymorphism 
Phenotyping (Polyphen : http://genetics.bwh.harvard.edu/pph/) and Sorting Intolerant from Tolerant 
(SIFT: http://sift.bii.a-star.edu.sg/) algorithms. Finally, filtering is applied to define high impact 
mutations where the variant allele frequency of a given mutation was > 10% across regions with a 
minimum read coverage of 20x. From the resulting data we can look across gene panels of interest as 
well as carry out discovery based studies. 
 
 
Figure 6. Workflow for WES processing and variant calling informatic pipelines 

EudraCT Number: 2013-001627-39 
 
 
125
Figure 7. Example “oncoplot” displaying most frequent mutations across genes of interest 
taken from existing LGSOC data generated in the Gourley lab. Key is shown below for 
mutation types.  
 
 

EudraCT Number: 2013-001627-39 
 
 
126
 Appendix VIII - UK Group Specific Appendix to GOG protocol (GOG-0281) (07/28/14) 
(12/14/15) (05/31/16) (09/19/16) (01/16/17)  
 
LOGS: A randomized phase II/III study  to assess the efficacy of trametinib (GSK 1120212) in 
patients with recurrent or progressive low-grade serous ovarian cancer of peritoneal cancer 
(GOG-0281) 
 
(EudraCT Number: 2013-001627-39) 
(NCT02101788) 
(NHS GG&C ref: GN12ON121) 
 
UK Group Specific Appendix: Version 7, 05th February 2020 
 
 
 
 
The study is being co-ordinated in UK by Cancer Research UK Clinical Trials Unit, Glasgow 
on behalf of the National Institute for Health Research (NIHR) Clinical Research Network Cancer and National Cancer 
Research Institute (NCRI) Gynaecology Clinical Study Group  
 
 
UK Study Co-ordinator/: 
 
Professor Charlie Gourley 
Chief Investigator 
 
 
Email: Charlie.gourley@ed.ac.uk 
 
 
 
IMPORTANT INFORMATION 
 
The protocol to which this appendix refers to has been initiated and written by the 
 Gynecologic Oncology Group (GOG) 
 
All technical and administrative aspects of the protocol specific to the UK (registration, responsibilities, safety 
reporting, etc.) are covered by this UK Group Specific Appendix. 
 
        
                    
            
    
              
 
 
 
         
 
 
Sponsor 
 
The Sponsor of this clinical trial in the UK is NHS Greater Glasgow and Clyde (NHSGG&C) and The University of 
Glasgow (GU). 

EudraCT Number: 2013-001627-39 
 
 
127
 
Sponsor Contacts:- 
Mrs. Joanne McGarry 
NHS Greater Glasgow and Clyde 
Clinical Research and Development Central 
Office, Dykebar Hospital 
Ward 11, Grahamston Road 
Paisley, PA2 7DE 
 
 
Tel no: 0141 232 1810 
Email: joanne.Mcgarry@ggc.scot.nhs.uk  
 
Dr Debra Stuart 
The University of Glasgow 
College of Medical, Veterinary and Life 
Sciences, University of Glasgow, Room 327 
Wolfson Medical School Building 
University Avenue 
Glasgow, G3 8SW  
 
Tel no: 0141 330 4539 
Email: debra.stuart@glasgow.ac.uk 
 
Sponsor Pharmacist 
Paula Morrison MRPharms 
Senior Pharmacist Oncology Clinical Trials 
NHS Greater Glasgow & Clyde  
Clinical Research and Development Central 
Office, Dykebar Hospital, Ward 11, 
Grahamston Road 
Paisley, PA2 7DE 
 
Tel No.: +44 (0)141 314 4019  
Email: paula.morrison@ggc.scot.nhs.uk 
 
 
 
 
 

EudraCT Number: 2013-001627-39 
 
 
128
Contact addresses for UK study co-ordinating centre 
 
UK Study Co-ordinator/:  
Professor Charlie Gourley 
Chief Investigator 
Edinburgh Cancer Research UK Centre, 
MRC IGMM, 
The University of Edinburgh, 
Crewe Road South,  
Edinburgh, 
EH4 2XR 
Tel no: +44 (0) 131 777 3555 
 
 
 
 
Email: charlie.gourley@ed.ac.uk 
 
UK Lead Pathologist: 
 
Dr David Millan 
 
 
 
 
Department of Pathology Laboratory 
 
 
 
 
Medicine + Facilities Management Building 
 
 
 
 
Southern General Hospital 
 
 
 
 
1345 Govan Road, Glasgow, G52 4TF 
 
 
 
 
Email: david.millan@ggc.scot.nhs.uk   
 
 
 
 
Project Manager:  
 
Karen Carty 
 
 
 
 
Cancer Research UK Clinical Trials Unit, Level 0 
The Beatson West of Scotland Cancer Centre 
1053 Great Western Road 
Glasgow, G12 0YN 
 
                                        Tel no:+44 (0) 141 301 7197 Fax no:++44 (0) 0141 301 7946 
 
 
 
 
Email: karen.carty@glasgow.ac.uk 
 
Clinical Trial Co-ordinator: 
Avril Trevethan 
 
 
 
 
Cancer Research UK Clinical Trials Unit, Level 0 
The Beatson West of Scotland Cancer Centre 
1053 Great Western Road 
Glasgow, G12 0YN 
 
                                 Tel no:++44 (0)141 301 7467 Fax no:++(0)141 301 7946 
 
   Email: avril.trevethan@glasgow.ac.uk  
 
Clinical Trial Monitor: 
 
Jill Fleming 
Cancer Research UK Clinical Trials Unit,  
Quality Assurance Office, Admin Building 
1055 Great Western Road 
Glasgow, G12 0XH 
 
 
 
 
Tel no:++ 44(0) 141 211 0237 
 
 
 
 
Email: jill.fleming@glasgow.ac.uk 
 
Pharmacovigilance: 
 
Lindsey Connery 
 
 
 
 
Pharmacovigilance Manager 
Cancer Research UK Clinical Trials Unit,  
Level 0, Room 15 Admin Building 
1055 Great Western Road 
Glasgow, G12 0XH 
 
 
 
 
Tel no. 0141 211 0352 Fax no: 0141 232 2157 
 
 
 
 
Email: mvls-ctu-pv@glasgow.ac.uk 

 
129 
 
UK Signatory Page 
 
Sponsor: 
 
 
 
_____________________________________________                    __________________ 
Sponsor’s Representative 
 
 
 
 
 
 
Date 
 
 
 
UK Study Coordinator/Chief Investigator: 
 
 
 
_____________________________________________                    __________________ 
Professor Charlie Gourley 
 
 
 
 
 
 
Date 
 
 
 

EudraCT Number: 2013-001627-39 
 
 
130
Table of Contents 
1. Trial Organisation 
 
132 
2. Investigator Authorisation Procedure 
 
132 
3. Patient Registration & Randomisation Procedure 
 
133 
3.1 UK Central Pathological Review (Prospective) 
133 
3.2 Crossover 
134 
4. Management and Handling of Investigational Medicinal Products (IMP) 
 
134 
4.1 General 
134 
4.2 Initial Shipment of Trametinib (GSK1120212) 
135 
4.3 Re-supply ordering of Trametinib (GSK1120212) 
135 
4.4 Accountability of IMPs 
136 
4.5 IMP Disposal & Destruction 
136 
5. Drug Interactions/ Contraindications with Concomitant Medications 
 
136 
6. Trial Management and Data Collection 
 
136 
6.1 Case report forms 
136 
6.2 Data Flow 
136 
7. Assessment of Safety/ Reporting of Serious Adverse Events 
 
