Conditions: Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the antitumor activity of trametinib determined by overall response rate (ORR) in patients that are stratified into groups based on: biomarker positive (neuroblastoma RAS viral \[v-ras\] oncogene homolog \[NRAS\], v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog \[KRAS\], v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\] mutated) and biomarker negative (without NRAS, KRAS, BRAF mutation).

SECONDARY OBJECTIVES:

I. To evaluate progression free survival (PFS) and duration of response (DOR) in the two stratified groups.

II. To document ORR after the addition of GSK2141795 (Akt inhibitor GSK2141795) to trametinib in patients who have developed progressive disease or have achieved less than a partial response (PR) after 4 cycles of treatment.

III. To evaluate PFS and DOR in patients receiving trametinib plus GSK2141795. IV. To evaluate the safety profile of trametinib with and without GSK2141795.

TERTIARY OBJECTIVES:

I. To explore the relationship between clinical response and pharmacodynamic (PD) markers.

II. To explore the relationship between v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) expression as determined by quantitative polymerase chain reaction (qPCR), chromosomal abnormalities detected by florescence in situ hybridization (FISH), and clinical response.

III. To explore the role of integrin beta7 as a biomarker of MAF expression. IV. To explore the relationship between objective clinical response as well as progressive disease and the tumor mutational profile.

V. To explore mechanism of phosphatidylinositol 3 kinase (PI3K)/v-akt Murine Thymoma Viral Oncogene Homolog 1 (AKT) and retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS)-mitogen-activated protein kinase kinase (MEK)-mitogen-activated protein kinase 1 (ERK) activation and correlate these with clinical response and PD markers.

IV. To explore the feasibility of extracting circulating free tumor DNA (cfDNA) from peripheral blood and detecting RAS and RAF mutations using cfDNA.

OUTLINE:

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 with progressive disease or who achieve less than PR after 4 courses may also receive Akt inhibitor GSK2141795 PO daily on days 1-28.

After completion of study treatment, patients are followed up for 4 weeks.

Arms:
arm 1: Patients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease or who achieve less than PR after 4 courses may also receive Akt inhibitor GSK2141795 PO daily on days 1-28.

Interventions: intervention 1: Laboratory Biomarker Analysis intervention 2: Pharmacological Study intervention 3: Trametinib intervention 4: Uprosertib
Intervention descriptions: intervention 1: Correlative studies intervention 2: Correlative studies intervention 3: Given PO intervention 4: Given PO

Protocol document:
Prot_SAP_000.pdf: 
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SUMMARY OF PROTOCOL CHANGES 
 
Version # / Version Date: 
Amendment #8 / 23Nov2016 
 
 
# 
Page 
Section 
Comments 
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All 
All 
Version date was updated on all pages. 
2 
1 
Version  
Added 
 
Amendment #8 / 23Nov2016 
 
Rationale: Protocol Amendment #8 version is submitted to match the Updated 
Consent dated 23Nov2016 as suggested by CTEP 
 
 
No Changes made to Protocol with this Amendment


NCI 9460 / PHL-091  
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1 
NCI Protocol #:  9460 
Local Protocol #: PHL-091 
Version # / Version Date: 
Initial / 24 July 2013 
 
 
 
 
 
 
 
 
Amendment #1 / 15 Nov 2013 
 
 
 
 
 
 
 
 
Amendment #2 / 06 Mar 2014 
 
 
 
 
 
 
 
 
Amendment #3 / 24 Sep 2014 
 
 
 
 
 
 
 
 
Amendment #4/ 20May2015 
 
 
 
 
 
 
 
 
Amendment #5/ 29Jul2015 
 
 
 
 
 
 
 
 
Amendment #6 / 05Nov2015 
                                                Amendment #7 / 15Apr2016 
 
 
 
 
 
 
 
 
Amendment #8 / 23Nov2016 
 
TITLE:  A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory 
Multiple Myeloma 
 
Coordinating Center: 
 
 
Princess Margaret Phase II Consortium (PMHC) 
 
Senior Scientific Investigator  Dr. Amit Oza 
 
 
 
 
 
 
 
 
 
Princess Margaret Hospital Phase II Consortium 
 
Department of Medical Oncology 
 
610 University Avenue, 5-700  
 
Toronto, Ontario, CANADA 
 
M5G 2M9  
 
Tel: 416-946-2818 
 
Fax: 416-946-2082 
 
amit.oza@uhn.ca 
 
Principal Investigator: 
Dr. Suzanne Trudel 
 
 
 
Princess Margaret Cancer Centre 
610 University Avenue, 10-721 
 
Toronto, Ontario, CANADA  
 
M5G 2M9  
 
Tel:  416-946-4566 
 
Fax:  416-946-2087 
 
strudel@uhnres.utoronto.ca 
 
Co-Investigators: 
Dr. Nizar Jacques Bahlis 
Foothills Hospital 
681-1403 29 Street NW  
Calgary, Alberta, CANADA 
T2N 2T9 
Tel:  403-944-1564  
Fax: 403-944-2102 
NBahlis@UCalgary.ca 
 
Dr. Christopher Venner  


NCI 9460 / PHL-091 
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  2 
Cross Cancer Institute 
11560 Unversity Avenue 
Edmonton, Alberta, CANADA 
T6G 1Z2 
Tel: 780-432-8757 
Fax: 780-432-8888 
ChristopherPaul.Venner@albertahealthservices.ca 
 
Dr. Annette Hay 
Cancer Centre of Southeastern Ontario at Kingston General 
Hospital 
25 King Street West 
Kingston, Ontario, CANADA 
K7L 5P9 
Tel: 613-533-2946 
Fax: 613-546-8219 
Email: AHay@ctg.queensu.ca  
 
 
 
 
 
 
 
Statistician: 
 
Study Coordinator: 
Lisa Wang 
Smitha Udagani 
Princess Margaret Cancer Centre 
Princess Margaret Cancer Centre 
610 University Avenue, Toronto 
 
 
610 University Avenue, Toronto 
M5G 2M9, Ontario, CANADA 
M5G 2M9, Ontario, CANADA 
Tel: 416-946-4501 ext. 4883 
 
 
 
Tel: 416-946-4501 ext. 3408 
Fax: 416-946-2154 
Fax: 416-946-2016 
 
lisawang@uhnresearch.ca 
smitha.udagani@uhn.ca 
 
Responsible Data Manager: 
Chantale Blattler 
Princess Margaret Cancer Centre 
 
610 University Avenue, Toronto 
M5G 2M9, Ontario, CANADA 
Tel: 416-946-4501 ext. 3692 
Fax: 416-946-2154 
 
chantale.blattler@uhn.ca 
 
 
NCI Supplied Agent(s):   
Trametinib dimethyl sulfoxide (GSK1120212B), NSC# 763093 
GSK2141795, NSC# 767034  


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  3 
 
 
SCHEMA 
 
This is a multi-center, open-label, non-randomized, two stage, phase II study of trametinib in 
patients with relapsed or refractory multiple myeloma (MM). Bone marrow (BM) samples 
from patients will be analyzed for NRAS, KRAS, BRAF mutations at baseline visit. Patients 
will be stratified into one of two study groups:  
• 
Biomarker positive (NRAS, KRAS, BRAF mutated as defined Appendix F) 
• 
Biomarker negative (without NRAS, KRAS, BRAF mutation) 
Patients will be independently recruited into either of the two groups based on biomarker 
positivity. All patients will receive trametinib 2 mg/day orally on a 28 day cycle. Patients who 
develop progressive disease on trametinib monotherapy or achieve less then a partial response 
(PR) after 4 cycles of treatment will have the option to continue on trametinib with the addition 
of GSK2141795. Progressive disease is defined by the IMWG, however in consultation with the 
Principle Investigator, GSK2141795 maybe added for progression not yet meeting the IMWG 
criteria if the treating physician feels that it is in the best interest of the patient.  The dosing of 
trametinib and GSK2141795 will be according to the recommended 1.5 mg trametinib and 50 
mg GSK2141795 daily dosing schedule. The M-protein level at the time of addition of 
GSK2141795 will be considered the new baseline, and the patients will be allowed to continue 
the new treatment schedule until further progression, toxicity, or patient/physician decision to 
discontinue. 
 
 
 


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  5 
TABLE OF CONTENTS 
 
SUMMARY OF PROTOCOL CHANGES................................................................................ i 
SCHEMA ............................................................................................................................... 3 
1 
OBJECTIVES .............................................................................................................. 7 
1.1 
Primary Objectives ....................................................................................................... 7 
1.2 
Secondary Objectives ................................................................................................... 7 
1.3 
Exploratory Objectives ................................................................................................. 7 
2 
BACKGROUND ......................................................................................................... 7 
2.1 
Multiple Myeloma........................................................................................................ 7 
2.2 
CTEP Agent(s)............................................................................................................. 8 
2.3 
Rationale.................................................................................................................... 19 
2.4 
Correlative Studies Background .................................................................................. 21 
3 
PATIENT SELECTION ............................................................................................. 22 
3.1 
Eligibility Criteria ...................................................................................................... 22 
3.2 
Exclusion Criteria ...................................................................................................... 24 
3.3 
Inclusion of Women and Minorities ............................................................................ 26 
4 
REGISTRATION PROCEDURES ............................................................................. 27 
4.1 
General Guidelines ..................................................................................................... 27 
4.2 
Registration Process ................................................................................................... 28 
5 
TREATMENT PLAN ................................................................................................ 28 
5.1 
Agent Administration ................................................................................................. 28 
5.2 
General Concomitant Medication and Supportive Care Guidelines............................... 30 
5.3 
Duration of Therapy ................................................................................................... 33 
5.4 
Duration of Follow Up ............................................................................................... 33 
5.5 
Criteria for Removal from Study................................................................................. 33 
6 
DOSING DELAYS/DOSE MODIFICATIONS........................................................... 34 
6.1 
Trametinib and/or GSK2141795 Dose Modifications................................................... 34 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS.......................... 48 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ........................ 48 
7.2 
Adverse Event Characteristics .................................................................................... 54 
7.3 
Expedited Adverse Event Reporting............................................................................ 54 
7.4 
Routine Adverse Event Reporting ............................................................................... 57 
7.5 
Secondary Malignancy ............................................................................................... 57 
7.6 
Second Malignancy .................................................................................................... 58 
8 
PHARMACEUTICAL INFORMATION .................................................................... 58 
8.1 
CTEP IND Agent(s) ................................................................................................... 58 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..................................... 62 


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9.1 
Biomarker Studies ...................................................................................................... 62 
9.2 
Pharmacodynamic (PD) Studies .................................................................................. 65 
9.3 
RAS and BRAF mutation detection using circulating free DNA (cfDNA) .................... 68 
9.4 
Laboratory Correlative Studies ................................................................................... 68 
10 
STUDY CALENDAR ................................................................................................ 69 
11 
MEASUREMENT OF EFFECT ................................................................................. 71 
11.1 
Antitumor Effect – Solid Tumors N/A ........................................................................ 71 
11.2 
Antitumor Effect – Hematologic Tumors .................................................................... 71 
11.3 
Other Response Parameters ........................................................................................ 73 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ....................................... 74 
12.1 
Data Reporting ........................................................................................................... 74 
12.2 
CTEP Multicenter Guidelines ..................................................................................... 75 
12.3 
Collaborative Agreements Language........................................................................... 75 
13 
STATISTICAL CONSIDERATIONS......................................................................... 77 
13.1 
Study Design/Endpoints ............................................................................................. 77 
13.2 
Sample Size/Accrual Rate........................................................................................... 78 
13.3 
Stratification Factors .................................................................................................. 79 
13.4 
Analysis of Secondary Endpoints ................................................................................ 79 
13.5 
Reporting and Exclusions ........................................................................................... 81 
REFERENCES...................................................................................................................... 82 
APPENDIX A 
PERFORMANCE STATUS CRITERIA .............................................. 87 
APPENDIX B 
CTEP MULTICENTER GUIDELINES................................................ 88 
APPENDIX C 
INFORMATION ON POSSIBLE DRUG INTERACTIONS................. 90 
APPENDIX D 
DATA MANAGEMENT GUIDELINES.............................................. 93 
APPENDIX E 
Diary Card........................................................................................... 94 
APPENDIX F 
MUTATIONAL PROFILING .............................................................. 98 
 
 
 


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1 
OBJECTIVES 
 
1.1 
Primary Objectives 
 
To evaluate the antitumor activity of trametinib determined by overall response rate (ORR) in 
patients that are stratified into groups based on: 
 
• 
Biomarker positive (NRAS, KRAS, BRAF mutated as defined Appendix F) 
• 
Biomarker negative (without NRAS, KRAS, BRAF mutation) 
 
1.2 
Secondary Objectives 
• 
To evaluate progression free survival (PFS) and duration of response (DOR) in the 
two stratified groups 
• 
To document ORR after the addition of GSK2141795 to trametinib in patients who 
have developed progressive disease or have achieved less then a partial response 
(PR) after 4 cycles of treatment 
• 
To evaluate PFS and DOR in patients receiving trametinib plus GSK2141795 
• 
To evaluate the safety profile of trametinib with and without GSK2141795 
 
1.3 
Exploratory Objectives 
• 
To explore the relationship between clinical response and pharmacodynamic (PD) 
markers 
• 
To explore the relationship between MAF expression as determined by quantitative 
PCR (qPCR), chromosomal abnormalities detected by florescence in situ 
hybridization (FISH), and clinical response 
• 
To explore the role of integrin β7 as a biomarker of MAF expression  
• 
To explore the relationship between objective clinical response as well as progressive 
disease and the tumor mutational profile 
• 
To explore mechanism of PI3K/AKT and RAS-MEK-ERK activation and correlate 
these with clinical response and PD markers 
• 
To explore the feasibility of extracting cfDNA from peripheral blood and detecting 
RAS and RAF mutations using cfDNA 
 
2 
BACKGROUND 
 
2.1 
Multiple Myeloma 
Multiple myeloma (MM) is a mature B cell malignancy characterized by the latent expansion of 
malignant plasma cells in the bone marrow (BM). In the majority of cases, MM is epitomized by 
the hypersecretion of monoclonal immunoglobulin (Ig) molecules in the serum, which can be 
detected as a sharp peak (M-spike) by serum protein electrophoresis, or as Bence Jones proteins 
in the urine when Ig light chains are secreted. Among hematological malignancies, MM tumour 
cells are unique in their ability to cause significant bone destruction, which can in turn lead to 
osteoporosis and hypercalcemia. Together, the MM tumour, its products, and its effect on the 
surrounding environment, collectively contribute to the clinical manifestations of MM, which 
include persistent lytic bone disease, renal insufficiency, immune suppression and anemia 
(Dalton et al., 2011; Rabb et a.l, 2009). On the molecular level, the malignant clonal plasma cells 


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can harbor numerical chromosomal abnormalities as well as translocation, some of which being 
of prognostic significance (Herve et al., 2011; Munshi et al., 2011).  
Approximately 22,000 cases of MM are diagnosed each year in the United States (U.S.), with 
over 11,000 reported deaths due to MM annually (Howlader et al., 2012). While the advent of 
autologous stem cell transplantation and advances novel biological agents have improved patient 
outcomes from a 3-year median life expectancy to 5 years, MM remains incurable (Dalton et al., 
2011; Rabb et al., 2009). And though novel therapies in MM including the proteosome inhibitor, 
bortezomib and the immunomodulatory drugs, thalidomide and lenalidomide are highly effective 
and have improved survival of patients with relapsed MM, their administration is not curative, 
not all patients respond, and drug resistance eventually develops (Lauback et al., 2009). Thus 
there remains a need for novel therapeutics approaches that target the underlying molecular and 
cellular mechanisms of disease and drug resistance. During the past decade, insights into the 
biology, genetics, and molecular pathology of the disease have provided a platform upon which 
novel therapeutic strategies that target the myeloma cells more specifically and effectively are 
being fashioned. One such target that has emerged is the RAS-MEK-ERK signaling pathway. 
 
2.2 
CTEP Agent(s) 
 
2.2.1 Trametinib Dimethyl Sulfoxide (GSK1120212B) 
 
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions.  Activation of 
the pathway can result from activation/mutations of the upstream receptor tyrosine kinases 
(RTKs) and RAS, or upregulation/mutations in RAF and MEK.  Upon activation, RAF acts as 
the MAPK kinase kinase and activates MAPKK (MEK1/2), which in turn catalyze activation of 
the effectors ERK1/ERK2.  Once activated, ERK1/2 translocates into the nucleus and 
phosphorylates a number of effector proteins and transcriptional factors that regulate cell 
proliferation, motility, differentiation, and survival.  Trametinib is one of the several MEK 
inhibitors in clinical development.  
 
On May 29, 2013, the U.S. Food and Drug Administration (FDA) approved trametinib for the 
treatment of patients with unresectable or metastatic melanoma with BRAFV600E or BRAFV600K 
mutations as detected by an FDA-approved test (U.S. Food and Drug Amdinistration, 2013).  On 
January 10, 2014, the Food and Drug Administration granted accelerated approval to trametinib 
and dabrafenib for use in combination to treat patients with unresectable or metastatic melanoma 
with a BRAF V600E or V600K mutation as detected by an FDA-approved test (U.S. Food and 
Drug Administration, 2014). 
  
Experience to date indicates that MEK is a valid target.  In a phase 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 (Flaherty et al., 2012).  However, single agent activities are 
limited.  Extensive research is underway to identify the patient selection markers and develop 
rational combination strategies.  Preclinical studies have provided strong rationale and proof of 
principle for combination of MEK inhibitors with RTK inhibitors (EGFR or IGF-1R) (Gopal et 
al., 2010; Ebi et al., 2011), PI3K/AKT inhibitors (Engelman et al., 2008; Hoeflich et al., 2009), 
and mTOR inhibitors.  On the other hand, the optimal dose/schedule and patient selection criteria 


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  9 
for combination regimens have not been defined.  Phase 1 results for a number of combinations 
have been reported:  Phase 1 AZD6244 + MK2206 (Tolcher et al., 2011), phase 1 GDC-0973 + 
GDC-094 (MEK + PI3K inhibitor) (Bendell et al., 2011). 
 
2.2.1.1 Mechanisms of Action and Preclinical Data with Trametinib 
 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, allosteric 
and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM against MEK1 and 
MEK2, respectively) (Gilmartin et al., 2011).  Trametinib inhibited MEK1/2 kinase activity and 
prevented RAF-dependent MEK phosphorylation (S217 for MEK1), producing prolonged 
pERK1/2 inhibition.  Trametinib showed better potency against unphosphorylated MEK1/2 (u-
MEK1/2) when compared with preactivated diphosphorylated MEK (pp-MEK), suggesting that 
u-MEK affords a higher affinity binding site for trametinib than does pp-MEK. 
 
The specificity of trametinib was confirmed against a panel of 183 kinases, including MEK5 (the 
closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 (Yamaguchi et al., 2011).  
Trametinib demonstrated equal potency against activated MEK1- and MEK2-mediated 
phosphorylation of ERK (sequence identity of 85% across the whole protein and 100% in the 
active site for humans).  Trametinib demonstrated preferential inhibition of RAF-mediated 
MEK1 activation (IC50 = 0.60 nM) over pMEK1 kinase activity (IC50 = 13 nM) (Investigator’s 
Brochure, 2012a). 
 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models showed 
the most significant mean tumor growth inhibition (TGI) (80% to 87%) at 3.0 mg/kg trametinib, 
with multiple complete and partial tumor regressions.  In the Colo205 model, tumor regression 
was observed even at a dose of 0.3 mg/kg (Yamaguchi et al., 2011).  Two KRAS-mutant 
xenograft models, HCT-116 and A549, also showed significant TGI (83% and 75%) but without 
significant tumor regressions (Gilmartin et al., 2011).  As predicted by cell proliferation assays, 
tumor xenograft lines with wild-type (wt) RAF/RAS (PC3, BxPC3, and BT474) were much less 
sensitive, showing only modest TGI (44-46%) with no tumor regressions. 
 
