Conditions: Hematopoietic and Lymphoid Cell Neoplasm Locally Advanced Malignant Solid Neoplasm Locally Advanced Melanoma Metastatic Malignant Solid Neoplasm Metastatic Melanoma Stage IIIC Cutaneous Melanoma AJCC v7 Stage IV Cutaneous Melanoma AJCC v6 and v7 Unresectable Malignant Solid Neoplasm Unresectable Melanoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 27
Healthy volunteers: no

Brief summary:
This phase I/II trial studies the side effects and the best dose of uprosertib when given together with dabrafenib and trametinib and to see how well they work in treating patients with stage IIIC-IV cancer. Uprosertib, dabrafenib, and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving uprosertib with dabrafenib and trametinib may be a better treatment for cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the safety of dabrafenib mesylate (dabrafenib) in combination with uprosertib (GSK2141795) and select the optimal dose of GSK2141795 for the phase II portion in patients with BRAF mutant cancer. (Effective November 15, 2014, this trial will not proceed to the phase II study of dabrafenib and GSK2141795, but will move to an evaluation of triple therapy). (Phase I) II. To assess the safety of dabrafenib and trametinib dimethyl sulfoxide (trametinib) and GSK2141795 in combination and select the optimal dose of the combination for the phase II portion in patients with BRAF mutant cancer. (Phase I) III. To evaluate the objective response rate (confirmed and unconfirmed, complete and partial responses) in patients with BRAF\^V600 mutant metastatic melanoma who have previously progressed on BRAF\^V600 inhibitor-based therapy (BRAFi), or BRAFi + MEK inhibitor-based therapy (MEKi). (Phase II)

SECONDARY OBJECTIVES:

I. To estimate overall survival and progression-free survival. II. To assess the toxicity profile of the recommended phase II dose. III. To assess response (complete and partial, confirmed and unconfirmed) of patients enrolled on each phase I portion).

TRANSLATIONAL MEDICINE OBJECTIVES:

I. To explore the molecular mechanisms of acquired resistance to BRAF inhibitor therapy using available biopsies of lesions that progressed during prior BRAF inhibitor-based therapy.

II. To explore potential drug-drug interactions between dabrafenib and GSK2141795 leading to changes in the expected exposure with either agent compared to prior experience. (Phase I)

OUTLINE: This is a phase I, dose-escalation study of uprosertib followed by a phase II study. Dose escalation of dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib will be initiated after completion of the dabrafenib + uprosertib phase I dose escalation.

Dabrafenib mesylate and uprosertib (Phase I): Patients receive dabrafenib orally (PO) twice daily (BID) and uprosertib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) scan, magnetic resonance imaging (MRI), and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

Dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib (Phase I and Phase II): Patients receive dabrafenib PO BID, trametinib PO QD, and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, magnetic MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

After completion of study treatment, patients are followed up every 3 months for 1 year and then every 6 months for 2 years.

Arms:
arm 1: Dabrafenib mesylate and uprosertib (Phase I): Patients receive dabrafenib PO BID and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

Dabrafenib mesylate, trametinib dimethyl sulfoxide, and uprosertib (Phase I and Phase II): Patients receive dabrafenib PO BID, trametinib PO QD, and uprosertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, MRI, and blood sample collection throughout trial. Patients may also undergo a biopsy throughout the trial.

Interventions: intervention 1: Biopsy intervention 2: Biospecimen Collection intervention 3: Computed Tomography intervention 4: Dabrafenib Mesylate intervention 5: Magnetic Resonance Imaging intervention 6: Trametinib Dimethyl Sulfoxide intervention 7: Uprosertib
Intervention descriptions: intervention 1: Undergo a biopsy intervention 2: Undergo blood sample collection intervention 3: Undergo a CT scan intervention 4: Given PO intervention 5: Undergo MRI intervention 6: Given PO intervention 7: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
Distribution Date: 
TBD 
Version Date: 
August 21, 2017 
 
TO: 
PHASE I SITES: U of CA LOS ANGELES (CA006), U OF 
SOUTHERN CALIFORNIA (CA011), U of CA SAN FRANCISCO 
(CA136), CALIFORNIA PACIFIC (CA222), U OF COLORADO 
(CO070), H. LEE MOFFITT CANCER CENTER (FL065), U OF 
MICHIGAN (MI014), OHIO STATE UNIV (OH007), CLEVELAND 
CLINIC (OH027), OREGON HEALTH SCIENCES UNIVERSITY 
(OR010), 
PROVIDENCE 
PORTLAND 
MC 
(OR014), 
U 
OF 
TENNESSEE – MEMPHIS (TN030), MD ANDERSON (TX035), U 
OF WASHINGTON (WA020) 
 
PHASE II:  SWOG 
 
FROM: 
Danae Campos, Protocol Coordinator (E-mail- dcampos@swog.org) 
 
RE: 
S1221, “Phase I/II Study of the Safety and Efficacy of the AKT 
Inhibitor GSK2141795 in Combination with Dabrafenib and 
Trametinib in Patients with BRAF Mutant Cancer.”  Study Chairs:  
Drs. A. Ribas, B. Chmielowski, R. Lo, and A Algazi. 
 
REVISION #10 
 
Study Chair:  Antoni Ribas, M.D., Ph.D. 
Phone Number:  310/206-3928 
E-mail:  aribas@mednet.ucla.edu 
 
IRB Review Requirements 
( √ ) 
Expedited review allowed 
 
Protocol changes 
( √ ) 
Informed Consent changes 
( √ ) 
Patient notification required (Patients currently 
receiving GSK2141795 must be reconsented.) 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent 
form changes have been approved by the CIRB and must be activated within 30 days 
of the CIRB posting of this notice.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or 
informed consent changes must be approved by local IRBs within 90 days of 
distribution of this notice. The changes in this revision are effective upon approval by 
the local IRB; however, any changes to eligibility become effective 6 weeks after 
distribution of this notice. 
 
 
REVISION #10 
 
 


 
S1221 
 
Revision #10 (contd.) 
 
Page 2 
 
 
 
The following revisions have been made in the protocol referenced above: 
 
1. 
Title Page: The version dates of the protocol and model consent form have been updated.  
 
2. 
ICF:  Page 13, under the section “What are the costs of taking part in this study”, the 
paragraph beginning “If your disease progresses before the new drug supply”, was deleted as 
there will be no additional supply of GSK2141795 available after 09/30/2018. 
 
This memorandum serves to notify the NCI and the SWOG Statistical Center. 
 
cc:  
PROTOCOL & INFORMATION OFFICE  
Syed Mahmood - Novartis 
 
 
 
 


 
 
S1221 
 
 
Page 1 
 
Version Date 8/21/17 
 
 
 
 
PRIVILEGED COMMUNICATION 
Activated July 1, 2013 
FOR INVESTIGATIONAL USE ONLY 
 
 
SWOG 
 
 
 
PHASE I/II STUDY OF THE SAFETY AND EFFICACY OF THE AKT INHIBITOR GSK2141795 IN 
COMBINATION WITH DABRAFENIB AND TRAMETINIB IN PATIENTS WITH BRAF MUTANT CANCER 
 
NCT #01902173 
 
 
STUDY CHAIRS: 
AGENTS: 
 
Antoni Ribas, M.D., Ph.D. (Medical Oncology) 
NCI-Supplied Investigational Agents: 
UCLA Medical Center 
Dabrafenib Mesylate (NSC-763760; IND-118705) 
Division of Hematology-Oncology 
GSK2141795 (NSC-767034; IND-118705) 
11-934 Factor Building 
Trametinib (NSC-763093; IND-119432) 
10833 Le Conte Avenue 
 
Los Angeles, CA 90095 
 
Phone: 310/206-3928 
 
FAX: 310/825-2493 
 
E-mail: aribas@mednet.ucla.edu 
BIOSTATISTICIANS 
 
 
 
Alain P. Algazi, M.D. (Medical Oncology) 
James Moon, M.S. 
University of California, San Francisco 
Megan Othus, Ph.D. 
1600 Divisadero, Box 1770 
SWOG Statistical Center 
San Francisco, CA 94143-1770 
1100 Fairview Ave North, M3-C102 
Phone:  415/353-7552 
P.O. Box 19024 
FAX:  415/353-7779 
Seattle, WA 98109-1024 
E-mail:  alain.algazi@ucsf.edu 
Phone: 206/667-4623 
 
FAX: 206/667-4408 
Bartosz Chmielowski, M.D., Ph.D. (Medical Oncology) E-mail: jmoon@fredhutch.org 
University of California, Los Angeles 
E-mail: mothus@fredhutch.org 
David Geffen School of Medicine 
Division of Hematology/Oncology 
10945 Le Conte Avenue, PVUB Suite 2333 
Los Angeles, CA  90095-7059 
Phone:  310/586-2650 
FAX:  310/443-0477 
E-mail:  bchmielowski@mednet.ucla.edu 
 
Roger S. Lo, M.D., Ph.D. (Translational Medicine) 
 
UCLA Medical Center 
 
Division of Dermatology 
 
52-121 CHS 
 
10833 Le Conte Ave 
 
Los Angeles, CA 90095 
 
Phone: 310/825-5420 
 
FAX: 310/206-9878 
 
E-mail: rlo@mednet.ucla.edu 
 
 
 


 
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Version Date 8/21/17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PARTICIPANTS 
PHASE I PORTION LIMITED TO THE FOLLOWING: 
CA006/U OF CA LOS ANGELES  
CA011/U OF SOUTHERN CALIFORNIA  
CA136/U OF CA SAN FRANCISCO 
CA222/CALIFORNIA PACIFIC 
CO070/U OF COLORADO  
FL065/H. LEE MOFFITT CANCER CENTER  
MI014/U OF MICHIGAN  
OH007/OHIO STATE UNIV  
OH027/CLEVELAND CLINIC  
OR010/OREGON HEALTH SCIENCES UNIVERSITY  
OR014/PROVIDENCE PORTLAND MC NCORP 
TN030/U OF TENNESSEE - MEMPHIS 
TX035/MD ANDERSON  
WA020/U OF WASHINGTON  
 