137 
7.1 Definitions 
137 
7.2 Detection of Adverse Events 
141 
7.3 Recording of Adverse Events 
141 
7.4  Assessment of Adverse Events 
142 
7.5  Serious Adverse Event Reporting 
142 
7.6 Identifying SUSARs 
142 
7.7 Reporting of a SUSAR 
142 
7.8 Reference Safety Information 
143 
7.9 Pregnancy Reporting 
143 
7.10 Development Safety Update Reports 
143 
8. Study Responsibilities 
 
143 
8.1 UK Co Sponsor Responsibilities (NHSGG&C/GU ) 
144 
8.2 CR-UK Clinical Trials Unit (CTU) 
144 
8.3 Chief Investigator (C.I.) 
144 
8.4 Participating Site 
144 
8.5 Principal Investigator (P.I.) 
144 
9. Liability and Indemnity 
 
144 
10. 
Regulatory Issues 
 
145 
10.1 Clinical Trials Authorisation (CTA) 
145 
10.2 Ethics and Research & Development Approval 
145 
10.3 Informed Consent 
145 
10.4  Confidentiality 
145 

EudraCT Number: 2013-001627-39 
 
 
131
10.5  Quality Assurance/Quality Control 
146 
10.6  Monitoring 
146 
10.7 Audits and Inspections 
146 
11. 
Patient Information Sheets and Consent Forms 
 
146 
12. 
GP Letter 
 
146 
13. 
Translational Research 
 
147 
14. 
Central Radiographic Image Review 
 
149 
14.1 Form 01 Central CT/MRI Scan Assessment Form 
 
151 
 
 
 
 
 
 
 
 
 
 
 
 

 
132 
 
1. Trial Organisation 
 
 This trial is an Intergroup Trial jointly conducted by Cancer Therapy Evaluation Program (CTEP)/Gynecologic 
Oncology Group (GOG) from USA and National Institute for Health Research (NIHR) Clinical Research 
Network Cancer United Kingdom. 
 CTEP is overall legal sponsor of the study and the Gynecologic Oncology Group (GOG) is lead coordinating 
group in this intergroup trial. 
 GOG as the lead coordinating group is therefore responsible for overall trial conduct (including trial design, 
protocol finalisation, trial activation, data management [including the quality control of data], statistical analysis 
and publication.) 
 
 The Sponsor of this clinical trial in the UK is NHS Greater Glasgow and Clyde (NHSGG&C) and The University 
of Glasgow (GU). 
 
 NHSGG&C (Legal name Greater Glasgow Health Board [GGHB] and GU have entered into an agreement with 
CTEP and GOG for the study which outlines the roles and responsibilities of each party in relation to UK 
participation in the trial. 
 
 In the UK the trial is being run under the auspices of the NIHR Clinical Research Network Cancer/NCRI 
Gynaecology Clinical Study Group. This study is endorsed by Cancer Research UK (CTAAC), and is part funded 
by Novartis under the terms of their collaboration with the NIHR Clinical Research Network Cancer. 
 
 The Cancer Research UK Clinical Trials Unit, Glasgow (CTU) is co-ordinating the UK participation in the trial 
on behalf of NCRI/NIHR Clinical Research Network Cancer, NHS GG&C and GU. 
 
 The Cancer Research UK Clinical Trials Unit, Glasgow will be the main point contact for UK sites. All questions 
in relation to the trial should be addressed to the Cancer Research UK Clinical Trials Unit. 
 
 The content of this appendix is applicable only for UK participating investigators; this appendix complements 
or supercedes the corresponding sections in the protocol. 
 
 This trial is an academic trial. 
 
2. Investigator Authorisation Procedure 
 
Investigators will be authorised to register and/or randomise patients to the trial when they have returned the following 
documents to the Cancer Research UK Clinical Trial Unit, Glasgow and completed the site initiation process for the trial:  
 
 Board/Trust R&D approval letter 
 Fully signed Clinical Study Site Agreement. 
 Completed Staff Contact and Responsibilities Sheets for all members of staff. 
 Up to date, signed and dated CV for the Principal Investigator The CV should detail the qualifications, experience 
and training (including GCP training) relevant to their role in the study, and should be updated yearly.  
 Up to date, signed and dates CVs for Co-Investigators and study team must be provided. The CV should detail 
the qualifications, experience and training (including GCP training) of site personnel relevant to their role in the 
study, and should be updated every 2 years. 
 Copy of GCP certificate for Principal Investigator, Co Investigators and study team (if no formal certificate is 
available, evidence should be present that GCP training has been undertaken [e.g. register log or email 
confirmation]. If PI has had no GCP training, this should be arranged as soon as possible, and evidence of this 
provided). 
 Local versions of Patient Information Sheets, Consent Forms and GP Letters on hospital headed paper. 
 Full contact details for all site personnel. 
 Biochemistry and Haematology normal ranges and laboratory accreditation certificates  
 Each site/institution participating in the study requires to hold a valid Federalwide Assurance (FWA) with the 
Office for Human Resource Protection (OHRP) in the US. 

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133
 Completed FDA 1572 Form (wet signature), Financial Disclosure Form and Supplemental Investigator Data 
Form for Principal Investigator * These forms required to be updated yearly* (The Cancer Research UK 
Clinical Trials Unit will forward these forms on behalf of UK sites along with copy of Principal Investigator’s 
CV to the Pharmaceutical Management Branch (PMB) of CTEP) 
 
Once all of the above documentation has been received and the site initiation process for the site is complete the Cancer 
Research UK Clinical Trials Unit will inform the NCI Cancer Trials Support Unit (CTSU) to enable the institution to be 
registered on the authorisation list. 
 
After authorisation of each site, the Cancer Research UK Clinical Trials Unit, Glasgow will take the necessary steps to 
request a username and password for each site and communicate this to the site. 
 
The site will be notified by email or fax when they are activated and are authorised to recruit patients to the trial. 
 
3. Patient Registration & Randomisation Procedure 
 
UK Investigators will register/randomise patients ONLY through the Cancer Research UK Clinical Trials Unit, 
Glasgow. The Cancer Research UK Clinical Trials Unit will perform the randomisation on behalf of UK sites via the 
NCI Cancer Trials Support Unit (CTSU) online registration system “OPEN”. 
 
Patient registration/randomisations will only be accepted from authorised investigators (see section 2 Investigator 
authorisation procedure). 
 
Registration forms should be faxed to the Cancer Research UK Clinical Trials Office (Fax no: +44 141 301 7228 during 
office hours Monday- Friday).Any further details relevant to UK Investigators for the registration & randomisation 
procedure will be provided at a later time in a separate document.  
 
*Please note: prior to registration /randomisation, UK Central Pathological Review is required. Please see below 
section regarding procedure to be followed for this* 
 
 
3.1 UK Central Pathological Review (Prospective) 
 
*Central pathology review is required to take place prior to entry to confirm patient eligibility.* 
This is mandatory for the study. 
 
Process for UK Central Pathology review: 
 
 As patients are identified for the trial and once informed consent has been given, Investigator or designee should 
contact the Cancer Research UK Clinical Trials Unit, Glasgow immediately to request a screening identifier for 
the patient. 
 
 Sites should then organise to send 3 H&E stained slides from their pathology department (the 3 most 
representative slides should be sent) obtained at primary surgery and/or relapse documenting low grade serous 
carcinoma to the UK Lead Pathologist for the study (Dr David Millan) at the below address to allow central 
pathology review to take place: 
 
Dr David Millan, Department of Pathology Laboratory 
Medicine + Facilities Management Building 
Southern General Hospital,1345 Govan Road, 

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134
Glasgow, G52 4TF 
 
The slides should be labelled with the screening identifier allocated to the patient and sent with a copy of the 
patient’s pathology report. Personal data of the patient must be anonymised (black out the patient’s name and 
any other identifiable information) and replaced with the screening identifier allocated to the patient.  
 