Pharmacodynamic studies were performed in mice treated with trametinib for 14 days (Gilmartin 
et al., 2011).  In the A375P F11s xenograft model, the first dose of trametinib (3 mg/kg) 
significantly reduced pERK for more than 8 hours on Day 1.  pERK inhibition was more 
sustained (over 24 hours) after the Day 7 dose, probably due to an increase in the steady-state 
levels of trametinib after repeated doses.  The average Cmax in blood was 1,410 nM on Day 7, 
with an estimated half-life (t1/2) of 33 hours.  In addition, immunohistochemistry (IHC) also 
confirmed inhibition of cell proliferation (reduced Ki67) and G1 cell cycle arrest (elevated 
p27Kip1/CDKN1B) following 4 days of treatment. 
 
2.2.1.2 Clinical Pharmacokinetics (PK) and Activity of Trametinib 
 
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
 
There are 3 parts in this ongoing study.  Part 1:  The dose-escalation portion involves 
administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients with solid tumors or 


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lymphoma in one of three schedules - (1) QD for 21 days followed by 7 days without drug, (2) 
loading dose on Day 1 or Day 1-2, followed by QD with the designated dose, or (3) QD dosing 
without a drug holiday.  Part 2:  cohort expansion at the recommended phase 2 dose (RP2D) for 
pancreatic cancer, melanoma, NSCLC, CRC, or any BRAF mutation-positive cancer.  Part 3:  
expansion to characterize the biologically active range of trametinib via analysis of 
pharmacodynamic biomarkers (biopsies or FDG-PET). 
 
The dose escalation part and some of the cohort expansion components have been completed.  
The MTD of trametinib was established as 3 mg QD, but the recommended phase 2 dose (RP2D) 
was chosen at 2 mg QD based on tolerability of repeated cycles (Infante et al., 2010). 
 
PK and metabolism of trametinib: 
PK measurements were conducted under fasting conditions.  After a single dose (Day 1), AUC0-
24 and Cmax values were dose-proportional up to 6 mg, lower than dose proportional following 8 
mg, and greater than dose proportional following the 10 mg dose.  Median Tmax was 1.5 hours. 
 
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 6.6 at the 
RP2D of 2 mg QD.  Between-subject variability in exposure ranged from 27-50% for Cmax and 
20-41% for AUC0-24 across all dosing regimens.  The effective t1/2 was approximately 4.5 days, 
and steady state was reached by approximately Day 15.  Trametinib had a small peak: trough 
ratio of ~2 (Infante et al., 2010).  At 2 mg QD on Day 15, mean AUC0-24 was 376 ng•h/mL and 
Cmax 23 ng/mL, and the mean trough concentrations ranged from 10.0 to18.9 ng/mL.  The long 
half life and small peak: trough ratio of trametinib allowed constant target inhibition within a 
narrow range of exposure. 
 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 [CYP450]-
mediated) with secondary oxidation or in combination with glucuronidation biotransformation 
pathways (Investigator’s Brochure, 2012a).  The deacetylation is likely mediated by hydrolytic 
esterases, such as carboxylesterases, or amidases.  Based on in vitro studies, trametinib is not an 
inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and CYP3A4. Trametinib has an overall 
low potential for drug-drug interactions.  
 
Pharmacodynamic effect and biomarkers: 
The relationship between dose and tumor biomarkers such as pERK, Ki67, and p27, were 
evaluated in patients with BRAF or NRAS mutation-positive metastatic melanoma 
(Investigator's Brochure, 2012a).  In general, increasing exposures and/or doses provided greater 
pharmacodynamic effects.  The median change observed at a dose of 2 mg QD was 62% 
inhibition of pERK, 83% inhibition of Ki67, and a 175% increase in p27. 
 
Antitumor Activity of Trametinib Monotherapy 
In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib at 2 mg 
QD (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 wt melanoma, 2 patients achieved a 
partial response (PR), and 3 stable disease (SD) (Infante et al., 2010).  In 26 evaluable pancreatic 


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  11 
cancer patients, there were 2 PRs (1 PR was KRAS mutation-positive) and 11 SD (2 achieved 
≥20% tumor reduction) (Messersmith et al., 2011).  Among the 27 CRC patients (without 
selection of RAS or RAF mutations), 8 SD were observed. 
 
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a BRAF 
V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) or 
chemotherapy (dacarbazine or paclitaxel) (Flaherty et al., 2012).  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).  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. 
 
Antitumor Activity of Trametinib in Cancer Other Than Melanoma 
 
In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or myelodysplastic syndrome 
(MDS) patients were given trametinib at dose levels from 1-2 mg QD.  Drug-related AEs in 45 
patients were similar to that observed in patients with solid tumors, and 2 mg PO QD was 
selected for further investigation in this patient population.  Twelve patients (23%) withdrew due 
to an AE, including cardiac failure (2) and infection (2).  Efficacy was reported in 39 patients 
(Borthakur et al., 2010).  The best response in 13 patients with KRAS or NRAS mutations 
included 3 CRs (23%), 7 SD (54%), and 1 PD (progressive disease) (5%).  In 26 patients with 
wild-type RAS or an unknown mutation, there were 2 PRs (8%). 
 
2.2.1.3 Safety Profile of Trametinib  
 
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. 
 
AEs of special interest: 
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis are 
considered AEs of special interest because they are either known class effects (i.e., have been 
observed with other MEK inhibitors) or are potentially life-threatening (Investigator’s Brochure, 
2012a). 
 
Rash:  Rash was a common AE observed across different dose levels and in different 


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  12 
combinations (Investigator’s Brochure, 2013).  At the 2 mg dose, rash was seen in 27% to 78% 
of patients in different trials.  Of the ~370 subjects with rash AEs at the 2 mg monotherapy dose 
(including crossover subjects) in five studies, the majority of rash AEs were grades 1 or 2 (24% 
to 73%); 0% to 9% of patients experienced grade 3 rash AEs, and four patients had a grade 4 
rash AE. 
 
In a randomized phase 3 trial of trametinib vs. chemotherapy, the overall incidence of skin 
toxicity (including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia syndrome, 
and erythema) was 87% in patients treated with trametinib and 13% in chemotherapy-treated 
patients.  Severe skin toxicity occurred in 12% of patients on the trametinib arm, most commonly 
for secondary infections of the skin  The median time to onset of skin toxicity was 15 days 
(range:  1 to 221 days), and median time to resolution was 48 days (range:  1 to 282 days).  Dose 
reduction was required in 12% for skin toxicities, and permanent discontinuation of trametinib 
was required in 1% of patients.  
 
Diarrhea: At the 2 mg monotherapy dose, 33% to 58% of patients in five trials had diarrhea 
(Investigator’s Brochure, 2013).  Of ~320 subjects (including crossover subjects) with diarrhea at 
this dose, the majority of diarrhea AEs were grade 1 or 2 in severity (33% to 56% of all study 
patients); 17 patients had grade 3 diarrhea, and none had grade 4 diarrhea. 
 
Visual disorders:  At the 2 mg monotherapy dose, 4% to 21% of the patients in five trials 
experienced visual disorders (Investigator’s Brochure, 2013).  Of the 85 total subjects (including 
crossover subjects) experiencing visual disorders at this dose level, the majority of visual 
disorders were grades 1 or 2 (4% to 20% of all study patients); six patients experienced grade 3 
visual disorders, and one patient experienced a grade 4 visual disorder. 
− 
Retinal Pigment Epithelial Detachment (RPED):  Also known as chorioretinopathy, RPED is a 
visual impairment due to fluid accumulation under the retina and causes blurry vision.  There 
were five cases of RPED, previously termed central serous retinopathy, reported from the 
integrated trametinib safety population consisting of subjects treated with trametinib 2 mg once 
daily from five studies (Investigator’s Brochure, 2013).  As of 23 June 2013, 14 cases of RPED 
were reported across the entire trametinib program amongst subjects treated with trametinib 
either as monotherapy or in combination with other anti-cancer agents (including cases from a 
MEK/BRAF combination study). 
 
− 
Retinal vein occlusion (RVO):  As of 23 June 2013, a total of four cases of RVO were reported 
across the entire trametinib program (including one case from a MEK/BRAF combination study) 
(Investigator’s Brochure, 2013).  All cases of RVO occurred in one eye only.  Study drug was 
stopped at time of diagnosis in all cases.  There was a decrease of visual acuity in two subjects 
with central RVO (CRVO) while the other two subjects had no meaningful decrease of visual 
acuity.  In the two subjects with CRVO, local treatment with intravitreal injections of anti-VEGF 
antibodies was initiated within 2 weeks after RVO diagnosis, and visual acuity improved in one 
subject and restored to baseline conditions in another subject, at the time of the data cutoff.  
Three of these four cases were considered related to study treatment by the investigators. 
 
 
Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been observed with 


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administration of trametinib (Investigator’s Brochure, 2013).  However, assessment of these 
cases was often confounded by co-morbid conditions (such as biliary obstruction), concomitant 
use of other potentially hepatotoxic drugs, and liver metastases.  At the 2 mg monotherapy dose, 
8% to 34% of patients in five trials had LFT abnormalities.  Of the 96 total patients (including 
crossovers) with LFT changes, the majority were grade 1 or 2 in severity (4% to 20% of all study 
patients); 26 had grade 3 events, and 6 patients had grade 4 events. 
 
Cardiac-related AEs:  At the 2 mg monotherapy dose, 3% to 21% of the subjects in six studies 
had cardiac-related AEs (Investigator’s Brochure, 2013).  Of the 65 total subjects (including 
crossover subjects) experiencing cardiac-related AEs at the 2.0 mg monotherapy dose in five of 
the studies, the majority of cardiac-related AEs were grades 1 or 2 in severity (0% to 16% of all 
study subjects); 18 subjects had grade 3 cardiac-related AEs, and no subjects had Grade 4 
cardiac-related AEs in any study.  No subject in one study, which evaluated the effect of repeat 
oral dosing of trametinib 2 mg QD on cardiac repolarization in subjects with solid tumors, had 
cardiac-related AEs.  One study subject receiving trametinib 2 mg QD had grade 5 (fatal) acute 
cardiac failure, with evidence of massive tumor invasion of the heart; this AE was considered not 
drug-related by the investigator. 
In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma (MEK114267), 
cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or decreased LVEF) 
occurred in 7% (14/211) of patients treated with trametinib, and in no patients in the chemotherapy 
arm.  Cardiomyopathy was identified within the first month of treatment in five of these 14 patients; 
median onset of cardiomyopathy was 63 days (range: 16 to 156 days).  Cardiomyopathy resolved in 
10 of these 14 (71%) patients.  Cardiac monitoring should be included in trametinib protocols, to 
include LVEF assessment by echocardiogram or MUGA scan at baseline, one month after 
initiation of trametinib and then at 2- to 3-month intervals while on treatment.  Refer to dose 
modification guidelines for cardiac AEs in the event of LVEF decline or symptomatic cardiac 
AEs. 
 
Pneumonitis:  At the 2 mg monotherapy dose, 0% to 4% of the subjects in five studies had 
pneumonitis (Investigator’s Brochure, 2013).  Of the nine total subjects (including crossovers) 
experiencing pneumonitis AEs at this dose, three subjects had grade 1 or 2 pneumonitis and six 
subjects had grade 3 pneumonitis. 
 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause fetal harm when 
administered to a pregnant woman.  Trametinib was embryotoxic and abortifacient in rabbits at 
doses greater than or equal to those resulting in exposures approximately 0.3 times the human 
exposure at the recommended clinical dose.  If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, the patient should be apprised of the potential 
hazard to a fetus. 
 
Incidence of common AEs reported from a phase III trial of trametinib vs. chemotherapy in 
patients with advanced melanoma: 
 
Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or current 
evidence of Class II or greater congestive heart failure (New York Heart Association) were 
excluded from this trial.  Selected adverse reactions (AR) occurring in patients receiving 


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trametinib as compared to patients in the chemotherapy arm are listed as below: 
 
Table:  Selected adverse reactions (ARs) occurring in ≥10% of patients receiving trametinib 
AND at a higher incidence than in the chemotherapy arm (high in the trametinib arm compared 
with chemotherapy by ≥5% in overall incidence or by ≥2% grade 3 or 4 AEs) 
 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
 
Table:  Percent-patient incidence of laboratory abnormalities occurring at a higher incidence in 
patients treated with trametinib versus chemotherapy (between-arm difference of ≥5% [all 
grades] or ≥2% [grades 3 or 4]) 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate aminotransferase 
(AST) 
60 
2 
16 
1 
Increased alanine aminotransferase (ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline phosphatase 
24 
2 
18 
3 
 
Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated with 
trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders (blurred 
vision, dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), cardiac 
disorders (bradycardia), gastrointestinal disorders (xerostomia), and musculoskeletal and 
connective tissue disorders (rhabdomyolysis).   
 
 
 


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2.2.1.4 Clinical Experience with the Combination of Trametinib + Dabrafenib 
 
Preliminary data on 45 patients participating in the phase 1/2 study of dabrafenib and trametinib, 
BRF113220, have been reported (Infante et al., 2011). 
 
PK 
The plasma levels of dabrafenib were higher in combination with trametinib as compared to that 
with monotherapy.  Geometric mean Day 15 AUC of dabrafenib in combination ranged from 
3539 to 5187 ng•hr/mL, and the AUC observed in the monotherapy study was 2619 ng•hr/mL.  
Further data are required to understand this difference. 
 
PK of trametinib did not appear to be affected by the addition of dabrafenib.  Preliminary results 
showed that the geometric mean dose-normalized AUC0-τ (CV%) for trametinib (dose 
normalized for the 2.0 mg QD dose) in combination with dabrafenib at 150 mg BID was 302 
ng•hr/mL (n=17; 35%) on Day 15.  Historical PK data from the trametinib FTIH study 
(MEK111054) indicated a mean Day 15 AUC0-τ (CV%) of 360 ng•hr/mL (31%). 
 
Safety and the RP2D for the combination of Trametinib and Dabrafenib 
One DLT of a recurrent grade 2 neutrophilic panniculitis occurred, and pyrexia was common 
(51%).  The RP2D was 150 mg BID dabrafenib plus 2 mg QD trametinib (both agents at the 
RP2D for single agent).  Of the 137 patients enrolled, 32 patients were treated at the RP2D.  
SAEs experienced by more than one patient include:  pyrexia (5%), hypotension (4%), nausea 
(3%), and 2% of patients had a constellation of AEs including vomiting, dehydration, or renal 
failure.  The only grade 4 AE was a sepsis-like syndrome with fever/hypotension.  Grade 3 AEs 
included generalized rash (n=2, 4%) and neutropenia (n=2, 4%).  Skin toxicity (rash) occurred in 
9 (20%) patients.  Of note, the rate of SCC was 2% in this study.  A single case of grade 5 
hyponatremia was reported.  Other common AEs are listed in the table below. 
 
Summary of selected AEs experienced by ≥5% of patients regardless of causality in 
BRF113220 (treated at RP2D) 
AE Term 
Dose Escalation Cohort 
(150mg BID/2 mg QD) 
(n=31) 
Any AE, n (%) 
24 (77) 
Pyrexia 
10 (32) 
Rash 
4 (13) 
Dermatitis 
acneiform 
1 (3) 
Hypotension 
4 (13) 
 
Activity 
Among 77 evaluable patients with melanoma who had not received prior BRAF inhibitors, there 
were 43 responses (56%), including 4 CRs (5%) and 39 PRs (51%) (Weber et al., 2012).  
Twenty-nine patients experienced SD, and three patients experienced PD.  Patients were treated 
on four escalating dose levels of dabrafenib/trametinib (mg BID/mg QD):  75/1, 150/1, 150/1.5, 
150/2.  The confirmed RR for each dose level, respectively, was 67% (n=6), 64% (n=22), 48% 


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(n=25), and 54% (n=24).  Median PFS (months) for each of the first three dose levels, 
respectively, was 8.7, 8.3, and 5.5; PFS data are not mature for the fourth (150/2) dose level.  
Overall PFS was 7.4 months. 
 
Currently, the randomized phase 2 portion (Part C) of the study of dabrafenib with or without 
trametinib has enrolled 162 patients as of September 1, 2011 (Investigator’s Brochure, 2012b). 
 
2.2.1.5 Clinical Experience with the Combination of Trametinib + GSK2141795 (AKT 
inhibitor) (TAC113886) 
 
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 
(Kurzrock et al., 2011).  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 regime of 1.5 mg trametinib + 50 mg 
GSK2141795 will be considered for further development.  Additional trials to explore alternate 
schedules (e.g., intermittent) and pharmacodynamic markers are ongoing. 
 
2.2.2 GSK2141795 
 
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. 
 
Unless otherwise specified, information provided herein regards AKT inhibitor GSK2141795 
dosed as a single agent.  Information on the combination of GSK2141795 and MEK inhibitor 
trametinib can be found 2.2.1.5. 
 
Pharmacokinetics (PK) 
Single-dose (Day 1) PK parameters of GSK2141795 were evaluated in the first-time-in-human 
(FTIH) study (PCS112689).  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 


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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. 
 
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) 
The MTD of single-agent GSK2141795 is 75 mg once-daily as determined by the FTIH study.  
The RP2D of single-agent GSK2141795 has not been determined. 
 
Potential Drug-drug Interactions 
In vitro data indicate that GSK2141795 is a CYP3A4 substrate.  Drugs that potently inhibit 
CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should either be 
prohibited or used with caution.  Drugs that are strong inducers of CYP3A and may result in 
lower exposures of GSK2141795 should also be prohibited.  GSK2141795 also appears to be a 
moderate in vitro inhibitor of CYP2C8 (50% inhibitory concentration [IC50] 3 mcM) and 
CYP3A4 (IC50 11 mcM).  Drugs that are substrates of CYP3A4 or CYP2C8 with a narrow 
therapeutic index may be prohibited.  Drugs that are sensitive substrates of CYP3A4 or CYP2C8 
should be used with caution. 
 
The following medications (including but not limited to) are prohibited during the study: 
 
PROHIBITED – highly sensitive and/or low therapeutic index CYP3A/CYP2C8/BCRP/CYP3A4 
substrates since concentrations of these drugs may be increased 
CYP3A Substrate 
Therapeutic Area 
cisapride 
Hypnotics and Sedatives 
pimozide 
Antidepressant, Antipsychotics, Antianxiety 
agents 
astemizole 
Antihistamine 
BCRP Substrate 
Therapeutic Area 
rosuvastatin,sulfasalazine 
HMG-CoA Reductase Inhibitors, gastrointestinal 
agents 
PROHIBITED – strong inducers/inhibitors of CYP3A4 
Strong CYP3A4 Inhibitor/Inducer 
Therapeutic Area 
clarithromycin, telithromycin, rifamycin class 
agents (e.g., rifampin, rifabutin, rifapentine), 
troleandomycin 
Antibiotics 
itraconazole, ketoconazole 
Antifungals 
nefazodone 
Antidepressants 
atazanzvir, delaviridine, indinavir, lopinavir, 
nelfinavir, ritonavir, saquinavir, nevirapine 
Antivirals 
carbamazepine, phenobarbital, phenytoin 
Anticonvulsants 
 
For a list of medications that may alter the concentrations of trametinib or GSK2141795 or have 
their elimination altered by trametinib or GSK2141795 and thus should be administered WITH 


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CAUTION is provided in section 5.2.3. 
 
GSK2141795 Safety Profile and Management 
Based on available adverse event (AE) data from 151 subjects dosed as of the data cut-off date of 
May 6, 2012, the most common toxicities of GSK2141795 monotherapy or in combination with 
trametinib are gastrointestinal (GI)-related (diarrhea, nausea, and vomiting) and fatigue 
(Investigator’s Brochure, 2012).  Hyperglycemia, hypoglycemia, mucositis, and rash are also 
commonly observed.  In addition, three cases of hypothyroidism have been noted. 
 