PHASE II PORTION: 
 
SWOG/SWOG 


 
 
 
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Version Date 8/21/17 
 
 
 
 
TABLE OF CONTENTS 
 
Page 
 
PARTICIPANTS ...................................................................................................................................... 2 
SCHEMA ................................................................................................................................................. 5 
1.0 
OBJECTIVES ............................................................................................................................ 6 
1.1 
Primary Phase I Portion Objective ............................................................................................. 6 
1.2 
Primary Phase II Portion Objective ............................................................................................ 6 
1.3 
Secondary Objectives ................................................................................................................ 6 
1.4 
Translational Medicine Objective ............................................................................................... 6 
2.0 
BACKGROUND ......................................................................................................................... 7 
3.0 
DRUG INFORMATION .............................................................................................................. 12 
3.1 
Dabrafenib mesylate (GSK2118436B) (NSC-763760) (CTEP IND# 118705) ........................... 12 
3.2 
GSK2141795 (GSK2141795C) (NSC-767034) (CTEP IND #118705) ...................................... 19 
3.3 
Trametinib Dimethyl Sulfoxide (GSK1120212B) (NSC-763093) (IND-119432) ........................ 23 
4.0 
STAGING CRITERIA (AJCC 7th Edition, 2010) ....................................................................... 31 
5.0 
ELIGIBILITY CRITERIA ............................................................................................................ 32 
5.1 
Phase I Portion Eligibility Criteria ............................................................................................... 32 
5.2 
Phase II Portion Eligibility Criteria .............................................................................................. 36 
6.0 
STRATIFICATION FACTORS ................................................................................................... 37 
7.0 
TREATMENT PLAN .................................................................................................................. 37 
7.1 
Treatment Overview ................................................................................................................... 37 
7.2 
General Concomitant Medication and Supportive Care Guidelines .......................................... 37 
7.3 
Treatment - Phase I  Dabrafenib + GSK2141795 (D+G) ........................................................... 38 
7.4 
Treatment - Phase I  Dabrafenib + Trametinib + GSK2141795 (D + T + G) ............................. 41 
7.5 
Treatment - Phase II Portion of the Study .................................................................................. 43 
7.6 
Guidelines for Administration ..................................................................................................... 43 
7.7 
Drug Compliance Documentation .............................................................................................. 44 
7.8 
Full CDUS Reporting Requirements .......................................................................................... 44 
7.9 
Criteria for Removal from Protocol Treatment ........................................................................... 44 
7.10 
Discontinuation of Treatment ..................................................................................................... 44 
7.11 
Follow-Up Period ........................................................................................................................ 44 
8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS .................................... 45 
8.1 
NCI Common Terminology Criteria for Adverse Events ............................................................ 45 
8.2 
General Dose Modification Considerations................................................................................ 45 
8.3 
Dose Modifications for Dabrafenib, Trametinib, and GSK2141795 ........................................... 45 
8.4 
Dose Modifications for GSK2141795 ......................................................................................... 63 
8.5 
Dose Modification Contacts ....................................................................................................... 64 
8.6 
Adverse Event Reporting ........................................................................................................... 64 
9.0 
STUDY CALENDAR .................................................................................................................. 64 
9.1 
Study Calendar – Phase I D+G Portion ..................................................................................... 65 
9.2 
Study Calendar – Phase I D+T +G Portion ................................................................................ 68 
9.3 
Study Calendar – Phase II D+T+G ............................................................................................ 71 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS............................................. 74 
10.1 
Measurability of Lesions............................................................................................................. 74 
10.2 
Objective Status at Each Disease Evaluation ............................................................................ 75 
10.3 
Best Response ........................................................................................................................... 76 
10.4 
Performance Status ................................................................................................................... 77 
10.5 
Progression-Free Survival.......................................................................................................... 77 
10.6 
Time to Death ............................................................................................................................. 77 
11.0 
STATISTICAL CONSIDERATIONS .......................................................................................... 77 
11.1 
Accrual Goals ............................................................................................................................. 77 
11.2 
Evaluation of Dabrafenib + GSK2141795 (D+G) ....................................................................... 78 
11.3 
Evaluation of Dabrafenib + Trametinib + GSK2141795 (D+T+G) ............................................. 79 
11.4 
Analysis of Secondary Endpoints .............................................................................................. 80 
11.5 
Analysis of Translational Medicine Component ......................................................................... 80 
11.6 
Data and Safety Monitoring ....................................................................................................... 81 


 
 
 
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12.0 
DISCIPLINE REVIEW ................................................................................................................ 81 
13.0 
REGISTRATION GUIDELINES ................................................................................................. 81 
13.1 
Registration Timing .................................................................................................................... 81 
13.2 
Slot Reservation ......................................................................................................................... 81 
13.3 
OPEN Registration Requirements ............................................................................................. 82 
13.4 
Registration Procedures............................................................................................................. 83 
13.5 
Exceptions to SWOG registration policies will not be permitted. ............................................... 84 
14.0 
DATA SUBMISSION SCHEDULE ............................................................................................ 84 
14.1 
Data Submission Requirement .................................................................................................. 84 
14.2 
Master Forms ............................................................................................................................. 84 
14.3 
Data Submission Procedures .................................................................................................... 84 
14.4 
Data Submission Overview and Timepoints .............................................................................. 85 
15.0 
SPECIAL INSTRUCTIONS........................................................................................................ 87 
15.1 
Phase I Portion:  Rapid Reporting ............................................................................................. 87 
15.2 
Phase I Portion:  Mandatory Conference Calls .......................................................................... 87 
15.3 
Phase I Portion:  Mandatory Pharmacokinetic (PK) Sampling .................................................. 87 
15.4 
Phase I & II Portions:  Mandatory Specimen Submission for Translational Medicine ............... 88 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................... 89 
16.1 
Adverse Event Reporting Requirements.................................................................................... 91 
17.0 
BIBLIOGRAPHY ........................................................................................................................ 96 
18.0 
APPENDIX ................................................................................................................................. 98 
18.1 
Determination of Expedited Adverse Event Reporting Requirements ....................................... 99 
18.2 
Translational Medicine ............................................................................................................... 101 
18.3 
Intake Calendar .......................................................................................................................... 102 
18.4 
Strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, Bcrp and possibly 2C8/9 and 2C19 ....... 103 
18.5 
New York Heart Association Classifications .............................................................................. 106 
18.6 
Information on Possible Drug Interactions ................................................................................. 107 
18.7 
Information on Possible Drug Interactions – Patient Wallet Card .............................................. 109 
18.8 
Instructions for Patients for Storage of Trametinib Tablets ........................................................ 110 
 
 
 
 


 
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SCHEMA 
 
Phase I portion (open to limited institutions as listed on the Title Page): 
 
Registration 
 
 
 
 
Dabrafenib + GSK2141795 
 
 
 
 
Assess dosing for triple therapy phase I portion 
 
 
 
 
 
Dabrafenib + Trametinib +GSK2141795 
 
 
 
 
 
Temporary closure to assess 
dosing for Phase II portion 
 
 
 
Phase II portion (open to all SWOG institutions): 
 
 
Registration 
 
 
 
 
Dabrafenib and Trametinib + GSK2141795 
 
 
 
A patient may be enrolled to either the Phase I portion or the Phase II portion, but not both. 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Phase I Portion Objective 
 
Dabrafenib + GSK2141795 
 
The primary objective of the Phase I Portion will be to assess the safety of dabrafenib in 
combination with GSK2141795 and select the optimal dose of GSK2141795 for the 
Phase II Portion in patients with BRAF mutant cancer. Effective November 15, 2014, this 
trial will not proceed to the Phase II study of dabrafenib and GSK2141795, but will 
moving to an evaluation of triple therapy.  See below) 
 
Dabrafenib + Trametinib + GSK2141795 
 
The primary objective of the Phase I portion will be to assess the safety of dabrafenib and 
trametinib and GSK2141795 in combination and select the optimal dose of the 
combination for the Phase II Portion in patients with BRAF mutant cancer. 
 
1.2 
Primary Phase II Portion Objective 
 
The primary objective of the Phase II portion will be to evaluate the objective response 
rate (confirmed and unconfirmed, complete and partial responses) in patients with 
BRAFV600 mutant metastatic melanoma who have previously-have previously progressed 
on BRAFV600 inhibitor-based therapy (BRAFi), or BRAFi + MEK inhibitor-based therapy 
(MEKi). 
 
1.3 
Secondary Objectives 
 
a. 
To estimate overall survival and progression-free survival. 
 
b. 
To assess the toxicity profile of the recommended Phase II dose. 
 
c. 
To assess response (complete and partial, confirmed and unconfirmed) of 
patients enrolled on each Phase I portion. 
 
1.4 
Translational Medicine Objective 
 
a. 
The translational medicine objective is to explore the molecular mechanisms of 
acquired resistance to BRAF inhibitor therapy using available biopsies of lesions 
that progressed during prior BRAF inhibitor-based therapy.  The analyses will 
include the following to detect MAPK-reactivation resistance: Detection of 
BRAFV600 amplification, BRAFV600 truncation, NRASQ61 mutations and MEK 
mutations, which are the most validated and readily detectable acquired MAPK-
reactivation resistance mechanisms.  Additional analyses to detect other 
mechanisms of resistance, particularly those involving the AKT pathway, will be 
explored, as will be targeted sequencing of genes in the P13K/AKT pathway. 
 
b. 
All patients participating in the Phase I portions of the study will have a limited PK 
sampling at baseline and at steady state on Days 15 and 29 before taking the 
study drugs on that day. In addition, three patients treated within the second 
cohort of each of the Phase I portions (D+G and D+T+G) will undergo an intense 
15 day pharmacokinetic (PK) sampling for circulating levels of the study drugs.  
This will be performed to explore potential drug-drug interactions between 
dabrafenib and GSK2141795 leading to changes in the expected exposure with 
either agent compared to prior experience.  


