Clinical trial NCT01964924
Conditions: Estrogen Receptor Negative HER2/Neu Negative Invasive Breast Carcinoma Progesterone Receptor Negative Recurrent Breast Carcinoma Stage IV Breast Cancer Triple-Negative Breast Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2013-10-02; Completion date: 2018-04-23
Enrollment: 37 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well trametinib and v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor GSK2141795 work in treating patients with triple-negative breast cancer (breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 \[HER2/neu\] protein) that has spread to other places in the body. Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the anti-tumor activity associated with trametinib monotherapy in patients with triple negative breast cancer (TNBC).

SECONDARY OBJECTIVES:

I. To assess the anti-tumor activity associated with trametinib in combination with AKT inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC.

II. To determine the progression-free survival following the initiation of treatment with trametinib monotherapy in patients with metastatic TNBC.

III. To determine the progression-free survival following the initiation of treatment with trametinib in combination with GSK2141795 in patients with metastatic TNBC.

IV. To determine the overall survival following the initiation of treatment with trametinib with GSK214179 in patients with metastatic TNBC.

V. To determine the nature and degree of toxicities associated with trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

VI. To determine the biomarker potential of phosphatase and tensin homolog (PTEN) to predict response to single agent trametinib.

VII. To determine molecular markers of sensitivity and resistance to trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

OUTLINE:

PART 1: Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.

PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 52 weeks.

Arms: arm 1: PART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2.

PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Akt Inhibitor GSK2141795 intervention 2: Laboratory Biomarker Analysis intervention 3: Trametinib
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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SUMMARY OF CHANGES 
 
NCI Protocol #: 9455 
Local Protocol #: OSU-13117 
 
NCI Version Date: January 30, 2018 
Protocol Version Date: January 30, 2018 
 
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PROTOCOL TYPE 
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MULTI SITE CONTACT 
The multi-center trial coordinator has been changed from Jennifer 
Sexton to Julie Agriesti, CCRC 
IV 
3.1.9 
6.1.1 
6.2.9 
22 
28 
44 
Per CTEP’s CTCAE v4.0 to CTCAE v5.0 Conversion Amendment 
Request, the Common Terminology Criteria for Adverse Event  
(CTCAE) version number has been updated to 5.0  
 
Please note: This CTCAE version change has not been made within 
the CAEPR(s) 
 
V 
7.2 
50 
ADVERSE EVENTS CHARACTERISTICS  
The statement regarding CTCAE has been updated to reflect the new 
version 5.0.  
The statement now reads:  
CTCAE term (AE description) and grade: The descriptions and 
grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized 
until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate 
treatment areas should have access to a copy of the CTCAE version 
5.0. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/c
tc.htm. 
 
7.3.3 
51 
EXPEDITED REPORTING GUIDELINES 
Clarified the reporting guidelines for death due to progressive disease.  
Death due to progressive disease should be reported as Grade 5 
“Disease progression” in the system organ class (SOC) “General 
disorders and administration site conditions.”… 


1 
NCI Protocol #: 
NCI 9455 
 
Local Protocol #: 
OSU 13117 
 
TITLE:   A SINGLE ARM, PHASE II STUDY OF SINGLE AGENT TRAMETINIB 
FOLLOWED BY TRAMETINIB IN COMBINATION WITH GSK2141795 IN 
PATIENTS WITH ADVANCED TRIPLE NEGATIVE BREAST CANCER 
 
Coordinating Center: 
 
 
James Cancer Hospital and Solove Research Institute,  
 
 
 
 
 
 
 
 
 
The Ohio State University 
 
*Principal Investigator: 
Bhuvaneswari Ramaswamy, MD 
 
B406 Starling Loving Hall 
 
320 W. 10th Ave  
 
Columbus, OH 43210 
 
Tel: 614-293-6401 
 
Fax: 614-293-4372 
 
bhuvaneswari.ramaswamy@osumc.edu  
 
Co-Investigators: 
*Cynthia Timmers, PhD 
460 12th Avenue, BRT Rm 486 
Columbus, OH 43210 
Tel: 614-366-9041 
cynthia.timmers@osumc.edu  
 
 
 
 
Maryam Lustberg, MD, MPH  
Assistant Professor of Internal Medicine  
Division of Medical Oncology  
B421 Starling Loving Hall  
320 West 10th Avenue  
Columbus Ohio 43210  
Tel: 614-293-0066  
Fax: 614-293-7529  
maryam.lustberg@osumc.edu 
   
Robert Wesolowski, MD  
Division of Medical Oncology  
B401 Starling Loving Hall  
320 West 10th Ave  
Columbus OH 43210  
Tel: 614-293-8541  
Fax 614-293-7529  
Robert.wesolowski@osumc.edu 
     
Lynn Schoenfield, MD 
N337B Doan Hall 
410 West 10th Avenue 
Columbus, Ohio 43210 


NCI Protocol #:9455 
Version Date: January 30, 2018 
 
2 
 
Tel: 614-688-8698 
Fax: 614-293-2779 
Lynn.Schoenfield@osumc.edu  
 
Shelly Jain, MD 
OSU Eye and Ear Institute 
915 Olentangy River Road, Suite 5000 
Columbus, Ohio 43212 
Tel: 614-293-8119 
Fax: 614-293-5207 
Shelly.Gupta@osumc.edu   
 
Matthew Ohr, MD 
OSU Eye and Ear Institute 
915 Olentangy River Road, Suite 5177 
Columbus, Ohio 43212 
Tel: 614-652-2600 
Fax: 614-652-2610 
Matthew.Ohr@osumc.edu   
 
Steven Katz, MD 
OSU Eye and Ear Institute 
915 Olentangy River Road, Suite 5199 
Columbus, Ohio 43212 
Tel: 614-293-6892 
Fax: 614-293-4719 
Steven.Katz@osumc.edu   
 
*Investigators will be involved in evaluating study data and 
correlative science but will not be involved in direct patient care.  
 
PARTICIPATING CENTERS  
 
Case Comprehensive Cancer Center 
University Hospitals  
 
 
Cleveland Clinic 
Case Medical Center  
 
 
Taussig Cancer Institute 
Seidman Cancer Center 
Joseph Baar, M.D., 
 
 
G. Thomas Budd, M.D. 
11100 Euclid Ave 
 
 
Taussig Cancer Institute, R35 
Cleveland, OH 44106 
 
 
9500 Euclid Avenue 
Phone: 216-286-4414 
 
 
Cleveland, OH 44195 
Fax: 216-201-5423 
 
 
Phone: 216-444-6480 
Joseph.Baar@uhhospitals.org 
 
 
buddg@ccf.org  
 
Roswell Park Cancer Institute  
 
Georgetown University Lombardi Cancer Center 
Ellis Levine, M.D. 
 
 
Claudine Isaacs, M.D. 
Carlton House Room A-403 
 
 
3800 Reservoir Road Northwest 
Elm & Carlton Streets 
 
 
Washington, DC 20007 


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Buffalo, NY 14263 
 
 
Phone: 202-444-3677 
Phone: 716-845-2300 
 
 
Fax: 202-444-1229 
Ellis.levine@roswellpark.org 
 
 
isaacsc@georgetown.edu  
 
Moffitt Cancer Center 
 
 
 
Roohi Ismail-Khan. M.D. 
 
 
. 
12902 Magnolia Drive 
 
 
 
Tampla, FL 33612 
 
 
 
Phone: 813-745-4933 
 
 
 
Roohi.Ismail-Khan@moffitt.org   
 
  
 
University of North Carolina Lineberger Comprehensive Cancer Center 
E. Claire Dees, M.D. 
Physician’s Office Building 
170 Manning Drive, CB#7305 
Chapel Hill, NC 27599 
Phone: 919-966-4431 
Claire_dees@med.unc.edu  
 
Virginia Commonwealth University Massey Cancer Center 
Andrew S. Poklepovic, M.D. 
1201 E. Marshall St., Rm 11-215  
Richmond, VA  23298-0070  
Phone: 804-628-2321 
Fax: 804-828-5406 
apoklepovic@mcvh-vcu.edu 
 
Statistician: 
 
Multi-Center Trial Coordinator: 
Mahmoud Abdel-Rasoul  
 
Julie Agriesti 
Center for Biostatistics 
CCC Ohio State University 
2012 Kenny Road  
660 Ackerman Road 
Columbus, OH 43221  
Columbus, OH 43202 
Tel: 614-293-0076 
Tel: 614-366-5642 
Fax: 614-293-7529 
Fax: 614-366-6652 
 
Mahmoud.abdel-rasoul@osumc.edu   
Email: OSUCCC-CTO-MCTP@osumc.edu 
 
 
Study Coordinator and Responsible Data Manager: 
Robyn Patrick 
JamesCare Comprehensive Breast Center, 2054 
1145 Olentangy River Rd 
Columbus, Ohio 43212 
(ph) 614-293-0194 
robyn.patrick@osumc.edu 
 
 
 
 


NCI Protocol #:9455 
Version Date: January 30, 2018 
 
4 
 
NCI Supplied Agent(s): Trametinib dimethyl sulfoxide (GSK1120212B) NSC 763093 
GSK2141795 NSC 767034  
 
 IND Sponsor:  NCI 
 
 
PROTOCOL TYPE / VERSION # / VERSION DATE: 
 
 
 
Original / Version 1 / January 11, 2013  
 
Revision / Version 2 / March 29, 2013 
 
Revision / Version 3 / April 22, 2013 
 
Revision / Version 4 / July 10, 2013 
 
Revision / Version 5 / August 16, 2013 
 
Revision / Version 6 / September 6, 2013 
 
Revision / Version 7 / November 13, 2013 (Disapproved) 
 
Revision / Version 7.1 / February 19, 2014 (Disapproved) 
 
Revision / Version 7.2 / March 13, 2014 
 
Revision / Version 7.3 / June 04, 2014 
 
Revision / Version 8 / January 06, 2015 
 
Revision / Version 9 / May 29, 2015 (Disapproved) 
 
Revision / Version 10 / June 23, 2015 
 
Revision / Version 11 / July 14, 2015 
 
Revision / Version 12 / December 03, 2015 
 
Revision / Version 13 / March 08, 2016 
 
Revision / Version 14 / May 06, 2016 
 
Amendment / Version 1 / November 18, 2016 
 
Amendment / Version 1 / November 23, 2016 
 
Amendment / Version 1 / January 27, 2017 
 
Amendment/ Version 1/ July 31, 2017 
 
Amendment/ Version 1/January 30, 2018 
 


NCI Protocol #:9455 
Version Date: January 30, 2018 
 
5 
 
FIGURE 1 
 
 
 
 
 
Metastatic TNBC with 
progression on 1 prior 
chemotherapy regimen  
 
 
Part 1: Trametinib 
monotherapy  
Part 2: Trametinib 
combined with 
GSK2141795.  
 
Note: GSK2141795 
added at time of 
progression on trametinib 
monotherapy 
 
Research biopsy prior to 
trametinib 
Participants remain on trametinib 
monotherapy until progression. 
Research biopsy at time of 
progression for patients with an  
initial clinical benefit to trametinib 
Participants remain on trametinib + 
GSK2141795 until progression.  
Research biopsy at time of 
progression for patients with an initial 
clinical benefit to trametinib + 
GSK2141795 
 
   PD 
Abbreviations: TNBC, triple negative breast cancer; PD, progressive disease  


NCI Protocol #:9455 
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6 
 
TABLE OF CONTENTS 
 
TITLE:   
A single arm, phase II study of single agent trametinib followed by trametinib in 
combination with GSK2141795 in patients with advanced triple negative breast cancer ...1 
Participating Centers ........................................................................................................................2 
Protocol Type / Version # / Version Date:.......................................................................................4 
Figure 1 ............................................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................6 
1. 
OBJECTIVES ......................................................................................................................8 
1.1. 
Primary Objectives...................................................................................................8 
1.2. 
Secondary Objectives...............................................................................................8 
2. 
BACKGROUND .................................................................................................................8 
2.1. 
Study Disease ...........................................................................................................8 
2.2. 
CTEP Agents ...........................................................................................................9 
2.3. 
Rationale ................................................................................................................17 
2.4. 
Correlative Studies Background ............................................................................19 
3. 
PATIENT SELECTION ....................................................................................................19 
3.1. 
Eligibility Criteria ..................................................................................................19 
3.2. 
Exclusion Criteria ..................................................................................................21 
3.3. 
Inclusion of Women and Minorities ......................................................................22 
4. 
REGISTRATION PROCEDURES ...................................................................................22 
4.1. 
General Guidelines.................................................................................................22 
4.2. 
Registration Process ...............................................................................................23 
5. 
TREATMENT PLAN ........................................................................................................23 
5.1. 
Research Biopsies ..................................................................................................23 
5.2. 
Agent Administration.............................................................................................23 
5.3. 
General Concomitant Medication and Supportive Care Guidelines ......................24 
5.4. 
Duration of Therapy ...............................................................................................25 
5.5. 
Duration of Follow Up ...........................................................................................25 
5.6. 
Criteria for Removal from Study ...........................................................................25 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................25 
6.1. 
Part 1 Dose Modifications for Trametinib Monotherapy ......................................25 
6.2. 
Dose Modifications for Part 2 Trametinib Combined with GSK 2141795 ...........35 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................42 
7.1. 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ...............43 
7.2. 
Adverse Event Characteristics ...............................................................................48 


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7.3. 
Expedited Adverse Event Reporting ......................................................................49 
7.4. 
Routine Adverse Event Reporting .........................................................................50 
7.5. 
Secondary Malignancy...........................................................................................51 
7.6. 
Second Malignancy ................................................................................................51 
8. 
PHARMACEUTICAL AGENT INFORMATION ...........................................................51 
8.1. 
CTEP Agent(s) .......................................................................................................51 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................55 
9.1. 
Collection of Specimen(s)......................................................................................55 
9.2. 
Laboratory Correlative Studies ..............................................................................57 
9.3. 
Site(s) Performing Correlative Studies ..................................................................61 
9.4 
Potential risks and procedures for minimizing risks ..............................................62 
10. 
STUDY CALENDAR .......................................................................................................65 
11. 
MEASUREMENT OF EFFECT........................................................................................67 
11.1. Antitumor Effect – Solid Tumors ..........................................................................67 
11.2. Other Response Parameters ...................................................................................73 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................73 
12.1. Data Reporting .......................................................................................................74 
12.2. CTEP Multicenter Guidelines ................................................................................74 
12.3. Collaborative Agreements Language .....................................................................75 
13 
STATISTICAL CONSIDERATIONS...............................................................................76 
13.1. Study Overview .....................................................................................................76 
13.2. Sample Size, Accrual, and Study Duration:...........................................................77 
13.3. Study design, primary endpoint analysis plans and power: ...................................77 
13.4. Secondary Endpoints .............................................................................................79 
13.5. Reporting and Exclusions ......................................................................................82 
REFERENCES ..............................................................................................................................84 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................87 
APPENDIX B 
CTEP MULTICENTER GUIDELINES ....................................................88 
APPENDIX C 
Medication Diary – PART 1 ......................................................................90 
APPENDIX D 
Medication Diary – PART 2 ......................................................................92 
APPENDIX E 
 Laboratory Manual....................................................................................97 
APPENDIX F:  BLOOD GLUCOSE TESTING DIARY – OSU-13117 (NCI-9455) ..................98 
APPENDIX G: 
INFORMATION ON POSSIBLE DRUG INTERACTIONS .................100 


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OBJECTIVES 
 
1.1. Primary Objectives 
 
To assess the anti-tumor activity associated with trametinib monotherapy in patients with triple 
negative breast cancer (TNBC) 
 
1.2. Secondary Objectives 
• To assess the anti-tumor activity associated with trametinib in combination with AKT 
inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC. 
• To determine the progression-free survival following the initiation of treatment with 
trametinib monotherapy in patients with metastatic TNBC.  
• To determine the progression-free survival following the initiation of treatment with 
trametinib in combination with GSK2141795 in patients with metastatic TNBC.  
• To determine the overall survival following the initiation of treatment with trametinib 
with GSK214179 in patients with metastatic TNBC.  
• To determine the nature and degree of toxicities associated with trametinib monotherapy 
and trametinib in combination with GSK2141795 in patients with metastatic TNBC.  
• To determine the biomarker potential of PTEN to predict response to single agent 
trametinib 
• To determine molecular markers of sensitivity and resistance to trametinib monotherapy 
and trametinib in combination with GSK2141795 in patients with metastatic TNBC. 
 
 
2. BACKGROUND 
 
2.1. Study Disease  
 
Breast cancer is heterogeneous disease in terms of presentation, morphology, molecular 
profile, and response to therapy. Triple negative breast (TNBC) accounts for 
approximately 20 to 25% of all types of breast cancer and is characterized on standard 
pathologic evaluation by lack of immunohistochemistry (IHC) expression of estrogen 
receptor (ER), progesterone receptor (PR) and HER-2 protein.2 TNBC is clinically the 
most aggressive phenotype of breast cancer. Women with TNBC have an increased 
likelihood of distant recurrence and death within 5 years of diagnosis.2, 3   TNBC is more 
likely to be poorly differentiated, occur in premenopausal patients and in African 
American women.4 No specific systemic therapy is recommended for the treatment of 
TNBC and only limited data is available to support the selection of appropriate treatment. 
This is in contrast to ER-positive or HER2-overexpressing breast cancers where the 
relevant targets are known and specific treatments directed against those targets (i.e. the 
anti-estrogen tamoxifen, aromatase inhibitors, or trastuzumab and lapatinib, respectively) 


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favorably affect clinical outcomes.  TNBC represents an important challenge due to the 
lack of responsiveness to available targeted regimens.  
 
 
2.2. CTEP Agents 
 
2.2.1 Trametinib Dimethyl Sulfoxide (GSK1120212B) 
 
The following information is summarized from the Trameinib Investigator’s Brochure 
2012.  
 
Mechanism of Action 
 
The RAF/MEK/ERK pathway plays a critical role in multiple cellular functions.  
Activation of this pathway can result from activation/mutations of upstream receptor 
tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and MEK.  Upon 
activation, RAF and activates 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 a dimethyl sulfoxide solvate compound with potent, allosteric and ATP 
non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and 
MEK2, respectively).5 Trametinib inhibited MEK1/2 kinase activity and prevented RAF-
dependent MEK phosphorylation, producing prolonged pERK1/2 inhibition.  BRAF-
mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models showed 
significant mean tumor growth inhibition with multiple complete and partial tumor 
regressions. Xenograft lines with wild-type RAF/RAS (PC3, BxPC3, and BT474) were 
much less sensitive, showing only modest tumor growth inhibition with no tumor 
regressions.  
 
In a phase III 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.6 
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, PI3K/AKT inhibitors and mTOR inhibitors. 
 