GI-related AEs 
Interim medical history, continuous assessment of AEs, physical examination, and clinical 
laboratory assessments will be used to identify and assess toxicity in the GI tract.  Supportive 
therapy will be provided according to standard medical practice.  Treatment will be discontinued 
for clinically significant toxicity. 
 
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.  Early diarrhea 
management for subjects taking GSK2141795 is critical and must be initiated as soon as the first 
episode of diarrhea has occurred.  Supportive care interventions should include dietary 
modifications, anti-diarrheal medications, and supplementary intravenous hydration as needed. 
 
Mucosal inflammation:  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 re-
challenge can ameliorate symptoms.  Supportive care interventions should include good oral 
hygiene, adequate pain control, prevention of superinfection, and maintenance of adequate of 
hydration with supplementary intravenous hydration as needed. 
 
Cutaneous AEs 
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.  Treatment will be dose reduced or discontinued for clinically 
significant toxicity not adequately controlled by supportive care measures. 
 
Glucose Abnormalities 
Hyperglycemia:  Hyperglycemia occurred in patients receiving ≥75 mg/day with the majority of 
events occurring at doses exceeding the maximum tolerated dose (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 


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ameliorate the hyperglycemia, although both intravenous and sliding scale insulin have been 
helpful. 
 
To reduce the risk of hyperglycemia, patients with abnormal fasting glucose values at screening 
will be excluded.  In addition, patients with Type 1 diabetes will also be excluded; however, 
patients with Type 2 diabetes will be allowed if diagnosed ≥6 months prior to enrollment, and if 
presenting with regular hemoglobin A1C (HbA1C) ≤8% at screening.  Patients will have glucose 
and insulin monitored during the study.  If hyperglycemia is observed, supportive therapy will be 
provided according to standard medical practice.  Treatment will be dose reduced or 
discontinued for clinically significant toxicity that cannot be adequately managed medically. 
 
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.  Careful monitoring of glucose levels 
and encouragement of adequate oral intake are recommended. 
 
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.  Continued 
monitoring for thyroid function (thyroid-stimulating hormone laboratory testing) will be 
incorporated in all clinical protocols.  Supportive therapy will be provided according to standard 
medical practice, and treatment will be discontinued if necessary. 
 
Other Glandular Events 
In both rats and dogs, several glandular structures (salivary, nasal, mammary, and Brunner’s 
glands) had reversible reductions in secretory content and/or apoptosis of individual acinar cells.  
The mechanism for this finding is not understood, although it may result in dry mouth, a toxicity 
that has been reported in some patients.  Frequent monitoring with medical history, physical 
examination, and clinical laboratory assessments will be done.  If clinically significant toxicity is 
observed, supportive therapy will be provided according to standard medical practice, and 
treatment will be discontinued if necessary. 
 
2.3 
Rationale 
There is substantial evidence validating the importance of RAF and MEK in cancer progression 
and in promoting cancer growth. Mutationally activated BRAF and RAS have been identified at 
high frequency in a variety of human cancers including MM (Santarpia et al., 2012; McCubrey et 
al., 1994). Further germline de novo mutational activation of HRAS, KRAS, BRAF and MEK1/2 
have been found in patients with developmental disorders that have an increased incidence of 
cancers (Tartaglia et al., 2011). Both constitutively activated RAS and RAF kinases are known to 
potently transform mouse fibroblast and inhibition of the downstream effectors, MEK or ERK 
are required for the transforming activities of RAS (McCubrey et al., 1994). As a result, 
considerable effort has been devoted to the development of cancer drugs directed against the 
RAS-MEK-ERK pathway. 
 
In addition to its well-documented role in solid tumors, many studies have highlighted the ability 


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of the RAS-MEK-ERK pathway to stimulate the proliferation and induce chemoresistance of 
MM cells. Activating mutations of KRAS, NRAS and BRAF have been reported in approximate 
27%, 24% and 4%, respectively of MM cases (Chapman et al., 2012; Morgan et al., 2012). RAS 
mutations are implicated in disease progression from MGUS to overt MM, aggressive phenotype 
and shorter survival (Corradini et al., 1994; Weiss  et al., 2010). Studies in myeloma cell line 
models demonstrate that ectopic expression of mutated RAS can confer cytokine independent 
growth, induces proliferation and resistant to certain chemotherapeutic drugs such as 
dexamethasone and doxorubicin (Billadeau et al., 1995; Rowley et al., 2002). Further in MM 
patients that harbor the t(4;14) translocation or translocations that dysregulate the MAF family of 
transcription factors (approximately 30% of MM patients) the MEK-ERK pathway appears to 
regulate expression of MAF and inhibition of MEK selectively induces apoptosis of MAF-
expressing myeloma tumors (Annunziata et al., 2011). These studies suggest that targeting the 
RAS-ERK-MEK pathway may be a valuable approach to treatment of MM and that MEK 
inhibitors may preferentially benefit patients whose tumors harbour mutations of RAS, RAF or 
overexpress MAF proteins.  
 
As MEK is a critical node in the RAS-MEK-ERK signaling pathway it represents an attractive 
focus for the development of novel targeted therapy potentially benefiting a large proportion of 
cancer patients whose tumors depend on this pathway. Experience to date indicates that MEK is 
valid therapeutic target. Single agent clinical activity has been reported in BRAF mutated 
melanoma, cholangiocarcinoma, and MM ((Flaherty et al., 2012; Bekaii-Saab et al., 2011; 
Zingone et al., 2011). In a phase II study of the MEK inhibitor, AZD6244 an intermin analysis 
reported 2 objective responses and 12 stable diseases were reported in 25 evaluable relapsed 
myeloma patients (Holkova et al., 2011). Interestingly, of the two responders one had a 
translocation t(4;14) and the other expressed MAF-B (Zingone et al., 2011). Although preclinical 
and clinical data suggest that cells with BRAF or RAS mutations are more likely to respond to 
MEK inhibitors, the response rate is low. Potential explanations include the intrinsic or induced 
activation of alternative signaling pathways and in particular the PI3K/AKT signaling. In 
myeloma tumors, the PI3K pathway is not frequently mutated however phosphorylated AKT, 
which is indicative of PI3K activity, is detected in approximately 50% of cases (Zöllinger et al., 
2008). Interestingly, DEPTOR a positive regulator of the PI3K pathway is upregulated, 
especially in cases of MAF-positive MM (Peterson et al., 2009). Pre-clinical studies suggest that 
AKT activation in MM tumors is independent of oncogenic RAS and that combined inhibition of 
RAS and AKT strongly enhances MM cell death Steinbrunn et al., 2011). The data suggests that 
additionally targeting the AKT pathway may increase MEK inhibitor response rates.  
 
These studies provide the rationale for targeting MEK with trametinib in myeloma. The pre-
clinical data supports the evaluation of MEK inhibitors in patients as a single-agent and in 
combination with an AKT inhibitor in MM for patients who fail to respond to MEK inhibition 
alone. The data also support the stratification of patients based on NRAS, KRAS, and BRAF 
mutational status and potentially MAF expression, factors that we hypothesize will influence 
response. Trametinib will be evaluated as single agent in a Phase II trial. GSK2141795 (AKT 
inhibitor) will be combined with trametinib for patients progress on treatment or who fail to 
respond to trametinib after 4 cycles of treatment. This period of time is anticipated to provide a 
reasonable estimate of the response to single-agent trametinib, as the median time to response for 
two active agents studied in previously conducted phase III trials (bortezomib and 


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  21 
lenalidomide/dexamethasone) estimated this to be 42 days (Richardson et al., 2005) and 2.1 
months (Dimpoulos et al., 2007). Indeed in the ECOG study of low dose vs high dose 
dexamethasone in combination with lenalidomide, only 5 patients of 445 upgraded their response 
to a partial remission after 4 cycles of treatment (Rajkumar et al., 2010). It is understood that 
given the addition of the AKTi after 4 cycles for patients who fail to achieve a PR or better, this 
trial will only provide an estimate of the overall response rate to single agent trametinib.  
 
2.4 
Correlative Studies Background 
Our hypothesis is that a MEK inhibitors evaluated in the context of a Phase II trial will induce 
clinical responses in a subset of myeloma patients and that biological correlates obtained from 
serial bone marrow (BM) sampling will provide insights into patient selection biomarkers and 
mechanisms of resistance. 
 
Next-generation sequencing analysis (NGS) : Our hypothesis is that patients whose tumors 
harbor mutations of RAS or RAF will preferentially respond to MEK inhibition. To test this 
hypothesis and to potentially enhance the effect size we have chosen to stratify patients based on 
the presence or absence of mutations of RAS or RAF. Mutational analysis will be performed by 
the University Health Network (UHN) CLIA laboratory. . Cases that are positive for mutations 
of RAS or RAF and an allele fraction of  > 10% will be stratified to the biomarker positive 
group.  
  
MAF expression: Pre-clinical studies demonstrate selective induction of apoptosis of MAF-
expressing myeloma tumors suggesting that this group of myeloma patients may preferentially 
respond to MEK inhibitors. RNA derived from screening BM samples will be used to quantify 
MAF expression (c-maf, MAF-B and MAF-A) by quantitative PCR (qPCR). As this assay has 
not been validated, results will not be used to stratify patients; however, clinical response rates 
will be correlated with MAF expression as an exploratory endpoint.  In additon, the relationship 
between MAF expression and chromosomal abnormalities will be evaluated by qPCR and 
florescence in situ hybridization (FISH).  FISH is a standard molecular assay performed in cases 
of multiple myeloma. Evidence suggests that high levels of MAF occur in myeloma tumors with 
translocations t(14:16) that dysregulates cMAF, t(14:20) that dyregulates MAFB, and t(4;14) that 
results in overexpression of FGFR3 and MMSET (Annunziata et al., 2011). As an exploratory 
endpoint we will therefore determine the correlation between these two molecular assays (qPCR 
and FISH).  We propose that this will provide information for better clinical interpretation of an 
assay that is already employed as standard of care for multiple myeloma. 
 
Integrin-β7 expression: Integrin-β7 is cell surface protein whose expression is regulated by the 
transcription factor MAF (Hurt et al., 2004).  Its cell surface expression can be detected by flow 
cytometry making integrin-β7 a potential biomarker that can easily translate to the clinical lab. 
As an exploratory endpoint we will measure integrin-β7 on CD138+ myeloma cells and correlate 
positivity with MAF expression and clinical responses.  
 
Pharmacodynamic (PD) Studies 
Multi-parameter Flow Cytometry (MFC) Studies: Myeloma cells will be evaluated for target 
modulation and the effects of trametinib with or without GSK2141795 on downstream signaling 
targets of RAS signaling and alternative pathways (PI3K/AKT). With the recent introduction of 


NCI 9460 / PHL-091 
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  22 
techniques that measure the activation states of signaling pathways using phosphospecific 
antibodies, the scope of MFC now extends into molecular therapeutic monitoring in the clinic 
(Tong et al., 2006). By using MFC applications, we will determine whether the MEK target 
ERK, is activated in myeloma cells pre-treatment and whether administration of trametinib 
inhibits ERK phosphorylation in primary MM cells. Further, we will determine whether at 
progression, ERK phosphorylation remains suppressed despite trametinib treatment providing 
valuable insights into whether escape mechanisms are ERK-independent or ERK-dependent. In 
addition, we will evaluate whether the PI3K/AKT pathway is activated at baseline or is induced 
in response to single agent trametinib or at progression, as a potential mechanism of resistance. 
The results will be correlated to response to trametinib +/- GSK2141795 and analyzed as an 
exploratory endpoint.  
 
Reversal Phase Protein Arrays (RPPA): RPPA is a quantitative assay that analyzes nanolitre of 
sample for potentially hundreds of proteins (Iadevaia et al., 2010).  This antibody-based assay 
determines levels of protein expression, as well as protein modifications such as 
phosphorylation.  RPPA allows concordant interrogation of multiple signaling molecules and 
their functional status. The integrated information has the potential to display the functional 
outcomes affected by therapeutics that may inform on predictors of response or mechanisms of 
resistance.  
 
The products of these correlative assays are to validate biomarkers related to MM responses and 
outcomes to MEK inhibitors that will serve to guide patient selection strategies for subsequent 
clinical trials. In addition, we expect to begin testing hypotheses around novel biomarkers and 
mechanisms of resistance that may inform combination strategies and guide the development of 
innovative, personalized therapeutics for MM and cancers and general.  
 
RAS and BRAF mutation detection using circulating free DNA (cfDNA) 
Currently the detection of RAS and BRAF mutations is carried out in tumor tissue by NGS. This 
requires bone marrow aspiration for derivation of tumor tissue and CD138 purification of 
myeloma tumor cells for DNA extraction. Recent studies have validated the detection of KRAS 
and BRAF mutations from circulating free tumor DNA (cfDNA). cfDNA was detected in 100% 
of patients with metastatic colorectal cancer and showed 100% specificity and sensitivity for 
BRAFV600E mutation and 98% specificity and 92% sensitivity for KRAS mutations (Thierry 
AR et al. 2014). Thus this represents a minimally invasive and cost-effective method for 
identification of patients that are most likely to benefit from targeted therapy. We postulate that 
patients with MM will similarly have detectable cfDNA and that mutations of RAS and RAF can 
be efficiently and effectively detected from cfDNA. 
 
3 
PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed Multiple Myeloma NOS 
(10028566). 
 


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  23 
3.1.2 Patients must have measurable disease as defined as at least one of the following (these 
baseline laboratory studies for determining eligibility must be obtained within 28 days 
prior to start of protocol therapy): 
• Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l) 
• Urine M-protein ≥ 200 mg/24 h 
• Serum free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) 
and an abnormal serum free light chain ratio (< 0.26 or > 1.65) 
• Biopsy proven plasmacytoma (should be measured within 28 days of first study 
drug administration). Prior biopsy is acceptable. 
• If the serum protein electrophoresis is unreliable for routine M-protein 
measurement, quantitative immunoglobulin levels on nephrolometry or 
turbidometry will be followed. 
 
3.1.3 A diagnosis of MM and documentation of relapsed or relapse/refractory status following 
at least 2 prior lines of therapy. 
 
3.1.4 Documented lab results confirming tumor mutational status (as outlined in Appendix F , 
Table 3) must be obtained at screening. Patients in whom mutational status cannot be 
determined will be deemed ineligible. 
 
3.1.5 Because no dosing or adverse event data are currently available on the use of trametinib 
with and without GSK2141795 in patients <18 years of age, children are excluded from 
this study. 
 
3.1.6 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.7 Life expectancy of greater than 6 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 v4 grade ≤1 (except alopecia) at 
the time of registration. Subjects with toxicities attributed to prior anti-cancer therapy 
which are not expected to resolve and result in long lasting sequelae are permitted to 
enroll. 
 
3.1.10 Patients must have normal organ and marrow function as defined below:   
• Absolute neutrophil count (ANC) ≥ 1.0 x109/L  
• Hemoglobin ≥ 8 g/dL 
• Platelets ≥ 50x109/L  
• Albumin ≥ 2.5 g/dL 
• Total bilirubin ≤ 1.5x institutional ULN (isolated bilirubin > 1.5x ULN is 
acceptable if bilirubin is fractionated and direct bilirubin < 35%) 
• Aspartate aminostransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5x 
institutional ULN 


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  24 
• Serum creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥ 30 mL/min OR 24-hour urine creatinine clearance ≥ 30 mL/min 
• Prothrombin time (PT)/International normalized ratio (INR) and partial 
thromboplastin time (PTT) ≤ 1.5x institutional ULN 
• Fasting serum glucose < 126 mg/dl (7 mmol/l) 
• Left ventricular ejection fraction (LVEF) ≥ institutional lower limit of normal 
(LLN) by ECHO or MUGA 
 
3.1.11 Subjects that have been previously diagnosed with Type 2 diabetes or steroid-induced 
diabetes must also meet the additional following criteria: 
• Diagnosed with diabetes > 6 months prior to enrolment 
• HbA1C < 8% at screening visit 
 
3.1.12 The effects of trametinib or GSK2141795 on the developing human fetus are unknown.  
For this reason and because MEK inhibitors as well as other therapeutic agents used are 
known to be teratogenic, 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.  Women of child-bearing potential 
must have a negative serum pregnancy test within 7 days prior to the start of protocol 
therapy.  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 administration. 
 
3.1.13 Ability to understand and the willingness to sign a written informed consent document. 
 
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 second 
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 Diabetes mellitus currently requiring insulin. Subjects with a history of steroid-induced 
hyperglycemia may be enrolled provided that HbA1C at screening visit is < 8%. 
 


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  25 
3.2.4 Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic 
therapy, or immunotherapy within 28 days prior to randomization and/or daily or weekly 
chemotherapy or other approved anti-myeloma therapy without the potential for delayed 
toxicity within 14 days prior to registration. 
 
3.2.5 Use of other investigational drugs within 28 days preceding the first dose of trametinib 
and during the study. 
 
3.2.6 Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression. 
 
3.2.7 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or 
GSK214795. 
 
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.  (note:  megestrol [Megace] if used as an 
appetite stimulant is allowed). 
• Concurrent treatment with bisphosphonates is permitted; however, treatment must be 
initiated prior to the first dose of study therapy.  Prophylactic use of bisphosphonates in 
patients without bone disease is not permitted, except for the treatment of osteoporosis. 
• Because the composition, PK, and metabolism of many herbal supplements are unknown, the 
concurrent use of all herbal supplements is prohibited during the study (including, but not 
limited to, St. John’s wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone 
[DHEA], yohimbe, saw palmetto, or ginseng). 
 
3.2.9 In vitro data indicate that GSK2141795 is a CYP3A4 substrate.  Drugs that potently 
inhibit CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should 
either be prohibited or used with caution.  Drugs which are strong inducers of CYP3A 
and may result in lower exposures of GSK2141795 should also be prohibited.  
GSK2141795 also appears to be a moderate in vitro inhibitor of CYP2C8 (50% inhibitory 
concentration [IC50] 3 mcM) and CYP3A4 (IC50 11 mcM).  Drugs that are substrates of 
CYP3A4 or CYP2C8 with a narrow therapeutic index may be prohibited.  Drugs that are 
sensitive substrates of CYP3A4 or CYP2C8 should be used with caution. (Refer to 5.2.3)   
 
3.2.10 History or current evidence/risk of retinal vein occlusion (RVO) or Retinal Pigment 
Epithelial Detachment (RPED): 
• History of RVO or RPED, or predisposing factors to RVO or RPED(e.g., uncontrolled 
glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, 
diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes). 
• Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor 
for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual 
field defects, and intraocular pressure >21 mm Hg. 


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  26 
 
3.2.11 History or evidence of cardiovascular risk including any of the following: 
• LVEF<LLN. 
• A QT interval corrected for heart rate using the Bazett’s formula QTcB ≥480 msec (> 500 
msec for subjects with bundle branch block) 
• History or evidence of current clinically significant uncontrolled arrhythmias (exception:  
patients with controlled atrial fibrillation for >30 days prior to randomization are 
eligible). 
• Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd 
degree atrioventricular (AV) block. 
• Subject with intra-cardiac defribillators or pacemakers. 
• History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization. 
• History or evidence of current ≥ Class II congestive heart failure as defined by the New 
York Heart Association (NYHA) functional classification system 
• Treatment-refractory hypertension defined as a blood pressure of systolic >140 mmHg 
and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy. 
• Known cardiac metastases. 
 
3.2.12 Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C 
Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV 
infection, which will be allowed). 
 
3.2.13 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. 
 