  
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2.0 
BACKGROUND 
 
The BRAF inhibitors vemurafenib and dabrafenib confer objective response in about half of 
treated patients with BRAFV600 mutant metastatic melanoma, which is mediated by the inhibition 
of oncogenic MAPK signaling. Their clinical use is limited by the development of acquired 
resistance to single agent BRAF inhibitor therapies, which typically develops within 6 months of 
continuous therapy with dabrafenib or vemurafenib. (1-7) 
 
Resistance to BRAF inhibitors does not follow the common pathways of resistance to other ATP-
competitive targeted kinase inhibitors in that no mutations in the actual target kinase have been 
described that would make the drug binding ineffective.  Notably, no mutations have been 
described in patient-derived samples that would correspond to the T315I resulting in resistance to 
imatinib in chronic myelogenous leukemia, or the T790M mutation resulting in resistance to 
gefitinib in non-small cell lung cancer. (8,9)  Instead, a variety of mechanistically different 
resistance pathways have been described in subsets of acquired resistant tumor biopsies.  These 
can be divided into two major groups when focusing on mechanisms reported to date in patient-
derived samples: 
 
1. 
Reactivation of the MAPK pathway:  Despite the lack of identified secondary acquired 
mutations in BRAF to date, several alterations leading to reactivation of oncogenic 
signaling through the MAPK pathway result in acquired resistance to BRAF inhibitors.  Of 
note, the resistant lesions universally maintain the BRAFV600 mutation.  However, there 
can be other changes in BRAF itself, including amplifications of the mutant BRAFV600 
gene and truncations in the BRAF protein through alternate splicing resulting in increased 
kinase activity due to increased dimerization. (10,11)  Secondary mutations upstream or 
downstream of BRAF would also be predicted to result in resistance, and secondary 
mutations in NRAS and MEK have been described in patient-derived samples. (12,13)  
However, some patients with a concurrent mutation in BRAFV600 and MEKP124 at baseline 
can still have clinical responses to BRAF inhibitors. (14)  Finally, overexpression of the 
MAPK protein COT without mutations has been suggested to also lead to acquired 
resistance. (15)  Overall, data derived from analyzing tumor samples from baseline and 
at the time of acquired resistance, indicate that resistance due to reactivation of the MAP 
kinase pathway is present in 70% of the cases with a known or proposed resistance 
mechanism.  (16)  Most of these resistance mechanisms could be blocked by 
downstream MAPK pathway inhibition at the level of MEK or ERK.  Combined BRAF and 
MEK inhibition has been tested in randomized Phase II and Phase III clinical trials using 
the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib. (17,18)  Combination 
therapy substantially increases median PFS compared with dabrafenib alone and the 
FDA has approved the combination of dabrafenib and trametinib for the first line 
treatment of BRAF mutant melanoma. This combination is generally well tolerated and 
the addition of trametinib to dabrafenib actually reduced the incidence of several 
significant adverse effects of BRAF inhibitors. Based on the favorable adverse effect 
profile of dabrafenib with trametinib, triple therapy with dabrafenib, trametinib, and an 
additional agent may be feasible. 
 
2.  
MAPK-independent pathways:  In approximately one-fourth to one-third of the cases of 
acquired resistance, the BRAF inhibitor continues to demonstrate ability to block 
oncogenic BRAFV600 signaling, and the cell adapts to gain MAPK-independent oncogenic 
signaling often leading to overactivation of the PI3K pathway. (12,16)  Mechanisms of 
resistance include overexpression or overactivation of receptor tyrosine kinases (RTKs), 
such as the platelet derived growth factor receptor beta (PDGFRb) the insulin-like growth 
factor receptor 1 (IGF-1R), or the epidermal growth factor receptor (EGFR). (12,19,20)  
Acquired resistance can also be induced by acquired activation mutations in PI3K 
pathway constituents including PIK3CA, PTEN, and PHLPP1. (16) Innate resistance to 
BRAF inhibitor therapy can be mediated by hepatocyte growth factor (HGF) binding to 
the RTK Met.  (21,22)  These RTKs share a common signaling hub, the PI3K-AKT 
pathway. In preclinical models this signaling can be inhibited by drugs that block PI3K, 
AKT or PI3K+TORC, restoring tumor responses in the acquired resistance setting.  


 
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(19,23-25)  Unpublished data also suggest that acquired resistance to dual BRAF and 
MEK inhibition may lead to increased reliance on MAPK-independent pathways during 
drug escape and combined BRAF, MEK and AKT inhibition demonstrates substantial 
synergy preclinically in treatment-naïve models (See Rationale for Triple Therapy). 
 
Clinical Experience with the Combination of Dabrafenib + Trametinib 
 
Data on 247 patients with metastatic melanoma and BRAFV600 mutations participating in the 
Phase I/II study of dabrafenib and trametinib, BRF113220, have been published (Flaherty et al., 
2012). 
 
PK 
Coadministration of dabrafenib 150 mg twice daily and trametinib 2 mg once daily resulted in no 
clinically relevant pharmacokinetic drug interactions.   
 
RP2D for the combination of trametinib and dabrafenib 
In the dose escalation portion (Part B) of study BRF113220, the MTD of the combination was not 
reached, and the RP2D was therefore 150/2 (Flaherty et al., 2012).  Pyrexia, chills, and nausea 
were the most common reasons cited for dose reductions; pyrexia, chills, and decreased ejection 
fraction were the most common reasons cited for dose interruptions.  Comprehensive safety data 
for the combination of dabrafenib and trametinib are presented in Section 3.0. 
 
Activity of dabrafenib + trametinib 
In the Phase II portion of study BRF113220, among 162 patients with BRAFV600E or BRAFV600K 
mutation-positive melanoma, were randomized to 3 arms: dabrafenib 150 mg BID + trametinib 2 
mg QD, dabrafenib 150 mg BID + trametinib 1 mg QD, and single-agent dabrafenib 150 mg BID, 
efficacy analyses were performed in the intention-to-treat population, with a median follow-up of 
14.1 months. (17)  All major efficacy endpoints were improved, including PFS, 12-month PFS, 
ORR, and duration of response (see table below).   
 
End Point 
(as assessed by the investigators) 
Dabrafenib 
Monotherapy 
(n=54) 
Combination 
150/1 
(n=54) 
Combination 
150/2 
(n=54) 
Progression-free Survival – months 
Median (95% CI) 
5.8 (4.6-7.4) 
9.2 (6.4-11.0) 
9.4 (8.6-16.7) 
Progression-free Survival at 12 mo. % 
(95% CI) 
9 (3-20) 
26 (15-39) 
41 (27-54) 
CR or PR 
Patients (% [95% CI]) 
29 (54 [40-67]) 
27 (50 [36-64]) 
41 (76 [62-86]) 
Duration of response 
Median months (95% CI) 
5.6 (4.5-7.4) 
9.5 (7.4-NA) 
10.5 (7.4-14.9) 
 
Safety data for trametinib in combination with GSK2141795 
 
The combination of trametinib and GSK2141795 has been examined in Phase I and Phase II 
clinical trials.  In Phase I testing, the most common adverse events (≥10%) were nausea (26%; 
G3/4 0%), AST elevation (22%; G3/4 9%), fatigue (22%; G3/4 0%), rash (22%; G3/4 0%), 
decreased appetite (17%; G3/4 0%), hypokalemia (17%; G3/4 0%), anemia (13%; G3/4 0%), 
confusional state (13%; G3/4 0%), dry mouth (13%; G3/4 0%), peripheral edema (13%; G3/4 
0%), and vomiting (13%; G3/4 0%). (26)  The recommended  Phase II dose is trametinib 1.5 mg 
daily with GSK2141795 50 mg daily.   


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Rationale for triple therapy 
Preclinical Rationale: 
Activating mutations in the PI3K pathway have been described in 22% of tumors that acquired 
resistance to BRAF inhibitors, most frequently in combination with activating mutations of the 
MAPK pathway. (16) There are emerging data suggesting that the PI3K pathway plays a pivotal 
role in the survival of senescent tumor cells after maximal response to MAPK pathway inhibitors 
(Roger Lo, unpublished data).  In preclinical testing, combined BRAF/MEK/AKT inhibition leads to 
profound decreases in BRAF mutant melanoma cell survival. 
 
 
Despite the improved PFS with dabrafenib and trametinib in the first line compared with 
dabrafenib alone, the addition of the MEK inhibitor trametinib alone to the BRAF inhibitor 
dabrafenib after disease progression on dabrafenib alone yields only modest clinical benefits with 
an objective response rate of only 9-15% and a median progression-free survival of only 3.6 
months. (27)  As a result, the combination of dabrafenib and trametinib after disease progression 
on a BRAF inhibitor has not been FDA approved and the vast majority of BRAF mutant 
melanoma patients treated with BRAF inhibitor monotherapy have no effective targeted therapy 
options after disease progression on these agents (median PFS 5-6 months). (3,4) The current 
study will examine the safety and efficacy of combined BRAF, MEK, and AKT inhibition based on 
preclinical data suggesting that resistance to MAPK inhibitors may be mediated by activating 
PI3K pathway mutations and non-mutational activation of the PI3K pathway. (12,16,19-25)  
Phase II testing of this combination in treatment naïve patients is based on data suggesting that 
1. PI3K activity may be essential for the survival of senescent cells after maximal tumor killing 
from dabrafenib and trametinib and 2. The molecular evolution of surviving tumors in patients with 
disease progression on BRAF inhibitors may make the addition of additional oncogenic pathway 
inhibitors less effective at the time of progression than at the time of the initiation of BRAF 
inhibitor therapy (Roger Lo, unpublished data).  
Lassen et al.  Molecular Cancer. 2014. 