Pharmacokinetics 
 
The phase 1 trial of trametinib monotherapy (MEK111054) reported the MTD of 
trametinib as 3 mg daily, but the recommended phase 2 dose (RP2D) was chosen at 2 mg 
daily based on tolerability of repeated cycles.7 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 


NCI Protocol #:9455 
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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 daily.  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 ~2.7 At 2 mg daily on Day 15, mean 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 Interactions 
 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 
[CYP450]-mediated) with secondary oxidation or in combination with glucuronidation 
biotransformation pathways. The deacetylation is likely mediated by hydrolytic esterases, 
such as carboxylesterases, or amidases. Although trametinib was found to be an in vitro 
inhibitor of CYP2C8, CYP2C9, and 2C19; inducer of CYP3A4; and inhibitor of 
transporters (OATP1B1, OATP1B3, P-glycoprotein [P-gp], and breast cancer resistance 
protein [BCRP]), its low efficacious dose, and low clinical systemic concentration 
relative to the in vitro inhibition/induction potency suggests an overall low potential for 
drug-drug interactions. 
 
Pharmacodynamics Markers 
 
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. In 
general, increasing exposures and/or doses provided greater pharmacodynamic effects.  
The median change observed at a dose of 2 mg daily was 62% inhibition of pERK, 83% 
inhibition of Ki67, and a 175% increase in p27. 
 
Antitumor Activity of Trametinib Monotherapy 
 
In the phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib at 2 mg 
daily (2 mg/day continuously, or 2 mg for 21 days followed by a 1 week break).  The 
overall objective response rate (ORR) was 43% (6/14), including 2 complete responses 
(CRs) (Investigator's Brochure, 2012a).  In 9 patients with BRAF wild type melanoma, 2 
patients achieved a partial response (PR), and 3 stable disease (SD).8 In 26 evaluable 
pancreatic cancer patients, there were 2 PRs (1 PR was KRAS mutation-positive) and 11 
SD (2 achieved ≥20% tumor reduction).9Among the 27 CRC patients (without selection 
of RAS or RAF mutations), 8 SD were observed. 
 
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, daily) 
or chemotherapy (dacarbazine or paclitaxel).6 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).  


NCI Protocol #:9455 
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11 
 
In the ITT analyses, the ORR was 22% in the trametinib group and 8% in the 
chemotherapy group; the median duration of PFS was 4.8 months in the trametinib group 
as compared with 1.5 months in the chemotherapy group; and the 6-month OS rate was 
81% in the trametinib group and 67% in the chemotherapy group. 
 
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 daily.  Drug-
related AEs in 45 patients were similar to that observed in patients with solid tumors, and 
2 mg PO daily 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.10 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%). 
 
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 7.1 of 
the protocol. 
 
Due to limited experience in human subjects, there is currently incomplete information 
available about the relationship of AEs and administration of trametinib.  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. 
 
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  
 
Rash:  Rash was a common AE observed across different dose levels and in different 
combinations.  The majority of rash observed with trametinib was acneiform and 
appeared to occur most frequently on the face, scalp, chest, and upper back.  At the 2 mg 
dose, rash was seen in 48% to 91% of patients in different trials.  The majority of rash 
AEs were grades 1 or 2 (68% to 80%); 1% to 18% of patients experienced grade 3 rash 
AEs, and one patient had a grade 4 rash AE. 
 
Diarrhea:  At the 2 mg monotherapy dose, 28% to 58% of patients in three trials had 
diarrhea.  Of 219 patients with diarrhea at this dose, the majority of diarrhea AEs were 
grade 1 or 2 in severity (28% to 56% of all study patients); 6 patients had grade 3 
diarrhea, and none had grade 4 diarrhea. 
 


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Visual disorders:  At the 2 mg monotherapy dose, 6% to 21% of the patients in three 
trials experienced visual disorders.  Of the 62 total patients experiencing visual disorders 
at this dose level, the majority of visual disorders were grades 1 or 2 (6% to 20% of all 
study patients); five patients experienced grade 3 visual disorders, and one patient 
experienced a grade 4 visual disorder. 
 
Central serous retinopathy (CRS):  CRS is a class side effect of MEK inhibitors.  As 
of 22 May 2012, 13 cases of CSR have been reported amongst approximately 1,600 
patients treated with trametinib, either as monotherapy or in combination with other 
anti-cancer agents:  two cases of grade 1, eight cases of grade 2, and three cases of 
grade 3.  All 13 resolved. 
 
Retinal vein occlusion (RVO):  As of 22 May 2012, four cases of RVO have been 
observed with trametinib.  All four cases occurred in one eye only, and study drug 
was stopped at time of diagnosis in all cases. There was a decrease in visual acuity in 
two patients with central RVO (CRVO), while the other two patients experienced no 
meaningful decrease of visual acuity.  Three of the 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.  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, 10% 
to 19% of patients in three trials had hepatic disorders.  Of the 56 total patients 
experiencing hepatic disorders, the majority were grade 1 or 2 in severity (7% to 15% of 
all study patients); 12 patients had grade 3 hepatic disorders, and 3 patients had grade 4 
hepatic disorders. 
 
Cardiac-related AEs:  At the 2 mg monotherapy dose in three trials, 3% to 21% of 
patients had cardiac-related AEs.  Of the 43 total patients experiencing cardiac-related 
AEs, the majority were grade 1 or 2 in severity (4% to 16% of all study patients); six 
patients at this trametinib dose level had grade 3 cardiac-related AEs (three left 
ventricular dysfunction, two decreased LVEF, and one ventricular dilatation), and one 
patient experienced a grade 4 cardiac-related AE (cardiogenic shock).  One patient died 
of 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), patients were monitored by serial echocardiogram or MUGA scans.  As 
of 23 June 2012, among 211 patients on the trametinib arm, 17 cardiac-related AEs were 
reported and included:  decreased LVEF (ten grade 1-2, and two grade 3), left ventricular 
dysfunction (two grade 2, and two grade 3), and one grade 3 cardiac failure. No cardiac-
related AEs have been observed on the chemotherapy arm of the study.  Cardiac-related 
AEs leading to permanent discontinuation of study drug included decreased LVEF (n=2), 
left ventricular dysfunction (n=2), cardiac failure (n=1), myocardial infarction (n=1), and 
tachycardia (n=1).  There was also one death due to cardiogenic shock secondary to 
ischemic heart disease, but it was not considered related to trametinib. 
 


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Pneumonitis: 20 cases of pneumonitis were reported in subjects treated with trametinib, 
either as monotherapy or in combination with other anti-cancer agents, in six studies:  
five cases of grade 1, five cases of grade 2, nine cases of grade 3, and one case of grade 4. 
 
2.2.2 GSK2141795  
 
The following information is summarized from the GSK2141795 Investigator’s Brochure 
2012.  
 
Mechanisms of Action  
 
AKT is a serine/threonine protein kinase with 3 isoforms (AKT1, AKT2 and AKT3) that 
participate in multiple pathways regulating several cellular processes, including survival, 
proliferation, tissue invasion and metabolism.11 Preclinical data suggest that blocking 
AKT activity can inhibit the proliferation of tumor cells and either induce an apoptotic 
response or sensitize tumors to undergo apoptosis in response to other cytotoxic agents. 
GSK2141795 is a member of the N-alkyl pyrazole class of orally available kinase 
inhibitors and has been shown to be a potent, pan-AKT inhibitor. GSK2141795 inhibited 
AKT1, 2 and 3 with IC50 values of 2, 16 and 4 nM, respectively. In vitro, GSK2141795 
caused a concentration- and time-dependent reduction in phosphorylation of multiple 
proteins downstream of AKT such as glycogen synthase kinase 3 (GSK-3)β, an insulin-
regulated inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) protein 
kinase (PRAS40), Forkhead gene product (FOXO), and caspase 9.  
 
In vivo studies conducted in immunocompromised mice bearing human tumor cell line 
xenografts showed GSK2141795 can inhibit multiple AKT substrates downstream of 
AKT in a dose- and time-dependent manner. A repeat oral administration of 
GSK2141795 for 3 weeks inhibited the growth of various tumor xenografts, including 
BT474 (breast), HCC1954 (breast), and SKOV3 (ovarian) in mice.  
 
Pharmacokinetics  
 
The pharmacokinetics, absorption, distribution, metabolism, and elimination of 
GSK2141795 have been investigated through a series of oral and IV studies in the CD-1 
mouse, Sprague Dawley rat, beagle dog, and cynomolgus monkey using unlabeled and 
[14C]-labeled drug. In these species, oral bioavailability of GSK2141795 was moderate 
to high (≥40%), blood clearance was low to moderate (20% to 50% of liver blood flow) 
and volume of distribution was high (>6 times total body water).  
 
In rat and human hepatocytes, the metabolism of GSK2141795 occurred by mono-
oxygenation, glucuronidation, oxidative deamination, and N-demethylation; there were 
no apparent human-specific metabolites, and cytochrome P450 (CYP) 3A4 was the 
primary enzyme responsible for the oxidative metabolism. In vitro, GSK2141795 
demonstrated the potential for oxidative bioactivation. No stereo-conversion to the R-
enantiomer was observed in vitro, and no rearrangement to an acyl migrated isomer of 
parent was observed either in vitro or following oral administration to mice.  


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In vitro, GSK2141795 was moderately to highly bound (93% to >95%) to plasma 
proteins, and had minimal to moderate association (0.99 to 1.64) with blood 
cells.GSK2141795 was a human P-glycoprotein (Pgp) and mouse breast cancer resistance 
protein (Bcrp 1) substrate and did not inhibit Pgp-mediated digoxin transport. 
GSK2141795 had moderate passive permeability (60 nm/sec) and low to moderate 
absorptive membrane permeabilities (3.0 to 11 nm/sec). GSK2141795 inhibited human 
organic anion transporting polypeptide (OATP) 1B1 (IC50 of 16 μM) and 1B3 (IC50 of 
21 μM) and BCRP-mediated transport of cimetidine (up to 50% of control at 3 μM). In a 
tissue distribution study following single oral administration of [14C] GSK2141795, 
consistent with its high volume of distribution, radioactivity was widely distributed into 
tissues, and most tissue concentrations were higher than those observed in blood. 
Concentrations of radioactivity generally declined over time, and by 7 days post dose, the 
levels of radioactivity were below the limit of quantification (BLQ) in most tissues. 
However, radioactivity was still quantifiable at 35 days post dose in the uveal tract, 
suggesting the potential for the selective association of drug-related material with 
melanin. 
 
In rats and dogs following single oral administration of [14C] GSK2141795, the major 
route of elimination of drug-related material was via the feces, while urinary excretion 
constituted a minor route in both species. In vitro intrinsic clearance for GSK2141795 
was low in hepatocytes and microsomes from the mouse, rat, dog, monkey, and human. 
Biliary and urinary recoveries indicate that approximately 50.6% of the oral dose was 
absorbed in rats. 
 
PCS112689 an open label, dose-escalation first in human study (FTIH) assessed the 
safety, pharmacokinetics, and pharmacodynamics of GSK2141795 in subjects with solid 
tumors or lymphoma. Preliminary data indicated that plasma concentrations for 
GSK2141795 were measurable for all subjects over the 72 hours after a single dose over 
the dose range tested (10 mg to 150 mg).  In addition, drug concentrations were 
measurable on Day 8, suggesting that GSK2141795 can still be found in the plasma at 
least 1 week after a single dose of study drug over the dose range tested (75 mg to 100 
mg). While the exposure for the 100 mg and 150 mg doses were similar following a 
single dose, drug exposure following multiple doses was approximately in proportion to 
dose.  GSK2141795 accumulated 2.5- to 8.4-fold with repeat daily dosing.  Mean area 
under the concentration-time curve [AUC(0-24)] and maximum plasma concentration 
(Cmax) values generally increased in a dose-proportional manner, although there was 
variability among subjects.  Median time to reach peak concentration (Tmax) across doses 
was 3 hours and ranged from 0 to 4 hours.  The mean value for the effective half-life of 
elimination (t½, eff), across subjects was 3.0 days and ranged from approximately 1.3 to 
5.5 days. The MTD of single-agent GSK2141795 was 75 mg once-daily as determined by 
the FTIH study.  
 
Drug Interactions 
 
The enzymes responsible for the oxidative metabolism of [14C] GSK2141795 (5 μM) 


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were investigated in vitro with human liver microsomes and recombinant CYP enzymes. 
The data from human liver microsomes with selective inhibitors and scaled results from 
recombinant CYP enzyme studies suggest that CYP3A4 is the primary cytochrome p450 
enzyme involved in oxidative metabolism of GSK2141795. GSK2141795 has the 
potential to have drug-drug interactions upon co-administration with CYP3A4, CYP2C8, 
Pgp and BCRP inhibitors or potent inducers. Drugs that potently inhibit CYP3A4 could 
lead to increased GSK2141795 exposure in patients and drugs that are strong inducers of 
CYP3A and may result in lower exposures of GSK2141795. GSK2141795 also appears 
to be a moderate in vitro inhibitor of CYP2C8 (IC50 3μM).  Therefore drugs that are 
sensitive substrates of CYP3A4 or CYP2C8 should be used with caution. Moreover, 
GSK2141795 is a human p-glycoprotein (P-gp, ABCB1) and breast cancer resistant 
protein (BCRP, ABCG2) substrate. Therefore, drugs that are inhibitors of P-gp and 
BCRP should be used with caution. Co-administration of drugs that are sensitive BCRP 
substrates, such as topotecan should be avoided.  Combination studies with GSK2141795 
have been performed with metformin, trametinib,pazopanib, and lapatinib. Co-
administration of GSK2141795 with metformin did not appear to have any impact on the 
efficacy of GSK2141795 for inhibiting tumor growth and was well tolerated as the 
treatment with GSK2141795 or metformin alone. 
 
No other pharmacodynamic studies have been performed to evaluate possible interactions 
of GSK2141795 with other drugs that may be co-administered. Lists of drugs that can 
possibly interact with GSK2141795 included under Section 5.2. 
 
 
Saftey Profile 
 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI Common 
Terminology Criteria for Adverse Events (CTCAE) terms is included in Section 7.1 of 
the protocol. 
 
Due to limited experience in human subjects, there is currently incomplete information 
available about the relationship of AEs and administration of GSK2141795.  Based on 
available adverse event data from 151 subjects, the most common toxicities of 
GSK2141795 monotherapy or in combination with trametinib were gastrointestinal (GI)-
related (diarrhea, nausea, and vomiting) and fatigue.  Hyperglycemia, hypoglycemia, 
mucositis, and rash are also commonly observed.  In addition, three cases of 
hypothyroidism have been noted. Therefore, clinical monitoring should consider in 
particular the GI tract, the hematopoietic system, glucose metabolism and thyroid 
function. Attention should also be given to glandular structures and the possibility of 
clinical signs due to reduced secretions. In PCS112689 a FTIH study the most common 
AEs occurring in ≥20% of all subjects in all dose groups were diarrhea (56%), nausea 
(45%), fatigue (32%), decreased appetite (30%), vomiting (25%), and hyperglycemia 
(21%). Maximum tolerated dose (MTD) was identified as 75 mg for both once daily 
dosing as well as for 7 days on/7 days off alternate dosing schedule. Most adverse effects 
were noted at dose greater than 75 mg. 
 


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Diarrhea:  This is the most frequent drug-related AE in patients receiving GSK2141795.  
Most diarrhea events reported were Grade 1 and 2.  Based on current data, the majority of 
cases of diarrhea occur within the first 3 to 4 weeks of starting the drug.  In most cases, 
diarrhea resolves with interruption of GSK2141795 dosing and implementation of 
supportive treatment.  Based on preliminary data, re-challenge with a reduced dose of 
GSK2141795 is tolerated.   
 
Mucosal inflammation:  This may be an on-target effect, i.e. the result of AKT inhibition 
on mucosal cell renewal or the result of direct irritation of the mucosal surface by the 
drug substance. Mucositis has been observed as a dose-limiting toxicity (DLT). Early 
intervention for signs and symptoms of mucosal inflammation is recommended and 
encouraged. Based on preliminary data, dose interruption followed by dose reduction on 
rechallenge can ameliorate symptoms.  
 
Rash: Rash may or may not be associated with pruritis.  Preliminary data suggest that 
drug interruption and dose reduction upon re-challenge ameliorate the symptoms.  Rash 
management should focus on symptom relief and maintenance of an intact integument. 
Dermatology consult is recommended when clinically appropriate.  Topical steroid 
creams have been found to provide some relief from symptoms.   
 
Hyperglycemia:  Hyperglycemia occurred in patients receiving ≥75 mg/day with the 
majority of events occurring at doses exceeding the MTD of 75 mg/day.  Treatment-
related grade 3 or grade 4 events were observed at 75 mg, 100 mg, and 150 mg daily 
doses.  The frequency and severity of hyperglycemia AEs is reduced at the 75mg/day 
dose as compared with higher doses.  It is not clear if oral anti-hyperglycemic drugs are 
useful to ameliorate the hyperglycemia, although both intravenous and sliding scale 
insulin have been helpful. 
 
Hypoglycemia:  Asymptomatic hypoglycemia occurred in patients receiving ≥75 mg/day.  
Treatment-related grade 3 or grade 4 events were observed at 75 mg and 100 mg daily 
doses.  The mechanism of hypoglycemia is currently unknown.   
 
Thyroid Events: Reversible minimal to mild hypertrophy of follicular cells was seen in 
the thyroid glands of dogs given 5 mg/kg/day for 4 weeks.  The relationship to 
GSK2141795 and clinical significance are unknown, although three cases of drug-related 
hypothyroidism have been reported 
 
 
2.2.3 Trametinib in Combination with GSK2141795 
 
 
GSK2141795 was combined in a 3-day cell proliferation study with trametinib (GSK 
1120212) against a panel of 26 colon, 15 lung, and 6 pancreatic cancer cell lines. 
GSK2141795 and trametinib were synergistic in cancer cell lines from colon (19 of 26), 
lung (4 of 15), and pancreas (2 of 6).  The anti-tumor activity of GSK2141795 alone (10 
or 30 mg/kg/day), trametinib alone (0.1, 0.3 or 10 mg/kg/day) or GSK2141795 in 


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combination with trametinib (10/0.1, 30/0.1, 10/0.3 or 30/0.3 mg/kg/day) was evaluated 
with once daily oral administration up to 90 days in female SCID mice (n=8/group) 
bearing established HPAC or Capan-2 human pancreatic tumor xenografts. In general, 
mice treated with GSK2141795 or trametinib alone had minimal body weight loss, but 
GSK2141795/trametinib combination doses appeared to be slightly less tolerated than the 
single agent treatments, particularly the combinations including a 30 mg/kg/day dose of 
GSK2141795.  Administration of trametinib in combination with GSK2141795 appeared 
to be more effective than either GSK2141795 or trametinib alone in HPAC xenografts. 
Treatment with both AKT and MEK inhibitors (GSK2141795 at 30 mg/kg/day and 
trametinib at 0.3 mg/kg/day), given alone or in combination, resulted in a reduction in 
proliferating cells (Ki67+) following treatment and up to a 200% increase in apoptosis (as 
measured by cleaved caspase-3). 
 