3.2.14 Animal reproductive studies have not been conducted with trametinib.  Therefore, the 
study drug must not be administered to pregnant women or nursing mothers.  Women of 
childbearing potential should be advised to avoid pregnancy and use effective methods of 
contraception.  Men with a female partner of childbearing potential must have either had 
a prior vasectomy or agree to use effective contraception.  If a female patient or a female 
partner of a patient becomes pregnant while the patient receives trametinib, the potential 
hazard to the fetus should be explained to the patient and partner (as applicable).  These 
potential risks may also apply to GSK2141795. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.  This study is 
designed to include minorities as appropriate.  However, the trial is not designed to measure 
differences in intervention effects.  The population of Southern Ontario is ethnically diverse and 
the proportion of different ethnic groups in the community is provided in the table below.  
Universal access to health care will ensure that there is no discrimination on the basis of race or 
gender (Guide to Canadian Human Rights Act: www.chrc-ccdp.ca/public/guidechra.pdf ). 
Individual hospital registries and databases do not routinely collect racial data, under the 
direction of the Canadian Human Rights Code. 


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  27 
 
The population demographics and distribution of minorities in Canada is included in the 
following table: 
 
Table: Visible minority population by Consortium Provinces  (2001 Census)  
 
British Columbia Alberta 
Ontario 
Nova Scotia 
Total 
Total population of province 3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Population % 
Population % 
Population % 
Population % 
Population % 
Black 
25,465 
1% 
31,390 
1% 
411,095 
4% 
19,670 
2% 
487,620 
3% 
Asian 
768,435 
20% 268,660 
9% 
1,513,825 
13% 12,630 
1% 
2,563,550 
13% 
Latin American (Hispanic) 
23,880 
1% 
18,745 
1% 
106,835 
1% 
520 
0% 
149,980 
1% 
Visible minority, not included 
elsewhere 
4,195 
0% 
4,220 
0% 
78,915 
1% 
1,170 
0% 
88,500 
0% 
Multiple visible minority 
14,465 
0% 
6,910 
0% 
42,375 
0% 
535 
0% 
64,285 
0% 
Total Visible minority 
population 
836,440 
22% 329,925 
11% 2,153,045 
19% 34,525 
4% 
3,353,936 
18% 
Source: Statistics Canada, Census of Population.  
 
Data from our consortium has been compiled regarding the representation of minorities on 
previous clinical trials, and the distribution is as follows: 
 
Population Percentage of Minority and Gender of entering PMHC Trials 
 
2010 
2011 
2012 
Visible Minorities 
 
 
 
Black 
0.9 
2.3 
1.2 
Asian 
10.1 
10.9 
11.6 
Hispanic 
10.1 
2.3 
3.5 
Total  
21.1 
15.5 
16.3 
Women 
59.6 
56.6 
44.2 
 
4 
REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The Study Coordinator at the Princess Margaret Consortium Central Office will enter eligible 
patients on study centrally.  All sites should call the Study Coordinator (listed on cover page) to 
verify biomarker cohort availabilities.  The required forms (Eligibility Checklist) will be 
provided upon site activation. 
 
Following registration, patients should begin protocol treatment within 3 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator (cc the central office 
study coordinator).  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study may be cancelled.  The Study Coordinator should be notified 


NCI 9460 / PHL-091 
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  28 
of cancellations as soon as possible. 
 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP.  A participating site may order agents 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 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the PMH Phase II Consortium Central Office.  The eligibility checklist will 
only be sent once this has been received.   
 
No patient can receive protocol treatment until registration with the Central Office has taken 
place.  All eligibility criteria must be met at the time of registration.  There will be no exceptions.  
Any questions should be addressed with the Central Office prior to registration.   
 
To register a patient, the following documents are to be completed by the research nurse or data 
manager and sent / faxed to the Central Office Study Coordinator: 
• 
Signed patient consent form 
• 
Eligibility Checklist CRF signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility 
has been confirmed: 
• 
Assign a patient study number 
• 
Assign the patient a dose 
• 
Register the patient on the study 
• 
Fax or e-mail the confirmation worksheet with the patient study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
study coordinator listed on the front sheet. Patient registration will be accepted between the 
hours of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central 
office will be closed. 
 
5 
TREATMENT PLAN 
 
5.1 
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 6.1.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
Patients will receive trametinib 2 mg taken orally once a day continuously of a 28 day cycle. 
Patients who develop progressive disease on trametinib monotherapy or achieve less then a PR 


NCI 9460 / PHL-091 
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  29 
after 4 cycles of treatment will have the option to continue on trametinib with the addition of 
GSK2141795. Progressive disease is defined by the IMWG, however in consultation with the 
Principle Investigator, GSK2141795 maybe added for progression not yet meeting the IMWG 
criteria if the treating physician feels that it is in the best interest of the patient.  The dosing of 
trametinib and GSK2141795 will be according to the recommended 1.5 mg trametinib and 50 
mg GSK2141795 daily dosing schedule. 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:  
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Trametinib 
Empty stomach; 
1hr before or 2hr 
after a meal 
 
2mg alone 
OR 
1.5mg in 
combination with 
GSK2141795 
oral 
daily 
28 days  
 
 
GSK2141795 
Empty stomach 1 
hour after a small 
snack and 2 hours 
before a meal 
50mg 
oral 
daily 
**Doses as appropriate for assigned dose level; refer to section 6.1.  
 Please refer to Appendix E for example drug administration regimen of combination treatment 
 
For patients in whom the trametinib dose during monotherapy has been reduced to 1.5 mg the 
dose of trametinib will not be further reduced upon the addition of GSK2141795.  For patients 
on trametinib monotherapy who have been dose reduced to 1.0 mg, their dose will remain at 1.0 
mg upon the addition of GSK2141795.  No dose re-escalation is permitted in the study (except 
for in the events defined in section 6).   
 
5.1.1 Trametinib 
 
The effect of food on trametinib absorption is unknown.  The current recommendation is to 
administer trametinib on an empty stomach, either 1 hr before or 2 hr after a meal; the 
recommendation to administer trametinib fasting may change based on emerging data. 
 
5.1.2 Other Agent(s) GSK2141795 
 
Capsules must be taken fasting 1 hour following a meal and 2 hours before the next meal. Based on 
nonclinical data and increasing clinical experience, it is possible that GSK2141795 may be a 
direct gastrointestinal mucosal irritant such that subjects with GI dysmotility or GERD may be 
predisposed to symptoms of dyspepsia. Therefore, in an effort to decrease this discomfort, we 
have the following recommendations. The following is recommended: 
• 
Eat a small snack followed by 60 minutes of fasting prior to taking 
GSK2141795.  Water is allowed during this fasting period. 


NCI 9460 / PHL-091 
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  30 
• 
If possible, take each GSK2141795 capsule approximately 5 minutes apart with 
divided amounts of fluid (4-8 oz with each capsule for a total of at least 12 oz). 
• 
Remain upright for 30 minutes after taking the last capsule of GSK2141795. 
• 
Fast for 2 hours after ingestion of the last capsule of GSK2141795. Water is allowed 
during this fasting period. 
• 
In more severe cases, consider sucralfate and/or Gaviscon as supportive care to be 
taken at least 2hr after ingestion of the last capsule of GSK2141795, so as to avoid 
any potential drug-drug interactions. 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 Permitted Medications 
 
Subjects will be instructed to inform the investigator prior to starting any new medications from 
the time of screening until the end of the clinical phase of the study. Any concomitant 
medications, including over-the counter medications, herbal preparations and alternative 
therapies, taken during the study will be recorded in the CRF.    
 
Subjects should receive full supportive care during the study, including transfusions of blood and 
blood products, erythopoeitin and G-CSF support, and treatment with antibiotics, antiemetics, 
antidiarrheals, and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines. Subjects should not receive those medications listed as prohibited in 
Section 5.2.2.  
 
5.2.2 Prohibited Medications 
 
Subjects should not receive other anti-cancer therapy or other investigational drug while on study 
treatment, except for megestrol [Megace] if used as an appetite stimulant is allowed. 
 
Patients should abstain from taking any herbal and dietary supplements within 5 half lives (or 14 
days if the drug is a potential enzyme inducer) prior to the first dose of either study drug until 
completion of the follow-up visit, unless in the opinion of the Investigator and sponsor there is 
little concern for a potential drug-drug interaction with the study drug(s).  These herbal 
medications include but are not limited to, St. John’s wort, kava, ephedra (ma huang), ginkgo 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. The investigator 
should contact a CTEP Medical Monitor before initiating treatment with any herbal preparation. 
 
The following medications (including but not limited to) are prohibited during the study: 
 


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  31 
PROHIBITED – highly sensitive and/or low therapeutic index CYP3A/CYP2C8/BCRP/CYP3A4 
substrates since concentrations of these drugs may be increased 
CYP3A Substrate 
Therapeutic Area 
Cisapride 
Hypnotics and Sedatives 
Pimozide 
Antidepressant, Antipsychotics, Antianxiety agents 
Astemizole 
Antihistamine 
BCRP Substrate 
Therapeutic Area 
Rosuvastatin,sulfasalazine 
HMG-CoA Reductase Inhibitors, gastrointestinal 
agents 
PROHIBITED – strong inducers/inhibitors of CYP3A4 
Strong CYP3A4 Inhibitor/Inducer 
Therapeutic Area 
clarithromycin, telithromycin, rifamycin class 
agents (e.g., rifampin, rifabutin, rifapentine), 
troleandomycin 
Antibiotics 
Itraconazole, ketoconazole 
Antifungals 
Nefazodone 
Antidepressants 
atazanzvir, delaviridine, indinavir, lopinavir, 
nelfinavir, ritonavir, saquinavir, nevirapine 
Antivirals 
carbamazepine, phenobarbital, phenytoin 
Anticonvulsants 
 
5.2.3 Cautionary Medications: 
 
The following medications (including but not limited to) that may alter the concentrations of 
trametinib or GSK2141795 or have their elimination altered by trametinib or GSK2141795 
should be administered WITH CAUTION: 
 
USE WITH CAUTION – Drugs Potentially Affecting trametinib or GSK2141795 concentrations 
Drug 
Therapeutic Area 
quinidine, diltiazem, verapamil 
Antiarrhythmics:   
fluvoxamine, fluoxetine, paroxetine,nefazodone 
Antidepressants: 
aprepitant, cimetidine 
Antiemetics 
fluconazole, terbinafine,  voriconazole 
Antifungals 
ciprofloxacin, erythromycin, isoniazid 
Anti-infectives 
Mibefradil, diltiazem, verapamil 
Calcium Channel Blockers 
aprepitant, oxandrolone, tizanidine, gemfibrozil 
Miscellaneous 
USE WITH CAUTION – Drugs that may inhibit P-gp and BCRP 
Drug 
Therapeutic Area 
Valspoda 
Miscellaneous 
Atorvastatin 
HMG-CoA Reductase Inhibitors 
Carvedilol 
Congestive Heart Failure 
Methadone 
Analgesic 
Meperidine 
Narcotic 
Omeprazole 
Proton Pump Inhibitor 
USE WITH CAUTION – Drugs that may have their concentrations altered by trametinib or 


NCI 9460 / PHL-091 
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  32 
GSK2141795 
Drug 
Therapeutic Area 
Repaglinide, rosiglitazone, pioglitazone 
Antidiabetics 
alfentanil, fentanyl 
Analgesics 
Quinidine 
Antiarrhythmics   
Cilostazole 
Anticoagulants and Antiplatelets 
Astemizole 
Antihistamines 
diergotamine, ergotamine, eletriptan 
Antimigraine agents 
Pimozide 
Antipsychotics 
Buspirone 
Anxiolytics 
Felodipine 
Calcium Channel Blockers 
sildenafil, tadalafil, vardenafil 
Erectile Dysfunction agents 
cerivastatin,ovastatin, simvastatin, atorvastatin 
HMG-CoA Reductase Inhibitors 
Alprazolam, diazepam, midazolam, triazolam 
Hypnotics and Sedatives 
cyclosporine, sirolimus, tacrolimus 
Immunosuppressive agents 
Cisapride 
Prokinetic agents 
cyclosporine, torsemide, chloroquine, zopiclone 
Miscellaneous 
Eperenone 
Selective Aldosterone Blockers 
chloroquine, zopiclone 
Thiazolidinediones 
 
Use of repaglinide, rosiglitazone, and/or pioglitazone is permitted only after consultation with 
the CTEP Medical Monitor. 
 
Oral steroids should be used with caution and subjects monitored for steroid-induced 
hyperglycemia.  Short courses (up to a maximum of 14 days) of oral corticosteroids intended to 
treat study treatment related rash or diarrhea are allowed.  Budenoside is recommended for 
supportive care of diarrhea.   
 
Subjects will be instructed to inform the investigator before taking any of these or any other 
medications.  Investigators (or their appropriate designee) will be expected to review 
concomitant medications with the subject at each clinical visit.  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 will be counseled on the risk of interactions 
with other agents, and what to do if new medications need to be prescribed or if the patient is 
considering a new over-the-counter medicine or herbal product.  Appendix C is a patient 
information sheet that can be used for this specific protocol and presented to the patient. 
 
5.2.4    Prophylaxis medications 
 
The following medications are recommended as prophylaxis during the first 4 cycles of 
treatment due to an increased incidence of Shingles and infection noted on patients in this trial: 
 
• Shingles prophylaxis: Valtrex 500mg OD is preferred otherwise acyclovir 400mg bid can 
be used 
 


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  33 
• Infection prophylaxis: Ciprofloxacin or Moxifloxacin 
 
The prophylaxis recommendations above are an additional care measure while determination as 
to whether there is reasonable possibility, that Trametinib and GSK2141795 caused the increased 
incidence of shingles or infection (urinary tract or upper respiratory) noted in the patients on this 
trial. 
 
5.3 
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,  
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator, 
• 
Clinical progression, 
• 
Patient non-compliance 
• 
Pregnancy 
• 
All women of child bearing potential (WOCBP) should be instructed to contact 
the investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. Institutional 
policy and local regulations should determine the frequency of on study 
pregnancy tests for WOCBP enrolled in the study. 
• 
The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
• 
Termination of the study by sponsor. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for 4 weeks after removal from study treatment or until death, 
whichever occurs first.  Adverse event(s) related to study treatment will be followed until 
resolution to a < grade 1 or until the adverse event remains stable at the same grade for at least 2 
months. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed in Section 5.3 applies.  The 
reason for study removal and the date the patient was removed must be documented in the Case 
Report Form. 
 
 
 
 
 


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6 
DOSING DELAYS/DOSE MODIFICATIONS 
 
6.1 
Trametinib and/or GSK2141795 Dose Modifications 
 
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications when dosing trametinib as a single agent: 
 
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg QD 
-1 
1.5 mg QD 
-2 
1 mg QD 
 
If GSK2141795 is added for disease progression after 2 cycles or because of failure to achieve a 
PR after 4 cycles then the dose of tramentinib will be reduced to 1.5 mg and combined with 50 
mg pf GSK2141795 administered daily.  
 
The table below outlines the dose levels to be used for any necessary trametinib dose 
modifications when trametinib is dosed with GSK2141795: 
 
Dose Level 
Trametinib Dose/Schedule 
0 
1.5 mg QD 
-1 
1.0 mg QD 
-2 
0.5 mg QD 
 
The table below outlines the dose levels to be used for any necessary GSK2141795 dose 
modifications: 
 
Dose Level 
GSK2141795 Dose/Schedule 
0 
50 mg QD 
-1 
25 mg QD 
 
A maximum of two Trametinib and/or one GSK2141795 dose level reductions are allowed. 
Patients may have up to 2 dose level reductions of Trametinib while taking Trametinib alone 
(lowest dose allowed is 1 mg QD). Patients may have a further 2 dose level reductions of 
Trametinib while taking Trametinib in combination with GSK2141795 (lowest dose allowed is 
0.5 mg QD).  
 


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6.1.1 Trametinib or GSK2141795 Dose Modification for Toxicities Hematological/ Non-Hematological Toxicities Not Otherwise 
Specified  in Subsequent Sections 
 
The investigator should use clinical judgment to determine which drug may be contributing to the toxicity necessitating dose 
adjustment and make the appropriate change for that drug. 
 
Study Drug(s) Modification for Clinically Significant Toxicities Deemed Related to Study Drug(s) 
(This section is not for specific AEs such as hypertension, rash, ejection fraction changes, pneumonitis, diarrhea, liver chemistry, QTc prolongation, visual changes, 
neutropenia, or thrombocytopenia.  Refer to other sections for these specific AEs). 
CTCAE v4 Grade 
Management Guideline 
Dose Modification 
Grade 1 
Monitor as clinically 
indicated.  Provide supportive 
care according to institutional 
standards 
Continue trametinib and/or GSK2141795 at current dose level. 
Grade 2 
• Interrupt trametinib and/or GSK2141795 until resolution to grade 1 or baseline.   
• Upon resolution, restart trametinib and/or GSK2141795 at current dose level. 
Grade 3 
• Interrupt trametinib and/or GSK2141795 until resolution to grade 1 or baseline.   
• Upon resolution to baseline or grade 1, restart the interrupted agent(s) with one level of dose reduction 
• If the Grade 3 toxicity recurs, interrupt trametinib and/or GSK2141795; When toxicity resolves to Grade 
1 or baseline, restart the interrupted agent(s)  reduced by another dose level 
Grade 4 
Permanently discontinue trametinib and/or GSK2141795. 
Study drug(s) should be discontinued if treatment delay is >28 days due to toxicities.  If the investigator concludes that continued study drug(s) will benefit a 
patient, the study chair and CTEP Medical Monitor may be consulted for the possibility of resuming study drug(s), provided that toxicities have resolved to 
baseline or grade 1. 
 
6.1.2 Trametinib and/or GSK2141795 Dose Modification for Rash 
 
Rash is a frequent AE observed in patients receiving trametinib (Investigator’s Brochure, 2012a) or GSK2141795.  Recommendations 
for supportive care and guidelines for dose modifications for rash are based on experience with other MEK inhibitors and EGFR 
inhibitors (Balagula et al., 2010; Lacouture et al., 2011). 
 
Further, two types of rashes may be seen with the trametinib + GSK2141795 combination: 
• Acneiform rash, typically associated with tramentinib. 
• 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.  


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In general, topical and oral antibiotics play a larger role in management of the tramentinib acneiform rash, while topical and oral 
steroids are more relevant to the management of the GSK2141795 maculopapular rash.  Subjects should contact the investigator 
immediately upon onset of a rash. Full supportive care should be provided to subjects who experience a rash while on study. The 
following information is a guideline. 
 
The institutional standards for the management of skin-related AEs can differ from these guidelines.  In this case, best clinical 
judgment should be applied and a consultation with the study chair or the CTEP Medical Monitor may be required. 
 
Guidelines for Supportive Care of Rash 
Type of Care 
Action 
Prevention/ 
Prophylaxisa 
 
• Avoid unnecessary exposure to sunlight. 
• Apply broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin protection factor (SPF) ≥15 at least twice daily. 
• Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol cream) on dry areas of the body at least twice daily. 
• Topical steroids and antibiotics should be applied at least twice daily, starting on Day 1 of study treatment, to body areas such as face, 
chest, and upper back.   
• Use mild-strength topical steroid (hydrocortisone 1% cream) or topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 
100 mg BID, minocycline 100 mg BID). 
Symptomatic Careb 
 
Upon the first signs of rash, mild strength topical steroid (e.g. hydrocortisone 1% cream) with escalation to higher strength and/or oral 
steroid as detailed below. 
• Upon the first signs of papulopustular (acneiform) rash consider doxycycline (100 mg BID) or minocycline (100 mg BID). 
• 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 and 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. 
• For subjects who had study drug reduced because of rash, re-escalation may be considered if toxicity does not recur with a re-challenge at a 
lower dose. 
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. 