Please also include the patient’s initials and protocol number (GOG-0281) on all pages of the pathology report. 
A supply of Royal Mail “Safeboxes” for transfer of slides will be provided to sites prior to activation to 
recruitment to the trial.  
 
 The slides will then be reviewed by the UK pathology review panel for study and agreement reached as to 
whether the accepted criteria are met. A majority decision will be acceptable. 
 
 The review decision will be emailed by Dr David Millan, to the Cancer Research UK Clinical Trials Unit, 
Glasgow who will subsequently inform the site. 
 
 Patients who meet the accepted criteria will then be able to be randomised to the trial. 
 
 
Further instruction for the processing, labelling, handling storage and shipment of these specimens will be provided in 
the LOGS translational research manual. 
 
3.2 Crossover 
 
In this study if a patient develops progressive disease on Arm A – Control Arm (as defined in study protocol section 
8.134), the patient will be given the opportunity to crossover to Arm B -Experimental Arm [Trametinib Arm].  
 
Prior to crossover, the following must occur; 
 
 The patient’s progression must be fully documented on the relevant GOG electronic case report forms (CRFs) 
and submitted via Medidata Rave Electronic Data Entry System (www.imedidata.com) online application which 
is being used for the study. The relevant CRFs require to be submitted prior to the patient starting crossover 
treatment. 
 
 All eligibility criteria as defined in study protocol section 3 must be met (with the exception of 3.143, 3.15, and 
3.114). This includes requirement that 4 weeks must elapse between the end of treatment with Arm A and start 
of treatment on Arm B. These requirements will be documented on the CRFs.  
 
If the patient meets all of the above noted requirements, she will be able to crossover and commence treatment on Arm 
B. 
 
4. Management and Handling of Investigational Medicinal Products (IMP) 
 
4.1 General 
 
The investigational medicinal products in this study are: 
 
Arm A Control Arm: 
Physician’s choice of: 
• 
Letrozole 2.5 mg PO daily continuously 
• 
Tamoxifen 20 mg PO twice daily continuously *Please note this is not UK standard dose* 
• 
Paclitaxel 80 mg/m2 IV D1, 8, 15 
• 
Pegylated Liposomal Doxorubicin 40 or 50 mg/m2 IV D1 
• 
Topotecan 4.0 mg/m2 D1, 8, 15 
 
Each cycle is 28 days. 
 

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135
Arm B Experimental Arm: 
• 
Trametinib (GSK1120212) 2.0 mg PO daily continuously 
 
Each cycle is 28 days. 
 
Trametinib (GSK1120212) will be provided free-of-charge by Novartis and supplied & distributed by Catalent to UK 
sites for use in study.  It will be labelled as investigational medicinal product clinical trial stock. The presentation may be 
either fully packaged clinical trial supplies or commercial stock over-labelled for clinical trial use, in accordance with 
current UK regulatory requirements. The transition from fully packaged clinical trial stock to over-labelled commercial 
stock will be managed by the UK Sponsor in conjunction with Novartis when the supplies of fully packaged clinical trial 
stock for the study have been used which is estimated to be towards end of 2016. 
 
All IMPs for use in the trial with the exception of Trametinib (GSK1120212) should be taken from routine pharmacy 
stock; there is no provision for funding, reimbursement or discounted stock.  Site stock of the IMPs in the control arm 
will not require ring fencing, but all prepared IMP for administration to trial subjects should be labelled at site in 
accordance with all applicable regulatory requirements with the addition of Annexe 13-compliant labels. 
 
 
Although specific formulations are mentioned in the protocol for the IMPs in the control arm, UK sites are permitted to 
use their locally approved formulations.  This must be confirmed to the Cancer Research UK Clinical Trials Unit, Glasgow 
during the initiation process. 
 
Chemotherapy doses may be recalculated every cycle during treatment if it is local practice to do so e.g. automatic updates 
by electronic prescribing systems.  Where it is not local practice to recalculate every cycle the doses MUST be recalculated 
if the subject’s weight changes by greater than or equal to 10% from baseline. 
 
BSA calculations should be performed as routine local practice and capped at 2.0m2. 
 
Chemotherapy doses may be dose-banded if it is routine local practice to do so.  The Cancer Research UK Clinical Trials 
Unit, Glasgow must be informed of this during the initiation process. 
 
The Investigator or a delegated individual (e.g. pharmacist) must ensure all IMPs are stored and dispensed in accordance 
with study protocol, local standard operating procedures, applicable regulatory requirements and the information 
contained within the current summary of product characteristics/investigator brochure for each product 
 
Full instructions regarding management, labelling, accountability and destruction of Trametinib (GSK1120212) and the 
control arm IMPs will be given in the IMP Management Document for the study. 
 
 
4.2 Initial Shipment of Trametinib (GSK1120212) 
 
The Cancer Research UK Clinical Trials Unit, Glasgow will trigger the initial supply of Trametinib (GSK1120212) at the 
time of site activation when all necessary documentation received and the initiation process completed as outlined in 
section 2 of this appendix.  
 
Drug supply will be addressed to the responsible Pharmacist recorded on Staff Contact and Responsibilities sheet for the 
site. Thereafter the site will be responsible for ensuring they have sufficient supplies of Trametinib (GSK1120212) and 
the stock is within date and there is stock rotation of supplies to ensure the shortest expiry date are used first. The size of 
the initial shipment will vary depending on anticipated recruitment rates at each site. 
 
 
4.3 Re-supply ordering of Trametinib (GSK1120212)  
 
After the initial shipment, Trametinib (GSK1120212) supplies will be managed using manual ordering systems. Further 
supplies can be obtained by completing the Clinical Trials Request and Receipt Form and forwarding by fax to the 
Cancer Research UK Clinical Trials Unit, Glasgow who will order the supplies on behalf of the site. The order form 
should be signed by a member of pharmacy clinical trial staff at the site who has delegated IMP management related 
responsibilities. The original signed order form should be retained in the pharmacy site file. 
 
Orders will take approximately 5 working days from the date of request to delivery at site. Please note deliveries will only 
be made to site pharmacies Monday to Friday. 

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136
 
 
4.4  
Accountability of IMPs 
 
IMP accountability logs will be provided by the UK Sponsor for recording the movement of all IMPs used within the 
study.  Each patient taking part in the study should have a log maintained of the IMP administered, the date of 
administration, the cycle number, the dose administered and the brand, batch number and expiry date of the product 
administered. 
 
Local documentation for accountability may be permitted after approval by the Cancer Research UK Clinical Trials Unit, 
Glasgow. 
 
Full accountability records for Trametinib (GSK1120212) are required, documenting receipt of bulk supplies as well as 
patient dispensing.  These must be accurately maintained and updated at the time of each dispensing or other drug 
movement for the duration of the study and should be kept in the study pharmacy file. 
 
 
4.5  
IMP Disposal & Destruction 
 
For the control arm, used or partially used vials, dose-banded infusions or syringes may be disposed of at site according 
to local hospital policy with no additional accountability required.  Oral products will require reconciliation of empty or 
part-used containers of IMP returned from patients, within the accountability logs, as a measure of patient compliance, 
before disposal as per local policy. 
 
Destruction of Trametinib (GSK1120212) un-dispensed stock, if necessary, should be undertaken after the Sponsor has 
given written permission, in line with local policies and procedures and a destruction log completed. A destruction log 
will be provided for use. 
 
 
5. Drug Interactions/ Contraindications with Concomitant Medications 
 
Please refer to the current Summary of Product Characteristics/ Investigator Brochure for the products for details on 
drug interactions and contraindications with concomitant medications. 
 