Twenty-three patients with advanced solid tumors received the combination using a zone-
based escalation procedure enabling evaluation of multiple combination doses in parallel 
cohorts.12 While the RP2D for single agent for single agent trametinib and GSK2141795 
are 2 mg/d and 75 mg/d, dose reductions were required for the combination.  DLTs 
include grade 2 AST and ALT elevation, and grade 3 chest pain with sustained 
ventricular tachycardia; all DLTs were reversible with drug interruption.  The most 
common AEs (≥10%) included nausea (26%), AST elevation (22%; grade 3/4, 9%), 
fatigue (22%) and rash (22%).  Three MTDs were defined for variable dose ratios:  2 mg 
trametinib + 25 mg GSK2141795; 0.5 mg trametinib + 75 mg GSK2141795; and 1.5 mg 
trametinib + 50 mg GSK2141795.  Three of 13 evaluable patients (unselected) had tumor 
shrinkage of 8% (ovarian), 16% (endometrial), and 17% (ovarian) after 8 weeks on study.  
The dose regimen of 1.5 mg trametinib + 50 mg GSK2141795 would be used in this 
study. Additional trials to explore alternate schedules (e.g., intermittent) and 
pharmacodynamic markers are ongoing. 
 
 
2.3. Rationale 
 
Triple negative breast cancer (TNBC) is often characterized by high expression of epidermal 
growth factor receptor (EGFR).13, 14 Hoeflich et al. demonstrated that activation of EGFR leads 
to cell signaling along the RAF/MEK/ERK pathway, and subsequent treatment with a MEK-
targeted drug caused reduced tumor growth in basal-like breast cancer models.15  One proposed 
mechanism of intrinsic resistance to MEK inhibition is through the ERK-independent PI3K/AKT 
pathway, as basal-like breast cancer cell lines with loss of PTEN (an inhibitor of the PI3K 
pathway) or high levels of AKT signaling were less responsive to MEK inhibition.15  This 
preclinical finding may be clinically relevant as 30% of women with basal-like breast cancer 
demonstrate evidence of PTEN loss.16-18  Additionally, treatment with a selective MEK inhibitor 
resulted in upregulation of the PI3K/AKT pathway.15   
 
To validate these findings, Dr. Ching-Shih Chen (Chair of Cancer Research and Therapy at the 
Ohio State University, scientific collaborator) performed a series of preclinical in vitro 
experiments. Basal-like breast cancer cell lines were treated with trametinib monotherapy 
(Unpublished data Chen, Olson). As predicted, treatment of basal-like breast cancer cell lines 


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with trametinib was associated with greater cell kill in the PTEN wild type MDA-MB-231 cell 
line compared to PTEN null MDA-MD-468 (Figure 2). Our results are consistent with the 
findings of Hoeflich et al. suggesting that MEK inhibition depends in part on PTEN status.  
 
Figure 2. Trametinib (GSK1120212) monotherapy in 
basal-like breast cancer cells MDA-MD468 (PTEN 
null) and MDA-MB-231 (PTEN wild type) 
(Unpublished data, Chen and Olson).  
 
Dual blockade of both PI3K/AKT and MEK signaling 
synergized to potently impair the growth of basal-like 
breast cancer models in vitro and in vivo.15  Other 
studies have also shown that inhibiting PI3K signaling 
in combination with RAS/RAF/MEK/ERK signaling 
is sufficient to induce apoptosis and suppress 
proliferation in other cancer models.19, 20  The RAF/MEK/ERK pathway is also implicated as a 
mechanism of resistance to chemotherapy in TNBC, providing rationale for targeting this 
pathway in patients with prior exposure to cytotoxic therapy.21, 22 Finally, O’Shaughnessy and 
colleagues recently presented data showing that a TNBC patient with co-activation of the MEK 
and PI3K/AKT pathways (via whole genome and transcriptome sequencing) demonstrated a near 
complete response to dual MEK and AKT inhibition.23, 24 
 
Given the close interaction of the RAS/RAF/MEK/ERK and PI3K/AKT pathways, biomarkers of 
response will likely involve proteins within these signaling networks.  For example, our work and 
others have demonstrated that PTEN loss results in upregulation of the PI3K/AKT pathway and is 
a major predictor of response to agents that target MEK in preclinical studies [Unpublished Data, 
Chen 
and 
Olson].15 
Similarly, 
DUSP4, 
a 
negative 
regulator 
of  
ERK1 and ERK2 activity, has been shown to be a mediator of resistance to chemotherapy and 
tumor suppressor in TNBC.  Loss of DUSP4 results in MAPK pathway activation and pre-
clinically was a biomarker of MEK sensitivity.22  We hypothesize that the anti-tumor activity of 
single agent MEK inhibition will depend on evidence of MAPK activation (i.e. loss of DUSP4) 
and down regulation of the PI3K/AKT pathway (i.e. intact PTEN).  Furthermore, based on the near 
complete clinical response seen in the phase I study,24, 25 we anticipate that patients with 
biomarkers demonstrating co-activation of MAPK and PI3K signaling to have an enhanced 
response to MEK and AKT inhibition. 
Given the preclinical data showing that 1) RAF/MEK/ERK pathway as a mechanism of 
resistance to chemotherapy therapy in TNBC,21, 22 2) the enhanced effect of MEK inhibition in 
basal-like breast cancer models with intact PTEN (i.e. reduced PI3K/AKT pathway activity),15 3) 
the mechanism of resistance to MEK inhibition through the PI3K/AKT pathway,15, 19, 20, 26 4) the 
30% incidence of PTEN loss in basal-like breast cancer16-18 led to the formulation of two testable 
hypotheses: that single agent trametinib will demonstrate efficacy in TNBC and the anti-tumor 
response will depend on the PTEN status of the tumor.  Moreover, the addition of AKT inhibitor 
GSK2141795 to trametinib will overcome intrinsic and acquired resistance to MEK inhibition. 
 


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To test these hypotheses, this is a phase II study of single agent trametinib in patients with 
advanced TNBC, with the addition of AKT inhibitor GSK2141795 to trametinib at time of tumor 
progression. This is the first trial to test the efficacy of single agent trametinib in this patient 
population and to determine if PTEN status will predict for response to therapy.  Additionally, 
we will assess the ability of GSK2141795 to overcome MEK inhibitor resistance.  Mechanisms 
of resistance to both single agent trametinib or in combination with GSK2141795 will be 
assessed via a comprehensive genomic and proteomic approaches on tissues collected after 
progression on either regimen..27  
 
2.4. Correlative Studies Background 
 
Detailed in Section 9 
 
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed metastatic invasive breast 
cancer that is negative for the estrogen receptor (ER), progesterone receptor (PR) and 
HER2 by institutional guidelines.   
 
3.1.2 Patients must have measurable disease (RECIST 1.1).   
 
3.1.3 Patients must have had exposure to at least 1 and no more than 3 prior chemotherapy 
regimens for the treatment of metastatic breast cancer.  
 
3.1.4 Patients must consent to both a pretreatment and a post-treatment mandatory research 
biopsy prior to enrolling on trial, and therefore, must have tissue (excluding bone or 
brain) that is amenable to biopsy.27 
 
3.1.5 Age ≥18 years.  Because no dosing or adverse event data are currently available on the 
use of trametinib monotherapy or in combination with GSK2141795 in patients <18 
years of age, children are excluded from this study, but will be eligible for future 
pediatric trials. 
 
3.1.6 ECOG performance status 0-1 (Appendix A). 
 


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3.1.7 Life expectancy of greater than 3 months. 
 
3.1.8 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 or major resection of the stomach or bowels. 
 
3.1.9 All prior treatment-related toxicities must be CTCAE v5 grade ≤1 (except alopecia) at the 
time of enrollment. 
 
3.1.10 Patients must have normal organ and marrow function as defined below:  
 
Absolute neutrophil count 
≥1,500/mcL 
 
Platelets 
≥75,000/mcL 
 
Total bilirubin 
≤1.5 × institutional upper limit of normal 
 
AST(SGOT)/ALT(SGPT) 
≤2.5× institutional upper limit of normal 
 
LVEF ≥ institutional lower limit of normal by ECHO or MUGA 
 
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 
 
 
3.1.11 Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg 
and diastolic < 90 mmHg.  Anti-hypertensive medications are permitted.  
 
3.1.12 Patients must be at least 4 weeks from last radiation dose. Patients must be at least 4 
weeks from last chemotherapy, targeted therapy, or biologic therapy (exception allowed 
for a 2 week washout for patients who were on chemotherapy at less than a standard of 
care dose, as long as all other eligibility criteria are met).  Patients must be at least 4 
weeks from last surgical procedure and recovered from all post-operative complications. 
 
3.1.13 The effects of trametinib monotherapy or trametinib in combination with GSK2141795 
on the developing human fetus are unknown.  For this reason, women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  Men treated or enrolled on this protocol must also agree to use adequate 
contraception prior to the study, for the duration of study participation, and 4 months 
after completion of trametinib monotherapy or in combination with GSK2141795 
administration. 
 
3.1.14 Ability to understand and the willingness to sign a written informed consent document. 
 
 
 
 
 


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3.2. Exclusion Criteria 
 
 
3.2.1 History of another malignancy. 
 
Exception:  Patients who have been disease-free for 3 years, or patients with a history of 
completely resected non-melanoma skin cancer and/or patients with indolent secondary 
malignancies, are eligible.  Consult the CTEP Medical Monitor if unsure whether second 
malignancies meet the requirements specified above. 
 
3.2.2 History of interstitial lung disease or pneumonitis. 
 
3.2.3 History of Type I diabetes mellitus.  If a patient has Type II diabetes, they must have a 
Hemoglobin A1C ≤ 8%.  Patients with a screening fasting glucose > 120 mg/dL will be 
excluded.   
 
3.2.4 Uncontrolled hypothyroidism.  Patients must have a normal TSH per institutional 
standards at baseline. 
 
3.2.5 Patients who are receiving any other investigational agents. 
 
3.2.6 Individuals with symptomatic or progressive brain metastases are ineligible. Subjects 
with treated brain metastases are eligible if they have no radiographic or other signs of 
progression in the brain for ≥ 3 weeks after completion of local therapy.  Any 
corticosteroid use for brain metastases must have been discontinued without the 
subsequent appearance of symptoms for ≥ 3 weeks prior to study enrollment. 
 
3.2.7 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to trametinib monotherapy or trametinib in combination with GSK2141795. 
 
3.2.8 Current use of a prohibited medication.  The following medications or non-drug therapies 
are prohibited: 
 
Other anti-cancer therapy while on study treatment (megestrol if used as an appetite 
stimulant is allowed). 
 
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, yohimbe, saw palmetto, or ginseng). 
 
Patients receiving strong inhibitors or inducers of CYP3A4 (See section 5.2) are 
ineligible.  
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as 
the Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient should be counseled on the risk 
of interactions with other agents, and what to do if new medications need to be 


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prescribed or if the patient is considering a new over-the-counter medicine or herbal 
product. 
 
3.2.9 History or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma 
or ocular hypertension, uncontrolled hypertension, history of hyperviscosity or 
hypercoagulability syndromes. Visible retinal pathology as assessed by ophthalmic exam 
that is considered a risk factor for RVO or CSR such as evidence of new optic disc 
cupping, evidence of new visual field defects, and intraocular pressure >21 mm Hg. 
 
3.2.10 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.11 Pregnant women are excluded from this study because trametinib monotherapy or 
trametinib in combination with GSK2141795 has potential for teratogenic or abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with trametinib monotherapy or trametinib 
in combination with GSK2141795, breastfeeding should be discontinued if the mother is 
treated with trametinib monotherapy or trametinib in combination with GSK2141795.  
 
3.2.12 HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with trametinib monotherapy or trametinib in 
combination with GSK2141795.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when indicated. 
 
3.3. Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.   
Because of the relative rarity of male breast cancer, we expect the majority of participants to be 
women.  It is expected that the mix of patients entering this study will reflect the demographics 
of our clinical population and geographic area.  We expect that participants will be racial/ethnic 
minorities which reflects the catchment area.   
 
 
4. REGISTRATION PROCEDURES 
 
4.1. General Guidelines 
 
OSU patients will be registered by the OSU research coordinator, as per their standard practice. 
 
Subsite patients will have eligibility verified and will be entered on study centrally at the The 
Ohio State University by the Subsite Coordinator, Jennifer Sexton.  All sites should call the 
Subsite Coordinator at 614-366-5642 to verify enrollment availability.  The required forms, 


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Enrollment Form and Eligibility Screening Worksheet can be found in the Supplemental Forms 
Document. 
 
Following registration, patients should begin protocol treatment within 5 days. Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Subsite Coordinator should be notified of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  Agents may be ordered by a participating site only after the initial 
IRB approval for the site has been forwarded by the Coordinating Center to the CTEP PIO 
(PIO@ctep.nci.nih.gov) except for Group studies. 
 
4.2. Registration Process 
 
To register a patient, the following documents should be completed by the research nurse or data 
manager and faxed (614-366-4721) or securely e-mailed (jennifer.sexton@osumc.edu) to the 
Subsite Coordinator: 
• Copy of all source documents used to verify eligibility 
• Signed patient consent form 
• Signed HIPAA authorization form 
• Eligibility Screening Worksheet, Enrollment Form)  
 
The research nurse or data manager at the participating site will then call (614-366-5642) or e-
mail (jennifer.sexton@osumc.edu) the Stubsite Coordinator to verify receipt of registration 
request.  To complete the registration process, the Coordinator will 
• assign a patient study number 
• register the patient on the study 
• assign the patient a dose 
• fax or e-mail the patient study number and dose to the participating site 
• call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
 
5. TREATMENT PLAN 
 
5.1. Research Biopsies 
 
Detailed in Section 9 
 
5.2. Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks are described in Section 7.  Appropriate dose modifications are described 
in Section 6.  Details regarding administration of study drugs are detailed in Section 8. 
No investigational or commercial agents or therapies other than those described below 


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may be administered with the intent to treat the patient's malignancy. 
 
The patient will be requested to maintain a medication diary of each dose of medication.  
The medication diary will be returned to clinic staff at the end of each course see 
Appendix C. 
 
5.2.1 Trametinib 
 
Treatment in Part 1 will consist of trametinib at a dose of 2 mg for a 28 day cycle. If a 
participant had a dose reduction of trametinib during Part 1, the participant will continue 
on this dose at the commence of Part 2 of the study.  If no dose reductions occurred, the 
patient will start on trametinib at the recommended dose of 1.5 mg oral daily for Part 2.  
During Part 2 of the study, the participant will be administered trametinib in combination 
with GSK2141795 per dosing recommendations below for a 28 day cycle.  
 
5.2.2 Trametinib in combination with GSK2141795 
 
.  
GSK2141795 will not be administered during Part 1.  Treatment in Part 2 will consist on 
GSK2141795 at 50 mg daily in combination with trametinib 1.5 mg daily for a 28 day cycle. 
 
 
  
The Trametinib can be taken by mouth on an empty stomach, either 1 hour before or 2 hours 
after a meal. The GSK2141795 must be taken 1 hour after a meal and two hours before the 
next meal. It is recommended that the Trametinib be taken in the morning and GSK 2141795 
in the evening, however this is not required. The medications will be taken once per day, at 
the same time each day. If a dose of the medication is missed, it should be taken as soon as it 
is remembered that day up to 6 hours past the scheduled time. If more than 6 hours has passed 
since the scheduled time, the missed dose should not be taken.  
 
5.3. General Concomitant Medication and Supportive Care Guidelines 
 
• Nausea/Vomiting – prophylactic pre-medications are not planned as trametinib alone or 
in combination with GSK2141795 is not highly emetogenic. However, if patients 
experience nausea during a treatment cycle, anti-emetics may be used per institutional 
guidelines.  
 
• Cytopenias – prophylactic growth factors (e.g. G-CSF, erythropoietin) are not permitted, 
however, if patients require admission for fever and neutropenia and the treating 
physician feels that the administration of growth factors may be beneficial then they can 
be given according to ASCO guidelines. Use of recombinant erythropoietin is not 
allowed. Platelets and red cell transfusions can be given as necessitated.  
 
• Short courses (up to a maximum of 14 days) of oral corticosteroids intended to treat study 
treatment related rash or diarrhea are allowed. Loperamide or lomotil is recommended for 
supportive care of diarrhea. Oral steroids should be used with caution and subjects 
monitored for steroid-induced hyperglycemia. 


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• The use of bisphosphonates for skeletal metastasis is permitted. 
 
• Because there is a low potential for interaction of trametinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent 
known to affect or with the potential to affect selected CYP450 isoenzymes.   
 
5.4. Duration of Therapy 
 
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), 
 
• 
Patient decides to withdraw from the study, or 
 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.5. Duration of Follow Up 
 
Patients will be followed for 52 weeks after removal from study or until death, whichever occurs 
first.  Patients removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
5.6. Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
 
6.1. Part 1 Dose Modifications for Trametinib Monotherapy  
 
 
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications as a single agent: 


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Dose Level 
Trametinib Dose/Schedule 
0 
2 mg daily 
-1 
1.5 mg daily 
-2 
1 mg daily 
 
A maximum of two trametinib dose level reductions are allowed.  If a third dose level reduction 
is required, treatment will be permanently discontinued. 
 
 
 
 
 
 
6.1.1 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 v5 
Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically indicated.  
Provide supportive care 
according to institutional 
standards 
Continue trametinib at current dose level. 
Grade 2 
• Interrupt treatment until resolution to grade 1 or baseline.   
• Upon resolution, restart treatment at current dose level. 
Grade 3 
• 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. 
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. 
 
 
 
6.1.2 Trametinib Dose Modification for Diarrhea 
 
Episodes of diarrhea have occurred in patients receiving trametinib (Investigator’s Brochure, 
2012a).  Other frequent causes of diarrhea including concomitant medications (e.g., stool 
softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, or partial bowel 
obstruction should be excluded. 
 
Guidelines regarding management and dose modification for diarrhea considered related to 
trametinib are provided in the table below. 
 
 


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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 hous:  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 > 21 days, 
discontinue trametinib. 


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Management and Trametinib Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
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. 
 
6.1.3 Trametinib Dose Modification for Rash 
 
Rash is a frequent AE observed in patients receiving trametinib. Recommendations for 
supportive care and guidelines for dose modifications for rash are based on experience with other 
MEK inhibitors and EGFR inhibitors.28 
 
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. 
 
 


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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). 
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 then restart 
trametinib at reduced dose level.3 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consider consulting a 
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. 
 


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6.1.4 Trametinib Dose Modifications for Visual Changes 
 
Episodes of visual changes have been observed in patients receiving trametinib, and can be 
caused by CSR or RVO. Patients are required to have a standard ophthalmic exam performed by 
an ophthalmologist at baseline and any time patients report visual disturbance. The exam will 
include indirect fundoscopic examination, visual acuity (corrected), visual field examination, 
tonometry, and direct fundoscopy with color photos. Special attention should be given to retinal 
(e.g., CSR) or retinal vein abnormalities (e.g., RVO).  
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 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Any grade of CRS or RVO should be reported as SAE to CTEP-AERS 
Grade 1 
Asymptomatic or symptomatic but 
not limiting ADL; intervention not 
indicated. 
 
 
 
 
• Consult ophthalmologist any 
time when patient reports 
visual disturbance. If there is 
visual loss or significant 
visual changes, consult 
ophthalmologist 
immediately (within 24 
hours)  
• Workup to rule out CSR or 
RVO.  
• Consult retinal specialist if 
available in case of CSR or 
RVO.  
• Continue follow up 
examination(s) (by retinal 
• Continue trametinib at the same 
dose level until ophthalmologic 
examination can be conducted.* 
• If ophthalmologic examination 
cannot be performed within 7 days 
of onset, interrupt trametinib until 
CSR and RVO can be excluded and 
symptoms resolve. 
• If CSR and RVO excluded restart 
trametinib at same dose level. 
• If CSR:  Interrupt trametinib until 
symptoms resolve and exam (by 
retinal specialist if available) shows 
resolution.  May restart trametinib 
with one dose level reduction.** 
• If RVO:  Permanently 
discontinue trametinib. 
 