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Study Drug(s) 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 and/or GSK2141795. 
• If rash does not recover to baseline within 2 weeks despite best supportive care, reduce 
trametinib and/or GSK2141795 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 and/or GSK2141795 by one dose level. 
• If rash recovers to ≤ grade 1 within 2 weeks, increase dose to previous dose level. 
• If no recovery to ≤ grade 1 within 2 weeks, interrupt trametinib until recovery to ≤ grade 1. 
• Restart trametinib and/or GSK2141795 at reduced dose level.3 
Grade ≥3 
 
• Use moderate strength topical steroids 
PLUS oral methyl-prednisolone dose 
pack.2 
• For papulopustular (acneiform) rash 
consider doxycycline 100 mg bid or 
minocycline 100 mg bid. 
• Consult dermatologist. 
• Interrupt trametinib and/or GSK2141795 until rash recovers to ≤ grade 1. 
• Restart with trametinib and/or GSK2141795 reduced by one dose level.3,4 
• If no recovery to ≤ grade 2 within 28 days, permanently discontinue trametinib and/or 
GSK2141795. 
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 >28 days of interruption. 
4.  Trametinib may be escalated to previous dose level if no rash is evident 4 weeks after restarting study treatment. 
 
6.1.3 Trametinib Dose Modifications for Visual Changes 
 
Trametinib is known to be associated with visual adverse events.  An ophthalmologist should be consulted if changes in vision 
develop.  However, if the visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), then monitor closely as 
it may be reasonable to defer ophthalmic examination.  Special attention should be given to retinal findings (e.g., retinal pigment 
epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central retinal vein occlusions [RVO]).   
The ophthalmology exam will include best corrected visual acuity, visual field examination, tonometry, direct fundoscopy, and 
indirect fundoscopy.  Optical coherence tomography is recommended at scheduled visits and if retinal abnormalities are suspected.  
Other types of ancillary testing including visual field examination, fundus photography, and fluorescein angiography may also be 
indicated as determined by clinical exam. 
 


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Guidelines regarding event management and dose reduction for visual changes considered to be related to study treatment are 
provided in the tables below. 
 
Management and Trametinib Dose Modification for Visual Changes 
and/or Ophthalmic Examination Findings 
Event 
CTCAE Grade 
Management Guideline 
Dose Modification 
Grade 1* 
 
 
• Consult ophthalmologist 
within 7 days of onset. 
 
• If dilated fundus examination cannot be performed within 7 days of onset, hold trametinib until RPED and RVO 
can be excluded by retina specialist/ophthalmologist. 
• If RPED and RVO excluded, continue/or restart trametinib at same dose level. 
• If RPED suspected/diagnosed:  See RPED dose modification table below (following this table); report as SAE. 
• If RVO diagnosed:  Permanently discontinue trametinib and report as SAE. 
Grade 2 and Grade 3 
 
• Consult ophthalmologist 
immediately. 
 
• Hold trametinib 
• If RPED or RVO excluded, restart trametinib at same dose level after visual AE is < grade 1.  If no recovery 
within 3 weeks, discontinue trametinib 
• If RPED diagnosed:  See RPED dose modification table below; report as SAE. 
• If RVO:  Permanently discontinue trametinib and report as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
• Report as SAE. 
• Hold Trametinib 
• If RPED/RVO excluded, may restart trametinib at same or reduced dose after discussion with the CTEP 
Medical Monitor. 
• If RVO or RPED, permanently discontinue trametinib. 
Abbreviations: RPED = retinal pigment epithelial detachments; RVO = retinal vein occlusion; SAE = serious adverse event 
*If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but ophthalmic examination is not required. 
 
Trametinib Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only) 
• Continue treatment with retinal evaluation monthly until resolution.  If RPED worsens, follow instructions below. 
Grade 2-3 RPED (Symptomatic with mild to 
moderate decrease in visual acuity; limiting 
instrumental ADL) 
• Interrupt trametinib. 
• Retinal evaluation monthly. 
• If improved to ≤ Grade 1, restart trametinib with one dose level reduction (reduced by 0.5 mg) or discontinue in patients taking 
trametinib 1 mg daily. 
• If no recovery within 4 weeks permanently discontinue trametinib 
 


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6.1.4 Trametinib and/or 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 may include concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, or partial bowel obstruction.  Those conditions should be excluded. 
 
Guidelines regarding management and dose modification for diarrhea considered related to trametinib and/or GSK2141795 are 
provided in the table below. 
 
Management and Study Drug(s) 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 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 study drug(s). 
• If diarrhea is grade 2 for > 48 h, 
interrupt study drug(s) until diarrhea 
resolves to grade ≤1. 
• Restart study drug(s) at the same dose 
level 
• If treatment delay is >28 days, 
discontinue study drug(s). 


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Management and Study Drug(s) 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 study drug(s) until diarrhea 
resolves to ≤ grade 1. 
• Restart with study drug(s) reduced by 
one dose level.4 
• If 3 dose reductions of study treatment 
are clinically indicated, permanently 
discontinue study drug(s). 
• If treatment delay is >28 days, 
discontinue study drug(s). 
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. 


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6.1.5 Trametinib and/or GSK2141795 Dose Modification for Liver Chemistry Changes 
 
Study Drug(s) Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
• ALT ≥3x ULN but <5x ULN and 
TB <2x ULN, without symptoms 
considered related to liver injury or 
hypersensitivity and who can be 
monitored weekly for 4 weeks 
 
• May continue study drug. 
• Report as SAE if CTEP-AERS reporting criteria is met. 
• If liver chemistry stopping criteria are met any time, proceed as described below. 
 
MONITORING: 
Repeat LFT (ALT, AST, ALK, bilirubin) until they return to normal/baseline or stabilise (LFT may be every 2 weeks after 4 weeks if 
ALT <3x ULN and TB <2 ULN). 
Criteria for discontinuing study 
drug:  When any of the liver stopping  
criteria below is met, discontinue 
trametinib  
 
1) ALT ≥3xULN and bilirubin ≥2x 
ULN  or >35% direct bilirubin 1, 2 
2) ALT ≥ 3xULN and INR >1.5, if 
INR measured2  (INR threshold 
does not apply if subject is on 
anticoagulant) 
3) ALT ≥5x ULN 
4) ALT ≥3x ULN persists for ≥4 
weeks 
5) ALT ≥3x ULN and cannot be 
monitored weekly for 4 weeks 
6) ALT  ≥3x ULN associated with 
symptoms3  (new or worsening) 
believed to be related to  liver 
injury or hypersensitivity 
 
 
Immediately discontinue study treatment. 
• 
Do not restart/rechallenge unless approved by CTEP trametinib medical monitor.  [ 
• 
Report as SAE if:  1) CTEP-AERS reporting criteria are met, or 2) patients meet criteria 1-2. 
• 
Perform liver event ASSESSMENT AND WORKUP (see below). 
• 
Monitor the subject until liver chemistries resolve, stabilize, or return to baseline (see MONITORING below). 
 
MONITORING: 
In patients stopping for criteria 1-2 (with abnormal TB and INR, indicating potentially more significant liver toxicities): 
• 
Repeat liver chemistries (ALT, AST, ALK, bilirubin) and perform liver event follow-up assessments within 24 hours. 
• 
Monitor subjects twice weekly until LFT return to normal/baseline or stabilize. 
• 
A specialist or hepatology consultation is recommended. 
In patients stopping for criteria 2-6: 
• 
Repeat LFT and perform liver event follow up assessments within  24-72 hrs  
• 
Monitor subjects weekly until LFTs return to normal/baseline or stabilize. 
 
ASSESSMENT and WORKUP: 
• 
Viral hepatitis serology.4 
• 
Serum CPK and LDH. 
• 
Fractionate bilirubin, if total bilirubin ≥2x ULN. 
• 
CBC with differential to assess eosinophilia. 
• 
Record clinical symptoms of liver injury, or hypersensitivity on AE CRF. 
• 
Record concomitant medications (including acetaminophen, herbal remedies, other over the counter medications). 
• 
Record alcohol use. 
Additional work up for patient stopping for criteria 1-2 (with abnormal TB and INR, indicating potentially more significant liver 
toxicities): 


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Study Drug(s) Dose Modification for Liver Function Test Abnormalities 
Event 
Treatment modifications and assessment/monitoring 
• 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies, and quantitative total 
immunoglobulin G (IgG or gamma globulins). 
• 
Serum acetaminophen adduct HPLC assay (in subjects with likely acetaminophen use in the preceding). 
• 
If there is underlying chronic hepatitis B (e.g. positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody.5 
• 
Liver imaging (ultrasound, MRI, CT) and /or liver biopsy. 
Footnotes: 
1.  Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, which indicates direct bilirubin elevations and suggesting liver injury. 
2.  All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5 (if INR measured) may indicate severe liver injury (possible 
“Hy’s Law”).  INR measurement is not required, and the threshold value stated will not apply to subjects receiving anticoagulants. 
3.  New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be 
related to hypersensitivity (such as fever, rash or eosinophilia) 
4.  Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral 
capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
5.  If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus (where needed) (Le Gal et al., 2005). 
 
 
 
 
 
 
 
 
 
 
 


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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. 
 
Management and Study Drug Modification Guidelines for Pneumonitis 
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 > 28 days, 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 > 28 days, permanently discontinue 
trametinib. 
Grade 4 
Same as grade 3. 
Permanently discontinue trametinib. 
Abbreviations:  BAL = bronchoalveolar lavage; CT = computed tomography. 
 
 
 


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6.1.7 Trametinib Dose Modification for Reduced Left Ventricular Ejection Fraction 
 
 
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).   
 
Trametinib Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of >10% in LVEF 
compared to baseline and ejection fraction 
below the institution’s LLN. 
• Interrupt trametinib and repeat ECHO/MUGA within 2 weeks.a 
• If the LVEF recovers within 4 weeks (defined as 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.b 
− Repeat ECHO/MUGA 2, 4, 8, and 12 weeks after re-start; continue in intervals of 12 weeks thereafter. 
• If LVEF does not recover within 4 weeks: 
− Consult with cardiologist. 
− Permanently discontinue trametinib. 
− Report as SAE 
− Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 weeks or until resolution. 
− Consult with the CTEP trametinib medical monitor.c 
 
Symptomaticb 
 
• Grade 3:  resting LVEF 39-20% or >20% 
absolute reduction from baseline 
• Grade 4:  Resting LVEF ≤20%. 
• Permanently discontinue trametinib. 
• Report as SAE. 
• Consult with cardiologist. 
• Repeat ECHO/MUGA after 2, 4, 8, 12, and 16 weeks or until resolution. 
a If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks after restarting of trametinib.  Approval from the CTEP trametinib medical 
monitor is required. 
c Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. 


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6.1.8 Trametinib and/or GSK2141795 Dose Modification for QTc Prolongation 
 
Study Drug(s) Withholding and Stopping Criteria for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• QTcB ≥501 msec, or 
• Uncorrected QT >600 msec, or 
• QTcB >530 msec for subjects with 
bundle branch block 
 
• Interrupt study treatment until QTcB prolongation resolves to grade 1 or 
baseline. 
• Test serum potassium, calcium, phosphorus, and magnesium.  If 
abnormal, correct per routine clinical practice to within normal limits. 
• Review concomitant medication usage for a prolonged QTc. 
• Restart at current dose level.b 
• If the event does not resolve or recurs after restarting, permanently 
discontinue study treatment. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using Bazett’s formula 
a Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued. 
b if the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and the CTEP trametinib medical monitor agree that the subject will benefit from further treatment. 
 
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. 
 
Monitoring:  All BP assessments should be performed under the following optimal conditions: 
 
• The subject has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor. 
• The subject is relaxed comfortably for at least 5 minutes. 
• Restrictive clothing has been removed from the cuff area, and the right cuff has been 
selected. 
• The subject’s arm is supported so that the middle of the cuff is at heart level. 
• The subject remains quiet during the measurement. 
• In subjects with an initial BP reading within the hypertensive range, a second reading 
should be taken at least 1 minute later, with the two readings averaged to obtain a final 
BP measurement.  The averaged value should be recorded in the eCRF. 
• Persistent hypertension is defined as an increase of systolic blood pressure (SBP) >140 
mmHg and/or diastolic blood pressure (DBP) >90 mmHg in three consecutive visits with 
blood pressure assessments from two readings as described above.  Visits to monitor 
increased blood pressure can be scheduled independtly from the per-protocol visits 
outlined in the study calendar.  Ideally, subsequent blood pressure assessments should be 
performed within 1 week. 


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Management and Trametinib Dose Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
Definitions used in the table: 
- Persistent hypertension:  Hypertension detected in two separate readings during up to three subsequent visits. 
- Well-controlled hypertension:  Blood pressure of SBP ≤140 mmHg and DBP ≤90 mmHg in two separate 
readings during up to three subsequent visits. 
- Symptomatic hypertension:  Hypertension associated with symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting or other symptoms indicative of hypertension) that resolve after the blood 
pressure is controlled within the normal range. 
- Asymptomatic hypertension: SBP >140 mmHg and/or DBP >90 mmHg in the absence of the above symptoms. 
(Scenario A) 
• Asymptomatic and persistent SBP 
of ≥140 and <160 mmHg, or DBP 
≥90 and <100 mmHg,  
or 
Clinically significant increase in 
DBP of 20 mmHg (but still below 
100 mmHg). 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP.  If BP is not well-controlled 
within 2 weeks, consider referral to 
a specialist and go to scenario (B). 
Continue trametinib at the current 
dose. 
(Scenario B) 
• Asymptomatic SBP ≥160 mmHg, 
or DBP ≥100 mmHg,  
or 
Failure to achieve well-controlled BP 
within 2 weeks in Scenario A. 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Interrupt trametinib if clinically 
indicated. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario C) 
• Symptomatic hypertension  
or 
Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive medication and 
dose reduction of trametinib 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt trametinib. 
• Once BP is well-controlled, restart 
trametinib reduced by one dose 
level.a 
(Scenario D) 
Refractory hypertension 
unresponsive to above interventions 
or hypertensive crisis. 
Continue follow-up per protocol. 
Permanently discontinue 
trametinib. 
a. Escalation of trametinib to previous dose level can be considered if BPs remain well controlled for 4 weeks 
after restarting of trametinib.  Approval from Medical Monitor is required. 
 
6.1.10 GSK2141795 Dose Modification for Hypo- and Hyperglycemia 
 
To reduce the risk of hyperglycemia, patients with abnormal fasting glucose values at screening 
will be excluded.  In addition, patients with Type 1 diabetes will also be excluded; however, 
patients with Type 2 diabetes will be allowed if diagnosed ≥6 months prior to enrollment, and if 
presenting with regular hemoglobin A1C (HbA1C) ≤8% at screening.  Patients will have glucose 
and insulin monitored during the study.  If hyperglycemia is observed, supportive therapy will be 
provided according to standard medical practice.  Treatment will be dose reduced or 
discontinued for clinically significant toxicity that cannot be adequately managed medically. 


NCI 9460 / PHL-091 
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  47 
 
• (Mild) Fasting blood glucose > 150mg/dL (8.3 mmol/l) 
 
Monitor fasting and preprandial glucose. 
 
• (ModeratetoSevere) Fasting blood glucose <70 mg/dL (3.9 mmol/l) OR any blood glucose 
>250 mg/dl (13.9 mmol/l) 
 Instruct subject to hold study drug(s) and notify investigator immediately. The investigator 
should discuss intervention and possible resumption of GSK2141795 with the study chair 
and CTEP sponsor  
 
If a blood glucose > 250 mg/dL (13.9 mmol/l) is observed the subject should be monitored for 
ketoacidosis as clinically indicated.  If subject has evidence of ketoacidosis, then treatment 
should be undertaken with awareness that the action of insulin or other antihyperglycemic agents 
(e.g. sulfonylureas, biguanides, etc.) may be substantially blocked by the action of the 
GSK2141795. The action of insulin or other antihyperglycemic agents should be restored as 
GSK2141795 is cleared. If an antihyperglycemic agent is administered, then the subject should 
be observed closely for rebound hypoglycemia as GSK2141795 is cleared. Intravenous insulin 
treatment is recommended. 
 
6.1.11 GSK2141795 Dose Modification for Mucositis 
 
Mucositis has been observed as a dose-limiting toxicity of GSK2141795 
. 
Event Name 
Mucositis 
Grade of Event 
Management 
Dose Modification 
Grade 1-2 
 
Encourage oral hygiene. Offer topical 
supportive anesthetics. Encourage 
adequate hydration. 
No change in dose 
Hold until ≤ Grade 1.  Resume at same 
dose level. 
Grade 3-4 
Above, plus systemic opiate 
administration as needed. Consider IV 
hydration and hospital admission as 
appropriate. Temporarily discontinue 
study drug(s) and discuss with GSK 
Medical Monitor. 
Temporarily discontinue GSK2141795 
and discuss with study monitor.  
Hold* until < Grade 2.  Resume at one 
dose level lower. 
*Patients requiring a delay of > 28 days should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
 
 
 
 
 
 
 
 


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  48 
6.1.12 Trametinib and/or GSK2141795 Dose Modification for Neutropenia 
 
Event Name 
Neutropenia 
Grade of Event 
Management  
Dose Modification 
Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3-4  
 
Hold only for febrile neutropenia 
(single temperature of > 38.3C OR a 
sustained temperature of > 38C for 
more then 1 hour) OR grade 4 
neutropenia (ANC < 500/ul) 
Hold until < Grade 2. GCSF therapy 
may be started at the discretion of the 
treating physician. The dose of study 
drug(s) may be maintained if 
neutropenia was the only study drug 
related toxicity requiring dose 
modification and GCSF treatments are 
continued. Otherwise decrease by one 
dose level.  
*Patients requiring a delay of > 28 days should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
6.1.13 Trametinib and/or GSK2141795 Dose Modification for Thrombocytopenia 
 
Event Name 
Thrombocytopenia 
Grade of Event 
Management 
Dose Modification 
Grade 1 
No change in dose 
No change in dose 
Grade 2 
No change in dose 
No change in dose 
Grade 3-4 
Hold only for grade 3 (< 50,000/ul) 
with bleeding ≥grade 2 OR grade 4 
thrombocytopenia (< 25,000/ul) 
Hold* until platelet count has 
recovered to 30,000/ul.  For grade 4 
thrombocytopenia resume at one 
dose level lower, if indicated. 
*Patients requiring a delay of > 28 days should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
 
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 (via CTEP-AERS) in addition to 
routine reporting.   
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
7.1.1 CAEPRs for CTEP IND Agent 
 
7.1.1.1 CAEPR for Trametinib dimethyl sulfoxide (GSK1120212B, NSC 763093) 
 
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 


NCI 9460 / PHL-091 
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  49 
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.   
 
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. Frequency is provided based on 968 patients. Below 
is the CAEPR for Trametinib dimethyl sulfoxide (GSK1120212B). 
 
Version 2.3, October 26, 20151 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 968] 
 
 
 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 
 
 
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) 
 
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) 


NCI 9460 / PHL-091 
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  50 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 968] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
Edema face 
 
Fatigue 
 
 Fatigue (Gr 3) 
 
Fever 
 Fever (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
 
INFECTIONS AND INFESTATIONS 
 
 
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) 
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 
 
 


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  51 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide (GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 968] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
 
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
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 retinal hemorrhage, corneal graft 
rejection, cyclitis, eye nevus, halo vision, intraocular pressure increased, macular edema, visual acuity 
reduced, 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. 
 