 
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The rationales for the S1221 treatment arms are summarized below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study outline 
 
Dabrafenib + GSK2141795:  
Phase I dose escalation will be performed according to a standard 3+3 scheme to identify the 
maximum tolerated dose (MTD) of dabrafenib with GSK795 prior to Phase 1 testing of 
dabrafenib, trametinib, and GSK2141795.  The dabrafenib + GSK795 combination without 
trametinib will not continue to Phase 2 testing under the current protocol. 
 
Dabrafenib + Trametinib + GSK2141795:  
3 + 3 dose escalation will be performed to identify the MTD of dabrafenib, trametinib, and 
GSK2141795 in combination.  Phase II testing will then be performed to obtain additional safety 
information and preliminary efficacy data in two populations:  1. Patients with prior disease 
progression on a BRAF inhibitor alone or a BRAF + MEK inhibitor combination and 2. Patients 
with no prior exposure to BRAF or MEK inhibitors.   
 
Hypothesis 
 
• 
The AKT inhibitor GSK795 can be combined safely with the BRAF inhibitor dabrafenib and 
the MEK inhibitor trametinib. 
• 
In patients with prior disease progression on BRAFi monotherapy or a BRAFi + MEKi 
combination, the addition of GSK795 and trametinib to dabrafenib will increase the overall 
response rate compared with historical controls treated with standard of care chemotherapy. 
• 
Triple therapy with dabrafenib, trametinib, and GSK795 will increase the overall response 
rate in BRAFi/MEKi naïve patients compared with historical controls treated with dabrafenib 
and trametinib without a PI3K pathway inhibitor. 
 
Treatment arm 
Prior treatment 
Rationale 
D + G Phase I 
(BRAFV600X solid tumors) 
Any 
Identify MTD. 
 
 
D + T + G Phase I 
(BRAFV600X melanoma) 
 
Any 
Identify MTD, 
Early response signal. 
D + T + G Phase II 
(BRAFV600X melanoma) 
 
Prior PD on BRAFi or BRAFi + 
MEKi 
Allows early assessment of 
benefit (ORR).   
Clinical need: Addition of 
MEKi alone after progression 
on BRAFi only modestly 
beneficial. 
No prior BRAFi or MEKi 
Preclinical data suggests 
potential for more durable 
benefit due to targeting of 
senescent cells and 
prevention of emergence of 
resistance due to PI3K 
pathway activation. 


 
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Inclusion of Women and Minorities 
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  The anticipated accrual in the ethnicity/race and sex 
categories is shown in the table below. 
 
Ethnic Category 
Females 
Males 
Total 
Hispanic or Latino 
2 
1 
3 
Not Hispanic or Latino 
32 
62 
94 
Total Ethnic 
34 
63 
97 
Racial Category 
American Indian or Alaskan Native 
2 
0 
2 
Asian 
0 
0 
0 
Black or African American 
0 
0 
0 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
32 
63 
95 
Racial Category: Total of all Subjects 
34 
63 
97 
 
 
 
 


 
 
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3.0 
DRUG INFORMATION 
 
Investigator’s Brochures: 
 
For information regarding Investigator’s Brochures, please refer to SWOG Policy 15. 
 
For this study, dabrafenib mesylate, trametinib, and GSK2141795 are investigational and are 
being provided under an IND held by the National Cancer Institute.  The Investigator Brochures 
may be obtained by contacting the NCI’s Pharmaceutical Management Branch (PMB) at 240/276-
6575. 
 
3.1 
Dabrafenib mesylate (GSK2118436B) (NSC-763760) (CTEP IND# 118705) 
 
a. 
DESCRIPTION 
 
Chemical Name:  
N-{3-[5-(2-Amino-4-pyrimidinyl)-2-(1,1-
dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-
difluorobenzene sulfonamide, methanesulfonate 
salt 
 
Other Names:  
GSK2118436, GSK2118436A (free base) 
 
Classification: 
 
BRAF inhibitor 
 
CAS Registry Number:  
1195768-06-9 
 
Molecular Formula: 
C23H20F3N5O2S2 ·CH4O3S 
 
Molecular Weight:  
615.68 (mesylate salt) 
 
Mode of Action: Dabrafenib mesylate (GSK2118436B) is a potent and selective 
BRAF kinase inhibitor. This inhibition suppresses downstream activity of pERK, a 
biomarker, and has antiproliferative activity against BRAF mutant tumors. The mode 
of action is consistent with ATP-competitive inhibition. 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Dabrafenib mesylate (GSK2118436B, NSC 763760) 
 
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/aeguide
lines.pdf for further clarification. Below is the CAEPR for Dabrafenib mesylate 
(GSK2118436B). 
 


 
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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 2.3, May 20, 20161 
 
 Adverse Events with Possible  
 Relationship to Dabrafenib mesylate (GSK2118436B) 
 (CTCAE 4.0 Term) 
[n= 1291] 
 
 Specific Protocol 
Exceptions to 
Expedited Reporting 
(SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but 
Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia2,3  
 
Anemia2,3 (Gr 2) 
EYE DISORDERS 
 
 
 
Eye disorders - 
Other (iritis)4 
 
 
 
Uveitis4 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain  
Abdominal pain (Gr 
3) 
 
Constipation 
 
Constipation (Gr 3) 
 
Diarrhea 
 
Diarrhea (Gr 3) 
Nausea 
 
 
Nausea (Gr 3) 
 
 
Pancreatitis 
 
 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills 
 
Chills (Gr 2) 
 
Edema limbs5 
 
Edema limbs5 (Gr 2) 
Fatigue 
 
 
Fatigue (Gr 3) 
Fever6 
 
 
Fever6 (Gr 2) 
 
Flu like 
symptoms 
 
Flu like symptoms 
(Gr 2) 
 
General 
disorders and 
administration 
site conditions - 
Other 
(hemorrhage)7 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction8  
INFECTIONS AND INFESTATIONS 
 
 
Infections and 
infestations - 
Other 
(nasopharyngitis) 
 
 


 
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INVESTIGATIONS 
 
 
Creatinine 
increased3 
 
Creatinine 
increased3 (Gr 2) 
 
Neutrophil count 
decreased3 
 
Neutrophil count 
decreased3  
(Gr 2) 
 
Platelet count 
decreased3 
 
Platelet count 
decreased3 (Gr 2) 
 
White blood cell 
decreased3 
 
White blood cell 
decreased3  
(Gr 2) 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
Anorexia (Gr 2) 
Hyperglycemia3 
 
 
Hyperglycemia3 (Gr 
2) 
 
Hypokalemia3 
 
Hypokalemia3 (Gr 2) 
 
Hyponatremia3 
 
Hyponatremia3 (Gr 
2) 
Hypophosphatemia3 
 
 
Hypophosphatemia3 
(Gr 2) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
Arthralgia 
 
 
Arthralgia (Gr 3) 
 
Back pain 
 
Back pain (Gr 3) 
 
Myalgia 
 
Myalgia (Gr 3) 
 
Pain in extremity  
Pain in extremity (Gr 
3) 
NEOPLASMS BENIGN, MALIGNANT AND 
UNSPECIFIED (INCL CYSTS AND POLYPS) 
 
 
Neoplasms 
benign, 
malignant and 
unspecified (incl 
cysts and 
polyps) - Other 
(squamous cell 
carcinoma or 
keratoacanthom
a)9 
 
Neoplasms benign, 
malignant and 
unspecified (incl 
cysts and polyps) - 
Other (squamous 
cell carcinoma or 
keratoacanthoma)9 
(Gr 2) 
 
Treatment 
related 
secondary 
malignancy (non-
SCC)10 
 
 
NERVOUS SYSTEM DISORDERS 
 
 
Dizziness 
 
Dizziness (Gr 2) 
Headache 
 
 
Headache (Gr 2) 
 
 
Syncope 
 


 
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RENAL AND URINARY DISORDERS 
 
 
 
Renal and 
urinary disorders 
- Other (renal 
failure) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Cough 
 
Cough (Gr 2) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 
 
Alopecia (Gr 2) 
 
Dry skin 
 
Dry skin (Gr 2) 
 
Hyperhidrosis 
 
Hyperhidrosis (Gr 2) 
 
Palmar-plantar 
erythrodysesthes
ia syndrome 
 
Palmar-plantar 
erythrodysesthesia 
syndrome (Gr 2) 
 
Pruritus 
 
Pruritus (Gr 3) 
Rash11 
 
 
Rash11 (Gr 2) 
 
Skin and 
subcutaneous 
tissue disorders - 
Other (abnormal 
hair texture) 
 
Skin and 
subcutaneous 
tissue disorders - 
Other (abnormal 
hair texture) (Gr 2) 
Skin and 
subcutaneous tissue 
disorders - Other 
(hyperkeratosis) 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other 
(hyperkeratosis) 
 (Gr 2) 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other 
(neutrophilic 
panniculitis)12 
 
Skin and 
subcutaneous tissue 
disorders - Other 
(skin papilloma) 
 
 
Skin and 
subcutaneous 
tissue disorders - 
Other (skin 
papilloma) (Gr 2) 


 
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Version Date 8/21/17 
 
 
 
 
 
 
 