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Management and Trametinib Dose Modification for Visual Changes 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Any grade of CRS or RVO should be reported as SAE to CTEP-AERS 
Grade 2 and 3 
Grade 2defined as:  Symptomatic 
with moderate decrease in visual 
acuity (20/40 or better; limiting 
instrumental ADL; local or non-
invasive intervention indicated.   
 
Grade 3 defined as:  Symptomatic 
with marked decrease in visual 
acuity or marked visual field defect 
(worse than 20/40 but better than 
20/200); severe pain or medically 
significant; operative intervention 
indicated. 
 
specialist if available) for CSR 
and RVO.  
•  
• Interrupt trametinib until signs and 
symptoms have resolved to 
baseline. 
• If CSR and RVO excluded and 
symptoms resolved to baseline, 
restart trametinib reduced by one 
dose level. 
• If CSR:  Interrupt trametinib until 
symptoms resolve and exam (by 
retinal specialist if available) shows 
resolution.  If CSR resolves restart 
trametinib reduced by one dose 
level.** 
• If RVO:  Permanently 
discontinue study treatment. 
Grade 4 
Sight-threatening consequences; 
urgent intervention indicated; 
blindness (20/200 or worse). 
Permanently discontinue 
trametinib. 
 
Abbreviations:  CSR = central serous retinopathy; 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. 
** If ocular toxicities do not resolve within 21 days, permanently discontinue trametinib. 
 
 
 
6.1.5 Trametinib Dose Modification for Liver Chemistry Changes 
 
Trametinib Dose Modification for Liver Function Test Abnormalities 
Liver chemistry stopping criteria are defined as follows.  When any of the liver chemistry stopping criteria are 
met, immediately discontinue trametinib, perform liver event follow-up assessments, and monitor the patient until 
liver chemistries resolve, stabilize, or return to baseline values. 
• 
ALT ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) (or ALT ≥3x ULN and international 
normalized ratio [INR] >1.5, if INR measured).  NOTE:  If serum bilirubin fractionation is not immediately 
available, trametinib should be discontinued if ALT ≥3x ULN and bilirubin ≥2x ULN.  Serum bilirubin 
fractionation should be performed if testing is available.  If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
• 
ALT ≥5x ULN. 
• 
ALT ≥3x ULN if associated with the appearance or worsening of symptoms of hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
• 
ALT ≥3x ULN persisting for ≥4 weeks. 
• 
ALT ≥3x ULN and cannot be monitored weekly for 4 weeks. 
 


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6.1.6 Trametinib Dose Modification for Pneumonitis 
 
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. 
 
6.1.7 Trametinib Dose Modification for Reduced LVEF 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  Therefore, ECHOs 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).   
 
 


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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 within 2 weeks.a 
• If the LVEF recovers within 4 
weeks (defined as LVEF ≥LLN and 
absolute decrease ≤10% compared 
to baseline): 
 Consult with the CTEP 
trametinib medical monitor and 
request approval for restart. 
 Restart treatment with 
trametinib at reduced dose by 
one dose level. 
 Repeat ECHO 2, 4, 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. 
 Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution. 
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 after 2, 4, 8, 12, and 
16 weeks or until resolution. 
a If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b Symptoms may include:  dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and 
edema. 
 
6.1.8 Trametinib Dose Modification for QTc Prolongation 
 
Trametinib Withholding and Stopping Criteria for QTc Prolongation 
Prolongation* 
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. 
• If the QTc prolongation resolves to grade 1 or baseline, trametinib may be 
resumed if the investigator and CTEP medical monitor agree that the 
subject will benefit from further treatment. 
• If the event does not resolve, permanently discontinue study 
treatment. 
• If the event recurs, permanently discontinue study treatment. 


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Trametinib Withholding and Stopping Criteria for QTc Prolongation 
Prolongation* 
Action and Dose Modification 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the bazett’s 
formula 
* 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. 
 
6.1.9 Trametinib Dose Modification for Hypertension 
 
Increases in blood pressure (BP) have been observed in patients receiving trametinib.  
Recommendations for BP monitoring and management are provided below. 
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. 
 
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) 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 persistenta 
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. 


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Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
(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. 
• Once BP is well-controlled, restart 
trametinib at a reduced dose. 
(Scenario C) 
• Symptomaticc hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of study treatment 
• 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 at a reduced dose. 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Discontinue trametinib. 
a 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 sponsor may be consulted for the 
possibility of resuming trametinib, provided that toxicities have resolved to baseline or grade 1. 
 
6.2. Dose Modifications for Part 2 Trametinib Combined with GSK 2141795 
 
If a participant had a dose reduction of trametinib during Part 1, the participant will continue on 
this dose at the commence of Part 2 of the study.  If no dose reductions occurred, the patient will 
start on trametinib at the recommended dose of 1.5 mg oral daily for Part 2.  GSK2141795 will 
be added at time of entry into Part 2 to trametinib, beginning at dose level 0.  
 
Dose Level 
Trametinib Dose/Schedule 
0 
1.5 mg daily 
-1 
1 mg daily 
 
Dose Level 
GSK2141795 Dose/Schedule 
0 
50 mg daily 
-1 
25 mg daily 
 
NOTE: AEs occurring in patients treated with GSK2141795 and trametinib may be related to  1) 
overlapping toxicities between the two agents (e.g., rash and diarrhea); 2) toxicities typically 
associated with trametinib (e.g., visual disturbance) or GSK2141795 (e.g., hyperglycemia or 
hypoglycemia).  However, toxicities associated with individual agents may be potentiated in the 
combination, or unanticipated AEs may occur.   
 
The dose modifications may involve one or both agents, and should be based on the nature, 
severity and attributions of the AEs.  General guidelines are provided below.  CTEP drug 


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monitors should be consulted if there are questions about the attribution of AEs and how the 
doses should be modified.     
 
6.2.1 Trametinib and GSK2141795 Dose Modification for Toxicities Not Specified in 
Subsequent Sections  
 
Toxicity Gradea 
Dose Modification 
Grade 1 
Continue at current dose level.  Consider supportive care recommendations. 
Grade 2 
Consider withholding dose of trametinib and/or GSK2141795 until toxicity resolves to 
grade 1 or baseline.  Upon resolution, then restart at current dose level.  Consider 
supportive care recommendations. 
Grade 3 
Withhold dose until toxicity resolves to grade 1 or baseline.  Upon resolution, resume at 
the next lower dose level of both trametinib and/or GSK2141795.  Consider supportive 
care recommendations. 
Grade 4 
Permanently discontinue trametinib and GSK2141795. 
a:  the guidelines are for AEs thought to be related to GSK2141795 and/or trametinib.  However, 
temporary interruption of the agent should be considered if the patient is critically ill due to AEs of 
any attribution 
 
6.2.2 Trametinib and GSK2141795 Dose Modification for Diarrhea 
Episodes of diarrhea have occurred in patients receiving trametinib or GSK2141795 
(Investigator’s Brochure, 2012a).  Other frequent causes of diarrhea including concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by Clostridium difficile or 


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other pathogens, or partial bowel obstruction should be excluded. 
 
Management and 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 
(bananas, 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 (octreotide, or 
tincture of opium) and oral 
antibiotics. 
• Continue treatment. 
• If diarrhea is grade 2 for >48 h, 
interrupt GSK2141795 and 
trametinib until diarrhea 
resolves to grade ≤1. 
• Restart treatment at the same 
dose level. 
• If treatment delay is > 21 days, 
discontinue both agents.  
(Resumption of trametinib or 
GSK2141795 alone may be 
considered based on toxicity-
benefit consideration and after 
consultation with CTEP). 


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Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
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 protocol therapy until 
diarrhea resolves to ≤ grade 1. 
• Restart with trametinib or 
trametinib and GSK2141795 
reduced by one dose level (for 
the combination, reduce both 
agents by one level).4 
• If more than one dose reduction 
of study treatment is clinically 
indicated, permanently 
discontinue treatment. 
• If treatment delay is >21 days, 
discontinue treatment. 
(resumption of trametinib or 
GSK2141795 alone may be 
considered based on toxicity-
benefit consideration and after 
consultation with CTEP). 
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 or trametinib and GSK2141795 to previous dose level(s) is allowed after 
consultation with the CTEP monitor and Study Chair and in the absence of another episode of 
complicated or severe diarrhea in the 4 weeks subsequent to dose reduction. 
 
6.2.3 Trametinib and GSK2141795 Dose Modification for Rash 
 
Two types of rashes may be seen with the trametinib and GSK2141795 combination: 
1. Acneiform rash, typically associated with MEK inhibitor therapy (trametinib). 
2. Maculopapular rash, often associated with pruritus (GSK2141795). 
If the diagnosis is unclear, a biopsy and photographs should be obtained as well as a dermatology 
consult.  In addition, if the investigator feels the rash is not consistent with a MEK inhibitor-
associated acneiform rash and is  Grade 2, a skin punch biopsy should be performed.     
In general, topical and oral antibiotics (doxycycline or minocycline) play a larger role in 
management of the MEK inhibitor acneiform rash, while topical and oral steroids are more 
relevant to the management of the AKT inhibitor maculopapular rash. 
 
The institutional standards for the management of skin-related AEs can differ from these 


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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. 
 
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 treatment. 
• If rash does not recover to baseline within 2 
weeks despite best supportive care, reduce 
trametinib or both agents by one dose level.3 
Grade 2 
 
• Initiate prophylactic and 
symptomatic treatment 
measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
 
• Continue treatment 
• Reduce trametinib or both agents by one dose 
level. 
• If rash recovers to ≤ grade 1 within 2 weeks, 
increase dose(s) to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, 
interrupt treatment until recovery to ≤ grade 1. 
• Restart trametinib or both agents at reduced 
dose level. 
Grade ≥3 
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt trametinib or both agents until rash 
recovers to ≤ grade 1. 
• Restart with trametinib or both agents with 
one dose level reduction3, 
• If no recovery to ≤ grade 2 within 3 weeks, 
permanently discontinue both agents 
(resumption of trametinib or GSK2141795 alone 
may be considered based on toxicity-benefit 
consideration and after consultation with CTEP).  
1.  Rash prophylaxis is recommended for the first 6 weeks of study treatment (refer to guidelines for 
trametinib). 
2.  Moderate-strength topical steroids:  Hydrocortisone 2.5% cream or fluticasone propionate 0.5% 
cream. 
3.  Trametinib or GSK2141795 may be escalated to previous dose level if no rash is evident 4 weeks 
after restarting study treatment. 


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6.2.4 Trametinib and GSK2141795 Dose Modifications for Liver Chemistry Changes 
Dose Modification for Liver Function Test Abnormalities 
Liver chemistry stopping criteria are defined as follows.  When any of the liver chemistry stopping criteria are 
met, immediately discontinue trametinib and GSK2141795, perform liver event follow-up assessments, and 
monitor the patient until liver chemistries resolve, stabilize, or return to baseline values. 
• 
ALT ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) (or ALT ≥3x ULN and international 
normalized ratio [INR] >1.5x ULN, if INR measured).  NOTE:  If serum bilirubin fractionation is not 
immediately available, treatment should be discontinued if ALT ≥3x ULN and bilirubin ≥2x ULN.  Serum 
bilirubin fractionation should be performed if testing is available.  If testing is unavailable, record presence of 
detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
• 
ALT ≥5x ULN. 
• 
ALT ≥3x ULN if associated with the appearance or worsening of symptoms of hepatitis or hypersensitivity 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
• 
ALT ≥3x ULN persisting for ≥4 weeks. 
• 
ALT ≥3x ULN and cannot be monitored weekly for 4 weeks. 
 
 
6.2.5 Trametinib and GSK2141795 Dose Modification for Hypertension, Pneumonitis, and 
Visual Disturbance 
 
• These AEs are typically associated with trametinib.  Please follow guidelines for 
trametinib. 
• GSK2141795 may continue when trametinib is on hold if AEs are < grade 2. 
• If the above AEs are grade 3-4, GSK2141795 should be held when trametinib is held.  
Once the AEs have resolved to grade 1 or baseline, GSK2141795 may resume at the 
same dose. 
• If GSK2141795795 has been held for >21 days, a discussion with the CTEP drug monitor 
is required before resuming treatment with the agent. 
 
6.2.6 Trametinib and GSK2141795 Dose Modifications for Reduced LVEF 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  GSK2141795 dose is to be modified the same as for trametinib.  ECHOs 
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). 
 
 
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. 
• Follow the instructions for 
trametinib.  When trametinib is 
on hold, GSK2141795 should 
be on hold. 


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Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Symptomatic b 
 
• Grade 3:  resting LVEF 39% or 
>20% absolute reduction from 
baseline 
• Grade 4:  Resting LVEF ≤20%. 
• Permanently discontinue 
trametinib and GSK2141795 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until 
resolution. 
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion 
and edema. 
 
 
 
6.2.7 Trametinib and GSK2141795 Dose Modification for QTc Prolongation  
 
GSK2141795 is not well known to cause prolongation of the QTc. Therefore, for QTc 
prolongation, participants should undergo dose modifications of trametinib as listed for Part 1 in 
Section 6.1.8 and GSK2141795 should be continued at the same dose.  GSK2141795 may be 
continued as monotherapy if trametinib must be permanently discontinued if otherwise tolerated.  
 
 
6.2.8 Trametinib and GSK2141795 Dose Modification for Hypertension 
 
GSK2141795 is not well known to cause hypertension. Therefore, for hypertension, participants 
should undergo dose modifications of trametinib as listed for Part 1 in Section 6.1.9 and 
GSK2141795 should be continued at the same dose or held and resumed as detailed in Section 
6.2.5 depending on the grade of the hypertension.  GSK2141795 may be continued as 
monotherapy if trametinib must be permanently discontinued if otherwise tolerated.  
 
6.2.9 Trametinib and GSK2141795 Dose Modifications for Hypo- or Hyperglycemia 
 
GSK2141795 may cause hypo- or hyperglycemia.  Trametinib is not known to cause hypo- or 
hyperglycemia.  Subjects will be required to monitor their blood glucose each morning 
preprandial during Part 2 of the study while receiving GSK2141795and record the results in the  
provided diary (Appendix F). Subjects should contact their study doctor for readings < 70 or > 
250 for physician instructions and management. 


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Management and Dose Modification Guidelines for Hypo- or Hyperglycemia 
Criteria 
Management Guidelines 
Study Drug Modification 
(For management purposes, refer to mild, moderate and severe intensity criteria; however for eCRF 
reporting use NCI-CTCAE version 5.0 Grades 1-5) 
Mild 
Fasting blood glucose > 
150mg/dL 
Monitor fasting and preprandial 
glucose. 
Continue study drug 
Moderate to Severe 
Fasting blood glucose <70 mg/dL 
OR any blood glucose > 
250mg/dL 
 
• If a blood glucose >250 mg/dL, 
monitor for ketoacidosis as 
clinically indicated. 
• When managing hyperglycemia 
associated with GSK2141795, 
be aware that the action of 
insulin or other 
antihyperglycemic agents (e.g., 
sulfonylureas, biguanides, etc.) 
may be substantially blocked by 
the study agent.  However the 
action of antihyperglycemic 
agents would be restored as 
GSK2141795 is cleared.  The 
patient should be observed 
closely for rebound 
hypoglycaemia as GSK2141795 
is held/or discontinued.   
• Intravenous insulin treatment is 
recommended. 
Hold drug(s) and notify 
investigator immediately.  The 
investigator should discuss 
intervention and possible 
resumption of study drug(s) with 
the CTEP monitor. 
 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (viaCTEP-AERS) in addition to 
routine reporting. 
 
 
 


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7.1. Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
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/electronic_applications/docs/aeguidelines.pdf for 
further clarification.  Frequency provided for trametinib is based on 356 patients. Frequency 
provided for GSK2141795 is based on 150 patients.  
 
NOTE:  The highest grade currently reported is noted in parentheses next to the AE in the 
SPEER.  Report ONLY AEs higher than this grade expeditiously viaCTEP-AERS.  If this 
CAEPR is part of a combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
7.1.1 CAEPRs for trametinib and GSK 2141795 
 
7.1.1.1. 
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 
'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 dimethyl sulfoxide 
(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 2.4, October 7, 20161 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 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 2) 
CARDIAC DISORDERS 
  
 
 
Heart failure 
  
 
 
Left ventricular systolic 
dysfunction 
  


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 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
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  
 
  
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 2) 
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) 
IMMUNE SYSTEM DISORDERS 
  
 
Allergic reaction3 
 
  
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
  
 
Paronychia 
 
 Paronychia (Gr 2) 
 
Skin infection 
 
 Skin infection (Gr 2) 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
 Alanine aminotransferase increased 
(Gr 2) 
 
Alkaline phosphatase increased  
 Alkaline phosphatase increased (Gr 2) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 2) 
 
CPK increased 
 
  
 
Ejection fraction decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Dehydration 
 
 Dehydration (Gr 3) 
 
Hypoalbuminemia 
 
  
 
Hypomagnesemia 
 
 Hypomagnesemia (Gr 2) 
 
Hyponatremia 
 
 Hyponatremia (Gr 3) 


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 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Back pain 
 
 Back pain (Gr 2) 
 
 
Musculoskeletal and 
connective tissue disorder - 
Other (rhabdomyolysis) 
  
 
Pain in extremity 
 
 Pain in extremity (Gr 2) 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness (Gr 2) 
 
Headache 
 
 Headache (Gr 2) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
 Dyspnea (Gr 2) 
 
 
Pneumonitis 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Dry skin 
 
 Dry skin (Gr 2) 
 
 
Palmar-plantar 
erythrodysesthesia syndrome 
  
 
Periorbital edema 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Skin and subcutaneous tissue 
disorders - Other (folliculitis) 
 
 Skin and subcutaneous tissue 
disorders - Other (folliculitis) (Gr 2) 
Skin and subcutaneous tissue 
disorders - Other (rash)4 
 
 
 Skin and subcutaneous tissue 
disorders - Other (rash)4 (Gr 3) 
VASCULAR DISORDERS 
  
 
Hypertension 
 
 Hypertension (Gr 2) 
Vascular disorders - Other 
(edema)5 
 
 
 Vascular disorders - Other (edema)5 
(Gr 2) 
 
Vascular disorders - Other 
(hemorrhage)6 
 
  
 
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. 
 
3Hypersensitivity (allergic reactions) may present with symptoms such as fever, rash, increased liver function tests, 
and visual disturbances. 
 
4Skin and subcutaneous tissue disorders - Other (rash) may include rash, rash acneiform, rosacea, erythematous rash, 
genital rash, rash macular, exfoliative rash, rash generalized, erythema, rash papular, seborrhoeic dermatitis, 
dermatitis psoriasiform, rash follicular, and skin fissures. 
 


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5Edema includes edema, lymphedema, and edema limbs. 
 