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  
EYE DISORDERS - Eye disorders - Other (corneal graft rejection); Eye disorders - Other 
(cyclitis); Eye disorders - Other (eye nevus); Eye disorders - Other (intraocular pressure 


NCI 9460 / PHL-091 
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  52 
increased); Eye disorders - Other (iritis); Eye disorders - Other (vitreous detachment); Eyelid 
function disorder; Flashing lights; Floaters; Glaucoma; Papilledema; Photophobia 
GASTROINTESTINAL DISORDERS - Ascites; Colitis; Enterocolitis; Esophagitis; Gastric 
ulcer; Gastritis; Gastrointestinal disorders - Other (obstruction gastric); Gastrointestinal disorders 
- Other (oropharyngeal pain); Gastrointestinal disorders - Other (pneumatosis intestinalis); 
Gastrointestinal fistula; Pancreatitis; Small intestinal obstruction 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Flu-like 
symptoms; General disorders and administration site conditions - Other (axillary pain); General 
disorders and administration site conditions - Other (pneumatosis); Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic pain  
INFECTIONS AND INFESTATIONS - Biliary tract infection; Device related infection; 
Enterocolitis infectious; Infections and infestations - Other (abscess limb); Pharyngitis; Upper 
respiratory infection  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Lipase increased; Platelet count decreased; Serum 
amylase increased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; 
Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Metabolism and nutrition 
disorders - Other (hyperphosphatemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 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; Stroke; Syncope; Transient 
ischemic attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression; Insomnia; Personality 
change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - 
Other (dysuria); Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal fistula 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Pleural effusion; 
Pneumothorax; Productive cough; Pulmonary hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous dermatitis; Photosensitivity; 
Skin and subcutaneous tissue disorders - Other (erythema nodosum); Skin ulceration; Urticaria 
VASCULAR DISORDERS - 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 (NSC 767034) 
 


NCI 9460 / PHL-091 
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  53 
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 
 
 
 
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 
 


NCI 9460 / PHL-091 
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  54 
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 for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• For expedited reporting purposes only:   
o 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. 
 
• Attribution of the AE: 
o Definite – The AE is clearly related to the study treatment. 
o Probable – The AE is likely related to the study treatment. 
o Possible – The AE may be related to the study treatment. 
o Unlikely – The AE is doubtfully related to the study treatment. 
o Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting 
 


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  55 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
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. Each site will submit the electronic version 
of the CTEP-AERS report to the PMH Phase II Consortium Central Office.  Once review 
by the lead group coordinator has taken place the report will be forwarded to NCI.  
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 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” 
under the system organ class (SOC) of the same name.  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.  
 
In order to ensure the timely fulfillment of both US and Canadian IND regulatory 
reporting requirements, all CTEP-AERS reports must be sent to the PMH Phase II 
Consortium Central Office within 3 working days from the date the event was known to 
the investigator. 
 
• 
In the unlikely event that an adverse event occurs that does not meet the 
reporting requirements for CTEP-AERS, but does meet the definition of a 
Serious Adverse Event, an CTEP-AERS report must still be completed and 
sent to the Central Office within 3 working days of the event being known to 
the investigator.  The event must be telephoned or e-mailed to Central Office 
within 1 working day.   


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  56 
 
• 
The PMH Phase II Consortium Central Office will be responsible for 
reporting to Canadian regulatory authorities all Serious Adverse Events that 
are both unexpected and related to study drug.  The Central Office will notify 
all Investigators of all Serious Adverse Events that are reportable to regulatory 
authorities in Canada from this trial or from other clinical trials as reported to 
the Central Office by the NCI U.S. 
 
Investigators must notify their local Research Ethics Boards (REB/IRBs), according to 
their guidelines, of all SAE reports from their centre and file the report in their regulatory 
study binder.   In addition, all reports sent out to centres by the PMH Phase II Consortium 
Central Office must be sent to local REB/IRBs, according to their guidelines.  
Documentation from the REB/IRB of receipt of these reportable events must be kept on 
file in each institution's regulatory binder.  
 
Late Phase 2 and Phase 3 Studies: 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/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 
24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via CTEP-
AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
report. 


NCI 9460 / PHL-091 
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  57 
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 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events 
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 Expedited Adverse Event Reporting Exclusions 
 
7.3.4.1 For this protocol only, the AEs/grades listed below do not require expedited reporting 
via CTEP-AERS. However, they still must be reported through the routine reporting 
mechanism (i.e. Adverse Events Form in the eCRF, see Section 7.4): 
 
CTCAE SOC 
Adverse Event 
Grade 
Blood and lymphatic system 
disorders  
Anemia 
Grade 3 
Investigations 
White blood cell decreased 
Grade 3 
 
Lymphocyte count decreased 
Grade 3 or 4 
 
Neutrophil count decreased 
Grade 3 
 
Platelet count decreased 
Grade 3 
Skin and subcutaneous tissue 
disorders 
Rash pustular 
Grade 3 
 
Rash acneiform 
Grade 3 
 
These exceptions only apply if the adverse event does not result in hospitalization. If the adverse 
event results in hospitalization, then the standard expedited adverse events reporting 
requirements must be followed. 
 
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. 
 
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 


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  58 
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 via CTEP-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 INFORMATION 
 
8.1 
CTEP IND Agent(s) 
 
8.1.1 Trametinib dimethyl sulfoxide (GSK1120212B) (NSC 763093) 
 
Chemical Name (IUPAC): equimolecular combination 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 
 
Molecular Formula:  C26H23FIN5O4  •  C2H6OS       M.W.: 693.54  
 
 
 
 
 
       
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. 
 


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  59 
How Supplied: Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as 
free base) tablets.  
 
Investigationally labeled bottles each contain 32 tablets packaged in high density 
polyethylene bottles with child-resistant closures including an induction seal liner. 
 
The tablet core contains mannitol, microcrystalline cellulose, hypromellose, 
croscarmellose sodium, magnesium stearate (non-animal), colloidal silicon dioxide 
and sodium lauryl sulfate.  
 
• 0.5 mg tablets are yellow, modified oval, biconvex and film-coated. Aqueous film 
coating consists of Opadry Yellow 03B120006 (hypromellose, titanium dioxide, 
polyethylene glycol, iron oxide yellow). 
 
• 2 mg tablets are pink, round, biconvex and film-coated. Aqueous film coating 
consists of Opadry Pink YS-1-14762-A (hypromellose, titanium dioxide, 
polyethylene glycol, polysorbate 80, iron oxide red). 
 
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 PMBAfterHours@mail.nih.gov for 
determination of suitability. 
 
Stability: Refer to the package label for expiration.  
 
Route of Administration: Oral. Take by mouth on an empty stomach, either 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, the dose can be taken if it is more than 12 


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hours until the next scheduled dose. 
 
Potential Drug Interactions: : In vitro studies suggest that trametinib dimethyl sulfoxide is not 
a substrate of CYP enzymes or of human BCRP, MRP2, OATP1B1, OATP1B3, OATP2B1, 
OCT1 or MATE1 transporters. Trametinib elimination by deacetylation to metabolite M5 is 
dependent on carboxylesterases (CES1b, CES1c and CES2). M5 is eliminated by CYP3A4 and 
other pathways, presenting the clinically relevant, albeit low, potential 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.  
.  
 
Availability:  Trametinib dimethyl sulfoxide (GSK1120212B) is an investigational agent 
supplied to investigators by the Division of Cancer Treatment and Diagnosis (DCTD), NCI. 
 
Trametinib dimethyl sulfoxide (GSK1120212B) is provided to the NCI under a Collaborative 
Agreement between the Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.3). 
 
8.1.2 GSK2141795 (NSC#) 
 
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.  
 
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 


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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. Capsules must be taken fasting 1 hour following a 
meal and 2 hours before the next meal. The following guidelines are recommended: 
Eat a small snack followed by 60 minutes of fasting prior to taking GSK2141795.  Water is 
allowed during this fasting period.  If possible, take each GSK2141795 capsule approximately 5 
minutes apart with divided amounts of fluid (4-8 oz with each capsule for a total of at least 12 
oz).  Remain upright for 30 minutes after taking the last capsule of GSK2141795. 
Fast for 2 hours after ingestion of the last capsule of GSK2141795. Water is allowed during this 
fasting period. 
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 
 
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-


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  62 
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) 276-6575Monday through Friday between 8:30 am and 4:30 pm (ET) or email 
PMBAfterHours@mail.nih.gov anytime. 
 
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 
Biomarker Studies 
 
As a companion study to the proposed clinical trial, we will conduct studies aimed at identifying 
predictors of response and pharmacodynamic (PD) studies to demonstrate target inhibition and to 
define mechanisms of action and resistance. For the purposes of the current trial, we will obtain a 
research peripheral blood sample* and BM aspirates at the following time points:  
1)  study screening +/- cycle 1/day 1 pre-dosing* 
2)  cycle 2/Day -2 to 1, 2-4 hours following administration of trametinib  
3)  progression on single agent trametinib** 
4)  cycle 2 (trametinib+GSK2141795)/Day -2 to 1, 2-4 hours following administration of 
trametinib in combination with GSK2141795  
5)  at progression on trametinib + GSK2141795** 
 
 
For biomarker positive patients only blood samples will only be collected at each BM sampling 
time point at every even cycle. All patients however require a peripheral blood sample at 
screening.  
*cycle 1/day 1 BM will only be done if insufficient material is obtained at screening for the 
proposed correlative studies 
**to be performed only if the patient has responded (PR or better) and then progressed 
 
9.1.1 Sample Procurement 
 
Sample procurement and shipping instructions are provided in the Protocol Lab Manual.  
 
Approximately 6-15 mls of bone marrow (2-5 mls from each from 3 separate pulls) will be 
procured for the purposes of correlative studies. Samples from all participating centers will be 
shipped overnight to PM Cancer Centre.. All samples will be sent directly to PM Cancer Centre 
by overnight shipment.  
 
The lab samples will be processed upon arrival. From the first tube, mononuclear cells (MNCs) 


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from will be prepared by Ficoll-Hypaque gradient and myeloma cells will be purified by 
immunoselection with anti-CD138-conjugated immunomagnetic beads. Experience indicates that 
approximately 4 million CD138 selected myeloma cells can be obtained from 2 mls of whole 
BM. One million cells will be aliquoted for DNA extraction and 1 million cells aliquoted for 
RNA extraction. Any remaining material will be employed to generate cytospin slides for tissue 
arrays and/or frozen in DMSO as viable cells and stored in liquid nitrogen. These will be banked 
for future validation and exploratory studies.  The second green-top tube will be reserved for 
flow cytometry studies as described below. The third tube will be reserved for reverse phase 
protein assays (RPPA) as discussed below. 
 
9.1.2 Next Generation Sequencing  
 
Our hypothesis is that patients whose tumors harbor mutations of KRAS, NRAS or RAF 
(reported in 21%, 19% and 7% of MM cases, respectively) will preferentially respond to MEK 
inhibition. To test this hypothesis and, to potentially enhance the effect size, we have chosen to 
stratify patients based on the presence or absence of mutations of RAS or RAF. For the purpose 
of patient stratification, mutational analysis will be performed by the University Health Network 
CLIA certified molecular diagnostic lab using the sequenom platform. This biomarker study is 
considered integral to the trial.  
 
Genomic DNA (450 ng) extracted from purified CD138 positive myeloma cells will be 
submitted to the clinical lab for next generation sequencing  that allows for a comprehensive 
screen of mutations including those of NRAS, KRAS and BRAF (see Appendix F Table 1 and 2 
for the complete list of genes and mutations for the TruSeq Amplicon Cancer Panel and TruSight 
Tumor Panel. Cases that are positive for mutations of RAS or RAF will be stratified to the 
biomarker positive groups (see Appendix F, Table 3 for the list of RAS and RAF mutations that 
define the biomarker positive group). The lower limit of detection of these next generation 
sequencing panels is 5-10%. This means mutations present at levels below 10% may be missed.  
 
The mutational profile will be provided to the site investigator and the report kept in the study 
chart. The information should be disclosed to the treating physician and patient and included in 
the clinical note. The Principal Investigator will be responsible for assignment of patients to the 
biomarker positive or negative groups. Each group will enroll 12 patients in the first stage. If the 
pre-determined response criteria are met during the first stage in either or both groups then an 
additional 25 patients will be enrolled in either or both groups in the second stage. 
 
9.1.3 MAF expression 
 
In MM tumors that harbor the t(4;14) translocation or translocations that dysregulate MAF 
transcription factors (30% of MM cases) the MEK-ERK pathway appears to upregulate 
expression of MAF and inhibition of MEK selectively induces apoptosis of MAF-expressing 
myeloma tumors (Annunziata et al., 2011). These pre-clinical studies suggest that this subgroup 
of myeloma patients may preferentially respond to MEK inhibitors. To test this hypothesis RNA 
derived from screening BM samples will be used to quantify MAF expression (c-maf, MAF-B 
and MAF-A) by quantitative RT-PCR (qPCR) as described in the lab manual (Mao et al., 2007). 
As shown in the figure 1, there is 100% correlation between cMAF and MAFB expression and 


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  64 
FISH translocation and protein expression by Western blot. As this assay has not yet been 
validated, the specificity and sensitivity of this assay is to be determined. As such, this assay will 
not be used to stratify patients; however, response rates will be correlated with MAF expression 
as an exploratory endpoint.  RNA from the first 12 patients enrolled in each stratification group 
(see above) will be batched and evaluated in an interim analysis for correlation with efficacy.  If 
the data indicate that MAF may be a predictive biomarker the protocol may be modified to 
enrich for this subgroup of patients. 
 
In additon to determining the correlation with response to trametinib, the relationship between 
MAF expression and chromosomal abnormalities will be detected by qPCR and FISH, 
respectively (figure 1). FISH is a standard molecular assay performed in cases of multiple 
myeloma. Evidence suggests that high levels of MAF occur in myeloma tumors with 
translocations t(14:16) that dysregulates cMAF, t(14:20) that dyregulates MAFB, as well as 
t(4;14) that results in overexpression of FGFR3 and MMSET (Annunziata et al., 2011). As an 
exploratory endpoint therefore we will determine the correlation between these two molecular 
assays (qPCR and FISH). We propose that this will provide information for better clinical 
interpretation of an assay that is already employed as standard of care for multiple myeloma. 
 
 
Figure 1. MAF expression by qPCR and Western blot analysis. The graph on the right demonstrates 
expression c-MAF by qPCR relative to the housekeeping gene h36B4 and SKMM2 cells as a negative 
control. Copy numbers correlate 100% with protein expression determined by Western blot (shown 
below) and t(14:16) and t(4;14) translocation. The graph on the left demonstrates expression of MAFB by 
qPCR. Expression of MAFB correlates with the t(14;20) translocation. Not shown is data for MAFA as 
no cell exist with translocations that dysregulate MAFA. 
 
9.1.4 Expression of integrin-β7 
 
Integrin-β7 is a cell surface protein whose expression is regulated by MAF transcription factors 
(Hurt et al., 2004). We hypothesize therefore that integrin-β7 may serve as a surrogate marker 


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  65 
for MAF-expressing myeloma tumors which as described above, represent a subgroup of 
myeloma tumors with increased sensitivity to MEK inhibitors. As cell surface expression can 
readily be detected by flow cytometry, integrin-β7 has the potential to serve as a predictive 
biomarker that can easily translate to the clinical lab. As an exploratory endpoint we will 
measure integrin-β7 on CD138 positive myeloma cells and correlate positivity with qPCR 
expression of MAF genes and clinical responses. An aliquot of whole BM obtained at screening 
will be labeled with anti-CD138-FITC and anti-integrin-β7-PE or isotype control. Flow 
cytometry will be done using a LSR II flow cytometer (BDIS), and offline listmode analysis will 
done using FlowJo software.  Details of the methodology are provided in the lab manual.  The 
sensitivity and specificity of the assay is yet to be determined. 
 
9.2 
Pharmacodynamic (PD) Studies 
 
9.2.1 Flow Cytometry PD Studies 
 
Myeloma cells from BM samples will be evaluated for target modulation and the effects of 
trametinib with or without GSK2141795 on downstream signaling targets of RAS-MEK-ERK 
signaling and alternative pathways (PI3K/AKT). Flow cytometry is a highly developed technique 
for the diagnosis of hematological malignancies, based on the correlated measurements of 
multiple surface immunophenotypic markers plus forward and orthogonal light scattering 
characteristics of cell subpopulations. However, the recent introduction of techniques that 
measure the activation states of signaling pathways using phosphospecific antibodies, the scope 
of flow cytometry now extends into molecular therapeutic monitoring in the clinic (Tong et al., 
2006). By using flow cytometry applications, we will determine whether the MEK target ERK, is 
activated in myeloma cells pre-treatment and whether administration of trametinib inhibits ERK 
phosphorylation in primary cells. Further, we will determine whether at progression, ERK 
phosphorylation remains suppressed despite trametinib treatment providing valuable insights into 
whether escape mechanisms are ERK-independent (ERK remains inactive) or ERK-dependent 
(ERK is phosphorylated). In addition, will evaluate whether the PI3K/AKT pathway is activated 
at baseline, is induced in response to single agent trametinib or at progression, as a potential 
mechanisms of acquired resistance. The results will be correlated to response to trametinib +/- 
GSK2141795 and analyzed as an exploratory endpoint. We hypothesis that patient with 
constitutive ERK phosphorylation and lacking AKT activation will respond to trametinib alone; 
that patients who fail to respond or progress on trametinib alone will benefit from the addition of 
GSK2141795, if AKT is constitutively activated in the cells; and that patients who progress by 
ERK-dependent mechanisms may not benefit from the addition of GSK2141795. 
 
We have experience at applying this technique for PD monitoring in early phase clinical trials 
(De et. al., 2013). As shown in Figures 2 and 3, we have developed an assay that captures 
dynamic changes in intracellular levels of phosphoproteins in myeloma and CLL primary cells 
derived from patients on clinical trials of PI3K/AKT inhibitors. In a representative case (Figure 
1) CD138 cells derived from a patient prior to dosing with SF1126 (PI3K inhibitor) demonstrate 
lack of constitutive AKT activity (ex vivo treatment with the PI3K inhibitor, LY294002 does not 
suppress AKT phosphorylation) however the pathway can be activated ex vivo by IGF-1. In this 
phase I study treatment with a subtherapeutic dose of SF1126 partially suppressed IGF-1 induced 
phosphorylation in CD138 cells derived post-dosing on days 1 of cycles 1 and 2. In the second 


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example, we observed modest constitutive activation of AKT and its downstream targets GSK3 
and pS6 in CLL cells derived from a patient prior to dosing with the AKT inhibitor, 
GSK2141795. This is suggested by the decrease in phosphorylation of these proteins in response 
to ex vivo LY294002 treatment. This pathway can be further activated by stimulating with anti-
IgM (BCR ligand) or by the addition of PMA. In contrast after 7 days of oral treatment with 
GSK2141795, basal and induced phosphorylation of downstream AKT targets (GSK3 and pS6) 
is completely suppressed in this same patient. On the other hand, RAS-MEK-ERK signaling is 
enhanced in post-treatment samples.  Details of the flow cytometry protocol are provided in lab 
manual.  The sensitivity of this assay is yet to be determined. 
 
 
Figure 2a: Methodology for PD analysis on SF1126 Phase I clinical trial for MM. Figure 2b: 
phospho-AKT expression in CD138 gated myeloma cells.  Pre-treatment (screening marrow), on cycle 
1 day1 and cycle 2 day 1 4 h after dosing with SF1126. IGF-1 can induces AKT phosphorylation however 
the response is reduced after treatment with SF1126. LY294002 fails to inhibit AKT phosphorylation 
suggesting that AKT is not constitutively activated (De et al., 2013). 
 


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Figure 3: Mean fluorescence intensity (MFI) phospho-proteins in CD19 gated CLL cells. Pre-
treatment (screening peripheral blood sample) on cycle 1 day 8 and after dosing with GSK2141795. Anti-
IgM activates PI3K/AKT signaling as shown by increased AKT, GSK3 and pS6 phosphorylation 
however the response is completely blunted after GSK2141795 treatment for 7 days. RAS-MEK-ERK 
signaling however is enhanced after treatment.  
 
9.2.2 Reversal Phase Protein Arrays (RPPA):  
 
RPPA is a quantitative assay that analyzes nanolitre of sample for potentially hundreds of 
proteins (Iadevaia et al., 2010). This antibody-based assay determines levels of protein 
expression, as well as protein modifications such as phosphorylation. RPPA allows concordant 
interrogation of multiple signaling molecules and their functional status. In essence, the RPPA 
study has major strengths in identification and validation of cellular targets, characterization of 
signaling pathways and networks, as well as determination of on and off target activity of drugs. 
We hypothesize that the integrated information derived from RPPA will display functional 
outcomes affected by MEK and/or AKT inhibition that will confirm target modulation and 
inform on predictors of response or mechanisms of resistance. As an exploratory endpoint each 
sample subjected to RPPA will be analyzed for effects on cell cycle, apoptosis, functional 
proteomics, and signaling network activity. The results across patients will be classified and 
compared with clinical responses to generate a “molecular signature” of functional outcomes 
affected by MEK and/or AKT inhibition.  
 