 
 
6. Trial Management and Data Collection 
 
6.1 Case report forms  
 
6.2 Data Flow 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data management system. For 
full instructions please see the data submission section of the protocol: section 10.2 GOG Data Management. 
 
In summary the data flow for the study will be as follow 
 
 All queries will be sent from GOG Statistical and Data Centre (SDC) to the participating sites via Medidata Rave 
Electronic Data Entry System (www.imedidata.com) online application. 
 
 Investigators/ Authorised personnel will submit GOG electronic case report forms via Medidata Rave Electronic 
Data Entry System (www.imedidata.com) online application. 
 
 
 The GOG SDC is responsible for raising validation checks and for overall quality control of trial data. 
 
 

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137
7. Assessment of Safety/ Reporting of Serious Adverse Events 
 
Safety assessments will be performed in line with the guidance specified in The Medicines for Human Use (Clinical 
Trials) Regulations 2004. 
 
7.1 
Definitions 
 
These definitions apply to all study participants from the first dose of study medication. 
 
Adverse Event (AE) 
An adverse event (AE) is any untoward medical occurrence in a subject to whom a medicinal product has been 
administered, including occurrences which are not necessarily caused by or related to that product. 
 
Adverse Reaction (AR) 
An adverse reaction (AR) is any untoward and unintended occurrence in a subject to whom a medicinal product has 
been administered which is thought to be caused by or related to that product. 
 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any of the following, whether or not considered related to the trial 
treatment: 
 
• 
Results in Death 
• 
Life-threatening (i.e. at the time of the event)* 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation** 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Is considered medically significant by the Investigator*** 
 
*Life threatening means that the patient was at immediate risk of death from the event as it occurred. It does not include 
an event that, had it occurred in a more serious form, might have caused death. 
**Requires in-patient hospitalisation should be defined as a hospital admission required for treatment of an AE. 
***Considered medically significant by the Investigator are events that may not result in death, are not life threatening, 
or do not require hospitalisation, but may be considered a serious adverse experience when, based upon appropriate 
medical judgement, the event may jeopardise the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
 
Please note in addition to above definitions of an SAE for this study there are additional SAE reporting 
requirements. 
 
A table is provided below of the Comprehensive Adverse Event and Potential Risks list (CAEPR) for Trametinib 
(GSK1120212). The 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 which require to be 
reported as SAEs (except as noted below).  Frequency is provided based on 1111 patients. Below is the CAEPR for 
trametinib dimethyl sulfoxide (GSK1120212B, ). 
 
 
NOTE: Report AEs on the SPEER as an SAE ONLY IF they exceed the grade noted in parentheses next to 
the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents 
and has an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 
 

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138
   Version 2.6, October 10, 20191 
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 3) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  
 
Sinus bradycardia 
 
  
EYE DISORDERS 
  
 
Blurred vision 
 
  
 
Dry eye 
 
  
 
 
Eye disorders - Other 
(chorioretinopathy also known 
as retinal pigment epithelial 
detachment) 
  
 
 
Eye disorders - Other (retinal 
vein occlusion) 
  
 
Eye disorders - Other (visual 
disorders)2 
 
  
 
 
Papilledema 
  
 
Periorbital edema 
 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
 
Colitis 
  
 
 
Colonic perforation 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Vomiting 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
 Chills (Gr 2) 
 
Edema face 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
 
Fever 
 
 Fever (Gr 2) 
Generalized edema3 
 
 
 Generalized edema3 (Gr 2) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction4 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Folliculitis 
 
 Folliculitis (Gr 2) 
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase 
increased (Gr 3) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase 
increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase 
increased (Gr 3) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  

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139
 
 Adverse Events with Possible  
 Relationship to Trametinib (GSK1120212B) 
 (CTCAE 5.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
 
 
Rhabdomyolysis 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 3) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Nail changes 
 
  
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
 
Skin and subcutaneous tissue 
disorders - Other (drug reaction 
with eosinophilia and systemic 
symptoms [DRESS]) 
  
Skin and subcutaneous tissue 
disorders - Other (rash)5 
  
 
 Skin and subcutaneous 
tissue disorders - Other 
(rash)5 (Gr 3) 
 
 
Stevens-Johnson syndrome6 
  
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 3) 
 
 
Thromboembolic event 
(venous) 
  
 
Vascular disorders - Other 
(hemorrhage)7 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to 
all Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
 
2Visual disorders include visual disturbance that can be associated with conjunctival hemorrhage, 
corneal graft rejection, cyclitis, eye nevus, halo vision, iritis, macular edema, retinal hemorrhage, visual 
acuity reduced, visual impairment, and vitreous detachment. 
 
3Generalized edema includes edema, lymphedema, and edema limbs. 
 
4Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver 
function tests, and visual disturbances. 
 

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5Skin and subcutaneous tissue disorders - Other (rash) may include rash, rosacea, rash acneiform, 
erythematous rash, genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash 
papular, seborrhoeic dermatitis, dermatitis psoriasiform, rash follicular, skin fissures, and skin 
chapped. 
 
6Stevens-Johnson syndrome has been observed in patients treated with trametinib and dabrafenib 
combination. 
 
7The majority of hemorrhage events were mild.  Major events, defined as symptomatic bleeding in a 
critical area or organ (e.g., eye, GI hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal 
intracranial hemorrhages have been reported. 
 
 
 
Adverse events reported on trametinib dimethyl sulfoxide (GSK1120212B) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility 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; Pneumothorax; Productive cough; 
Pulmonary hypertension; Respiratory failure; Sinus disorder 

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; Purpura; 
Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension 
 
 
Note: Trametinib (GSK1120212B) 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. 
 
 
 
Serious Adverse Reaction (SAR) 
A serious adverse reaction (SAR) is a SAE that may be related to trial treatment. The assessment of “relatedness” is 
primarily the responsibility of the Principal Investigator (PI) at site or agreed designee. 1**NOTE: SAEs will be 
considered related if the SAE is documented as possibly, probably or definitely related to protocol treatment. SAEs will 
be considered unrelated if the SAE is documented as unrelated or unlikely related to protocol treatment. ** The 
assessment of relatedness is made using the following: 
  
Relationship 
Attribution 
Description 
Unrelated to protocol 
treatment1  
Unrelated 
There is no evidence of any causal relationship. 
Unlikely 
There is doubtful evidence of any causal relationship. 
 
 
 
Related to protocol 
treatment1 
Possible 
There is some evidence to suggest a causal relationship 
(e, g. the event occurs within a reasonable time after 
administration of the trial medication).  However the 
influence of other factors may have contributed to the 
event (e.g. the patient’s clinical condition, other 
concomitant treatments). 
Probable 
There is evidence to suggest a causal relationship and 
the influence of other factors in unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship 
and other possible contributing factors can be ruled out. 
 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Relation (SUSAR) is any suspected SAR that is unexpected. Unexpected is 
any reaction that is not a known reaction listed in the section of the current regulatory approved Comprehensive Adverse 
Event and Potential Risks list (CAEPR)or Summary of Product Characteristics (SmPC), which is acting as the reference 
safety information (RSI) for the trial treatments.  Please note the version of the RSI that has regulatory approval may not 
be the most up-to-date version of the CAEPR or SmPC that has been provided to Investigators for advice on the clinical 
management of their trial patients. 
 