6The 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; Papilledema; 
Photophobia; Retinal detachment 
GASTROINTESTINAL DISORDERS - Anal hemorrhage; Ascites; Duodenal ulcer; Enterocolitis; Esophageal 
necrosis; Esophageal ulcer; Esophagitis; Gastric hemorrhage; Gastric ulcer; Gastritis; Gastrointestinal disorders - 
Other (intestinal obstruction); Gastrointestinal disorders - Other (oropharyngeal pain); Gastrointestinal disorders - 
Other (pneumatosis intestinalis); Gastrointestinal fistula; Gingival pain; Hemorrhoidal hemorrhage; Ileus; Lower 
gastrointestinal hemorrhage; Obstruction gastric; Pancreatitis; Rectal hemorrhage; Small intestinal obstruction; 
Upper gastrointestinal hemorrhage 
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; Rash pustular; Sepsis; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased; Electrocardiogram QT corrected interval 
prolonged; GGT increased; Investigations - Other (blood lactate dehydrogenase increased); Lipase increased; 
Lymphocyte count decreased; Platelet count decreased; Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hyperuricemia; 
Hypocalcemia; Hypoglycemia; Hypokalemia; Metabolism and nutrition disorders - Other (hyperphosphatemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Generalized muscle weakness; 
Musculoskeletal and connective tissue disorder - Other (compression fracture); Musculoskeletal and connective 
tissue disorder - Other (muscle spasm); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage; 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; Hematuria; Proteinuria; 
Renal and urinary disorders - Other (dysuria); Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Epistaxis; Hypoxia; Laryngeal edema; 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 and subcutaneous tissue disorders - Other (nail 


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disorder); Skin and subcutaneous tissue disorders - Other (skin fissures); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension; Thromboembolic event (venous) 
 
 
Note: Trametinib dimethyl sulfoxide (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. 
 
7.1.1.2. 
CAEPR for GSK2141795 
   
 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
GSK2141795 (NSC 767034) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI via CTEP-AERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf for further 
clarification.  Frequency is provided based on 150 patients. Below is the CAEPR for GSK2141795. 
 
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 2.1, July 26, 20131 
 
 Adverse Events with Possible  
 Relationship to GSK2141795 
 (CTCAE 4.0 Term) 
[n= 150]  
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
GASTROINTESTINAL DISORDERS 
  
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
Esophagitis 
 
  
 
 Gastrointestinal mucositis2 
 
  
Nausea 
 
 
 Nausea (Gr 2) 
 Vomiting 
 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
 Hyperglycemia (Gr 2) 
 
Hypoglycemia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Respiratory mucositis3 
 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Rash maculo-papular 
 
  
 


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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. 
 
2Gastrointestinal mucositis may include Anal mucositis, Mucositis oral, Rectal mucositis, or Small 
intestinal mucositis under the GASTROINTESTINAL DISORDERS SOC. 
 
3Respiratory mucositis may include Laryngeal mucositis, Pharyngeal mucositis, or Tracheal mucositis 
under the RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC 
 
Also reported on GSK2141795 trials but with the relationship to GSK2141795 still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Cardiac arrest, Left ventricular systolic dysfunction, Ventricular tachycardia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Wound infection  
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase increased; Aspartate 
aminotransferase increased; Ejection fraction decreased; GGT increased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia; Hyponatremia, Hypophosphatemia 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Dysphasia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
VASCULAR DISORDERS - Thromboembolic event 
 
 
Note: GSK2141795 in combination with other agents could cause an exacerbation of any adverse event 
currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
7.2. Adverse Event Characteristics  
 
•  
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
• .For expedited reporting purposes only:   
- 
AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 7.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in 
section 7.3.4. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 


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- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3. Expedited Adverse Event Reporting 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov).  These requirements are briefly outlined in the tables below 
(Section 7.3.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician.  CTEP-AERS provides a copy feature for 
other e-mail recipients.  
 
7.3.3 Expedited Reporting Guidelines 
 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” in 
the system organ class (SOC) “General disorders and administration site conditions.”.  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Submitted CTEP-AERS reports must be forwarded to the Subsite Coordinator via fax or 
secure email. 
 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1, 2 


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FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar days of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
7.3.4 Additional Protocol – Specific Expeditied Adverse Event Reporting Exclusions 
 
N/A 
 
 
7.4. Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported through 
CTEP-AERS must also be reported in routine study data submissions. 


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7.5. Secondary Malignancy 
 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent under an 
NCI IND/IDE be reported viaCTEP-AERS. Three options are available to describe the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
 
7.6. Second Malignancy 
 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy).  Second malignancies require ONLY routine reporting 
via CDUS unless otherwise specified.  
 
 
8. PHARMACEUTICAL AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agents, 
trametinib and GSK2141795 administered in this study can be found in Section 7.1. 
 
8.1. CTEP Agent(s) 
 
8.1.1 Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
  
 
 
Chemical Name (IUPAC): equimolecular combination of acetamide, N-[3-[3-cyclopropyl-5-[(2-
fluoro-4-iodophenyl)amino]-3,4,6,7-tetrahydro6,8-dimethyl- 2,4,7-trioxopyrido[4,3-
d]pyrimidin-1(2H)-yl]phenyl] with 1,1’-sulfinylbis[methane] 
 
Other Names: trametinib, GSK1120212, JTP-74057, JTP-78296, JTP-75303, Mekinist 
 
CAS Registry Number: 1187431-43-1 
 
Classification: MEK inhibitor 
 


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Molecular Formula:  C26H23FIN5O4  •  C2H6OS 
M.W.: 693.53  
 
 
 
 
 
 
 
 
 
Approximate Solubility: Trametinib dimethyl sulfoxide is almost insoluble in water (<0.0001 
mg/mL at 25° C) 
 
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. 
 
Description:  Trametinib dimethyl sulfoxide is a white to almost white powder. 
 
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as free 
base) tablets. Each commercially-labeled bottle contains 30 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 with ‘GS’ debossed 
on one face and ‘TFC’ on the opposing face. Aqueous film coating consists of 
hypromellose, titanium dioxide, polyethylene glycol, iron oxide yellow. 
• 2 mg tablets are pink, round, biconvex and film-coated with ‘GS’ debossed on one face 
and ‘HMJ’ on the opposing face. Aqueous film coating consists of hypromellose, 
titanium dioxide, polyethylene glycol, polysorbate 80, iron oxide red. 
 
Storage: Store tablets at 2°C -8°C in the original bottle. Do not repackage tablets or remove 
desiccant. Bottles should be protected from light and moisture. 
 
If a storage temperature excursion is identified, promptly return trametinib to 2°C -8°C 
and quarantine the supplies.  Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to  
for drug-drug interaction. 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 dimethyl sulfoxide 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 
CYP3A4 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 P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2 MRP2 and 
MATE1.  
 
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. Refer to the protocol document for specific guidance 


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8.1.2 GSK 2141795 (NSC 767034 ) 
 
Chemical Name:  N-[(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl]-5-chloro-4-(4-
chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide 
 
Other Names: GSK2141795C 
 
Classification: pan-AKT inhibitor 
 
CAS Registry Number: 1047634-65-0 
 
Molecular Formula: 
 C18H16Cl2F2N4O2       
 
 
M.W.: 429.25 g/mol 
 
Approximate Solubility: Very slightly soluble in water at room temperature (0.18 
mg/mL). Solubility decreases as pH increases; for example solubility in gastric fluid at 
37° C is >11 mg/mL.  
 
Mode of Action: GSK2141795 is an ATP competitive pan-AKT inhibitor. AKT, a 
serine/threonine protein kinase with three isoforms, is active in several pathways that 
regulate survival, proliferation, tissue invasion and metabolism. Since AKT-mediated 
pathways are important in tumor proliferation and survival, AKT kinases are promising 
targets for therapeutic intervention. Hyperactivation of the AKT pathway can also 
correlate with chemotherapy resistance and poorer prognosis. 
 
Description: white to off-white powder 
 
How Supplied: GSK2141795 capsules are supplied by GlaxoSmithKline and distributed 
by the DCTD, NCI. The 25 mg capsule is a size 2 Swedish orange opaque body and 
Swedish orange opaque cap with no markings. The capsule contains active 
pharmaceutical ingredient, microcrystalline cellulose, and magnesium stearate. The 
capsules are packaged in white high density polyethylene (HDPE) bottles with white 
plastic, induction-seal, child-resistant caps. Each bottle contains 35 capsules. 
 
GSK does not have stability data to support repackaging GSK2141795 capsules. 
Capsules must be dispensed in the original container. 
 
Storage: Store bottles at 2-8° C (36-46° F). 
 
Stability: Shelf life studies of GSK2141795 are on-going.  
 
Route of Administration: Oral administration. GSK2141795 must be taken fasting 1 hour 
following a meal and 2 hours before the next meal. If possible take each capsule about 5 minutes 


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apart. Water is allowed during fasting. 
  
Potential Drug Interactions: In vitro data suggest GSK2141795 is a substrate of 
CYP450 3A4. Potent inhibitors and inducers of 3A4 are prohibited. GSK2141795 
appears to be a moderate inhibitor of CYP 2C8 and 3A4 by in vitro testing. Drugs that are 
substrates of these isoenzymes should be used with caution and ones with a narrow 
therapeutic index should be avoided. 
 
 
GSK2141795 is a substrate of p-glycoprotein (P-gp) and breast cancer resistant protein 
(BCRP). It is also an inhibitor of BCRP and OATP1B1. Administration of sensitive 
BCRP substrates should be prohibited, such as topotecan. 
 
Availability 
 
GSK 2141795 is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. GSK 2141795 is provided to the NCI 
under a Collaborative Agreement between GlaxoSmithKline and the DCTD, NCI (see 
Section 12.3). 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1. 
NCI-supplied agents may be requested by the Principal Investigator (or 
their authorized designee) at each participating institution.  Pharmaceutical 
Management Branch (PMB) policy requires that agent be shipped directly to 
the institution where the patient is to be treated.  PMB does not permit the 
transfer of agents between institutions (unless prior approval from PMB is 
obtained).  The CTEP-assigned protocol number must be used for ordering all 
CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an 
annual submission of FDA Form 1572 (Statement of Investigator), Curriculum 
Vitae, Supplemental Investigator Data Form (IDF), and Financial Disclosure 
Form (FDF).  If there are several participating investigators at one institution, 
CTEP-supplied investigational agents for the study should be ordered under 
the name of one lead investigator at that institution. 
 
Active CTEP-registered investigators and investigator-designated shipping 
designees and 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. 
 


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8.1.3.2. 
Agent Inventory Records – The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of the inventory 
and disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form (DARF).  (See the NCI Investigator’s Handbook 
for Procedures for Drug Accountability and Storage.) 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1. Collection of Specimen(s)  
 
The primary hypothesis of the correlative component to this trial is that biomarkers of 
sensitivity and resistance to MEK inhibition can occur through ERK-dependent and ERK-
independent pathways.  To test this hypothesis we propose correlative studies on research 
biopsies acquired at these time points 1) in all patients prior to trametinib monotherapy 
(mandatory) 2)all patients after progression on  Part 1 with trametinib (mandatory) 3) all 
patients at time of progression on trametinib combined with GSK2141795 (optional).  In 
addition, archival FFPE sections, plasma and a whole blood samples will be collected.. 
 
 
9.1.1  Blood and Tissue Requirements:  
 
A list and detailed preparation procedures for all required specimens is included in the 
Specimen Laboratory Manual, see Appendix E.   
 
• A whole blood sample should be collected prior to treatment for subsequent DNA 
extraction and use as a germline for subsequent sequencing analyses.  Whole blood (6 
mL) should be collected in an EDTA tube and stored at -70oC or below until shipping.  
The tube should be labeled with the protocol number, subject number, date and 
institution.   
 
• Biopsies will be performed preferably under image-guidance, although biopsy 
method will be chosen based on feasibility for each individual patient and tumor 
location.  Collection will be per the Standard Operating Procedure included in the 
laboratory manual.  Briefly however, five to six core needle biopsies (preferably using 
an 18 gauge needle, except when contraindicated [i.e. 20G for lung biopsies is 
acceptable]) will be taken depending on the size of the tumor.  Two of the cores will be 
placed within 5 minutes in 10% neutral buffered formalin, processed using standard 
operating procedures and embedded in paraffin.  At least 2 cores will be frozen within 5 
minutes in Optimal Cutting Temperature (OCT) compound.  The fifth and 6th core (if 
possible), should be flash frozen in liquid nitrogen. All frozen specimens should be 
stored in liquid nitrogen or at -80°C until shipping.).  Blocks should be labeled with the 
protocol number, subject number, date and institution.   
 
• An additional 10mL whole blood samples will be collected to obtain a plasma 
sample for all patients prior to treatment on Cycle 1 Day 1, Cycle 2 Day 1, at time of 
progression on trametinib, then prior to dosing on Day 1 of 2nd cycle of combination 


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therapy and at time of progression on combination.  Whole blood should be collected in 
EDTA tubes and centrifuged at 1900 x g for 10 minutes at +4oC within 1 hour of 
collection to limit degradation and lysis.  Plasma supernatant should be carefully 
aspirated without disturbing the buffy coat layer. About 4-5 mL plasma can be 
obtained. Aliquot plasma into 4 properly labeled 1.5 mL cryovials (1 to 1.25 mL per 
tube).  Store at - 70oC or below until shipping.   
 
• If available, an archival tissue block containing tumor or a minimum of ten slides 
cut at 4-5 microns (unstained and placed onto poly-l-lysine-coated or plus (+) slides) 
will be required for IHC and genomic analyses.   
 
9.1.2 Shipping of Blood and Tissue Specimen(s): 
 
Samples to be collected and prepared in this study include whole blood, plasma, FFPE 
core biopsies, fresh frozen and OCT embedded frozen core biopsies and archival FFPE 
tumor blocks or sections. Samples should be shipped in batches according to 
requirements along with the specimen submission form (included in the laboratory 
manual). 
 
All frozen specimens should be packed in dry ice in styrofoam shippers with enough dry 
ice to ensure that the samples will not thaw within a 48-hour period.  A minimum 5 kg 
of dry ice should be used.  Dry ice should be placed along the bottom of the styrofoam 
container.  Each set of frozen specimens should be placed in a plastic resealable bag, 
grouped according to the subject.  A paper towel should be wrapped around the samples.  
Each plastic bag for each patient should be identified with the following information:  
protocol number, institution name, patient study ID number.  Before plastic bags are 
placed into the styrofoam box a layer of paper towels should be placed on top of the dry 
ice.  The plastic bag should then be placed into the box, and additional dry ice should be 
placed along its sides.  The styrofoam container should be sealed with strapping tape and 
placed into a sturdy cardboard mailing box.  Copies of all completed “RESEARCH 
SPECIMEN REQUEST FORM” (included in laboratory manual) should be included in 
a plastic resealable bag and placed on top of the Styrofoam container.  The box should 
subsequently be sealed but in a way that will permit carbon dioxide to escape as the dry 
ice sublimates.  Frozen specimens should be shipped overnight by carrier of choice on 
Monday, Tuesday, or Wednesday.  Shipments should not be made on Thursday or Friday. 
Deliveries on Weekends and holidays will not be accepted. 
 
FFPE core biopsies should be placed in a resealable plastic bag (separate bags per 
patient) and can be shipped with the frozen samples but on the outside of the styrofoam 
container.  If not shipping with the frozen samples, place bags in a cardboard box and 
place in a padded envelope.  These specimens with the specimen submission form can 
be sent by regular US mail or UPS ground. 
 
FFPE slides should be packaged in a slide holder and shipped in a well cushioned box. 
These specimens with the relevant pathological report/s can be sent by regular US mail 


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or UPS ground.  
 
 
Blood and Tissue Specimens should be shipped to the following address: 
  
 
 
 
 
 
Cynthia Timmers, Ph.D. 
 
 
 
 
 
Room 460B Biomedical Research Tower 
 
 
 
 
460 West 12th Avenue  
 
 
Columbus, Ohio 43210  
 
 
Tel. (614)-366-9041 
Cynthia.timmers@osumc.edu  
 
9.2.  
Laboratory Correlative Studies 
 
To perform the correlative studies in this trial, we are request 5-6 tumor core biopsies 
from patients.  Two will be fixed in formalin for IHC assays, 2 will be embedded in 
OCT for the RPPA assay and DNA/RNA preparations and 1-2 flash frozen for the 
kinome assay.  Because it may not be possible to obtain this many cores or because the 
cores may have limited tumor content, we will prioritize the following planned studies 
accordingly. Each core collected should be the largest size that can be obtained safely 
and will depend on the site from which it is collected.  18 gauge cores will be preferred; 
however, it will be per institutional standard practice.  
 
1)  Whole exome sequencing 
2)  RPPA assay 
3)  IHC for PTEN 
4)  Whole transcriptome sequencing and DUSP4 expression 
5)  QTAP/Kinome Assay 
6)  IHC for other biomarkers 
 
9.2.1  Pathway Activation Evaluation  
 
9.2.1.1. 
  Immunohistochemistry (IHC) 
 
To evaluate the status of several proteins in the PI3K and RAS/RAF/MEK 
pathways before and after trametinib, immunohistochemistry (IHC) will be 
performed on pretreatment and post-treatment biopsies by the OSU Solid Tumor 
Translational Science Resource using antibodies that have been validated by the 
laboratory.  Formalin-fixed paraffin embedded (FFPE) tissue sections of biopsies 
will be analyzed for expression of PTEN and other relevant protein identified in 
the RPPA assay.  Sections from archival material may also be used in cases where 
insufficient material was obtained from the fresh biopsies.  An H&E stained 
section will be reviewed by a pathologist to verify the presence of tumor.  
Negative control slides without primary antibody will be included for each 
staining as well as a positive control.  Following processing with appropriate 
secondary antibodies, slides will be analyzed and scored by two independent 


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pathologists.  Staining intensity will be rated on a semi-quantitative scale: -, 
negative with no staining; +, weak staining intensity in >10% of the tumor cells; 
++, moderate staining intensity in >10% of the tumor cells' +++, strong staining 
intensity in >10% of the tumor cells. 
 
 
9.2.1.2. 
Reverse Phase Protein Assay (RPPA) 
 
In addition to IHC, we will plan to perform other methods of assessing protein 
levels such as RPPA.  This assay will be run by MD Anderson Cancer Center 
RPPA-Functional Proteomics Core Facility, website below:  
 
http://www.mdanderson.org/education-and-research/resources-for-
professionals/scientific-resources/core-facilities-and-services/functional-
proteomics-rppa-core/index.html  
 
Sections of the OCT embedded core biopsies will be evaluated by a pathologist to 
verify tumor content.  Tissue will then be cut out of the OCT and protein will be 
extracted using standard methods.  The protein will be denatured, diluted and 
arrayed on nitrocellulose coated slides.  The slides will be probed with a set of 
150 validated antibodies (including antibodies to proteins being analyzed by IHC) 
and spot density determined by MiroVigene software.  Samples will be 
normalized for protein loading and concentrations will be determined using the 
Super Curve Fitting program.  Supervised and un-supervised hierarchical 
clustering analysis will then be performed.  This data will be compared to results 
derived by IHC and used to determine differences in protein expression between 
patients that respond to treatment and those that do not.  Proteins of interest that 
are included in this assay are; PTEN, PI3KCA, Cyclin D1 and total and 
phosphorylated forms of AKT, 4E-BP1, p70-S6, ERK and MEK. 
 