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of revision.  
The current version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  
Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
2 The 
incidence 
of 
anemia 
is 
increased 
when 
dabrafenib 
mesylate 
(GSK2118436B) is used in combination with trametinib dimethyl sulfoxide 
(GSK1120212B). 
3 The frequencies of these events are based upon laboratory findings rather than 
being due to patient-reported outcomes. 
4 Dabrafenib mesylate (GSK2118436B) has been associated with ocular 
toxicities including chorioretinitis, retinitis, iridocyclitis, iritis, and uveitis. 
5 Edema limbs (peripheral edema) is a risk associated when dabrafenib 
mesylate (GSK2118436B) is used in combination with trametinib dimethyl 
sulfoxide (GSK1120212B) compared to dabrafenib mesylate (GSK2118436B) 
alone. 
6 Fever (pyrexia) can be associated with hypotension and/or (in rare cases) 
syncope. The frequency of fever and serious febrile events is increased when 
dabrafenib mesylate (GSK2118436B) is used in combination with trametinib 
dimethyl sulfoxide (GSK1120212B). 
7 Treatment with dabrafenib mesylate (GSK2118436B) in combination with 
trametinib dimethyl sulfoxide (GSK1120212B) resulted in an increased 
incidence and severity of hemorrhagic events compared to patients treated 
with dabrafenib mesylate (GSK2118436B) as a single agent.  Sites of 
hemorrhage may include, but are not limited to, intracranial, reproductive tract, 
respiratory tract, and gastrointestinal hemorrhage. 
8 Manifestations of allergic reactions (hypersensitivity) to dabrafenib mesylate 
(GSK2118436B) may include bullous rash (bullous dermatitis). 
9 Squamous cell carcinoma (SCC), including SCC of the skin, SCC in situ 
(Bowen’s disease), and keratoacanthoma have been observed. 
10 New non-SCC malignancies have been reported including primary melanoma, 
basal cell carcinoma, and non-cutaneous malignancies. 
11 Rash includes the terms: rash, rash acneiform, rash papular, rash maculo-
papular, and erythema. 
12 Recurrent neutrophilic panniculitis has been observed in at least one patient 
treated with dabrafenib mesylate (GSK2118436B) in combination with the MEK 
inhibitor trametinib dimethyl sulfoxide (GSK1120212B). 
13 Venous thromboembolic events (including deep vein thrombosis and 
pulmonary embolism) is a risk associated when dabrafenib mesylate 
(GSK2118436B) is used in combination with trametinib dimethyl sulfoxide 
(GSK1120212B). 
 
Adverse events reported on Dabrafenib mesylate (GSK2118436B) trials, but 
for which there is insufficient evidence to suggest that there was a 
reasonable possibility that Dabrafenib mesylate (GSK2118436B) caused the 
adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic 
system disorders - Other (agranulocytosis); Blood and lymphatic system 
disorders - Other (pancytopenia); Disseminated intravascular coagulation; Febrile 
neutropenia; Hemolysis 
VASCULAR DISORDERS 
 
 
Vascular 
disorders - Other 
(venous 
thromboembolic 
event)13 
 
 


 
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CARDIAC DISORDERS - Acute coronary syndrome; Atrial fibrillation; Atrial 
flutter; Heart failure; Left ventricular systolic dysfunction; Mitral valve disease; 
Myocardial infarction; Sinus tachycardia 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Eye disorders - Other (amaurosis fugax); Eye 
disorders - Other (visual acuity reduced); Eye disorders - Other (visual 
impairment); Eye disorders - Other (vitreous detachment); Floaters; Photophobia; 
Retinopathy 
GASTROINTESTINAL DISORDERS - Colitis; Colonic perforation; Dry mouth; 
Dyspepsia; Gastritis; Stomach pain 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Localized edema; Non-cardiac chest pain; Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic pain 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Bruising 
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase 
increased; Aspartate aminotransferase increased; Blood bilirubin increased; CD4 
lymphocytes decreased; Ejection fraction decreased; Electrocardiogram QT 
corrected interval prolonged; GGT increased; Lipase increased; Lymphocyte 
count decreased; Weight loss 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hypernatremia; Hypocalcemia; Hypoglycemia; Hypomagnesemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; 
Generalized muscle weakness; Musculoskeletal and connective tissue disorder - 
Other (muscle spasms); Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Leukemia secondary to oncology chemotherapy; Myelodysplastic 
syndrome; Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
- Other (mycosis fungoides) 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Dysgeusia; 
Intracranial hemorrhage; Lethargy; Nervous system disorders - Other 
(intracranial pressure increased); Paresthesia; Seizure; Somnolence 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Depression 
RENAL AND URINARY DISORDERS - Hematuria; Renal calculi; Urinary 
frequency 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Menorrhagia; 
Reproductive system and breast disorders - Other (hematospermia) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Nasal 
congestion; 
Respiratory, 
thoracic 
and 
mediastinal 
disorders 
- 
Other 
(oropharyngeal pain); Sore throat; Stridor; Voice alteration 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Photosensitivity; Purpura; 
Skin and subcutaneous tissue disorders - Other (palmoplantar keratoderma) 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypertension; Hypotension 
 
Note: Dabrafenib mesylate (GSK2118436B) in combination with other agents 
could cause an exacerbation of any adverse event currently known to be caused 
by the other agent, or the combination may result in events never previously 
associated with either agent. 


 
 
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c. 
PHARMACOLOGY 
 
How Supplied: Dabrafenib mesylate (GSK2118436B) capsules are supplied by 
Novartis and distributed by the DCTD, NCI as 50 mg and 75 mg capsules 
(equivalent to the free-base) for oral administration.  
 
1. 
Each investigationally-labeled bottle is white, opaque, high density 
polyethylene (HDPE) with child-resistant closure and contains 28 
capsules.  
 
• 
50 mg capsule is Swedish orange, size 2 with markings of four black 
bars.  
 
• 
75 mg capsule is pink, size 1 with markings of four black bars.  
 
Capsule excipients include microcrystalline cellulose, magnesium 
stearate (vegetable source), colloidal silicon dioxide. Shell composition 
consists of an opaque hypromellose capsule, composed of red iron oxide 
(E172), titanium dioxide (E171), and hypromellose (E464). Four black 
bars are printed on the hypromellose capsules using black ink. The black 
ink contains black iron oxide (E172), shellac, propylene glycol, and 
ammonium hydroxide. 
 
2. 
Each commercially-labeled bottle contains 120 capsules and a silica gel 
desiccant. 
 
• 
50 mg capsule is dark red and imprinted with ‘GS TEW’ and ‘50 mg.’  
 
• 
75 mg capsule is dark pink and imprinted with ‘GS LHF’ and ‘75 mg.’  
 
Capsule excipients include microcrystalline cellulose, magnesium 
stearate (vegetable source), and colloidal silicon dioxide. Capsule shells 
contain hypromellose, red iron oxide (E172), and titanium dioxide (E171). 
 
Storage: Store between 15°C to 30°C (59°F to 86°F). 
 
Stability: Shelf-life studies of dabrafenib mesylate (GSK2118436B) are ongoing. 
 
Route of Administration: Oral administration. Patients should take dabrafenib at 
least one hour prior to or two hours after a meal due to a potential food effect on 
dabrafenib absorption. A food effect study showed that food may decrease the 
dabrafenib Cmax and AUC(0-∞) by 60% and 33% respectively. If a dose is missed, 
it should not be taken if it is less than 6 hours until the next dose. 
 
Potential Drug Interactions: Dabrafenib mesylate (GSK2118436B) induces 
CYP3A4, 2C9 and possibly 2B6, 2C8, and 2C19 enzymes. Use caution in patients 
who are taking substrates that are metabolized in these enzyme pathways, such as 
warfarin. 
 
Dabrafenib mesylate (GSK2118436B) metabolism appears to be mediated by 
CYP3A4 and CYP2C8. Use caution if strong inducers or inhibitors of CYP2C8 or 
3A4 are co-administered with dabrafenib. 
 
Dabrafenib solubility is pH-dependent and experiences decreased solubility at 
higher pH. Use caution in patients who are taking drugs that elevate gastric pH due 
to the theoretical risk of decreasing oral bioavailability of dabrafenib.  


 
 
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Patient Care Implications: In the case of overdose, patients should be treated 
symptomatically since there is no specific antidote. Hemodialysis is likely to be 
ineffective since dabrafenib mesylate is highly bound to plasma proteins. 
 
d. 
SUPPLIER 
 
Dabrafenib is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. Dabrafenib is provided to the 
NCI under a Collaborative Agreement between Novartis and the DCTD, NCI. 
 
Drug Ordering: 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. Drug may be requested by 
submitting agent requests through the PMB Online Agent Ordering Processing 
(OAOP) 
application 
(https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). 
Access to OAOP requires the establishment of a CTEP Identity and Access 
Management (IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the 
maintenance of an "active" account status and a "current" password. 
 
Drug Returns: All unused drug supplies should be returned to the PMB. When it 
is necessary to return study drug (e.g. sealed vials remaining when expired vials 
are recovered by the PMB), investigators should return the study drug to the 
PMB using the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition and return 
of all drugs received from the PMB using the Drug Accountability Record Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between 
8:30 
a.m. 
and 
4:30 
p.m. 
Eastern 
time 
or 
by 
emailing 
PMBAfterHours@mail.nih.gov anytime. 
 
3.2 
GSK2141795 (GSK2141795C) (NSC-767034) (CTEP IND #118705) 
 
a. 
DESCRIPTION 
 
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 


 
 
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Version Date 8/21/17 
 
 
 
Classification: 
pan-AKT inhibitor 
 
CAS Registry Number: 1047634-65-0 
 
Molecular Formula: 
C18H16Cl2F2N4O2 
 
Molecular Weight:  
429.25 g/mol 
Approximate Solubility: Very slightly soluble in water at room temperature (0.18 
mg/mL). Solubility decreases as pH increases; for example solubility in gastric fluid 
at 37° C is >11 mg/mL. 
 