 
7.2 
Detection of Adverse Events 
 
Participants will be asked at each study visit about the occurrence of AEs since their last visit. 
AEs will be recorded, notified, assessed, reported, analysed and managed in accordance with the Medicines for Human 
Use (Clinical Trials) Regulations 2004 (as amended) and the study protocol.   
AEs must be recorded as they are reported, whether spontaneously volunteered or in response to questioning about well-
being at trial visits.  The questioning about AEs will cover the current visit as well as the period of time between the 
previous and the current visit.  All AEs must be documented in the patient’s medical records whether they are required to 
be recorded in the CRF or not. 
 
7.3    Recording of Adverse Events 
 
Full details of AEs including the nature of the event, start and stop dates, severity, relationship to study drug and outcome 
will be recorded in the patient’s medical records and on the study case report form as required by the study protocol.  All 
AEs must be followed until resolution, or for at least 30 days after discontinuation of study medication, whichever comes 

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first or until toxicity has resolved to baseline or ≤ grade 1, or until the toxicity is considered to be irreversible.  Perceived 
lack of efficacy is not an AE. 
 
An exacerbation of a pre-existing condition is an AE. 
 
 
7.4    Assessment of Adverse Events 
 
All AEs and toxicities must be coded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP website 
(http://ctep.cancer.gov).   
AEs must be assessed for seriousness, causality and severity. This assessment is the responsibility of the PI (or designee). 
The assessment of expectedness for regulatory reporting will be undertaken by the CTU and CI. 
 
7.5    Serious Adverse Event Reporting 
 
For guidance on completing the initial and follow up serious adverse event report forms please refer to the serious adverse 
event form completion guidelines, which will be provided to UK sites by the Pharmacovigilance Office, Cancer Research 
UK Clinical Trials Unit, Glasgow 
 
If a Serious Adverse Event occurs, a Serious Adverse Event form should be completed and faxed within 24 hours of 
becoming aware of the event to: 
 
Pharmacovigilance Office, CR-UK CTU, Glasgow 
Fax No: +44 (0) 141 301 7213 
Tel No:  +44(0) 141 301 7211/7953/7209 
 
The UK Chief Investigator will receive notification, by email, of all UK SAEs received.  
 
SAEs must be reported locally by the Principal Investigator at each site in accordance with the local practice at their 
site (i.e. R&D Office). 
 
A follow-up report must be completed when the SAE resolves, is unlikely to change, or when additional information 
becomes available.  If the SAE is a suspected SUSAR then follow up information must be provided as quickly as 
possible and as requested by the CR-UK CTU and Chief Investigator. All follow-up information is required to be 
reported as per the SAE Completion Guidelines.  
 
SAEs are required to be reported from randomisation for up to 30 days after last administration of study treatment. Any 
SAE that occurs after 30 days post treatment (with no time limit) is also required to be reported if the Investigator 
thinks that the SAE is related to protocol treatment (is a SAR), or is medically important. 
 
The Pharmacovigilance Department of the CR-UK CTU, Glasgow will enter all UK SAE reports into 
AdEERs/CTEP-AERS. 
 
For any questions relating to SAE reporting, please contact the pharmacovigilance team at CR-UK CTU, Glasgow. 
 
 
7.6 
Identifying SUSARs 
 
The assessment of expectedness for SAEs and regulatory reporting will be undertaken by the CR-UK CTU and UK Chief 
Investigator based on the section of the trial Reference Safety Information (RSI) that has regulatory approval at the time 
the SAE is received. 
 
 
7.7 
Reporting of a SUSAR 
 

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CR-UK CTU on behalf of the UK (Co) Sponsors is responsible for the expedited reporting of all SUSARs to the 
required Regulatory Authorities, Main Research Ethics Committee, PI at trial sites and the trial Sponsor(s) as well as 
pharmaceutical company (if applicable). 
• 
Fatal or life threatening SUSARs will be reported within 7 days of the CR-UK CTU receiving the first 
notification of the unexpected event. Any additional information will be reported within eight days of 
sending the initial report 
• 
All other SUSARs will be reported within 15 days of the CR-UK CTU receiving the first notification of 
the unexpected reaction. 
 
 
7.8 
Reference Safety Information  
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) for Trametinib (GSK1120212) as detailed in 
study protocol section 4.612 and UK appendix to protocol section 7.1 will act as the RSI for the trial for trametinib 
(GSK1120212). The CAEPR with current regulatory approval for use in the trial will be used to assess SAE reports to 
identify SUSARs. 
 
The contents of Section 4.8 Undesirable Effects in the Summary of Product Characteristics (SmPC) identified by UK 
Sponsor for: 
• 
Letrozole  
• 
Tamoxifen  
• 
Paclitaxel  
• 
Pegylated Liposomal Doxorubicin 
• 
Topotecan 
Will act as the reference safety information for the trial. The UK Sponsor is responsible for identifying and informing 
the CR-UK CTU of updates to the reference SmPC.  The SmPC with current regulatory approval for the trial will be 
used to assess SAE reports to identify SUSARs 
 
 
7.9 
Pregnancy Reporting 
 
Pregnancy occurring in a clinical trial participant while not considered an AE or a SAE, requires monitoring and follow-
up. The Investigator must collect pregnancy information for female trial subjects.  This includes subjects who become 
pregnant while participating in a clinical trial of an investigational medicinal product or during a stage where the foetus 
could have been exposed to the IMP. 
 
Any pregnancy occurring in a female subject who becomes pregnant while participating in a trial will be reported by the 
Principal Investigator (PI) to the Pharmacovigilance Office of the Cancer Research UK Clinical Trials Unit, Glasgow 
using the Pregnancy Notification Form (PNF). This notification must be made within 2 weeks of the PI first becoming 
aware of the pregnancy. The PI will update the PNF with the outcome of the delivery or if there is a change in the subject’s 
condition such as miscarriage. The updated PNF must be sent to Pharmacovigilance Office of the Cancer Research UK 
Clinical Trials Unit, Glasgow as soon as the information becomes available, 
 
7.10 Development Safety Update Reports 
 
Development Safety Update Reports (DSURs) will be prepared and submitted by the UK Chief Investigator and CR-UK 
CTU in conjunction with GOG/CTEP on behalf of the UK sponsor. DSURs will be submitted to the Regulatory 
Authorities, Main Research Ethics Committee, Trial Sites, Trial Sponsor(s) and Pharmaceutical Company on the 
anniversary of obtaining the UK Clinical Trial Authorisation or aligned to the Investigational New Drug (IND) 
application. 
 
8. Study Responsibilities 
 
The co-sponsors of this clinical trial in the UK are NHS Greater Glasgow and Clyde (NHSGG&C) and The University 
of Glasgow (GU). 
 

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Prior to study initiation, a non-commercial funded clinical trial co-sponsorship agreement will be put in place between 
NHS GG&C and GU. The role and liabilities each organisation will take under The Medicines for Human Use (Clinical 
Trials) Regulations, 2004 SI 2004: 1031 are laid out in this agreement signed by both organisations. GU shall be 
responsible for carrying out the obligations and responsibilities set out in the aforementioned agreement, and shall be 
deemed the “sponsor” for the purposes of, Part 3 of the regulations in relation to the study. NHS GG&C shall be 
responsible for carrying out the obligations and responsibilities set out in the agreement, and shall be deemed the 
“sponsor” for the purposes of, Parts 4,5,6 and 7 of the Regulations in relation to the study. 
 
Prior to study initiation, an intergroup agreement will be put in place between CTEP, GOG and NHS GG&C and GU. 
The roles and responsibilities of each party in relation to UK participation in the trial are laid out in this agreement signed 
by all three organisations. 
 