 
9.2.1.3. 
Quantitative Targeted Absolute Proteomics (QTAP) 
 
If sufficient biopsy material is available, we will also evaluate changes in 
expression or phosphorylation levels of key protein kinases using QTAP.  This 
assay will be performed in the laboratory of Dr. Gary Johnson at the University of 
North Carolina School of Medicine.  The QTAP/MRM technique has been 
previously used to quantitatively define TNBC oncogenic kinome signatures in 
human cell lines, mouse xenograft models and human tumor biopsy samples31. 
When comparing non-treated samples to those treated with a targeted MEK 
inhibitor, this assay was also able to mechanistically define kinome 
reprogramming and potentially predict combination therapies to overcome 
resistance. 
 
QTAP is an LC/MS technology that uses multiplexed Multiple Reaction 
Monitoring (MRM) for the absolute quantitation of targeted peptides.  Protein 


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lysates will be made from the flash frozen core biopsies collected pre-treatment 
and at the time of progression and analyzed as previously described.32  In brief, 
lysates will be passed through columns of kinase inhibitor-conjugated beads to 
isolate protein kinases.  After several washes, bound proteins will be eluted and 
digested with trypsin.  Digested peptides will then be labeled with iTRAQ and 
separated by a Tempo LC MALDI Spotting System.  Data obtained from the 
MALDI TOF/TOF will be processed with the ProteinPilot software to identify 
proteins from databases searches and the Paragon Algorithm software will be 
used to quantify changes in bound kinase levels.  Human cell lines and mouse 
xenograft tumors were used in pre-clinical studies to define kinome activation 
state and response to targeted kinase inhibition. Synthetic peptides with 
incorporated heavy isotopes (13C, 15N-labeled arginine and lysine) serve as 
quantitative internal standards and can be made in phosphorylated and non-
phosphorylated forms. The method will be multiplexed so many kinases (~25-50) 
can be monitored simultaneously. Main proteins to be included in kinome analysis 
include: EGFR, PDGFR, RAF, RAS, RSK, MEK, ERK, PTEN, P13K, AKT and 
MYC.  Other proteins in the MAPK and PI3K pathways, cell cycle regulators, 
stress response, and receptor tyrosine kinases will also be included.  
 
9.2.2 Genome and Transciptome Analysis 
 
In conjunction with the Garraway Laboratory (Levi Garraway, MD and Nikhil Wagle, 
MD; scientific collaborators, Boston, MA) we will perform massively parallel exome 
and transcriptome sequencing on tumor samples collected pretreatment. They have 
previously reported the development of a targeted, massively parallel sequencing 
approach to detect genomic alterations in 137 cancer genes from FFPE tumor 
samples.29  They used this approach to identify a novel genetic mechanism of resistance 
to the BRAF-inhibitor vemurafenib in a patient with metastatic melanoma who 
developed resistance after an initial dramatic response.30 More recently, they have 
performed whole exome sequencing on FFPE tumor and normal DNA from 15 patients 
with a wide variety of cancer types, including lung adenocarcinoma, prostate 
adenocarcinoma, leiomyosarcoma, and urothelial carcinoma.31 
 
In this project, they will employ unbiased, comprehensive studies of patient-derived 
breast tumor tissue to identify clinical mechanisms of response and resistance to 
trametinib and/or GSK2141795 in triple-negative breast cancer.  To accomplish this, 
they will perform whole exome analysis using massively parallel sequencing, analyzing 
“sets” consisting of pre-treatment and post-progression samples (when applicable) 
together with corresponding matched normal DNA from blood samples on an estimated 
18 patients with an initial clinical response (CR, PR) to trametinib monotherapy (n=9) 
or to trametinib combined with GSK2141795 (n=9). They will also sequence all of the 
mRNA transcripts (the transcriptome) in the frozen breast cancer samples from these 
patients.  The processes for whole exome sequencing and whole transcriptome 
sequencing have been thoroughly validated by Dr. Nikhil Wagle in the laboratory of 
Dr. Levi Garraway of the Broad Institute.29, 32 


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All of the sequencing data will be combined to generate a catalogue of candidate 
genomic alterations that cause resistance to these targeted therapies.  High priority 
genetic lesions will be introduced into cell lines to confirm that they cause resistance to 
these therapies.  In addition, recurrent alterations in the pre-treatment samples can be 
correlated with response, with emphasis on exquisite sensitivity/durable responses. 
 
Whole exome and whole transcriptome sequencing will be performed at the Broad 
Institute Sequencing platform.  Genomic DNA will be extracted from OCT embedded 
tissue after verification of tumor content.  Cores that contain the highest amount of 
tumor tissue (>50%) will be used for the purification of DNA using the Promega 
Maxwell 16 System and Tissue DNA purification kit.  DNA derived from archival 
sections may be used in cases where insufficient material was obtained in the pre-
treatment biopsy.  The resulting DNA will be quantitated by PicoGreen fluorescence 
and 100 ng of DNA will be used for library construction, although as little as 50 ng can 
be used if needed. The exome will be selected using the solution-phase hybrid capture 
method and sequencing will be performed using the Illumina HiSeq instrument, 
yielding an average depth of coverage of 150-fold.  Data analysis will be conducted in 
collaboration with computational biologists in the Garraway lab / Broad Cancer 
Program computational group.  Whole exome sequencing data will be analyzed for base 
substitutions, small insertions and deletions, copy number alterations, and loss of 
heterozygosity.  Selected alterations of interest will be validated by Sequenom 
genotyping or orthogonal technologies in use in the lab. 
 
In parallel to exome sequencing, we will also sequence all of the mRNA transcripts (the 
transcriptome) from frozen OCT biopsy samples that contain >50% tumor.   Total RNA 
will be extracted using the Promega Maxwell 16 System and simplyRNA purification 
Table 3. Example of cancer genes to be included  by massively parallel 
sequencing.1 


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kit.  Quality of RNA will be evaluated using an Agilent Bioanalyzer and quantitated 
using a Nanodrop.  Approximately 200 ng of RNA from each patient samples will be 
used to prepare a library using the Illumina TruSeq RNA-seq library preparation kit 
following the manufacturer’s directions.  Each sample will be sequenced with an 
Illumina HiSeq instrument. Transcriptome data will be analyzed for gene fusions, 
chimeric read-through transcripts, point mutations, and instances of alternative splicing. 
RNA-seq data will also be used to determine gene expression levels for the entire breast 
cancer transcriptome.  
 
9.2.3 DUSP4 Expression 
 
Quantitative gene expression levels for DUSP4 and several control genes (defined in 
Balko et al.22) will be detected using real-time PCR with the ABI PRISM 7900HT 
Sequence Detection System (Applied Biosystems, Foster City, CA) and TaqMan MGB 
probes (FAM dye labeled). Primers and probes for all genes analyzed will be purchased 
from Applied Biosystems Assays-on-Demand Gene Expression products.  Total RNA 
will be purified from tissue as previously described and will be used to synthesize cDNA 
for RT-PCR reactions.  Relative quantification will be applied using a standard curve 
method and normalization to control gene expression.  
 
 
9.2.4 Additional Studies 
 
 
It is anticipated that future studies will include evaluation of genetic, epigenetic, 
immunologic, hormonal, and/or other issues related to breast cancer.  In particular, we will 
be collecting and storing plasma samples to test future potential circulating biomarkers.  
We will inform participants in the informed consent document that we may use their 
specimens for research related to breast cancer and other cancers.   
 
 
9.3. 
Site(s) Performing Correlative Studies 
 
• IHC assay and DUSP4 expression analysis will be performed at the OSU 
Solid Tumor Translational Science Shared Resource. 
 
• Whole exome and transcriptome sequencing will be performed at the Broad 
Institute. 
 
• The RPPA assay will be performed by MD Anderson Cancer Center RPPA-
Functional Proteomics Core Facility. 
 
• The kinome assay will be performed in the laboratory of Dr. Gary Johnson at 
the University of North Carolina at Chapel Hill. 
 
 


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9.4 
Potential risks and procedures for minimizing risks 
 
9.4.1 Risks of blood draws 
 
All blood draws will be performed by trained personnel that use standard sterile 
techniques.  Infection is unlikely since stringent aseptic techniques are followed 
during all venipuncture procedures. 
 
9.4.2 Risks of biopsy  
 
The risks of this study relate primarily to the risk of a biopsy. In general, these 
procedures are associated with a small risk of pain, bleeding, infection, and damage 
to adjacent organs.  The magnitude of this risk depends somewhat upon the site of 
the procedure.   
 
Potential risks according to site are: 
 
Risks of core breast biopsy: 
• Likely: local discomfort and minor bleeding.  
• Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, 
pneumothorax, damage to adjacent organs. 
 
Risks of skin/chest wall punch biopsy: 
• Likely: local discomfort and minor bleeding.  
• Less likely: moderate or major bleeding, or infection 
 
 
Risks of lymph node or soft tissue core needle biopsy: 
• Likely: local discomfort and minor bleeding.  
• Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, 
pneumothorax, damage to adjacent organs. 
• Additional risks may be present if i.v. conscious sedation is required. 
 
Risks of liver core needle biopsy: 
• Likely: local discomfort and minor bleeding 
• Less likely: moderate or major bleeding, need for blood transfusion, 
hospitalization due to bleeding or other complications, infection, bowel 
perforation or damage to adjacent organs 
• Additional risks may be present if i.v. conscious sedation is required. 
 
Lung biopsy core needle biopsy 
• Likely: local discomfort and minor bleeding 
• Less Likely: moderate or major bleeding, need for blood transfusion, lung 
collapse, hospitalization due to bleeding or other complications, infection, 


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damage to nearby organs, allergic reaction to the numbing medicine 
 
In order to minimize the risk of a biopsy, only qualified personnel will perform 
these procedures.  Prior to the procedure, the physician performing the procedure 
will discuss the risks with each study participant, answer any questions, and obtain 
separate procedure consent.  For biopsies of lesions that are not superficial and 
clearly palpable, imaging studies such as CT, ultrasound, or MRI will be used to 
guide the biopsy in order to minimize the risk of damage to adjacent structures. 
After lymph node biopsies, patients will be observed for approximately 2 hours 
(range 2-4 hours) after the procedure, or per institutional standard guidelines.  After 
liver biopsies, patients will be observed for approximately 4 hours (range 4-6 hours) 
after the procedure, or per institutional standard guidelines.  Less than the goal 
quantity of tissue is acceptable for each type of biopsy, and will be left to the clinical 
judgment of the physician performing the procedure.   
 
All grade 3 or 4 events attributable to any of the study procedures will be reported 
to the Principal Investigator within 24 hours of occurrence.  Adverse events will be 
reported by the PI to the IRB consistent with standard procedures.   
 
 
9.4.3 Anesthesia Risk 
 
Risks of local anesthesia 
 
All biopsy procedures require local anesthesia using lidocaine, xylocaine, or related 
compounds.  There is a small risk of an allergic reaction associated with these 
drugs. 
 
In order to minimize the risk of local anesthesia, only qualified personnel will 
perform the biopsy procedure.  Patients will be queried if they have had previous 
allergic reactions to local anesthetics.   
 
Risks of intravenous conscious sedation 
 
Certain biopsy procedures, such as lymph node or liver biopsies, may require 
intravenous conscious sedation (IVCS).  IVCS is a minimally depressed level of 
consciousness that retains the patient’s ability to maintain a patent airway 
independently and continuously and respond appropriately to physical stimulation 
and verbal commands. 
 
The risks of intravenous conscious sedation include: inhibition of the gag reflex 
and concomitant risk of aspiration, cardiopulmonary complications (myocardial 
infarction, cardiac arrhythmias, hypoxemia), and allergic reactions to the sedative 
or analgesic medications.  These risks are small but real; for example, in a 
prospective study of 14,149 patients undergoing IVCS during upper gastrointestinal 
endoscopies, the rate of immediate cardiopulmonary events was 2 in 1000. The 30-


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day mortality was 1 per 2,000 cases.  In this study, there was a strong association 
between lack of monitoring and use of high-dose benzodiazepines with adverse 
outcomes.  There was also an association between the use of local anesthetic sprays 
to the oropharynx and the development of pneumonia. 
 
In order to minimize the risk of intravenous conscious sedation, only qualified 
personnel will be responsible for conscious sedation as per institutional protocols.  
A minimum of two individuals will be involved in the care of patients undergoing 
conscious sedation—the physician performing the biopsy procedure, and the 
individual (M.D. or R.N.) who monitors the patients and his/her response to both 
the sedation and the procedure, and who is capable of assisting with any supportive 
or resuscitative measures.  The room where the procedure utilizing IVCS takes 
place will have adequate equipment to provide supplemental oxygen, monitor vital 
signs, and maintain an airway should this be necessary.  An emergency cart will 
also be immediately accessible to the room where the procedure is to take place, 
and emergency support services will be available on page.  Patients will be screened 
and evaluated for their fitness to undergo conscious sedation by a trained physician. 
Following the procedure, patients will be observed closely in the recovery room 
according to standard institutional guidelines.  
 
 
 
9.4.4 
Risk of imaging studies 
 
Some biopsy procedures require imaging studies, either to plan or guide the 
procedure.  Imaging studies that may be used in obtaining tissue samples include 
CT scans and ultrasound.  CT scans will expose study participants to controlled 
amounts of radiation.  The total dose of radiation from these tests is not 
anticipated to cause any adverse effects.  There is also a risk of an allergic 
reaction to the intravenous contrast dye used during CT imaging, as well as a risk 
of experiencing feelings of anxiety or claustrophobia while undergoing a CT scan.  
There are no anticipated risks with the use of ultrasound. 
In order to minimize these risks, patients will be queried, as per standard 
institutional practice, regarding their history of reactions to intravenous contrast 
dye.  If a patient has had such a reaction, she/he will be premedicated, or dye will 
not be used, as per standard institutional practice.  If a patient has previously 
experienced anxiety or claustrophobia while undergoing a CT scan, anxiolytics 
may be considered as indicated. 
 
 
 


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10. STUDY CALENDAR  
 
Baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy.  Appropriate delays in study treatment or procedures are 
allowed to adjust for holidays or weekends.   
 
Study Calendar 
 
Study 
Assessment
s1 
Screen 
Part 1 
Trametinib 
monotherapy 
Part 2 
Trametinib in 
combination with 
GSK2141795 
Final Study 
Visit3 
Post Treatment 
Follow Up3 
Informed 
Consent 
X 
 
 
 
 
Baseline 
Demographic
s 
X 
 
 
 
 
Medical 
History / 
Interim 
History 
X 
Day 1 (± 3 days) of 
each cycle  
Day 1 (± 3 days) of each 
cycle 
X 
 
Concomitant 
Medications 
X 
Continuous 
 
Physical 
Exam 
X 
Day 1 (± 3 days) of 
each cycle 
Day 1 (± 3 days) of each 
cycle 
X 
 
ECOG 
Performance 
Status 
X 
Day 1 (± 3 days) of 
each cycle 
Day 1 (± 3 days) of each 
cycle 
X 
 
Vital Signs 
(BP, HR, 
Temperature, 
weight) 
X 
Day 1 (± 3 days) of 
each cycle 
Day 1 (± 3 days) of each 
cycle 
X 
 
Hematology, 
Clinical 
Chemistry4 
X 
Day 1 (± 3 days) of 
each cycle 
Day 1 (± 3 days) of each 
cycle 
X 
 
Pregnancy 
Test5 
X 
 
 
 
 
Hemoglobin 
A1C, TSH, 
fasting 
glucose 
X 
Repeated every 3 cycles ± 7 days or as Clinically Indicated 
 
Fingerstick 
blood glucose 
 
 
At home daily monitoring 
for weeks 1 -4, then as 
clinically indicated 
As Clinically 
Indicated 
 
12-Lead ECG 
X 
 
Prior to dosing on Week 1 
day 1 and day 15, and 
then every 4 weeks 
(Week 5, Week 9, etc.) ± 
7 days or as clinically 
indicated 
 
 


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Study 
Assessment
s1 
Screen 
Part 1 
Trametinib 
monotherapy 
Part 2 
Trametinib in 
combination with 
GSK2141795 
Final Study 
Visit3 
Post Treatment 
Follow Up3 
LVEF 
(ECHO) 
X 
Repeated every 3 
cycles ± 7 days during 
Part 1 or as Clinically 
Indicated 
Week 5, Day 1  of Part 2 
and then at the start of 
every 12 weeks  ± 7 days 
or as clinically indicated 
As Clinically 
Indicated  
 
Ophthalmic 
Exam6 
X 
As Clinically Indicated 
 
Blood 
sample7 
 
Day 1 (± 3 days) of 
cycle 1 
 
 
 
Plasma8 
X 
Day 1 cycle 2 and at 
progression 
Day 1 of cycle 2 (prior to 
dosing) 
X 
 
Research 
Biopsy(s) 9 
Mandatory 
research 
biopsies 
will be 
attempted 
on all 
patients 
prior to the 
initiation of 
study 
treatment 
on Part 1 
Mandatory research 
biopsies will be 
attempted on all 
patients at time of 
progression on Part 1 
Optional research 
biopsies will be attempted 
on  patients at time of 
progression on Part 2 
 
 
Study Agents 
 
 Trametinib will be administered daily in Part 1. Trametinib will be 
administered in combination with GSK2141795 in Part 2. Please see 
Section 6 for Dose Modifications. 
 
Tumor 
measurement
s2  
X 
Staging will occur after every 2 cycles ± 7 days or as Clinically Indicated 
 
Adverse 
Events 
 
Continuous 
 
Follow Up 
Data3 
 
 
X 
 
1. 
Assessments scheduled on days of dosing should be done prior to administration of study drug(s), 
unless otherwise specified.  
2. 
Tumor measurements within 4 weeks of first dose. Documentation (radiologic) must be provided for 
patients removed from study for progressive disease. If subject was withdrawn due to progression of 
disease (PD), disease assessments do not need to be repeated at the Final Study Visit. CT 
chest/abdomen/pelvis preferred.  Bone scan, MRI, PET scan may be used at the discretion of the 
treating physician.   
3. 
Final Study Visit should occur 21 days (7 days) after last dose of study drug. Follow up will 
continue for 52 weeks after removal from study or until death, whichever occurs first. Follow up will 
be every 3 months to confirm patient’s living status and whether the patient has progressed (if 
patient did not progress on protocol therapy) gathered from clinic notes or telephone calls (no 
patient visit required).  
4. 
Should include alkaline phosphatase, total bilirubin, creatinine, glucose,  potassium, SGOT, SGPT, 
sodium. 
5. 
Perform only in women of child-bearing potential.   
6. 
Ophthalmic exam will include indirect and direct fundoscopy, visual acuity, visual field examination, 
tonometry and color fundus photos.  Additional ophthalmic exams will be performed if 
symptomatically warranted. 
 


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Study 
Assessment
s1 
Screen 
Part 1 
Trametinib 
monotherapy 
Part 2 
Trametinib in 
combination with 
GSK2141795 
Final Study 
Visit3 
Post Treatment 
Follow Up3 
7. 
Whole blood (6 mL) should be collected in an EDTA tube and stored at -70C or below until 
shipping. 
8. 
Plasma should be purified from 10 mL of blood collected in an EDTA tube.  Aliquots should be 
stored at -70C or below until shipping. 
9. 
Research biopsies may include breast core biopsy, skin or chest wall biopsy, lymph node biopsy, 
liver biopsy, or lung biopsy. 
 