In order to preserve the phospho-epitopes in samples that are shipped overnight and thus reduce 
the risk of false PD readouts, a BM pull will be immediately placed into a collection tube 
containing fix/lyse buffer. We have used this whole BM fixation and RBC lysis protocol for flow 


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cytometry applications (Chow et al., 2008) and demonstrated that phospho-epitopes and CD 
surface markers are preserved and thus allows for CD138 selection of myeloma cells. The 
CD138 selected cells will then be snap frozen and serial samples batched for preparation of 
protein lysates using and shipping to the MD Anderson RPPA core facility. Their RPPA 
platform incorporates 130 validated antibodies that cover a wide spectrum of signaling 
molecules. A more detail description of sample preparation for RPPA is provided in the lab 
manual.  The MD Anderson RPPA facility has extensively validated antibodies suitable for 
RPPA however the feasibility of the protein extraction for RPPA application is yet to be 
determined. 
 
The products of these correlative studies are to validate and identify novel biomarkers related to 
MM responses and outcomes to MEK inhibitors that may then enter into development as clinical 
assays. In addition, we expect to begin testing hypotheses around novel biomarkers and 
mechanisms of resistance that may inform combination strategies and guide the development of 
innovative, personalized therapeutics for MM and cancers and general.  
 
9.3 
RAS and BRAF mutation detection using circulating free DNA (cfDNA) 
 
As a pilot study within this protocol, the feasibility of deriving cfDNA from patients for 
detection of mutations of RAS and BRAF will be assessed. Currently, the detection of RAS and 
BRAF mutations is carried out in tumor tissue by next generation sequencing. This requires bone 
marrow aspiration for derivation of tumor tissue and CD138 purification of myeloma tumor cells 
for DNA extraction. Recent studies have validated the detection of KRAS and BRAF mutations 
from circulating free tumor DNA (cfDNA). cfDNA was detected in 100% of patients with 
metastatic colorectal cancer and showed 100% specificity and sensitivity for BRAFV600E 
mutation and 98% specificity and 92% sensitivity for KRAS mutations (Thierry AR et al. 2014). 
Thus, this represents a minimally invasive and cost-effective method for identification of patients 
that are most likely to benefit from targeted therapy.  
 
For patients that are biomarker positive peripheral blood will be collected at all applicable time 
points and will be processed as per the Study Lab Manual. cfDNA will be extracted using the 
QIAamp DNA MINI Blood kit (Qiagen) according to the manufacturer’s protocol. The DNA  
will be used to perform ultra-deep sequencing of KRAS, NRAS and BRAF using a two-step 
PCR-based approach, TAm-Seq followed by Illumina sequencing.  
 
Our goals are first to determine our ability to derive cfDNA at multiple time points. To compare 
the sensitivity and specificity of RAS and RAF mutational analysis of peripheral blood cfDNA 
compared to detection using standard methods from tumor specimens. To determine whether 
mutational load over the treatment course can be evaluated from cfDNA. It is hoped that this will 
lead to the development of a less invasive and more efficient platform for the identification of 
MM patients that may benefit from targeted therapies.  
 
9.4 
Laboratory Correlative Studies 
 
Please see lab manual for Correlative studies collection, shipping, and process instructions.  


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10 STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy, unless 
specified differently in the study calendar.  Scans and x-rays, ECHO/MUGA, and 
Ophthalmology exam 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.  If pre-study assessments were done within 3 days 
of treatment initiation, they do not need to be repeated for cycle 1 day 1.  For subsequent cycles 
(2+), day 1 assessments can be completed up to 48 hrs prior to day 1. All day 15 assessments can 
be completed up to 48 hrs prior to day 15. Baseline myeloma disease assessment can be done <4 
weeks prior to the start of therapy (see 11.2.1). Response assessment can be done up to < 7 days 
prior to the start of the next cycle to allow for treatment decisions to be made with regards to the 
addition of GSK2141795 for stable disease or progression prior the initiation of the next cycle. 
    
PROCEDURES 
Screen 
Cycle 1-2 
Single Agent 
(cycle=28 days) 
Cycles 3+ 
Single Agent 
Cycle 1-2 
Combination 
Cycles 3+ 
Combination 
Off 
Study 
Safety 
Follow-up 
 
Pre- 
Study 
Day1 
 
Day15 
 
At the start 
of every 
Cycle 
Day1 
 
Day 15 
 
At the start 
of every 
cycle 
 
4 weeks (+ 
3 days) 
after last 
treatment 
Trametinib 
 
A------------------------------------A 
A*------------------------------------A* 
 
 
GSK2141795 
 
 
 
 
 B--------------------------------------B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
   X----------------------------------------------------------------------------------------X 
X 
 
Physical exam 
X 
X 
 
X 
  X 
 
         X 
X 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
  X 
X 
 
Performance status 
X 
X 
X 
X 
X 
X 
  X 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
  X 
X 
 
Fasting serum chemistrya 
X 
X 
X 
X 
X 
X 
  X 
X 
 
TSH 
X 
 
 
 
  X 
 
Xj 
X 
 
Serum viscositym 
X 
 
 
 
 
 
 
 
 
ECGb  
X 
X 
X 
X 
 
X 
 
X 
 
Echocardiogram or 
MUGA 
X 
Every 12 weeks (use same methodology for baseline and follow up). 
 
Ophthalmology examl 
X 
as clinically indicatedk 
Visual acuity examk 
X 
X 
 
X 
X 
 
X 
X 
 
Adverse event evaluation 
 
  X-----------------------------------------------------------------------------------------X 
X 
Xi 
Myeloma disease 
assessmentc 
(section 11.2.1) 
X 
Assessments are repeated every 4 weeks.  Documentation must be provided for 
patients removed from study for progressive disease. 
X 
 


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  70 
Radiologic evaluationd 
X 
Radiologic measurements, if indicated, for assessment of extramedullary disease 
should be performed every 12 weeks or upon clinical suspicion of progressive 
disease.   
X 
 
B-HCGe 
 X 
X 
 
 
 
 
 
X 
 
Glycosulated Hemoglobin 
(HbA1c) 
     X 
 
 
 
  X 
 
 
 
 
PT/INR & PTT  
     X 
X 
 
 
X 
 
 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
 
Skeletal Surveyg 
     X 
 
 
 
 
 
 
 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
X 
Correlative studiesh: 
Peripheral blood and BM 
aspirate 
X 
On Day -2 to 1 of Cycle 2, 2-4 h after 
dosing with trametinib AND at 
progression And peripheral blood 
sample every even cycle for biomarker 
positive patients only 
On Day -2 to 1 of Cycle 2, 2-4 h after 
dosing with trametinib and GSK2141795 
AND at progression And peripheral blood 
sample every even cycle for biomarker 
positive patients only 
 
 
A. [Trametinib]:  2 mg daily of a 28 day cycle 
A* Trametinib 1.5 mg daily of a 28 day cycle (when used in combination with GSK2141795) 
B.  [GSK2141795]:  50 mg daily of a 28 day cycle 
a.  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine,  LDH, magnesium, phosphorus, potassium, 
total protein, SGOT [AST], SGPT [ALT], sodium, fasting serum glucose. Weight and serum creatinine will be used to calculate creatinine 
clearance (eGFR and eCCr). Also see protocol guidelines for patient management and reporting of elevated liver function tests. 
b. A single 12-lead ECG should be performed at screening and on the indicated visits. The QT interval corrected for heart rate should be 
calculated uing the Bazett’s formula. (QTb=QT/√RR) 
c. Myeloma lab tests: ß2Microglobulin (collected at screening only); serum immunoelectrophoresis, immunoglobulin assay, M band 
confirmation by immunofixation and quantitation by SPEP, free light chain and 24 hour urine collection for Bence Jones protein to be 
performed at baseline prior to study, prior to each cycle thereafter and at time of study discontinuation (if last tests were > 4 weeks).  
FreeLyte test should occur if indicated by the Investigator.  Not all tests may be required at each assessment time point.  Tests can be done 
up to 7 days prior to day 1 of each cycle. 
d. Radiological assessment for clinically suspected extramedullary disease should be performed prior to study (28 days) and every 12 weeks or 
upon clinical suspicion of progressive disease.  This may include CT scan of the abdomen/pelvis, CT or x-ray of the chest, or ultrasound of 
the liver/spleen or abdomen. To ensure comparability, the baseline radiographs/scans and subsequent radiographs/scans to assess response 
should be performed preferably using identical techniques. The same method, radiological or physical, should be employed and assessed by 
the same individual on each occasion if possible. 
e. Serum pregnancy test (women of childbearing potential). 
g. Skeletal survey (including skull, all long bones, pelvis and chest) required if previous survey >12 weeks from study entry and at any time 
when clinically indicated. 
h. Details on collection of samples, handling and shipping are provided in the Study Lab Manual. The patient may be dosed prior to study visit  
on cycle 2 day 1 (of single agent trametinib) and cycle 2 day 1 (of combination) to facilitate 2-4 h waiting for bone marrow aspiration. 
Baseline correlatives can be > 4 weeks prior to start of protocol therapy providing collection is after informed consent. 
i.  Refer to section 5.4 
j.  TSH testing to be done at the beginning of every 4th cycle 
k. Snellen Chart and Visual Field Testing.  If results of visual testing are abnormal the patient will be referred for an urgent full ophthalmologic 
exam 
l. The exam will include indirect fundoscopic examination, visual acuity (corrected), visual field examination, tonometry, and direct fundoscopy. 
m. To be performed if available at the treating institution. 
 
 
 


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11 MEASUREMENT OF EFFECT 
 
11.1 Antitumor Effect – Solid Tumors N/A 
 
11.2 Antitumor Effect – Hematologic Tumors 
 
11.2.1 Methods for Evaluation of Measurable Disease 
 
Measurable disease. Measurable disease is defined as at least one of the following (these baseline 
laboratory studies for determining eligibility must be obtained within 28 days prior to 
enrollment): 
1. Serum M-protein ≥ 0.5 g/dl (≥ 5 g/l) 
2. Urine M-protein ≥ 200 mg/24 h 
3. Serum free light chains (FLC) assay: Involved FLC level ≥ 10 mg/dl (≥ 100 mg/l) and an 
abnormal serum free light chain ratio (< 0.26 or > 1.65) 
4. Biopsy proven plasmacytoma (should be measured within 28 days of first study drug 
administration). Prior biopsy is acceptable. 
5. If the serum protein electrophoresis is unreliable for routine M-protein measurement, 
quantitative immunoglobulin levels on nephrolometry or turbidometry will be followed. 
 
Patients will be evaluated under local Investigator review for disease response according to the 
International Myeloma Working Group (IMWG) uniform response criteria (see 11.2.2; Rajkumar 
2011). 
 
Listed above are the minimal required tests to assess response based on the characteristics of 
disease at study initiation. 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. 
 
In order to be classified as a hematologic response, confirmation of serum monoclonal protein, 
serum immunoglobulin free light chain (when primary determinant of response) and urine 
monoclonal protein (when primary determinant of response) results must be made by verification 
on two consecutive determinations.   
 
Tests Required To Assess Response (Must Be Done At Each Disease Measurement Visit) 
On Study Baseline Value 
SPEP  24 hr 
UPEP  
Ig FLC Plasmacytoma 
assessment 
Serum M-spike ≥ 0.5 g/dl, and urine M-spike ≥ 200 mg/24 hrs 
X 
X 
 
 
Serum M-spike ≥ 0.5 g/dl, but urine M-spike < 200 mg/24 hrs 
X 
 
 
 
Serum M-spike < 0.5 g/dl, and urine M-spike ≥ 200 mg/24 hrs 
 
X 
 
 
Serum M-spike < 0.5 g/dl, urine M-spike < 200 mg/24 hrs, but 
involved Ig FLC is ≥10 mg/dL 
 
 
X 
 
Plasmacytoma 
 
 
 
Xa 
Immunofixation studies of both serum and urine are required to document CR regardless of 
registration values, and in addition FLC measurement and BM immunophenotyping is required to 
document sCR. 
a Complete evaluations done at baseline with same technique Q 12 weeks. 


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  72 
• Bone marrow aspirate and biopsy are only required to document or confirm CR or sCR, 
except for patients with evaluable disease only, where BM assessment is required to 
document all response categories including progression. However, a second confirmatory 
BM is not required to confirm response. 
• Radiographic studies are not required to satisfy these response requirements, however, if 
radiographic studies were performed there should be no evidence of progressive or new bone 
lesions. 
• Progression does not require confirmation, but treating physician may continue an additional 
cycle to confirm progression if clinically indicated. 
 
Bone progression: Caution must be exercised to avoid rating progression or relapse on the basis 
of variation of radiologic technique alone.  Compression fracture does not exclude continued 
response and may not indicate progression.  When progression is based on skeletal disease alone, 
it should be discussed with the Principal Investigator before removing the patient from the study. 
 
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. 
 
11.2.2 Response Criteria 
 
International Myeloma Working Group Response Criteria (Rajkumar et al., 2011) 
Response categories include sCR, CR, nCR, VGPR, PR, SD, and PD. In addition, minor 
response (MR) will be evaluated as an alternate response (see Section 11.3 for definition).   
 
Response 
IMWG criteria 
sCR 
CR as defined below plus:  
• 
normal FLC ratio and  
• 
absence of clonal cells in bone BM by immunohistochemistry or 2 – 4 color 
flow cytometry 
CR 
• 
Negative immunofixation on the serum and urine and  
• 
disappearance of any soft tissue plasmacytomas and  
• 
< 5% plasma cells in BM.   
• 
In patients with only FLC disease, a normal FLC ratio of 0.26–1.65 is 
required.  
VGPR 
• 
Serum and urine M-protein detectable by immunofixation but not on 
electrophoresis or 
• 
> 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h.   
• 
In patients with only FLC disease, >90% decrease in the difference between 
involved and uninvolved FLC levels is required. 
PR 
1. 
50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by >90% or to < 200 mg/24 h 
• 
If the serum and urine M-protein are unmeasurable,3 a > 50% decrease in the 


NCI 9460 / PHL-091 
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  73 
difference between involved and uninvolved FLC levels is required in place of 
the M-protein criteria 
• 
If serum and urine M-protein are not measurable, and serum free light assay is 
also not measureable, > 50% reduction in plasma cells is required in place of M-
protein, provided baseline BM plasma cell percentage was > 30% 
• 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in 
the size of soft tissue plasmacytomas is also required 
Stable Disease 
2. 
Not meeting criteria for CR, VGPR, PR or progressive disease 
Progressive 
disease 
3. 
Increase of > 25% from lowest response value in any one of the following: 
1. 
Serum M-component (the absolute increase must be > 0.5 g/dL)4 and/or  
2. 
Urine M-component (the absolute increase must be > 200 mg/24 h) and/or  
3. 
Only in patients without measurable serum and urine M-protein, the 
difference between involved and uninvolved FLC levels. The absolute 
increase must be > 10 mg/dL 
4. Only in patients without measurable serum and urine M-protein and without 
measurable disease by FLC levels, bone marrow plasma cell percentage 
(absolute % must be ≥ 10%)  
5. 
Definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue 
plasmacytomas 
6. 
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL ) 
that can be attributed solely to the plasma cell proliferative disorder 
 
All relapse categories (CR, sCR, VGPR, and PD) require two consecutive assessments made at 
any time before the institution of any new therapy; complete response and PR and SD categories 
also require no known evidence of progressive or new bone lesions if radiographic studies were 
performed.  VGPR and CR categories require serum and urine studies regardless of whether 
disease at baseline was measurable in serum, urine both or either.  Radiographic studies are not 
required to satisfy these response requirements. BM assessments need not be confirmed.  For 
progressive disease, serum M-component increases of ≥ I gm/dl are sufficient to define response 
if starting M-component is ≥ 5 g/dl.     
 
IMWG clarification for coding PD:  Clarified that BM criteria for PD are to be used only in 
patients without measurable disease by M protein and by FLC levels.  The 25% increase refers to 
M protein, FLC, and BM results, and does not refer to bone lesions, soft tissue plasmacytomas or 
hypercalcemia.  Note the lowest response value does not need to be a confirmed value. 
 
11.3 Other Response Parameters 
 
Additional response criteria for specific disease states: 
 
Minor response in patients with relapsed and 
refractory myeloma adapted from the EMBT 
criteria3 
≥ 25% but < 49% reduction of serum M 
protein and reduction in 24 hour urine M 
protein by 50 – 89%, which still exceeds 
200 mg/24hrs. 


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  74 
 
In addition to above; if present at baseline, 
25-49% reduction in the size of soft tissue 
plasmacytomas is also required 
 
No increase in size or number of lytic bone 
lesions (development of compression 
fractures does not exclude response) 
Immunophenotypic CR 
Stringent CR plus 
Absence of phenotypic abarrent PC 
(clonal) in BM with a minimum of one 
million of total BM cells analyzed by 
miltiparamtric flow cytometry (with ≥4 
colors) 
Molecular CR 
Stringent CR plus negative ASO-PCR 
(sensitivity 10-5) 
Near Complete Response (adapted from the 
EMBT criteria 3) 
Patients, in whom all criteria for a CR are 
satisfied with exception of a positive or an 
unconfirmed immunofixation result, will 
be considered a near CR (nCR). 
 
 
 
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). 
 
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. 
 


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  75 
12.1.2 Responsibility for Data Submission 
 
Study participants are responsible for entering their data into the Medidata Rave system and 
submitting copies of their source notes to the Central Office / Coordinating Centre within 3 
weeks of the end of cycle.  Please refer to APPENDIX D 
DATA MANAGEMENT 
GUIDELINES, Data Management Guidelines, for further details regarding data submission 
requirements. 
 
 
The Central Office / Coordinating Centre 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 CTEP 
MULTICENTER GUIDELINES 
• 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. 
 
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. 


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  76 
 
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 
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 


NCI 9460 / PHL-091 
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  77 
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 Design/Endpoints 
This is a multi-center, open-label, non-randomized, two stage, phase II study of trametinib in 
patients with relapsed or refractory MM. BM samples from patients will be analyzed for NRAS, 
KRAS, BRAF mutations (next generation sequencing) at baseline visit. Patients will be statified 
into one of two study groups:  
 
• 
Biomarker positive (NRAS, KRAS, BRAF mutated as defined in Appendix F) 
• 
Biomarker negative (without NRAS, KRAS, BRAF mutation) 
Patients will be independently recruited into either of the two groups based on biomarker 
positivity. 
 
This study will use a two-stage design for both patient groups. Each group will enroll 12 patients 
in the first stage and an additional 25 patients in the second stage, if the pre-determined response 
criteria are met during the first stage. The target enrollment is a minimum of 24 evaluable 
subjects and a maximum number of 74 if both groups accrue to the second stage.  
Individual patients will receive a minimum of 2 cycles and may remain on treatment as long as 
there is no evidence of disease progression or unacceptable toxicity or patient/physician decision 
to discontinue. As a secondary objective, patients who develop progressive disease on trametinib 
monotherapy or achieve less then a PR after 4 cycles of treatment will have the option to 
continue on GSK2141795 supplemented trametinib regimen. The dosing of trametinib and 
GSK2141795 will be according to the recommended 1.5 mg trametinib and 50 mg GSK2141795 
daily dosing schedule. The M-protein level at the time of addition of GSK2141795 will be 
considered the new baseline, and the patients will be allowed to continue the new treatment 
schedule until further progression, toxicity, or patient/physician decision to discontinue. 
 