A Clinical Study Agreement will be put in place between NHS GG&C and each of the participating sites. This agreement 
outlines the responsibilities of each party’s responsibilities in the running of the trial; the co-sponsors, the Chief 
Investigator (C.I.), the Cancer Research UK Clinical Trials Unit, Glasgow (CTU), the Principal Investigator (P.I.) at the 
Participating Site and the Participating Site. In summary, they are as follows: 
 
 
8.1  
UK Co-Sponsor Responsibilities (NHSGG&C/GU ) 
The Sponsor’s responsibilities will be for Authorisation and Ethics Committee opinion, GCP and Conduct and 
Pharmacovigilance. In the UK the majority of the Sponsor’s responsibilities have been delegated to the CI who performs 
these via the CTU as the co-ordinating centre for the study in the UK. As such, the main role of the Sponsor is to ensure 
that the CI and CTU fulfil their responsibilities as outlined in the Clinical Study Agreement and to ensure that any 
identified “risks” either have controls or action points put in place. 
 
8.2  
CR-UK Clinical Trials Unit (CTU) 
The CTU is responsible for the co-ordination of the clinical trial in the UK. This includes all regulatory submissions 
(ethics, R&D and CTA), all administration relating to the submissions and any amendments, circulation of all 
correspondence to participating sites, ongoing communication with participating sites, management of SAE/SUSAR 
reporting, and where applicable the management of any financial arrangements (e.g. payments to sites for pathology 
samples etc). 
 
8.3 
 Chief Investigator (C.I.) 
The CI has delegated the majority of his/her responsibilities to the CTU. The C.I. is directly responsible for ensuring the 
protocol and any amendments are in place, for review of SAE forms and determination of whether they meet the criteria 
for a SUSAR, and to provide advice and recommendations on medical issues that arise involving the management of the 
patients on the study. As the CI is external to the Co Sponsors an agreement will be put in place between the CI’s employer 
and the Co-Sponsors for this study to outline the responsibilities of each party. 
 
8.4 
 Participating Site 
The Participating Site is responsible for the management of the trial within their site. This includes ensuring local 
management approval has been given, ensuring the study is conducted according to ICH GCP requirements, and 
ensuring the appropriate insurance or indemnity is in place. The Participating Site is also responsible for arranging 
access for on-site monitoring and auditing as identified in the study protocol and also for regulatory inspections. 
 
8.5 
 Principal Investigator (P.I.) 
The P.I. is responsible for the delegation of study activities within their unit and ensuring all personnel are adequately 
trained and qualified to carry out their responsibilities. The P.I will be required to provide evidence of GCP training 
(usually a certificate) or  undergo the required GCP training. Regarding the management of patients within their site, the 
P.I. is responsible for the safety and well being of trial patients, reporting any deviations from the protocol to the CTU 
as well as any SAEs or safety issues. Full details of the responsibilities of the P.I. are outlined in the Clinical Study 
Agreement. Two original copies of this will be held – one with the sponsor and the other at the Participating Site. A 
photocopy of the signed agreement will also be held within the CTU. 
 
 
9. Liability and Indemnity 
 
The Health Board/NHS Trust at each participating site is responsible for the following: 
 

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1. 
Acts and omissions of its own staff and others engaged by it, including the Clinical Trials Unit and PI; 
2. 
Ensuring the appropriate insurance administered by the National Health Service Litigation Authority is in place; 
3. 
Ensuring any non-NHS employee involved in the clinical trial has an Honorary Contract with the Trust to cover 
access to patients and liability arrangements. 
 
These responsibilities are outlined and agreed within the Clinical Study Agreement.  
 
No special insurance is in place for patients in this study other than standard NHS liability insurance providing indemnity 
against clinical negligence. This does not provide cover for non-negligence e.g. harm caused by an unexpected side effect 
of participating in a study. 
 
 
10. 
Regulatory Issues 
 
10.1 Clinical Trials Authorisation (CTA) 
 
On behalf of the Co-Sponsor the Cancer Research UK Clinical Trials Unit, Glasgow will apply to the MHRA for a 
clinical trials authorisation (CTA) to conduct the trial in the UK and will also be responsible for the maintenance of the 
CTA. 
 
10.2 Ethics and Research & Development Approval 
 
Ethics favourable opinion will be sought for the study from a Main REC prior to commencement of this trial.  Further to 
that approval each participating site will be responsible for obtaining their own local approval by submitting an SSI to 
their appropriate R&D department for management approval. 
 
10.3 Informed Consent 
 
Consent to enter the study must be sought from each participant only after full explanation has been given, the participant 
has been given an information sheet and a minimum of 24 hours to consider trial participation.  Signed participant consent 
must be obtained, the consent forms should also be signed by the person undertaking the consent procedure at site, who 
must be detailed on the Staff Contact and Responsibility Log as having this authorisation. The Principal Investigator is 
responsible for ensuring if taking consent is delegated to a designee, the designee is suitably qualified by training or 
experience to take informed consent. 
 
 The right of the participant to refuse to participate without giving reasons must be respected.  After the participant has 
entered the trial the clinician remains free to give alternative treatment to that specified in the protocol at any stage if 
he/she feels it is in the best interests of the participant, but the reasons for doing so must be recorded.  In these cases the 
participants remain within the study for the purposes of follow-up and data analysis.  All participants are free to withdraw 
at any time from the protocol treatment without giving reasons and without prejudicing further treatment. 
 
An original completed consent form must be retained at each site in the appropriate section of the Investigator Site File, 
and a copy placed in the patient’s medical records. All patients must be given an original of the signed patient information 
sheet and consent form for their records. Consent forms must be retained on site and not submitted to the Trials Office. 
 
10.4  Confidentiality 
 
National Health Service Guidelines for storage, transmittal and disclosure of patient information will be followed at all 
times. 
 
This study will be carried out in accordance with ICH GCP Guidelines. Following formal admission to the study, patient 
data will be recorded in the hospital case record in the usual way including the circumstances of their entry to the study. 
Additionally data will be held in  study case report forms (CRF). These files will be identified by a trial number and 
patient initials only. 
 
Representatives from the Study Sponsors and from the regulatory authorities will be given access to the records that relate 
to the study. They will have full access to the anonymous CRF for the purposes of data validation. 
 

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Results of the study may be communicated at scientific meetings and will contribute to the scientific literature. At no time 
will this be done in such a way that an individual patient may be identified. 
 
10.5  Quality Assurance/Quality Control 
 
Quality Assurance/Quality Control will be maintained by the following requirements and activities: 
 
• 
All study sites taking part in the trial will be required to participate in site initiation to ensure compliance with 
the protocol and allow training on study procedures and data collection methods. 
 
• 
Trial Investigators and site staff must ensure that the trial is conducted in compliance with the protocol, GCP 
and applicable regulatory requirements. 
 
• 
The CR-UK CTU, Glasgow will the assist the Trial Investigators and check they are complying with protocol, 
GCP and regulatory requirements by monitoring trial documentation. Trial data and documentation will be 
checked for completeness, accuracy and reliability at monitoring visits.  
 
 
10.6  Monitoring 
 
Central Monitoring 
Study sites will be centrally monitored by checking CRFs and other study documents for protocol compliance, data 
accuracy and completeness. 
 
On-Site and Telephone Monitoring 
All UK participating study sites will be monitored remotely by the CR-UK Clinical Trials Unit monitoring team on behalf 
of the Sponsor(s) by telephone and will also be visited for on site monitoring visit(s). The PI will allow the study staff 
access to source documents as requested. In addition, the pharmacy department responsible for the trial will be visited to 
allow monitoring of the pharmacy site file and review of security, storage and accountability of trial drug. Investigators 
and site staff will be notified in advance about forthcoming monitoring visits. On occasion, members of the CR-UK CTU 
monitoring team may be accompanied by other trial staff from the unit for training purposes. Where a participating site 
is using electronic data reporting systems or electronic patient records and hard copies are not available, the CR-UK CTU 
monitor will require access to a computer for the duration of the visit in order to verify all relevant source data against 
the case report forms. This may involve being given a temporary log-in. If this is not permitted by local policy, there must 
be a member of site staff available to provide access to the monitor. 
 