11. MEASUREMENT OF EFFECT 
 
11.1. Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained every 8 weeks following 
initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1).33 Changes in the largest diameter (unidimensional measurement) of the tumor 
lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST 
criteria. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with trametinib and GSK 214179. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest 
x-ray or as ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 


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


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


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may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published 
[JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 
2008].  In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria which are to be integrated with objective tumor assessment for use in 
first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 


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is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively 
described in the protocol and supported by disease-specific medical literature for the 
indication.  However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
11.1.4 Response Criteria 
 
11.1.4.1. Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
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. 
 
11.1.4.2. Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-pathological in size (<10 mm 
short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 


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disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.4.3. Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 


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Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
11.1.7 Response Review 
 
All responses will be reviewed by an expert(s) independent of the study at the study’s 
completion.  Simultaneous review of the patients’ files and radiological images will 
occur. 
 
11.2. Other Response Parameters 
 
N/A 
 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 


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12.1. Data Reporting 
 
12.1.1 Method 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative protocol- and patient-specific CDUS data will be submitted electronically to 
CTEP on a quarterly basis, either by FTP burst of data or via the CDS web application.  
Reports are due January 31, April 30, July 31, and October 31.  Instructions for 
submitting data using the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 
Note:  If your study has been assigned to CDUS-Complete reporting, all adverse events 
(both routine and expedited) that have occurred on the study and meet the mandatory 
CDUS reporting guidelines must be reported via the monitoring method identified above.  
If your study has been assigned to CDUS-Abbreviated reporting, no adverse event 
reporting (routine or expedited) is required to be reported via CDUS. 
 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for submitting CDUS data and/or data forms to either 
the Coordinating Center or to the Lead Organization on the study quarterly.  The date for 
submission to the Coordinating Center or to the Lead Organization will be set by them.  
CDUS does not accept data submissions from the participants on the study.  When setting 
the dates, allow time for Coordinating Center compilation, Principal Investigator review, 
and timely submission to CTEP by the quarterly deadlines (see Section 12.1.1).  For 
trials monitored by CTMS, a quarterly report of data will be provided by Theradex to the 
Coordinating Center. 
 
Either the Coordinating Center or the Lead Organization is responsible for compiling and 
submitting CDUS data to CTEP for all participants and for providing the data to the 
Principal Investigator for review.   
12.2. CTEP Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines.  
The specific responsibilities of the Principal Investigator and the Coordinating Center (Study 
Coordinator) and the procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions for 
submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP.  Agents may be ordered by a participating site only 
after the initial IRB approval for the site has been forwarded by the Coordinating Center 
to the CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 


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


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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 Collaborator’s confidential/ 
proprietary information. 
 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1. Study Overview 
 
This is an open label, two-stage phase II study designed to assess the proportion of 
patients who have a partial or complete response to treatment with trametinib in 
advanced TNBC patients, followed by trametinib in combination with AKT inhibitor 
GSK2141795 at time of tumor progression (Figure 1, Schema).  Preclinical data from 
the Ohio State University and others suggest that a subset of triple negative breast 
cancer (TNBC) patients that are PTEN wild type may demonstrate sensitivity to single 
agent MEK inhibition (Unpublished Olson, Chen),15 and dual targeting of the 
RAS/RAF/MEK/ERK pathway and PI3K/AKT pathways may result in durable 
response after progression on MEK inhibitor monotherapy.15 Therefore, we have two 
parts to this study, where the primary driving hypotheses are two-fold: (1) that the 
anti-tumor response to the single agent trametinib will depend on the PTEN status of 
the tumor, with wild type PTEN having a higher likelihood of response than PTEN 


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77 
 
null tumors; and  (2) that simultaneous inhibition of the RAS/RAF/MEK and 
PI3K/AKT pathway with trametinib and GSK2141795 will overcome both intrinsic 
and acquired resistance to trametinib monotherapy. In addition to evaluating clinical 
efficacy of this regimen, we will also assess correlative markers in relation to clinical 
outcomes of interest. Part 1 focuses on evaluation of efficacy after treatment with 
single agent trametinib, and Part 2 is focused on evaluating salvage efficacy of 
treatment with the combination of trametinib and GSK2141795 in patients who 
progress on trametinib alone.  
 
13.1.1 Primary Endpoint 
 
The primary endpoint for this trial is the objective response rate, defined as the proportion 
of patients who have had a partial response (PR) or complete response (CR) within the first 
6 months after initiation of therapy with trametinib. All eligible patients who have received 
at least one dose of the study regimen will be evaluable for response. Participants will be 
re-evaluated for response every 2 cycles (8 weeks). Response, stable disease and 
progression will be evaluated using the international criteria proposed by the Response 
Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guideline.33  In addition to a 
baseline scan, confirmatory scans will be obtained after approximately 8 weeks following 
initial documentation of a clinical benefit.   
 
In determining this rate, the number of patients with RECIST 1.1 based PR or CR will be 
divided by the number of evaluable patients. All evaluable patients will be used for this 
analysis. Evaluable patients will be defined as only those participants who have 
received at least one cycle of therapy, and have had their disease re-evaluated.  Exact 
binomial 95% confidence intervals for the true PR+CR response rate will be calculated. 
 
13.2. Sample Size, Accrual, and Study Duration: 
 
This study design requires a minimum of 12 and a maximum of 37 evaluable patients. 
In addition, we expected to accrue an additional 10% to accommodate the potential for 
problem cases (i.e. patients who are not evaluable for some reason). The first 45 
evaluable patients will be used in the decision analysis for this part of the trial, and 
estimates will also be generated using all evaluable patients.  We expect approximately 
3 breast cancer patients to be enrolled per month. This will translate to a total of 26 
months to accrue a maximum of 50 patients and allowing for the 6 months interim 
analysis in both Part 1 and Part 2.   
The number of patients inevaluable due to screen failure was higher than expected. As 
such, a total of 50 patients were consented across all sites in order to enroll 37 evaluable 
patients 
 
 
13.3. Study design, primary endpoint analysis plans and power: 
 
To test these hypotheses, we propose a single arm, two-stage phase II trial of single 
agent trametinib in advanced TNBC patients, followed by trametinib in combination 


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with AKT inhibitor GSK2141795 at time of tumor progression (Figure 1, Schema).  
This design was chosen because trametinib monotherapy is more tolerable than 
trametinib in combination with GSK2141795, and therefore, it is vital to first assess if 
there is a subpopulation of TNBC patients (such as those that are PTEN wild type) that 
will derive benefit from anti-MEK therapy alone before exposing patients to dual 
MEK and AKT inhibition.  GSK2141795 will be added at time of tumor progression 
to determine if the addition of AKT inhibition will overcome the primary proposed 
mechanism of resistance to trametinib through blockade of the PI3K/AKT pathway.   
 
The goals of this study are to evaluate whether or not trametinib alone provides 
sufficient clinical response in this patient population (Part 1), and to evaluate if the 
combination of trametinib plus GSK2141795 in patients who progress will improve the 
objective response in this patient population (Part 2). To minimize the expected number 
of subjects treated if the trametinib monotherapy is not sufficiently active in this setting, 
a Simon two-stage Optimum Design will be used for Part 1 that allows for early 
termination of accrual if insufficient activity with monotherapy is observed. In addition, 
upon completion of Part 1 of this study we will further evaluate the combination of 
trametinib plus GSK2141795 in those patients in Part 1 who progress (Part 2). Similarly, 
to limit the number of patients accrued if this combination regimen proves to be 
insufficiently active, we will utilize a Fleming Two-Stage Design. As in any two-stage 
design, the 2nd stage will only commence and accrue additional patients if the specified 
decision criteria are met for the 1st stage.  Even though Part 2 is directly linked to Part 
1 (in the fact that those who progress on Part 1 are able to go on to Part 2) each part will 
have its own study design and decision criteria associated with them. The primary 
evaluation and goal of interest is Part 1, where the Part 2 evaluation is a secondary goal 
of this trial.    
 
For Part 1:  We hypothesize that the true ORR with monotherapy is at least 20% versus 
a null hypothesis that the ORR is at most 5%, reflecting that any treatment success 
(clinical response) is due to chance alone. Under this Simon Optimal two-stage design, 
we aim to test the null hypothesis H0: ORR ≤ 5% vs. H1: ORR ≥ 20% to evaluate the 
efficacy of trametinib monotherapy. With 90% power and a Type I error rate of 10%, 
the interim analysis for this design requires that at least one patient of the first 12 
evaluable patients enrolled have observed objective response (CR+PR); otherwise, if no 
patients have an objective response to treatment, then we will consider this sufficient 
early evidence that this treatment regimen is not worth pursuing further as monotherapy. 
At this point, we will evaluate the combination regimen in Part 2 in any patients 
subsequently enrolled on the trial and not just those who fail monotherapy in Part 1. If 
at least 1 patient has clinical response out of the first 12 enrolled patients treated with 
combination therapy, we will continue accrual to the second stage and accrue an 
additional 25 patients for a total of 37 patients. In the final analysis, we would need to 
see at least 4 patients with clinical response as defined above out of the first 37 evaluable 
patients accrued to determine that this monotherapy has promising associated activity 
and thus is worth pursuing further. Otherwise, if 3 or fewer have clinical benefit, then 
we will consider this monotherapy to not be sufficiently active on its own.  
 


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For Part 2:  In this part of the trial, we will focus on evaluating the ability to obtain 
clinical response in those patients in Part 1 who progress on monotherapy; we expect 
that about 80% of patients will progress and remain free of limiting toxicity to go on to 
Part 2. With our planned over-accrual and if all are evaluable, we will have 32 patients 
available for this portion of the trial. If we observe issues with patients going off study 
during Part 1, the study team will discuss with CTEP potential solutions and if patients 
who cannot tolerate the MEK inhibitor as single agent therapy will be replaced in the 
overall sample size to facilitate subsequent evaluation of the combination regimen in 
Part 2. However, in evaluation of the primary outcome of the MEK inhibitor as single 
agent therapy, any such patient who is unable to tolerate therapy and/or goes off study 
during Part 1 will still be included in the analyses and decision rule evaluations.  
 
Since this is also a relapsed/refractory setting, our goals are the same as those in Part 1. 
Therefore, we hypothesize that the objective response rate of this combination therapy 
is at least 20% versus the null hypothesis that it is at most 5%. With 90% power and a 
Type I error rate of 10%, this Fleming two-stage design has an interim analysis after the 
first 16 evaluable patients are accrued. If no patients have documented objective 
response (CR+PR) out of the first 16 enrolled patients the trial cohort then we will 
consider this sufficient early evidence that this is not a promising regimen and accrual 
will be terminated.  If at least 1 patient has clinical response out of the first 16 enrolled 
patients, then accrual will continue and an additional 16 patients will be accrued for a 
total 32 evaluable patients. In the final analysis, if at least 4 patients have clinical 
response as defined above, then we will consider this a promising regimen and worthy 
of further study.     
 
Assuming that the number of responses is binomially distributed, we will estimate 
objective response rates independently for parts 1 and 2, and generate corresponding 
95% binomial confidence intervals.  
 
 
13.4. Secondary Endpoints  
 
The Kaplan-Meier method will be used to estimate overall survival and progression-free 
survival distributions.  Each of these variables will be measured from the start date of the 
treatment to the date of the event (i.e., death or disease progression) or the date of last 
follow-up to evaluate that event. Similarly, we will also evaluate duration of objective 
response in the subset of patients who achieve a response to treatment, where we will define 
this from the date of documentation of response to the date of progression and/or death. 
This will be more exploratory and descriptive given the expected response rate, but we will 
use the methods of Kaplan and Meier to evaluate this. Overall survival will only be 
evaluated for Part 2, where for Part 1 patients who progress and go on to Part 2 will be 
censored at that time making the estimation not as informative. Progression-free survival 
will not be confounded due to the fact that Part 1 patients need to progress first before going 
to the Part 2 treatment regimen. The clinical benefit rate (CR+PR+SD) will be reported for 
patients after Part 1 and after Part 2.   
 


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Toxicity and tolerability: As per NCI CTCAE v4.0, the term toxicity is defined as adverse 
events that are classified as either possibly, probably, or definitely related to study 
treatment. The maximum grade for each type of toxicity will be recorded for each patient, 
and frequency tables will be reviewed to determine toxicity patterns. In addition, we will 
review all adverse event data that is graded as 3, 4, or 5 and classified as either “unrelated” 
or “unlikely to be related” to study treatment in the event of an actual relationship 
developing. The incidence of severe (grade 3+) adverse events or toxicities will be 
described. We will also assess tolerability of the regimens for part 1 and part 2 through 
assessing the number of patients who required dose modifications and/or dose delays. In 
addition, we will also capture the proportion of patients who go off treatment due to adverse 
reactions or even those who refuse further treatment for lesser toxicities that inhibit their 
willingness to continue participation on the trial. These tolerability measures will be 
assessed within each of the treatment parts independently. All patients who have received 
at least one dose of any of the therapeutic agents will be evaluable for toxicity and 
tolerability.  
 
Correlative endpoints:  
The statistical analysis corresponding to the correlative studies will be descriptive and 
exploratory in nature.  
RPPA: 
For each patient the protein intensity fold-change ratios will be calculated from the RPPA 
intensity values.  Ratios between tumors sampled prior to initiating trametinib single 
agent treatment and at time of progression on either single agent trametinib or the 
combination  (TOP/pre-treat ratio), will be calculated.  These ratios will be median-
centered and clustered using Cluster 2.0 software (http://rana.lbl.gov/EisenSoftware.htm).  
Student’s t-test for differences between average protein intensity ratios at these intervals 
will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.  
 
Table 4 
Biomarker Prevalence  
 10% 
20% 30% 
40%  50% 


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These results and exploratory analyses will be 
used in planning future studies of this 
combination treatment regimen in this patient population. Biomarker analyses on required 
research biopsies at study entry will be conducted to assess the predictive value of PTEN 
and other biomarkers on patient outcome. For example, we will assess impact of PTEN 
status and other markers on survival outcomes as well as ORR and CBR. For survival-
based outcomes, Table 4 shows detectable hazard ratios between marker groups for 
varying prevalence rates and at least 80% power. The Type I error constraint is quite lax 
in this setting, reflecting a phase II approach and relaxation of constraints but also in the 
univariate setting can be used to cast a wider net to capture potential markers of interest 
that may provide insights for the development of future biomarker-driven therapeutic 
strategies.  Fisher exact tests will also be used to identify potential differences in ORR 
and CBR rates between biomarker groups as well, although depending on prevalence 
rates we will likely have sufficient power to only detect large differences (e.g. 35%) if we 
constrain Type I error to 0.05. Again, these will be largely exploratory, and lack of 
significant results will be viewed with caution given these limitations but will provide 
insights into potential relationships and 
mechanisms. To assess mechanisms of acquired 
resistance, research biopsies will be conducted at 
time of progression on trametinib monotherapy 
and at time of progression to the combination of 
trametinib and GSK2141795. Restaging will 
occur after every 2 treatment cycles (8 weeks).   
 
Whole exome and transcriptome sequencing: 
Genetic alterations from whole exome sequencing data would be tabulated. Data analysis 
will be conducted in collaboration with computational biologists in the Garraway lab / 
Broad Cancer Program computational group. Whole exome sequencing data will be 
analyzed for base substitutions, small insertions and deletions, copy number alterations, 
and loss of heterozygosity. Selected alterations of interest will be validated by Sanger 
sequencing or related orthogonal technologies in use in the Garraway lab. Data will be 
compiled to generate a catalogue of candidate genomic alterations that cause resistance to 
MEK and ATK inhibition.  Genes listed above in Section 9, Table 3 will be the first to be 
examined as well-known genes related to cancer growth and survival.  Molecular 
alterations of known significance will be reported.  Molecular alterations of unknown 
significance will also be presented; however, assessment of the clinical significance will 
be investigated by in vitro studies (i.e. site-directed mutagenesis, growth inhibition 
analysis, immunoblot studies, and kinase assays)..  Identified markers of interest will be 
explored in relation to several clinical outcomes of interest for each treatment component. 
Specifically, we will look at incidence of mutations and marker expression levels similar 
to that described above, where we will first look graphically at associations with 
objective response as well as with progression-free survival. Model-based evaluations 
may also be used in an exploratory manner to better assess these relationships in a 
quantitative manner, but will be limited given the sample size available for these 
analyses.  
 
  HR 
 0.43 
0.51 0.55 
0.56  0.57 
Table   1:   Statistical   Considerations   
for Biomarker   Analysis.   Maximum   
detectable hazard  ratios  (HR)  using  one-
sided  log-rank test with 80% power and 
alpha=0.2, assuming a sample size of 37, 26 
months accrual and 12 months follow-up. 


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QTAP/Kinome assay: 
 
 
 
 
 
 
 
For the QTAP/Kinome assay: Paragon Algorithm software will be used to quantify 
changes in bound kinase levels. As seen in Table 5, a two-sided paired sample t-test will 
have at least 80% power to detect a 3-fold change in bound kinase levels before and after 
treatment with 9 patients in each group (assuming Type I error of 0.05). Based on 
preliminary data,34 we assume that 100 kinases are captured, of which 10% of them are 
truly differentially expressed between pre- and post- treatment and a common standard 
deviation of 0.95 (in log2 scale, Table 5). Given the limited paired sample size, 
nonparametric tests will be used (i.e. Wilcoxon signed rank test) if approximate normality 
is not achievable through transformation.  
 
 
 
 
 
 
13.5. Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients would be evaluable for toxicity from the time of their first treatment with 
trametinib monotherapy or trametinib in combination with GSK2141795  
 
13.5.2 Evaluation of Response 
 
All patients included in the study would be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible.  Each patient would 
be assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) would be included in the main analysis of the 
response rate.  Patients in response categories 4-9 would be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration would not result in exclusion from the analysis of the response rate.   
 