The UHN Data Safety and Monitoring Board (DSMB) will evaluate the safety of the trial after 
completion of enrollment of the first 24 patients and/or biannually during phase II. If greater than 
20% of subjects experience grade 4 diarrhea or rash despite optimal management or if greater 
then 10% subjects experience RPED or RVO or > 3 pneumonitis, a detailed review of these 
toxicities will be performed by an independent safety committee to determine whether the trial 
should be stopped. 
 
The primary objective is to evaluate the antitumor activity of trametinib determined by overall 
response rate (ORR), in groups of patients with relapse or refractory multiple myeloma that are: 


NCI 9460 / PHL-091 
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  78 
 
• 
Biomarker positive (NRAS, KRAS, BRAF mutated as defined Appendix F) 
• 
Biomarker negative (without NRAS, KRAS, BRAF mutation) 
 
The endpoint for the primary objective, ORR, is evidenced by confirmed response rate, defined 
as number of patients with partial response or better by IMWG criteria divided by the number of 
patients in the applicable group (biomarker positive or negative). All patients included in the 
study will be assessed for response to treatment, even if there are major protocol treatment 
deviations or if they are ineligible (see section 13.5.2).  The patient will be classified as having 
had a response if he/she has a confirmed response per the definitions in section 11.2.2. (i.e., a 
stringent complete response, or complete response or near complete response or very good 
partial response or partial response noted as the objective status of two consecutive assessments). 
The rate of minor response (MR) and progressive disease (PD) will also be observed. 
 
13.2 Sample Size/Accrual Rate 
 
A two-stage design will be used for each group to test the null hypothesis that the extended ORR 
is 5% or less, versus the alternative hypothesis that the extended ORR is greater then 5% using a 
one-sided test with a 10% level of significance and 90% power at the alternative extended ORR 
of 20%. The null hypothesis of extended ORR=0.05 and the alternative extended ORR=0.20 are 
chosen with reference to response rate with trametinib in BRAF mutated melanoma of 22% 
(Flaherty et al., 2012) and the response rates of single agent carfilzomib (17%) (Jagannath et al., 
2012) and pomalidomide (7%) (Dimopoulos et al, 2012). The design is standard for such single-
arm Phase II studies and appropriately minimizes the number of expected study participants 
when the experimental treatment is truly ineffective.  
 
The target enrollment therefore is a minimum of 24 evaluable subjects and a maximum of 74 if 
both groups (biomarker positive and biomarker negative) accrue to the second stage. After 
testing the drug on 12 patients in each group, the trial will go to the second stage if one or more 
subjects respond. If the trial goes to the second stage, a total of 37 patients will be studied. If the 
total number of responding is more than or equal to to 4, the drug is accepted. The same design 
as above will apply to both strata.  The maximum number of this study would be 74 patients for 
both strata. The distribution of PFS and DOR will be summarized for each cohort using the 
Kaplan-Meier method. For each of these endpoints, patients will be right-censored at the date at 
which they were last known not to have the corresponding event.  
 
Subjects who receive at least one dose of trametinib will be evaluable for safety. AEs will be 
coded according to the Medical Dictionary for Regulatory Activities (MedDRA) adverse event 
dictionary. The results will be tabulated to examine their frequency, organ systems affected, and 
relationship to study treatment. The results of laboratory assessments will be evaluated similarly. 
Interim safety data will be examined on an ongoing basis to ensure subject safety.  
 
Exploratory analyses of the association of response with pharmacogenomic and 
pharmacodynamic will be descriptively summarized. Overall, given the limited sample size these 
analyses will be largely hypothesis-generating. 
 


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  79 
13.3 Stratification Factors 
BM samples from patients will be analyzed for NRAS, KRAS, BRAF mutations (next 
generation sequening) at baseline visit. Patients will be stratified into one of two study groups 
as strategy for biomarker-based patient enrichment:  
• 
Biomarker positive (NRAS, KRAS, BRAF mutated as defined Appendix F) 
• 
Biomarker negative (without NRAS, KRAS, BRAF mutation) 
 
Patients in both groups will receive 2.0 mg daily oral trametininb. Each group will enroll 12 
patients in the first stage and an additional 25 patients in the second stage, if the pre-determined 
response criteria are met during the first phase. 
 
13.4 Analysis of Secondary Endpoints 
 
The secondary objectives are to: 
• To evaluate progression free survival (PFS) and duration of response (DOR) in the 
two stratified groups 
• To document ORR after the addition of GSK2141795 to trametinib in patients who 
have developed progressive disease or have achieved less then a partial response (PR) 
after 4 cycles of treatment 
• To evaluate PFS and DOR in patients receiving trametinib plus GSK2141795 
• To evaluate the safety profile of trametinib with and without GSK2141795 
 
The endpoints for secondary objectives, ORR is defined in sections 13.1 and 13.5.2 and will 
employ the M-protein level at the time of addition of GSK2141795 as the new baseline for 
response assessment.  
 
Safety analyses will review adverse events, electrocardiogram results, laboratory tests 
(hematology, clinical chemistry, and coagulation test), vital signs and physical examinations. 
Any patient who receives any amount of the study drug will be evaluated for toxicity. Safety will 
be measured in terms of type, frequency and severity of adverse event reactions reported 
according to CTCAE v4.0.  
 
PFS will be evaluated as defined by the time from the date of start of treatment to the date of 
documented progression (based on IMWG criteria) or death due to any cause. For patients who 
are not known to have died and who do not have objective evidence of tumor progression, and 
who are either removed from study treatment or who are given antitumor treatment other than 
the assigned study treatment, PFS will be censored at the last complete disease assessment.  
Patients who complete the study and have not progressed at the cut-off date for final analysis will 
be censored at the last complete disease assessment.  Patients with two or more missing 
assessments immediately prior to the next visit with a documented progression will be censored 
for PFS at the last assessment with documentation of no progression. 
 
The DOR 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 
or to death due to multiple myeloma (taking as reference for progressive disease the smallest 


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  80 
measurements recorded since the treatment started). For patients with responding tumors who do 
not have objective evidence of tumor progression and are either removed from study treatment or 
who are given antitumor treatment other than the study treatment or who die from non-disease 
causes, duration of response will be censored.  
 
The exploratory objectives are:  
• To explore the relationship between clinical response and pharmacodynamic (PD) 
markers 
• To explore the relationship between MAF expression and chromosomal abnormalities 
as determined by qPCR and FISH, respectively, and clinical response 
• To explore the role of integrin β7 as a biomarker of MAF expression  
• To explore the relationship between objective response as well as progressive disease 
and the tumor mutational profile 
• To explore mechanism of PI3K/AKT and RAS-MEK-ERK activation and correlate 
these with clinical response and PD markers 
• To explore the feasibility extracting cfDNA from peripheral blood and to detect RAS 
and RAF mutaitons using cfDNA 
 
The activation state of the PI3K/AKT, RAS-MEK-ERK and additional signaling pathways pre 
and post-treatment will be determined by phospho-flow cytometry and RPPA and correlated with 
clinical response. 
 
The level of MAF expression at baseline will be determined by qPCR. The cutoff value for the 
qPCR assay will be determined by calculating the median ratio and range relative copy number 
for 20 myeloma cell lines that are MAF positive (t(14;16) and t(4:14) cell lines) and 20 cell lines 
that are negative. Results of the PCR reactions will be compared to Western blot to confirm 
MAF expression and determine the sensitivity and specificity of the assay and its cutoff. To 
determine the performance of the assay in the clinical samples we will compare results obtained 
by qPCR to FISH data Although this assessment will be done retrospectively, the data will be 
available for inerim analysis for correlation with clinical response. If the data indicate that MAF 
may be a predictive biomarker the protocol may be modified to enrich for this subgroup of 
patients. 
 
The cell surface expression of integrin β7 will be determined by flow cytometry on CD138 
positive myeloma cells derived from screening BM samples. Correlation with MAF expression 
will be determined.  
 
Next generation sequencing (Truseq or Trusight)  for mutational profiling will be performed on 
samples obtained at screening and at progression to identify mutations that are associated with 
response and acquired resistance to trametinib. Although this assessment will be done 
retrospectively, the data will be available for inerim analysis for correlation with clinical 
response. If the data indicate that a particular mutation and molecular pathway may be a 
predictive a predictive biomarker the protocol may be modified to enrich for this subgroup of 
patients. 
 
The effect of trametinib on PI3K/AKT and RAS-MEK-ERK with and without the addition of 


NCI 9460 / PHL-091 
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  81 
GSK2141795 evaluated by phospho-flow cytometry will be used to determine whether escape 
mechanisms are ERK-dependent or ERK-independent and driven by PI3K/AKT signaling. 
cfDNA will be extracted from peripheral blood samples. Ultra-deep sequencing will be 
performed on cfDNA to assess the feasibility of detecting mutations of NRAS, KRAS and BRAF 
from peripheral blood samples.  
 
 
13.5 Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evalable for toxicity from the time of their first treatment with trametinib. 
Toxicity analyses will review adverse events, electrocardiogram results, laboratory tests 
(hematology, clinical chemistry, and coagulation test), vital signs and physical examinations.  
Safety will be measured in terms of type, frequency and severity of adverse event reactions 
reported according to CTCAE v4.0.  
 
13.5.2 Evaluation of Response 
 
All patients included in the study will be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each patient will be assigned one of 
the following categories:  1) stringent complete response, 2) complete response, 3) very good 
partial response 4) partial response, 5) minimal response 6) stable disease, 7) progressive disease, 
8) early death from malignant disease, 9) early death from toxicity, 10) early death because of 
other cause, or 11) unknown (not assessable, insufficient data).   
 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate.  Patients 
in response categories 7-10 should be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.  
 
All conclusions on treatment efficacy will be based on all eligible patients. Sub-analyses for 
objective response rate will be performed on all patients meeting the eligibility criteria, who have 
signed a consent form, and have begun study drug treatment, and had at least one follow-up 
assessment or progressive disease. This analysis will clearly report the reason for exclusion that 
may be based on major protocol deviations such as early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc. Further, the 95% confidence 
intervals will be provided.  
 
 


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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. 
• Audits may be accomplished in one of two ways:  (1) source documents and research 
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. 
 


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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information:  
 The title page must include the name and address of each participating institution and 
the name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required.  The procedures for registration must be 
stated in the protocol. 
 Data collection forms should be of a common format.  Sample forms should be 
submitted with the protocol.  The frequency and timing of data submission forms to 
the Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly 
to CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
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 
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 dimethyl sulfoxide and/or 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.  
 
Trametinib dimethyl sulfoxide or GSK2141795 interact 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:  
 
Trametinib dimethyl sulfoxide or GSK2141795  interact with (a) certain specific enzyme(s) in 
your liver.  
• The enzyme(s) in question are CYP 3A4 and 2C8.  CYP 3A4 is responsible for breaking 
down trametinib dimethyl sulfoxide in your liver.  Trametinib dimethyl sulfoxide or 
GSK2141795 may prevent other drugs from being broken down in your liver by CYP 
2C8   
• Trametinib dimethyl sulfoxide or 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 activity of CYP 3A4 (“inducers”) could reduce the 
effectiveness of trametinib dimethyl sulfoxide or GSK2141795, while substances 
that decrease that enzyme’s activity (“inhibitors”) could result in high levels of 
the active drug, increasing the chance of harmful side effects. 
o Trametinib dimethyl sulfoxide or GSK2141795 is considered an “inhibitor” of 
CYP 2C8, meaning that it can affect the levels of other drugs that are processed 
by that enzyme.  This can lead to harmful side effects and/or reduce the 


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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.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors” of CYP 3A4 or  
highly sensitive substrates of  CYP3A4 or CYP 2C8. 
• 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:  
• If you take acetaminophen regularly:  You should not take more than 4 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. 
• If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
• If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking trametinib dimethyl sulfoxide. 
 
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  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 
 
 


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INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
trametinib dimethyl sulfoxide and GSK2141795.  This clinical trial is 
sponsored by the NCI.  Trametinib dimethyl sulfoxide 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. 
Trametinib dimethyl sulfoxide interacts with a specific liver enzyme 
called CYP 3A4 and 2C8, and must be used very carefully with other 
medicines that interact with this enzyme.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP3A4 and 2C8.” 
 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 _______________________________.  


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APPENDIX D 
DATA MANAGEMENT GUIDELINES 
 
Case Report Form Submission Schedule 
 
Data required for the study will be collected in Case Report Forms provided by the PMH Phase 2 
Consortium Central Office.  The site will be required to complete a paper Eligibility Checklist 
case report form (CRF) at the time of patient registration.  All other data will be collected on 
electronic case report forms (eCRFs) in the Medidata Rave system.  Site staff access to Medidata 
Rave will be initiated at the time of site activation.  The form submission schedule is outlined 
below. 
 
Case Report Form 
Submission Schedule 
Eligibility Checklist 
At the time of registration 
Baseline eCRFs 
Within 3 weeks of on study date 
On Treatment (Cycle) eCRFs 
Within 3 weeks of each visit 
Off Treatment eCRFs 
Within 3 weeks of the patient 
coming off-study 
Short Follow-up eCRFs 
Within 3 weeks of the patient 
coming to clinic.   
Final eCRFs 
Within 3 weeks from the follow-
up period being complete or of the 
patient's death being known to the 
investigator unless this constitutes 
a reportable adverse event when it 
should be reported according to 
CTEP-AERS guidelines 
 
Case Report Form Completion 
 
The paper Eligibility Checklist CRF must be completed using black ink.  Any errors must be 
crossed out so that the original entry is still visible, the correction clearly indicated and then 
initialed and dated by the individual making the correction. 
 
eCRFs will be completed according to the schedule noted above and all relevant supporting 
documentation such as scans, progress notes, nursing notes, blood work, pathology reports, etc., 
will be submitted to the PMHC Phase 2 Consortium Central Office for review.  All patient 
names or other identifying information will be removed prior to being sent to the Central Office 
and the documents labeled with patient initials, study number and the protocol number.   
 
eCRF completion guidelines are available for all sites. 
 
Monitoring 
 
Central data monitoring will take place throughout the trial at the Central Office.  On-site 
monitoring will be performed once a year at participating sites during which a subset of PMHC 


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studies will be picked for on-site monitoring.  
 
Data in the Medidata Rave eCRFs will be monitored on a regular basis and quality assurance 
measures will be performed.  Electronic data queries as well as paper query letters may be issued 
to the site prior to the quarterly submission of data to CDUS. 
 
Patient Registration 
 
• Refer to section 4 of the protocol 
 
Data Safety 
 
A Data Safety and Monitoring Board, an independent group of experts, will be reviewing the 
data from this research throughout the study to see if there are unexpected or more serious side 
effects than described in the consent. 
 
Regulatory Requirements 
 
• Please submit all required documents to the PMH Phase 2 Consortium Central Office. 
• Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. 
• All investigators must have a current NCI investigator number on file with the PMH 
Phase 2 Consortium Central Office. 
• All investigators must have an up-to-date CV (signed within 2 years) on file with the 
PMH Phase 2 Consortium Central Office. 
• Laboratory certification/accreditation and normal ranges are required 
• Confirmation of all investigators having undergone training in the Protection of Human 
Research Subjects is required.  It is preferred that other staff involved in the trial also 
undergoes such training. 
• Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
• OPRR assurance numbers for each institution are required 
• Consent forms must be reviewed by the Central Office before submission to the local 
ethics regulatory board (REB/IRB) and must include a statement that 1) information will 
be sent to and 2) medical records will be reviewed by the PMH Phase 2 Consortium 
Central Office. 
• A Membership list of the local ethics board is required. 
• A copy of the initial approval letter from the ethics board must be submitted to the PMH 
Phase 2 Consortium Central Office. 
• A completed Site Participant List/Training Log is required and must be submitted to 
PMHC 
• Continuing approval will be obtained at least yearly until follow-up on patients is 
completed and no further data is being obtained for research purposes. 
 
 
APPENDIX E 
DIARY CARD 


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Physician’s Office will complete this section: 
The above information has been reviewed with the patient:  
Patient Name: _______________ 
Physician/Nurse Signature __________________________________ 
Date ________________________ 
 
INSTRUCTIONS – Trametinib Monotherapy 
1. You will take 2 mg trametinib tablets or 1.5 mg trametinib once a day.  Trametinib tablets must be 
taken on an empty stomach either 1 hour before or 2 hours after a meal.   
2. Swallow each tablet whole.  Do not crush or chew the tablets. 
3. Record the date you took the Trametinib and indicate time that the dose was taken.  
4. If you have any comments or notice any side effects, please record them in the Comments column.   
5. Please bring this form at each clinic visit. 
6. In case of errors, please place a single slash mark through the error and initial it.  Please do not 
white out any error or scribble it out with ink.  Please do not write the correct information directly 
over the error, but on a separate line next to the error. 
7. If you miss any of the doses or you vomit one of the tablets, do not take any extra dose, and call 
your study doctor. 
Day 
Date - Time 
Trametinib Dose 
Comments 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10 
 
 
 
11 
 
 
 
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28 
 
 
 
INSTRUCTIONS – Trametinib and GSK2141795 Combination Therapy 
1. You will take ___ 0.5 mg trametinib tablets (___ mg total dose) once a day on an empty stomach; either 1 
hour before or 2 hours after a meal. 
2. ___ 25 mg GSK2141795 capsules (___ mg total dose) are taken once a day; fasting 1 hour after a small 


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Physician’s Office will complete this section: 
The above information has been reviewed with the patient:  
Patient Name: _______________ 
Physician/Nurse Signature __________________________________ 
Date ________________________ 
snack and 2 hours before the next meal.  
 Eat a small snack followed by 60 minutes of fasting prior to taking GSK2141795 capsules. Water is 
allowed during this fasting period.  If possible, take each capsule approximately 5 minutes apart with 
divided amounts of fluid (4-8oz with each capsule for a total of at least 12 oz).For example: Eat 
breakfast.  Take GSK2141795 one hour after eating, and then wait 2 hours.  Take trametinib, and wait 
one hour before eating the next meal. 
3. Swallow each capsule whole.  Do not crush or chew the capsules. 
4. Stay upright (standing or sitting up) for at least 30 minutes after taking the last GSK2141795 
capsule for each dose.  
5. Fast for 2 hours (water is allowed) after taking the last GSK2141795 capsule for each dose.  
6. Record the date you took Trametinib/ GSK2141795, and indicate the time that the dose was taken. 
7. If you have any comments or notice any side effects, please record them in the Comments column.   
8. Please bring this form at each clinic visit. 
9. In case of errors, please place a single slash mark through the error and initial it.  Please do not white 
out any error or scribble it out with ink.  Please do not write the correct information directly over the 
error, but on a separate line next to the error. 
10. 
If you miss any of the doses or you vomit one of the tablets or capsules, do not take any extra 
dose, and call your study doctor. 
Day 
Date - Time 
Trametinib Dose 
GSK2141795 Dose 
Comments 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
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9 
 
 
 
 
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APPENDIX F 
MUTATIONAL PROFILING  
 
 
TABLE 1: TruSeq Amplicon Cancer Panel 
 
 
 
TABLE 2: TruSight Cancer Panel 


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TABLE 3: KRAS, NRAS, BRAF Mutation List  
 
KRAS 
exon 2 
exon 3 
exon 4 
exon 5 
TruSeq 
Met1_Glu31 
Asp38_Gln70 
Arg97_Gln150 
N/A 
TruSight Met1_Glu37 
Asp38_Arg97 
Arg97_Gln150 
Gly151_189X 
 
 
 
 
 
NRAS 
exon 2 
exon 3 
exon 4 
exon 5 
TruSeq 
Met1_Asn26 
Asp38_Gln70 
N/A 
N/A 
TruSight Met1_Glu31 
Asp38_Arg97 
Arg97_Gln150 
Gly151_190X 
 
 
 
 
 
BRAF 
exon 11 
exon 15 
 
 
TruSeq 
Lys439_His477 Asn581_Leu613  
 
TruSight Lys439_His477 Asn581_Trp619