10.7 Audits and Inspections 
 
Trial Investigators must permit trial related monitoring, audits, REC review and regulatory inspections as required, by 
providing direct access to source data, CRFs and other documents (patients medical records, trial site file, and other 
pertinent data). 
 
The study may be subject to inspection and audit by NHS GG&C and GU under their remit as Co Sponsors, the CR-UK 
CTU and other regulatory bodies, i.e. the MHRA, to ensure adherence to GCP, GOG as the lead co-ordinating group for 
the trial and CTEP as overall legal sponsor of the study. 
 
If an inspection is scheduled at any participating site, the site must notify the CR-UK CTU at the earliest opportunity. 
 
11. 
Patient Information Sheets and Consent Forms 
 
The UK Patient Information Sheet and Consent Forms will be provided separately for this study. Please check local 
approval letters to ensure the most current approved Patient Information Sheets and Consent Forms are being used. 
 
12. 
GP Letter 
 
The UK GP letter will be provided separately for this study. Please check local approval letters to ensure the most 
current approved GP letter is being used. 
 

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13. 
Translational Research 
 
In this study, tissue specimens will be collected for future translational research. These specimens include a mandatory 
pre-treatment fresh frozen biopsy and non-mandatory collections of archival formalin fixed paraffin embedded (FFPE) 
specimen(s), plasma drawn at various points in the patient journey and optional on-treatment/post-progression tumour 
biopsies. Specimens will be collected from enrolled patients who have consented to the future translational research. 
 
Tissue specimens collected within the translational study (TransLOGS) will be collected and stored in the approved 
biobank at the Edinburgh Experimental Cancer Medicine Centre. The LOGS Translational Research Committee will 
assess and approve translational research projects after which samples will be distributed for analysis. 
 
Sample collection, storage and processing: 
Detailed instructions for the processing, labelling, handling storage and shipment of these specimens will be provided in 
the LOGS translational research manual 
 
A table providing a summary of the specimen requirements for the study is detailed on the next page: 
 
 
 Summary of Specimen Requirements 
 
The patient must give permission for her fresh tissue biopsy specimen to be used for translational research. Participating institutions are 
required to submit the biopsy specimen as outlined below. 
 
If the patient gives permission for her fixed tissue and blood specimens to be used for translational research, then the participating institution is 
required to submit the patient’s specimens as outlined below. 
 
Required Specimen 
(Specimen Code) 
Collection Time Point 
Ship To 
Fresh Recurrent Primary Biopsy (RRP01 and 
RRPO2)1  
Prior to trial treatment (either arm) 
Mandatory (eligibility requirement) 
Two cores to be taken, one snap 
frozen in liquid nitrogen (RRP01 and 
second placed into Tissue-Tek Xpress 
fixative (RRPO2) 
Send biopsies placed in fixative to 
Edinburgh Cancer Centre within 1 
week of registration, snap frozen 
biopsies will be batch transferred 2 
FFPE Primary Tumor (FP01) 
1st Choice: block 
2nd Choice: 20 unstained slides (10 charged, 
5µm + 10 uncharged 10 µm) 
Prior to trial treatment (either arm) 
 
Optional3 
 
Edinburgh Cancer Centre within 8 
weeks of registration2 
 
FFPE Metastatic Tumor (FM01) 1st Choice: 
block 
2nd Choice: 20 unstained slides (10 charged, 5µm 
+  10 uncharged 10 µm) 
Prior to trial treatment (either arm) 
Optional3 
 
FFPE Recurrent Primary Tumor 
(FRP01) 
1st Choice: block 
2nd Choice: 20 unstained slides (10 charged, 5µm 
+  10 uncharged 10 µm) 
Prior to trial treatment (either arm) 
Optional3 
 
FFPE Recurrent Metastatic Tumor (FRM01) 
1st Choice: block 
2nd Choice: 20 unstained slides (10 charged, 5µm 
+  10 uncharged 10 µm) 
Prior to trial treatment (either arm) 
Optional3 
 
Fresh frozen tissue taken at the time of original 
diagnosis; if available and stored in liquid 
nitrogen (FF01) 
Either study arm; these fresh frozen samples can 
remain in liquid nitrogen prior to batch transfer 
(it is accepted that few patients will have archival 
fresh frozen samples available). 
Optional 3 
  Samples will be batch  
 transferred2 

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Pre-Treatment whole blood (WBO1); 10ml of 
blood drawn into EDTA tube(s); this specimen 
can be taken at the same time as PB01 (below). 
Prior to trial treatment (either arm) 
Optional3 
Samples will be batch transferred  from 
sites to Edinburgh Cancer Centre 
periodically e.g. every 6 months or 
annually depending on recruitment2 
 
 
 
Pre-Treatment Plasma (PB01) prepared from 7-
10mL of blood drawn into EDTA tube(s)4 
Prior to trial treatment (either arm) 
 
Optional3 
 
C3D1 Pre-Treatment Plasma (PB06) prepared 
from 7-10mL of blood drawn into EDTA tube(s)4 
Cycle 3, day 1, prior to 
administering treatment 
Optional3 
C6D1 Pre-Treatment Plasma (PB08) prepared 
from 7-10mL of blood drawn into EDTA tube(s)4 
Cycle 6, day 1, prior to 
administering treatment 
Optional3 
Disease Progression Plasma (PB09) prepared from 
7-10mL of blood drawn into EDTA tube(s)4 
Within 4 weeks of documented 
disease progression 
Optional3 
 
Fresh Progression Tumour Biopsy (PTB01 and 
PTBO2)3  
Within 4 weeks of documented 
disease progression 
Optional3 
Two cores to be taken, one snap frozen in liquid 
nitrogen (PTB01) and the second placed into 
Tissue-Tek Xpress fixative (PTBO2) 
Send biopsies placed in fixative to 
Edinburgh Cancer Centre within 1 week 
of being taken, snap frozen biopsies will 
be batch transferred2 
 
1 
Please note the protocol-specific biopsy processing instructions described in the laboratory manual. 
2 
Please ship all specimens to: Mr Alex MacLellan, Experimental Cancer Medicine Centre, University of Edinburgh Cancer Research UK 
Centre, Crewe Road South, Edinburgh, EH4 2XR, UK. 
3 
Centres are encouraged to submit optional specimens wherever possible. 
4 
Please note the protocol-specific plasma processing instructions described in the laboratory manual 
 
 
 
 
 
Additional plasma specimens for PK testing will be collected from a subset of patients (approximately 12 US and 
12 UK) 
 

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1 
Please note the protocol-specific plasma processing instructions described in the laboratory manual. 
 
 
14. 
Central Radiographic Image Review  
 
Retrospective central radiographic review is planned for this study. It is therefore a requirement for sites to send 
anonymised scans on disc for patients for all scans the patient receives whilst on study. 
 
Timing of scans 
• 
The timing of the radiological assessments is the same for both arms of the study.  
 
• 
As outlined within the protocol the scheduled scanning of patients will take place at baseline (must be performed 
within 28 days of randomisation) and every 8 weeks for the first 15 months then every 3 months thereafter until 
disease progression (even if the patient withdraws from treatment). Please note scanning should continue after 
progression in patients who crossover from the standard arm to the Trametinib arm and should continue in that 
arm until progression. 
 
• 
Assessments must be performed on a calendar basis (i.e. not delayed due to delays in administering study 
medication).  
 
Type of scan 
 
• 
Contrast CT or MRI of chest, abdomen and pelvis. 
 