Mode of Action: GSK2141795 is an ATP competitive pan-AKT inhibitor. AKT, a 
serine/threonine protein kinase with three isoforms, is active in several pathways 
that regulate survival, proliferation, tissue invasion and metabolism. Since AKT-
mediated pathways are important in tumor proliferation and survival, AKT kinases 
are promising targets for therapeutic intervention. Hyperactivation of the AKT 
pathway can also correlate with chemotherapy resistance and poorer prognosis. 
 
b. 
TOXICOLOGY 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
GSK2141795 (NSC 767034) 
 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an 
agent using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited 
Reporting (SPEER), appears in a separate column and is identified with bold and 
italicized text. This subset of AEs (SPEER) is a list of events that are protocol 
specific exceptions to expedited reporting to NCI via CTEP-AERS (except as 
noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm 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) 


 
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Version Date 8/21/17 
 
 
 
 
 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%) 
 
 
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  
  
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be disbuted 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. 
2 Gastrointestinal mucositis may include Anal mucositis, Mucositis oral, Rectal 
mucositis, or Small intestinal mucositis under the GASTROINTESTINAL 
DISORDERS SOC. 
3 Respiratory mucositis may include Laryngeal mucositis, Pharyngeal mucositis, 
or Tracheal mucositis under the RESPIRATORY, THORACIC AND 
MEDIASTINAL DISORDERS SOC 
 
Also reported on GSK2141795 trials but with the relationship to 
GSK2141795 still undetermined: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Cardiac arrest, Left ventricular systolic dysfunction, 
Ventricular tachycardia 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-
cardiac chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure 
INFECTIONS AND INFESTATIONS - Wound infection  
INVESTIGATIONS - Alanine aminotransferase increased; Alkaline phosphatase 
increased; Aspartate aminotransferase increased; Ejection fraction decreased; 
GGT increased 
METABOLISM AND NUTRITION DISORDERS - Hypokalemia; Hyponatremia, 
Hypophosphatemia 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Dysphasia 
RENAL AND URINARY DISORDERS - Acute kidney injury 
VASCULAR DISORDERS - Thromboembolic event 
 
Note: GSK2141795 in combination with other agents could cause an 
exacerbation of any adverse event currently known to be caused by the other 
agent, or the combination may result in events never previously associated with 
either agent. 


 
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c. 
PHARMACOLOGY 
 
How Supplied: GSK2141795 capsules are supplied by GlaxoSmithKline and 
distributed by the DCTD, NCI.  The 25 mg capsule is a size 2 Swedish orange 
opaque body and Swedish orange opaque cap with no markings.  The capsule 
contains active pharmaceutical ingredient, microcrystalline cellulose, and 
magnesium stearate.  The capsules are packaged in white high density 
polyethylene (HDPE) bottles with white plastic, induction-seal, child-resistant 
caps.  Each bottle contains 35 capsules. 
 
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 one 
hour following a meal and two hours before the next meal.  These are the 
recommendations from the pharmaceutical collaborator. 
 
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. 
 
d. 
SUPPLIER 
 
GSK2141795 is an investigational agent supplied to investigators by the Division 
of Cancer Treatment and Diagnosis (DCTD), NCI. GSK2141795 is provided to 
the NCI under a Collaborative Agreement between GlaxoSmithKline, Inc. and the 
DCTD, NCI. 
 
Drug Ordering: 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. 
 
Drug may be requested by submitting agent requests through the PMB Online 
Agent 
Ordering 
Processing 
(OAOP) 
application 
(https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). 
Access 
to 
OAOP 
requires 
the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an "active" account 
status and a "current" password. 


 
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Drug Returns: All unused drug supplies should be returned to the PMB. When it 
is necessary to return study drug (e.g. sealed vials remaining when expired vials 
are recovered by the PMB), investigators should return the study drug to the 
PMB using the NCI Return Agent Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition and return 
of all drugs received from the PMB using the Drug Accountability Record Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
Questions about drug orders, transfers, returns or accountability should be 
addressed to the PMB by calling 240/276-6575 Monday through Friday between 
8:30 a.m. and 4:30 p.m. Eastern time by emailing PMBAfterHours@mail.nih.gov 
anytime. 
 
3.3 
Trametinib Dimethyl Sulfoxide (GSK1120212B) (NSC-763093) (IND-119432) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Trametinib 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 
interferes with cellular signal-transduction and inhibits proliferation by inducing 
cell apoptosis, with selective activity towards B-RAF serine/threonine protein 
kinase (BRAF) and v-ras oncogene homolog GTPase (RAS) mutant cancer cell 
lines and hematopoietic cancer cells from acute myeloid leukemia (AML) and 
chronic myeloid leukemia (CML) origins.  
 
b. 
PHARMACOKINETICS 
 
Absorption: Peak plasma concentrations are observed at 1.5 hours following 
single dose oral administration of trametinib under fasted conditions in humans.  
Administration of trametinib with a high-fat, high-calorie meal resulted in a 70% 
decrease in the maximum concentration (Cmax) and 10% decrease in the area 
under the concentration curve (AUC) compared to fasted conditions.  Therefore, 
it is recommended that trametinib be administered under fasting conditions.  The 
absolute oral bioavailability of a 2 mg tablet is moderate to high (72%) relative to 
a co-administered IV microdose (5 micrograms).   
 
Distribution: Trametinib is highly bound to plasma proteins (97.4%), and has a 
high volume of distribution (Vd) of 1060 L.   
 
Metabolism: Following single dose oral administration in humans, approximately 
50% of plasma radioactivity is present as the parent compound.  Trametinib is 
primarily metabolized via deacetylation mediated by hydrolytic esterases, such 
as carboxylesterases or amidases, with secondary oxidation or in combination 
with 
glucuronidation 
biotransformation 
pathways. 
 
The 
high 
absolute 
bioavailability and low clearance relative to liver blood flow (3.21 L/hr) suggest 
low hepatic extraction of trametinib in addition to low first-pass metabolism. 
 
Elimination:  Trametinib has a long terminal half-life of 5.3 days and accumulates 
with repeat once daily dosing.  Fecal excretion is the major route of elimination 
accounting for >80% of excreted radioactivity recovered.  Urinary excretion 
accounted for <19% of excreted radioactivity recovered (<10% of the radioactive 
dose). 


 
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c. 
ADVERSE EFFECTS  
 
1. 
Comprehensive Adverse Events and Potential Risks list (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 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 
1,111 patients. Below is the CAEPR for trametinib dimethyl sulfoxide 
(GSK1120212B). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted 
in parentheses next to the AE in the SPEER.  If this CAEPR is part of a 
combination protocol using multiple investigational agents and has an AE 
listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
 
Version 2.4, October 7, 20161 
 
 
 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide 
(GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
 
Anemia 
 
Anemia (Gr 2) 
CARDIAC DISORDERS 
 
 
 
Heart failure 
 
 
 
Left ventricular 
systolic dysfunction 
 
 
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) 
 


 
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 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide 
(GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
EYE DISORDERS (contd.) 
 
 
Eye disorders - 
Other (visual 
disorders)2  
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal pain 
 
Abdominal pain 
(Gr 2) 
 
 
 Colitis 
 
 
 
 Colonic perforation 
 
 
Constipation 
 
Constipation (Gr 2) 
Diarrhea 
 
 
Diarrhea (Gr 3) 
 
Dry mouth 
 
Dry mouth (Gr 2) 
 
Dyspepsia 
 
Dyspepsia (Gr 2) 
 
Mucositis oral 
 
Mucositis oral (Gr 
2) 
Nausea 
 
 
Nausea (Gr 3) 
 
Vomiting 
 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE 
CONDITIONS 
 
 
Chills 
 
Chills (Gr 2) 
 
Edema face 
 
 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
Fever (Gr 2) 
IMMUNE SYSTEM DISORDERS 
 
 
Allergic reaction3 
 
 
INFECTIONS AND INFESTATIONS 
 
 
Lung infection 
 
 
 
Paronychia 
 
Paronychia (Gr 2) 
 
Skin infection 
 
Skin infection (Gr 
2) 
INVESTIGATIONS 
 
 
Alanine 
aminotransferase 
increased 
 
Alanine 
aminotransferase 
increased (Gr 2) 
 
Alkaline 
phosphatase 
increased 
 
Alkaline 
phosphatase 
increased (Gr 2) 
 
Aspartate 
aminotransferase 
increased 
 
Aspartate 
aminotransferase 
increased (Gr 2) 
 
CPK increased 
 
 
 
Ejection fraction 
decreased 
 
 


 
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 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide 
(GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
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 
 
 
 
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) 
 
 
 
 


 
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 Adverse Events with Possible  
 Relationship to Trametinib dimethyl sulfoxide 
(GSK1120212B) 
 (CTCAE 4.0 Term) 
[n= 1111] 
 
 Specific Protocol 
Exceptions to 
Expedited 
Reporting (SPEER) 
 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
VASCULAR DISORDERS 
 
 
Hypertension 
 
Hypertension (Gr 
2) 
Vascular disorders 
- Other (edema)5 
 
 
Vascular disorders 
- Other (edema)5 
(Gr 2) 
 
Vascular disorders - 
Other 
(hemorrhage)6 
 
 
 
1 This table will be updated as the toxicity profile of the agent is revised.  
Updates will be distributed to all Principal Investigators at the time of 
revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, 
the protocol and the agent should be included in the e-mail. 
2 Visual disorders include visual disturbance that can be associated with 
conjunctival hemorrhage, corneal graft rejection, cyclitis, eye nevus, 
halo vision, iritis, macular edema, retinal hemorrhage, visual acuity 
reduced, visual impairment, and vitreous detachment. 
3 Hypersensitivity (allergic reactions) may present with symptoms such 
as fever, rash, increased liver function tests, and visual disturbances. 
4 Skin 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. 
5 Edema includes edema, lymphedema, and edema limbs. 
6 The majority of hemorrhage events were mild.  Major events, defined 
as symptomatic bleeding in a critical area or organ (e.g., eye, GI 
hemorrhage, GU hemorrhage, respiratory hemorrhage), and fatal 
intracranial hemorrhages have been reported. 
 