Table 5. Power calculation to detect kinase difference 
D=Difference in log2 scale 
1.00 
1.58 
2.00 
2.32 
Fold change (2D) 
2 
3 
4 
5 
Power (%) 
8.93 
81.69 
97.39 
99.61 
Table 5 summarizes the power to detect a true difference of D with a 
sample size of 9 patients in each group (pre and post treatment)  


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


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REFERENCES 
 
1. Wagle N, Berger MF, Davis MJ, Blumenstiel B, DeFelice M, Pochanard P, et al. 
High-Throughput Detection of Actionable Genomic Alterations in Clinical Tumor Samples by 
Targeted, Massively Parallel Sequencing. Cancer Discovery. 2011. 
2. Santana-Davila R, Perez E. Treatment options for patients with triple-negative breast 
cancer. Journal of Hematology & Oncology. 2010; 3(1): 42. 
3. Hudis CA, Gianni L. Triple-Negative Breast Cancer: An Unmet Medical Need. The 
Oncologist. 2011; 16(suppl 1): 1-11. 
4. Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with 
triple-negative breast cancer. Clin Breast Cancer. 2009; 9 Suppl 2: S73-81. 
5. Gilmartin AG, Bleam MR, Groy A, Moss KG, Minthorn EA, Kulkarni SG, et al. 
GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable 
pharmacokinetic properties for sustained in vivo pathway inhibition. Clinical cancer research : an 
official journal of the American Association for Cancer Research. 2011; 17(5): 989-1000. 
6. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved 
survival with MEK inhibition in BRAF-mutated melanoma. The New England journal of 
medicine. 2012; 367(2): 107-14. 
7. Infante JR, Fecher LA, Falchook GS, Nallapareddy S, Gordon MS, Becerra C, et al. 
Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor 
trametinib: a phase 1 dose-escalation trial. The lancet oncology. 2012; 13(8): 773-81. 
8. Infante JR, L.A. Fecher, S. Nallapareddy, et al.  . Safety and efficacy results from the 
first-in-human study of the oral MEK 1/2 inhibitor GSK1120212.  . J Clin Oncol  28:Abstract 
2503. 2010. 
9. Messersmith WA, G.S. Falchook, L.A. Fecher, et al. Clinical activity of the oral 
MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.  . J Clin Oncol  
29:Abstract 246. 2011. 
10. Borthakur G, J.M. Foran, T. Kadia, et al. GSK1120212, a MEK1/MEK2 inhibitor, 
demonstrates acceptable tolerability and preliminary activity in a dose rising trial In subjects 
with AML and other hematologic malignancies. .  Blood (ASH Annual Meeting Abstracts)  
116:Abstract 3281. 2010. 
11. Morgensztern D, McLeod HL. PI3K/Akt/mTOR pathway as a target for cancer 
therapy. Anti-cancer drugs. 2005; 16(8): 797-803. 
12. Kurzrock R, A. Patnaik, L. Rosenstein, et al.  . Phase I dose-escalation of the oral 
MEK1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral AKT inhibitor 
GSK2141795 (GSK795). J Clin Oncol  29:Abstract 3085. 2011. 


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13. Carey L, Rugo H, Marcom P, Irvin WMF, E. Burrows, X. He, C. M. Perou, E. P. 
Winer TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-
negative (basal-like) breast cancer 2008. 
14. Hoadley K, Weigman V, Fan C, Sawyer L, He X, Troester M, et al. EGFR associated 
expression profiles vary with breast tumor subtype. BMC Genomics. 2007; 8(1): 258. 
15. Hoeflich KP, O'Brien C, Boyd Z, Cavet G, Guerrero S, Jung K, et al. In vivo 
Antitumor Activity of MEK and Phosphatidylinositol 3-Kinase Inhibitors in Basal-Like Breast 
Cancer Models. Clinical Cancer Research. 2009; 15(14): 4649-64. 
16. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She Q-B, Maurer M, et al. Poor 
prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor 
suppressor pathway activity. Proceedings of the National Academy of Sciences. 2007; 104(18): 
7564-9. 
17. Saal LH, Gruvberger-Saal SK, Persson C, Lovgren K, Jumppanen M, Staaf J, et al. 
Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient 
DSB repair. Nat Genet. 2008; 40(1): 102-7. 
18. Gonzalez-Angulo AM, Ferrer-Lozano J, Stemke-Hale K, Sahin A, Liu S, Barrera JA, 
et al. PI3K Pathway Mutations and PTEN Levels in Primary and Metastatic Breast Cancer. 
Molecular Cancer Therapeutics. 2011; 10(6): 1093-101. 
19. Rahmani M, Anderson A, Habibi JR, Crabtree TR, Mayo M, Harada H, et al. The 
BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant 
inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. Blood. 2009; 114(20): 4507-16. 
20. Faber AC, Li D, Song Y, Liang M-C, Yeap BY, Bronson RT, et al. Differential 
induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. 
Proceedings of the National Academy of Sciences. 2009; 106(46): 19503-8. 
21. McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, et al. 
Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug 
resistance. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2007; 1773(8): 
1263-84. 
22. Balko JM, Cook RS, Vaught DB, Kuba MG, Miller TW, Bhola NE, et al. Profiling of 
residual breast cancers after neoadjuvant chemotherapy identifies DUSP4 deficiency as a 
mechanism of drug resistance. Nat Med. 2012; advance online publication. 
23. O'Shaughnessy J. Next Generation Sequencing Reveals Co-Activating Events in the 
MAPK and P13K/AKT Pathways in Metastatic Triple Negative Breast Cancers.  San Antonio 
Breast Cancer Symposium; 2011; San Antonio, TX; 2011. 
24. Shimizu T, Tolcher AW, Papadopoulos KP, Beeram M, Rasco DW, Smith LS, et al. 
The Clinical Effect of the Dual-Targeting Strategy Involving PI3K/AKT/mTOR and 
RAS/MEK/ERK Pathways in Patients with Advanced Cancer. Clinical Cancer Research. 2012; 


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18(8): 2316-25. 
25. Craig DW, O'Shaughnessy JA, Kiefer JA, Aldrich J, Sinari S, Moses TM, et al. 
Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast 
cancer uncovers therapeutic vulnerabilities. Molecular cancer therapeutics. 2013; 12(1): 104-16. 
26. Balmanno K, Chell SD, Gillings AS, Hayat S, Cook SJ. Intrinsic resistance to the 
MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or 
strong PI3K signalling in colorectal cancer cell lines. International Journal of Cancer. 2009; 
125(10): 2332-41. 
27. Olson EM, Lin NU, Krop IE, Winer EP. The ethical use of mandatory research 
biopsies. Nat Rev Clin Oncol. 2011; 8(10): 620-5. 
28. Lacouture M. Clinical practice guidelines for the prevention and treatment of EGFR 
inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011; 19(8): 1079-95. 
29. Wagle N, Berger MF, Davis MJ, Blumenstiel B, Defelice M, Pochanard P, et al. 
High-throughput detection of actionable genomic alterations in clinical tumor samples by 
targeted, massively parallel sequencing. Cancer discovery. 2012; 2(1): 82-93. 
30. Wagle N, Emery C, Berger MF, Davis MJ, Sawyer A, Pochanard P, et al. Dissecting 
therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 2011; 29(22): 
3085-96. 
31. Van Allen et al OpAAM. 
32. Fisher S, Barry A, Abreu J, Minie B, Nolan J, Delorey TM, et al. A scalable, fully 
automated process for construction of sequence-ready human exome targeted capture libraries. 
Genome biology. 2011; 12(1): R1. 
33. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009; 45(2): 228-47. 
34. Duncan James S, Whittle Martin C, Nakamura K, Abell Amy N, Midland Alicia A, 
Zawistowski Jon S, et al. Dynamic Reprogramming of the Kinome in Response to Targeted 
MEK Inhibition in Triple-Negative Breast Cancer. Cell. 2012; 149(2): 307-21. 
 
 
 


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


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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
 
If an institution wishes to collaborate with other participating institutions in performing a 
CTEP sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information 
Office (PIO).  The Protocol Chair is responsible for the coordination, development, 
submission, and approval of the protocol as well as its subsequent amendments.  The 
protocol must not be rewritten or modified by anyone other than the Protocol Chair.  
There will be only one version of the protocol, and each participating institution will use 
that document.  The Protocol Chair is responsible for assuring that all participating 
institutions are using the correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office 
for Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible 
for assuring that each participating institution has an OHRP assurance and must maintain 
copies of IRB approvals from each participating site.  
• Prior to the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each 
participating site prior to the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports.  There are two 
options for AE reporting: (1) participating institutions may report directly to CTEP with a 
copy to the Coordinating Center, or (2) participating institutions report to the 
Coordinating Center who in turn report to CTEP.  The Coordinating Center will submit 
AE reports to the Protocol Chair for timely review. 
o Routine AE reporting: Participating institutions report to the Coordinating Center 
who in turn report to CTEP. 
o Expedited AE reporting: Participating institutions will report directly to CTEP via 
CTEP-AERS and will copy the Coordinating Center. The CTEP-AERS-generated 
email with the study#, subject#, and ticket# must be forwarded by the 
participating institution to the Subsite Coordinator either via fax (614-366-4721) 
or secure email (jennifer.sexton@osumc.edu)   
• Audits may be accomplished in one of two ways:  (1) source documents and research 


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records for selected patients are brought from participating sites to the Coordinating 
Center for audit, or (2) selected patient records may be audited on-site at participating 
sites.  If the NCI chooses to have an audit at the Coordinating Center, then the 
Coordinating Center is responsible for having all source documents, research records, all 
IRB approval documents, NCI Drug Accountability Record forms, patient registration 
lists, response assessments scans, x-rays, etc. available for the audit. 
• Data from participating institutions must be sent to the Coordinating Center within 2 
weeks of each patient visit. 
• Safety Reports and Action Letters from CTEP will be distributed by the Subsite 
Coordinator to the participating institutions. 
 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP.  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been 
forwarded by the Coordinating Center to the CTEP PIO.  
 
 
 


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APPENDIX C 
MEDICATION DIARY – PART 1 
 
PATIENT ID: 
_______________ 
PATIENT INITIALS (F  M  L): _____   _____   _____ 
PART ______  
CYCLE#: _____ 
Dose of trametinib _________ daily.   
 
Date 
Day of 
Treatmen
t 
Day of 
the 
Week 
Time 
Check Box if 
Dose Missed 
Patient Comments 
Exampl
e 1: 
5/21/12 
1 
Monday 
    3   :  15      
□ AM   PM 
□ 
  
Exampl
e 2: 
5/22/12 
2 
Tuesday 
_____:_____   
□ AM   □ PM 

  Forgot to take my pills and 
didn't remember until the next 
day. 
  
1 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
2 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
3 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
4 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
5 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
6 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
7 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
8 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
9 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
10 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
11 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
12 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
13 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
14 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
15 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
16 
  
_____:_____   
□ AM   □ PM 
□ 
  


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91 
 
Date 
Day of 
Treatmen
t 
Day of 
the 
Week 
Time 
Check Box if 
Dose Missed 
Patient Comments 
  
17 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
18 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
19 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
20 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
21 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
22 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
23 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
24 
  
_____:_____   
□ AM   □ PM 
□ 
  
  
25 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
26 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
27 
  
_____:_____  
 □ AM   □ PM 
□ 
  
  
28 
  
_____:_____   
□ AM   □ PM 
□ 
  
DIRECTIONS:    Take by mouth on an empty stomach, either 1 hour before or 2 hours 
after a meal. You will take the mediciation once per day, at the same time each day.   If 
you miss a dose of your mediciation, you should take it as soon as you remember that 
day up to 6 hours past the scheduled time. If more than 6 hours has passed since the 
scheduled time, do NOT take the missed dose.   Please inform your study doctor of 
any new medications you are taking. 
Please be sure to bring this calendar and all pill bottles with you when you return to the clinic at 
the end of this cycle. Please remember to give everything to the research staff member that 
gave them to you. Please sign and date below. Thank you! 
Patient's Signature: ___________________________________________________________                
Date: __________________________ 
For Official Use Only 
Official Use Section Completed 
by: 
Medication Amt Dispensed 
____________________________ 
Date Dispensed 
______________________ 
Name: 
_________________________
___________________ 
Medication Amt Returned 
____________________________
_ 
Date Returned 
_______________________ 
Date: 
_____________________ 
 


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APPENDIX D 
MEDICATION DIARY – PART 2 
 
PATIENT ID: 
_______________ 
PATIENT INITIALS (F  M  L): _____   _____   _____ 
PART ______  
CYCLE#: _____ 
Dose of trametinib _________ daily.   
Dose of GSK2141795 _________ daily. 
Date 
Day of 
Treatment 
Day of 
the 
Week 
Time 
Check Box 
if Dose 
Missed 
Patient 
Comments 
(please indicate if 
both pills were 
taken) 
Example 
1: 
5/21/12 
1 
Monday 
Trametinib 
  7 : 15         AM     □ PM 
  
GSK2141795 
  6 : 30        □ AM    PM 
□ 
 
 
□ 
 
  
Example 
2: 
5/22/12 
2 
Tuesda
y 
Trametinib     
  7 : 00         AM     □ PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 




   
 
 
Forgot to take my 
pills and didn't 
remember until the 
next day. 
  
1 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
2 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
 
□ 
 
□ 
 
  
  
3 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
4 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
5 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
 
□ 
 
 
□ 
  


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_____:_____□ AM   □ PM 
  
6 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
 
□ 
 
 
□ 
  
Date 
Day of 
Treatment 
Day of 
the 
Week 
Time 
Check 
Box if 
Dose 
Missed 
Patient 
Comments  
  
7 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
8 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
9 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
10 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
11 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
12 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
13 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____□ AM   □ PM 
□ 
 
 
□ 
  


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14 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
 
□ 
 
 
□ 
  
  
15 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
16 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
Date 
Day of 
Treatment 
Day of 
the 
Week 
Time 
Check 
Box if 
Dose 
Missed 
Patient 
Comments  
  
17 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
18 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
19 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____ □ AM   □ PM 
□ 
 
 
□ 
  
  
20 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
21 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
22 
  
Trametinib     
□ 
 
  


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_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
 
□ 
  
23 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
24 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
25 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
26 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
 
□ 
 
 
□ 
  
Date 
Day of 
Treatment 
Day of 
the 
Week 
Time 
Check 
Box if 
Dose 
Missed 
Patient 
Comments  
  
27 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
  
28 
  
Trametinib     
_____:_____    □ AM  □ 
PM 
 
GSK2141795 
_____:_____  □ AM   □ PM 
□ 
 
 
□ 
  
DIRECTIONS:    Take trametinib by mouth on an empty stomach, either 1 hour before 
or 2 hours after a meal. GSK2141795 must be taken 1 hour after a meal and two hours 
before the next meal. It is recommended that you take trametinib in the morning and 
GSK2141795 in the evening, however this is not required. You will take the medication 
once per day, at the same time each day.   If you miss a dose of your medication, you 
should take it as soon as you remember that day up to 6 hours past the scheduled 
time. If more than 6 hours has passed since the scheduled time, do NOT take the 
missed dose.   Please inform your study doctor of any new medications you are taking. 


NCI Protocol #:9455 
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96 
 
Please be sure to bring this calendar and all pill bottles with you when you return to the clinic at 
the end of this cycle. Please remember to give everything to the research staff member that 
gave them to you. Please sign and date below. Thank you! 
Patient's Signature: ___________________________________________________________                
Date: __________________________ 
For Official Use Only 
Official Use Section Completed by: 
Medication Amt Dispensed 
____________________________ 
Date Dispensed 
____________________
__ 
Name: 
___________________________
_________________ 
Medication Amt Returned 
_____________________________ 
Date Returned 
____________________
___ 
Date: _____________________ 
 
 
 
 


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APPENDIX E 
 LABORATORY MANUAL 
 
The laboratory manual from the Solid Tumor Shared Resource of the Ohio State 
University is available upon request from the Director Dr. Cynthia Timmers  
 
Cynthia Timmers, Ph.D. 
Director, Solid Tumor Translational Science Resource 
The Ohio State University Comprehensive Cancer Center- 
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 
 460 12th Avenue, BRT Rm 486 
Columbus, OH 43210 
PH: 614-366-9041 
Cell: 414-617-5466 
cynthia.timmers@osumc.edu  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX F:  BLOOD GLUCOSE TESTING DIARY – OSU-13117 (NCI-9455) 
 
 
Patient ID: ___________________________ 
 
 
Patient Initials (F M L):   ____  ____  ____ 
 
Directions: Take your blood sugar each morning before you eat or drink anything. 
Record your blood sugar readings, date, time and comments in this diary. Call your 
doctor if your blood sugar reading is less than 70 or greater than 250. 
 
Date 
MM/DD/YY 
Time 
____:____ 
AM/PM 
Blood Glucose 
Reading 
Patient Comments 
Example 1: 
11/15/13 
 
8:00 AM 
 
120 
 
 
Example 2: 
11/16/13 
 
7:30 AM 
 
64 
Called doctor to report low blood 
sugar. Drank orange juice and 
repeated blood sugar per doctor 
instructions. Repeat blood sugar at 
8:15 AM = 106 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Please be sure to bring this diary with you when you return to the clinic for every visit. 
 
Patient’s Signature:___________________________________  Date: 
___________________ 
 
For Official Use Only: 
 
Diary Received By: ___________________________________   Date: 
___________________ 
(Study Staff Name) 
 
 
 


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APPENDIX G: 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
[Note to investigators:  This appendix consists of an “information sheet” to be handed to the 
patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip 
out and retain at all times.] 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent trametinib DMSO and GSK2141795.  This clinical trial is sponsored by 
the National Cancer Institute.  This form is addressed to the patient, but includes important 
information for others who care for this patient.  
GSK2141795 interacts with many drugs that are processed by your liver.  Because of this, it is 
very important to tell your study doctors about all of your medicine before you start this study.  It 
is also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort. 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
GSK2141795 interacts with certain specific enzymes in your liver.  
• The enzymes in question are CYP450 3A4 and 2C8.  GSK2141795 levels are affected by 
some of these enzymes and can lower the levels of other medicines you take. 
• GSK2141795 must be used very carefully with other medicines that need these liver 
enzymes to be effective or to be cleared from your system. 
• Other medicines may also affect the activity of the enzyme. 
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects.  GSK2141795 should not be taken with any other drugs 
that are strong inducers or inhibitors of CYP 3A4.  Prohibited medications include 
azole antifungals, some antiepileptic drugs, some antibiotics and some 
immunosuppressants.  Please check with the study investigator before prescribing 
or dispensing strong inhibitors/inducers of CYP 3A4. Mild/moderate 
inhibitors/inducers should be used with caution. 
o  GSK2141795 is considered an inhibitor of CYP 3A4 and 2C8, meaning that it 
can increase the levels of other drugs that are processed by these enzymes.  This 
can lead to harmful side effects and/or reduce the effectiveness of those 
medications.    
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category. 


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• Before you start the study, your study doctor will work with your regular prescriber to 
switch any prohibited medicines that are considered “strong inducers/inhibitors or 
substrates of CYP 3A4.” 
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
•  or consult a medical reference to see if any medicine they want to prescribe is on a list of 
drugs to avoid. 
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction. 
• Be careful: 
o If you take acetaminophen regularly:  You should not take more than 3 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit, Seville oranges, pummelos, exotic 
citrus fruits or grapefruit hybrids:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking GSK2141795. 
 
Other medicines can be a problem with your study drugs.  
• You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement. 
 
• Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is  
 
Bhuvaneswari Ramaswamy, MD and she can be contacted at : 
 
Phone number: 614-293-6401 
 
 


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INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the experimental agents 
trametinib DMSO and GSK2141795.  This clinical trial is sponsored 
by the NCI.  GSK2141795 interacts with drugs that are processed by 
your liver.  Because of this, it is very important to: 
➢ Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
➢ Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
➢ Check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement. 
GSK2141795 interacts with specific liver enzymes called CYP 3A4 
and CYP 2C8, and must be used very carefully with other medicines 
that interact with these enzymes. 
➢ Before you start the study, your study doctor will work with your 
regular prescriber to switch any prohibited medicines that are 
considered “strong inducers/inhibitors or substrates of CYP 3A4.” 
➢ Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a list 
of drugs to avoid, or contact your study doctor.   
➢ Your study doctor’s name is _____________________________ 
and can be contacted at _____________________________.