• 
A contrast CT scan is the preferred modality.  
 
• 
The same diagnostic method, including use of contrast when applicable, must be used throughout the study to 
evaluate each lesion. 
 
Preparation and transfer of scans 
 
• 
The CR-UK Clinical Trials Unit, Glasgow will provide a batch of CDs for use within the trial before the trial 
site opens to recruitment. The CR-UK Clinical Trials Unit, Glasgow should be contacted for further supplies. 
 
• 
Referring to the patient’s schedule of assessments, the Research Nurse or Clinical Trial Co-ordinator/Data 
Manager is aware that scan has been/is to be performed and contacts the radiology department to prompt the 
scan must be anonymised and downloaded to CD. 
 
Required Specimen 
( Secimen Code) 
Collection Time Point 
Ship To 
C1D15 4-8 Hour Post-Treatment (PB02) prepared 
from 7-10mL of blood drawn into EDTA tube(s)4 
Cycle 1, day 15, 4 to 8 hours (±15 minutes) 
after administering trametinib 
 
 
 
 
 
 
Samples will be batch transferred from 
sites every 6 months to Covance in US. 
 
 
 
 
 
C1D29 Pre-Treatment Plasma (PB03) prepared 
from 7-10mL of blood drawn into EDTA 
tube(s)4 
The last day of cycle 1, prior to 
administering trametinib 
C1D29 2 Hour Post-Treatment Plasma (PB04) 
prepared from 7-10mL of blood drawn into 
EDTA tube(s)4 
The last day of cycle 1, 2 hours (±15 
minutes) after administering trametinib 
C2D1 30 Minute Post-Treatment Plasma 
(PB05) prepared from 7-10mL of blood 
drawn into EDTA tube(s)4 
Cycle 2, day 1, 30 minutes (±5 
minutes) after administering 
trametinib 
C3D1 30 Minute Post-Treatment Plasma 
(PB07) prepared from 7-10mL of blood 
drawn into EDTA tube(s)4 
Cycle 3, day 1, 30 minutes (±5 
minutes) after administering 
trametinib 

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• 
The radiology department prepares an anonymised CD ensuring that: 
- 
Only the patients trial ID and initials are present 
- 
The scan is it fit for diagnostic purposes 
- 
DICOM images and viewing tool is used 
- 
The date of the scan is clearly identifiable 
- 
Vertical and/or horizontal scales are included 
- 
Electronic callipers or an equivalent measurement tool is included 
 
• 
The Research Nurse or Clinical Trial Co-ordinator/Data Manager makes the patients trial ID, initials, date of 
scan and “ LOGS:GOG-0281 study” on the CD, completes Form 01 Central CT/MRI Scan Assessment Form 
and includes in envelope. 
 
• 
The Research Nurse or Clinical Trial Co-ordinator/Data Manager posts the CD together with Form 01 Central 
CT/MRI Scan Assessment Form  to the following address: 
 
LOGS (GOG-0281) Clinical Trial Co-ordinator 
CR-UK Clinical Trials Unit, Level 0 
The Beatson West of Scotland Cancer Centre 
1053 Great Western Road 
Glasgow, G12 OYN 
 
• 
The Research Nurse of Clinical Trial Co-ordinator/Data Manager notifies the CR-UK Clinical Trials Unit, 
Glasgow by email to confirm dispatch of CD and that a delivery should be expected. 
 
 
Central Review 
 
• 
The CR-UK Clinical Trials Unit will notify the Research Nurse or Clinical Trial Co-ordinator/Data Manager by 
email or fax to confirm receipt of anonymised scan and to confirm that is fit to for diagnostic purposes. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

EudraCT Number: 2013-001627-39 
 
Version 7, 05th February, 2020 
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14.1 Form 01 Central CT/MRI Scan Assessment Form 
 
 Central CT/MRI Scan Assessment Form 
LOGS Trial: A randomised phase II/III study to assess the efficacy of trametinib (GSK1120212) in patients with 
recurrent or progressive low-grade serous ovarian cancer or peritoneal cancer (GOG-0281) 
(EudraCT no: 2013-001627-39) 
Patient Initials:  
(forename) ____   (surname) ____ 
Patients Trial Identifier:  
 
 
/ 
 
       / 
 
 
                
 
Institution No               Study No            Sequential on Study No 
To be completed for every CT/MRI scan performed.  
Scans should be sent to:  LOGS (GOG-0281) Clinical Trial Co-ordinator, CR-UK Clinical Trials Unit, Level 0, The 
Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow, G12 0YN 
Section A – Scan Details (To be completed by site and sent with each CT/MRI scan) 
Date of CT/MRI Scan: 
  
   / 
 
   / 
    Day  
Month  
Year 
Scan number: 
                    
                                          
                     (i.e. Baseline = 01, 8 weeks =02 etc)                                                     
                                                     
 
 
     
Type of scan performed: 
 Contrast CT (chest, abdomen and pelvis) 
 
 Non-contrast CT (chest, abdomen and pelvis).  
      If a non-contrast CT has been performed, please state reason below; 
 
      ____________________________________________________ 
 MRI scan (chest, abdomen and pelvis) 
Contact details at site: 
Name:  
 
_____________________________ 
Email:  
 
_____________________________ 
Fax: 
 
 
_____________________________ 
Postal Address: _____________________________ 
 
 
 
_____________________________ 
 
 
 
_____________________________ 
 
 
 
_____________________________ 
 
 
 
_____________________________ 
Section A completed by: 
Signature: ___________________________    Date: ______________ 
Form continues on next page 
Prior to returning this form to the CR-UK Clinical Trials Unit, please make a copy of the form for retention at site. 
 
 Central CT/MRI Scan Assessment Form 
 
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EudraCT Number: 2013-001627-39 
 
Version 7, 05th February, 2020 
152
LOGS Trial: A randomised phase II/III study to assess the efficacy of trametinib (GSK1120212) in patients 
with recurrent or progressive low-grade serous ovarian cancer or peritoneal cancer (GOG-0281) 
(EudraCT no: 2013-001627-39) 
Patient Initials:  
(forename) ____   (surname) ____ 
Patients Trial Identifier:  
 
 
/ 
 
       / 
 
 
                
 
Institution No               Study No            Sequential on Study No 
Section B – Scan Assessment (To be completed by CR-UK Clinical Trials Unit and Central Radiologist) 
Date scan received by       CR-UK 
Clinical Trials Unit: 
  
   / 
 
   / 
    Day  
Month  
Year 
Date sent to Central Radiologist: 
  
   / 
 
   / 
    Day  
Month  
Year 
Date received by Central 
Radiologist: 
  
   / 
 
   / 
    Day  
Month  
Year 
Checks performed by Central 
Radiologist: 
 
Does the patient trial identifier 
noted on form match the 
identifier recorded on CD? 
Yes 
 
 
No 
 
Date of scan on the CD: 
                /                       / /                                                                                                      
Day             Month                   Year 
Do the images on the disc fulfil 
the requirements of study?  
Yes 
 
 
No 
 
If no, please state reasons below: 
_____________________________________________________________ 
Section B completed by Central 
Radiologist: 
 
Signature: ___________________________    Date: ______________ 
Date completed form and disc 
sent back to CR-UK Clinical 
Trials Unit: 
               /   /                           /                                                                                                 
      Day              Month                       Year  
Section C – Final Receipt CR-UK Clinical Trials Unit (To be completed by CR-UK Clinical Trials Unit) 
Date completed form and disc 
received CR-UK Clinical Trials 
Unit: 
                   /                        /                                                                                                    
 
Day             Month                    Year 
Section C completed by: 
Signature: ___________________________    Date: ______________ 
 
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