Adverse events reported on Trametinib dimethyl sulfoxide 
(GSK1120212B) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that Trametinib 
dimethyl sulfoxide (GSK1120212B) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Disseminated 
intravascular coagulation; Febrile neutropenia; Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Cardiac arrest; Myocardial 
infarction; Restrictive cardiomyopathy; Sinus tachycardia 
EYE DISORDERS - Corneal ulcer; Eyelid function disorder; Flashing 
lights; 
Floaters; 
Glaucoma; 
Papilledema; 
Photophobia; 
Retinal 
detachment 
GASTROINTESTINAL DISORDERS - Anal hemorrhage; Ascites; 
Duodenal ulcer; Enterocolitis; Esophageal necrosis; Esophageal ulcer; 
Esophagitis; 
Gastric 
hemorrhage; 
Gastric 
ulcer; 
Gastritis; 
Gastrointestinal disorders - Other (intestinal obstruction); Gastrointestinal 
disorders - Other (oropharyngeal pain); Gastrointestinal disorders - Other  


 
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(pneumatosis 
intestinalis); 
Gastrointestinal 
fistula; 
Gingival 
pain; 
Hemorrhoidal hemorrhage; Ileus; Lower gastrointestinal hemorrhage; 
Obstruction gastric; Pancreatitis; Rectal hemorrhage; Small intestinal 
obstruction; Upper gastrointestinal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Flu like symptoms; General disorders and administration site conditions - 
Other (axillary pain); Localized edema; Malaise; Non-cardiac chest pain; 
Pain 
HEPATOBILIARY DISORDERS - Cholecystitis; Hepatic failure; Hepatic 
pain; Hepatobiliary disorders - Other (hepatic encephalopathy) 
INFECTIONS AND INFESTATIONS - Biliary tract infection; Catheter 
related infection; Device related infection; Endocarditis infective; 
Enterocolitis infectious; Hepatitis viral; Infections and infestations - Other 
(abscess limb); Infections and infestations - Other (necrotizing fasciitis); 
Infections and infestations - Other (oral infection); Pharyngitis; Rash 
pustular; Sepsis; Upper respiratory infection; Urinary tract infection 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - 
Bruising 
INVESTIGATIONS - Blood bilirubin increased; Creatinine increased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; 
Investigations - Other (blood lactate dehydrogenase increased); Lipase 
increased; Lymphocyte count decreased; Platelet count decreased; 
Serum amylase increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; 
Hyperkalemia; 
Hyperuricemia; 
Hypocalcemia; 
Hypoglycemia; 
Hypokalemia; 
Metabolism 
and 
nutrition 
disorders 
- 
Other 
(hyperphosphatemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Generalized muscle weakness; Musculoskeletal and connective tissue 
disorder - Other (compression fracture); Musculoskeletal and connective 
tissue disorder - Other (muscle spasm); Myalgia; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (tumor hemorrhage); Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; 
Intracranial hemorrhage; Lethargy; Nervous system disorders - Other 
(diplopia); Seizure; Somnolence; Stroke; Syncope; Transient ischemic 
attacks 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; 
Hallucinations; Insomnia; Personality change 
RENAL AND URINARY DISORDERS - Acute kidney injury; Cystitis 
noninfective; Hematuria; Proteinuria; Renal and urinary disorders - Other 
(dysuria); Urinary incontinence 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Vaginal 
fistula; Vaginal hemorrhage 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchopulmonary hemorrhage; Epistaxis; Hypoxia; Laryngeal edema; 
Pleural 
effusion; 
Pneumothorax; 
Productive 
cough; 
Pulmonary 
hypertension; Respiratory failure; Sinus disorder 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Bullous 
dermatitis; Photosensitivity; Purpura; Skin and subcutaneous tissue 
disorders - Other (erythema nodosum); Skin and subcutaneous tissue 
disorders - Other (nail disorder); Skin and subcutaneous tissue disorders 
- Other (skin fissures); Skin ulceration; Urticaria 
VASCULAR DISORDERS - Hematoma; Hot flashes; Hypotension; 
Thromboembolic event (venous) 


 
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2. 
Pregnancy and Lactation: There are no adequate and well-controlled 
studies of trametinib in pregnant women.  Animal studies have shown 
reproductive toxicity, decreased maternal and fetal weight, fetal 
malformations, and early termination of pregnancy.  Therefore, trametinib 
should not be administered to pregnant women. Women of childbearing 
potential should use effective methods of contraception during therapy 
and for 4 months following discontinuation.  If trametinib is used during 
pregnancy, or if the subject becomes pregnant while taking trametinib, 
the subject should be informed of the potential hazard to the fetus. 
 
It is not known whether trametinib is excreted in human milk.  Because of 
the potential for drugs to be excreted in human milk, the risk to the 
nursing infant cannot be excluded and therefore trametinib should not be 
administered to nursing mothers. 
 
3. 
Drug Interactions: In vitro studies suggest that trametinib may be a 
substrate for CYP3A4 metabolism and consideration should be used 
when trametinib is given in combination with a strong CYP3A4 inducer or 
inhibitor. Trametinib is a weak CYP2C8 inhibitor and may affect 
medications that are substrates of CYP2C8.  Trametinib is not a 
substrate for human P-glycoprotein (Pgp), breast cancer resistance 
protein (BCRP), OATP1B1, or OATP1B2 transporters. 
 
Patients who are taking concomitant medications that have the potential 
to interact with trametinib may continue taking them, but should be 
monitored for additional toxicities. 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan 
 
2. 
Administration Instructions:  Administer orally, on an empty stomach, either 
1 hour before or 2 hours after food. 
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Store tablets at 2°C – 8°C in the original bottle. Do not package tablets or remove 
desiccant. Bottles should be stored in the manufacturer’s package carton for light 
protection. Protect from moisture. Shelf life surveillance of the intact bottles is 
ongoing. 
 
Patient Storage Instructions: 
 
- 
Study drug can be transported home in the bottle(s) that were dispensed to 
the patient at room temperature.  Avoid exposing the bottle(s) to prolonged 
temperature extremes (i.e. do not leave bottle(s) in a hot car while doing 
errands) 
- 
At home, store the study drug in the refrigerator, 2°C – 8°C (36°F - 46°F).  Do 
not freeze the bottles. 
- 
Keep the tablets in the original bottle(s).  Do not remove tablets from the 
bottle(s) and put them in a pill box or daily dispenser. 
- 
Keep desiccant cylinder in the bottles in order to keep tablets dry.  
 
f. 
HOW SUPPLIED 
 
1. 
Novartis supplies and CTEP, NCI, DCTD distributes 0.5 mg and 2 mg (as 
free base) tablets.  


 
 
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Version Date 8/21/17 
 
 
 
 
a. 
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). 
 
b. 
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. 
 
2. 
Supplied by:  Trametinib is an investigational agent supplied to 
investigators by the Division of Cancer Treatment and Diagnosis 
(DCTD), NCI. Dabrafenib is provided to the NCI under a Collaborative 
Agreement between Novartis and the DCTD, NCI. 
 
3. 
Drug Ordering: 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. 


 
 
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Drug may be requested by submitting agent requests through the PMB 
Online Agent Ordering Processing (OAOP) application (https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) 
account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an 
"active" account status and a "current" password. 
 
4. 
Drug Returns: All unused drug supplies should be returned to the PMB. 
When it is necessary to return study drug (e.g. sealed vials remaining 
when expired vials are recovered by the PMB), investigators should 
return the study drug to the PMB using the NCI Return Agent Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
5. 
Drug Accountability: The investigator, or a responsible party designated 
by the investigator, must maintain a careful record of the receipt, 
disposition and return of all drugs received from the PMB using the Drug 
Accountability Record Form available on the NCI home page 
(http://ctep.cancer.gov). 
 
6. 
Contact Information:  Questions about drug orders, transfers, returns or 
accountability should be addressed to the PMB by calling 240/276-6575 
Monday through Friday between 8:30 a.m. and 4:30 p.m. Eastern time or 
by emailing PMBAfterHours@mail.nih.gov anytime. 
 
4.0 
STAGING CRITERIA (AJCC 7th Edition, 2010) 
 
Stage IIIC 
Colon 
T4a 
N2a 
M0 
T3-T4a 
N2b 
M0 
T4b 
N1-N2 
M0 
 
 
Stage IIIC 
Ovarian 
T3c 
N0 
M0 
Any T 
N1 
M0 
 
STAGE IIIC  
 
Melanoma 
T1-4b 
N1b 
M0 
T1-4b 
N2b 
M0 
T1-4b 
N2c 
M0 
Any T 
N3 
M0 
 
Stage IV 
 
Melanoma 
Any T  
 
Any N  
M1 
 
Distant Metastasis (M) 
 
M1 
Distant metastasis 
M1a 
Metastases to skin, subcutaneous or distant lymph nodes 
M1b 
Metastases to lung 
M1c 
Metastases to all other visceral sites or distant metastases to any site combined with an 
elevated serum LDH 
 
NOTE:  for all other disease sites Stage IV is defined as any distant metastasis for this 
study. 
 
 


 
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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered eligible for 
registration.  Use the spaces provided to confirm a patient's eligibility.  For each criterion requiring test 
results and dates, please record this information on the Onstudy Form and submit via Medidata Rave® 
(see Section 14.0).  Any potential eligibility issues should be addressed to the Data Operations Center in 
Seattle at 206/652-2267 prior to registration. 
 
In calculating days of tests and measurements, the day a test or measurement is done is considered Day 
0.  Therefore, if a test is done on a Monday, the Monday 2 weeks later would be considered Day 14.  This 
allows for efficient patient scheduling without exceeding the guidelines.  If Day 14, 28 or 42 falls on a 
weekend or holiday, the limit may be extended to the next working day. 
 
SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
5.1 
Phase I Portion Eligibility Criteria 
 
a. 
Patients must have BRAFV600 mutant metastatic cancer irrespective of the 
histology or prior therapy.  BRAFV600 mutant status must be documented by a 
CLIA-certified laboratory.  Use of an FDA-approved test is preferred although 
other BRAF tests at a CLIA-certified laboratory may also be accepted. 
 
b. 
Patients must have locally advanced unresectable Stage IIIC or metastatic Stage 
IV cancer with either progression to prior therapy or a newly diagnosed cancer 
that does not have an available treatment with curative intent.  See Section 4.0 
for staging criteria. 
 
c. 
Patients must have a complete physical examination and medical history within 
28 days prior to registration. 
 
d. 
Patients must have measurable or non-measurable disease as defined in Section 
10.1.  All measurable lesions must be assessed (by physical examination, CT, or 
MRI scan) within 28 days prior to registration.  Tests to assess non-measurable 
disease must be performed within 42 days prior to registration.  All disease must 
be assessed and documented on the Baseline Tumor Assessment Form 
(RECIST 1.1). 
 
e. 
All patients must undergo a CT or MRI of the brain within 42 days prior to 
registration.  Patients with asymptomatic brain metastases or previously treated 
brain metastases that are stable (i.e. not requiring corticosteroids) at the time of 
registration will be eligible. 
 
f. 
Patients 
may 
have 
received 
prior 
systemic 
therapy 
(chemotherapy, 
immunotherapy, biologic therapy, or combination regimens).  All adverse events 
associated with prior treatment must have resolved to < Grade 1 prior to 
registration. 
 


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
g. 
Patients progressing on a prior BRAF inhibitor-based therapy will be eligible, as 
are patients naïve to BRAF inhibitor therapy. Resistance to BRAF inhibitor-based 
therapy will be defined as progressive disease by RECIST 1.1 criteria while 
receiving therapy with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in 
combination with a MEK inhibitor).  This may be innate resistance (patients who 
never achieved a tumor response while on BRAF inhibitor therapy) or acquired 
resistance (progression after having a tumor response to BRAF inhibitor 
therapy). There will not be a period of break between progression on the prior 
BRAF inhibitor-based therapy and the start of dabrafenib, trametinib and 
GSK2141795. 
 
h. 
Patients may have received prior surgery (for both the primary and Stage IV 
disease).  All adverse events associated with prior surgery must have resolved to 
≤ Grade 1 prior to registration. 
 
i. 
Patients may have received prior radiation therapy.  All adverse events 
associated with prior radiation therapy must have resolved to ≤ Grade 1 prior to 
registration. 
 
j. 
Patients must be willing to submit blood for pharmacokinetics (see Section 15.3).  
Sites must order S1221 PK kit immediately after registration (see Section 18.6).  
The SWOG patient ID number must be provided on the S1221 PK Kit Request 
Form.  
 
 
k. 
Patients must have available and be willing to submit baseline tissue taken at the 
time of disease progression to prior BRAF inhibitor-based therapy (either fresh 
frozen [preferred], or paraffin-embedded tumor blocks) OR must have a site of 
disease that can be biopsied within this study for translational medicine studies 
outlined in Section 15.4 and Section 18.2.  Tissue may be from an archival 
biopsy or a new biopsy after the patient has been registered to the protocol.  
Since patients are referred to this protocol after progression on prior BRAF 
inhibitor-based therapy, the biopsy taken at the time of progression will be used 
as the baseline biopsy for this study.  Patients must be willing to submit plasma 
and whole blood for translational medicine studies as outlined in Section 15.4 
and Section 18.2. 
 
l. 
Patients must have Zubrod Performance Status ≤ 1 (see Section 10.4). 
 
m. 
Patients must have adequate bone marrow function as evidenced by all of the 
following:  ANC ≥ 1,200/ul; platelets ≥ 100,000/ul; and hemoglobin ≥ 9 g/dL.  
These results must be obtained within 28 days prior to registration. 
 
n. 
Patients must have adequate liver function as evidenced by the following: total 
bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) (or ≤ 2.5 x ULN for 
patients with Gilbert’s syndrome), and AST and ALT ≤ 2.5 x IULN (or < 5 x IULN 
for patients with known liver metastases). Patients must have a serum albumin ≥ 
2.5 g/dL.   These results must be obtained within 28 days prior to registration.  


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
o. 
Patient must have adequate renal function as evidenced by ONE of the following: 
serum creatinine ≤ 1.5 mg/dL OR measured or calculated creatinine clearance ≥ 
50 mL/min.  This result must have been obtained within 28 days prior to 
registration. 
 
Estimated creatinine clearance = (140 - age) x wt (kg) x 0.85 (if female) 
72 x creatinine (mg/dl) 
 
p. 
Patient must have a left ventricular ejection fraction ≥ institutional lower limit of 
normal (LLN) by ECHO or MUGA within 28 days prior to registration. 
 
q. 
Patients must not have a corrected QT (QTc) interval ≥ 480 msecs within 28 
days prior to registration  
 
r. 
Patients must not have a history of acute coronary syndromes (including 
unstable angina), myocardial infarction within  6 months, coronary angioplasty, or 
stenting within the past 24 weeks; Class II, III, or IV heart failure as defined by 
the New York Heart Association (NYHA) functional classification system (see 
Appendix 18.6); or history of known cardiac arrhythmias (such as atrial 
fibrillation) unless it has been stably controlled for > 30 days prior to registration. 
Abnormal cardiac valve morphology (≥ Grade 2) documented by echocardiogram 
(subjects with Grade 1 abnormalities [i.e., mild regurgitation/stenosis]) can be 
entered on study.  Subjects with moderate valvular thickening are not eligible. 
 
s. 
Patients with melanoma must have a serum lactate dehydrogenase (LDH) test 
performed within 28 days prior to registration. 
 
t. 
Patients with HIV are eligible if they are not on antiviral agents and have 
adequate CD4 counts (≥ 500 mm3). 
 
u. 
Patients receiving anticoagulation treatment are allowed to participate with INR 
established within the therapeutic range. (See Section 7.2b).  
 
v. 
At the time of registration, patients must not be receiving any medications or 
substances that are strong inhibitors or inducers of CYP3A or CYP2C8.  Patients 
must not be planning to use herbal remedies (e.g., St. John’s wort), or strong 
inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer resistance protein 
1 (Bcrp1).  See Appendix 18.4 for list of medications. 
 
w. 
Women of childbearing potential must have a negative pregnancy test within 14 
days of registration. 


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
x. 
Patients must not be pregnant or nursing due to unknown teratogenic side 
effects.  Women/men of reproductive potential must have agreed to use an 
effective contraceptive method.  A woman is considered to be of "reproductive 
potential" if she has had menses at any time in the preceding 12 consecutive 
months.  In addition to routine contraceptive methods, "effective contraception" 
also includes heterosexual celibacy and surgery intended to prevent pregnancy 
(or with a side-effect of pregnancy prevention) defined as a hysterectomy, 
bilateral oophorectomy or bilateral tubal ligation. Hormonal contraception is not 
allowed due to drug interactions which can render hormonal contraceptives 
ineffective.  However, if at any point a previously celibate patient chooses to 
become heterosexually active during the time period for use of contraceptive 
measures outlined in the protocol, he/she is responsible for beginning 
contraceptive measures. 
 
y. 
Patient must not have uncontrolled intercurrent illness including, but not limited 
to, ongoing or active infection, previously diagnosed Type 1 diabetes 
mellitus/Type 2 diabetes, psychiatric illness/social situations, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, that would 
limit compliance with study requirements.  Patients must not have any evidence 
of mucosal or internal bleeding. Patients must not have a history of pneumonitis 
or interstitial lung disease. Patients must not have received any major surgery 
within four weeks prior to registration. 
 
z. 
Patients must not have an active Hepatitis B Virus (HBV) or Hepatitis C Virus 
(HCV) infection. 
 
aa. 
Patients must not have a history of allergic reactions attributed to compounds of 
similar chemical or biologic composition to dabrafenib or other agents used in 
this study including dimethyl sulfoxide (DMSO). 
 
bb. 
Patients must be able to retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels. Patients 
who have feeding tubes can enroll in the study provided that the capsules do not 
need to be modified. 
 
cc. 
Patients or their legally authorized representative must be informed of the 
investigational nature of this study and must sign and give written informed 
consent in accordance with institutional and federal guidelines. 
 
dd. 
As a part of the OPEN registration process (see Section 13.3 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that 
the current (within 365 days) date of institutional review board approval for this 
study has been entered in the system. 
 
ee. 
Patients must be ≥ 18 years of age.  
 
ff. 
Patients must have a serum albumin ≥ 2.5 g/dL within 28 days prior to 
registration.   


 
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SWOG Patient No.   
 
 
Patient's Initials (L, F, M)   
 
 
gg. 
Patients with known history or current evidence of retinal vein occlusion (RVO) 
are not eligible: 
 
• 
History of RVO, or predisposing factors to RVO (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 such as: 
• 
Evidence of new optic disc cupping 
• 
Evidence of new visual field defects 
• 
Intraocular pressure > 21 mmHg 
 
• 
NOTE:  Ophthalmic exam is required for all patients.  Exam must be 
obtained within 28 days prior to registration. 
 
hh. 
Patients must not have uncontrolled hypertension (defined as systolic blood 
pressure > 140 mm Hg and/or diastolic blood pressure > 90 mm Hg which cannot 
be controlled by anti-hypertensive therapy), 
 
5.2 
Phase II Portion Eligibility Criteria 
 
All the same criteria from Section 5.1 above, but eligibility will be restricted to the 
following: 
 
a. 
Patients must have histologically confirmed melanoma with BRAFV600 mutation.  
Patients must have Stage IIIC or Stage IV disease as outlined in Section 4.0. 
 
b. 
Patients must have received prior BRAF inhibitor therapy (e.g. dabrafenib, 
vemurafenib) within 56 days prior to registration.  Prior trametinib therapy is 
permitted.  Patients are not required to interrupt BRAF or MEK inhibitor therapy 
prior to the initiation of three agent combination therapy on study. 
 
c. 
Patients must have measurable disease as defined in Section 10.1.  All 
measurable lesions must be assessed (by physical examination, CT, or MRI 
scan) within 28 days prior to registration.  Tests to assess non-measurable 
disease must be performed within 42 days prior to registration.  Patients whose 
only measurable disease is within a previous radiation therapy port must 
demonstrate clearly progressive disease (in the opinion of the treating 
investigator) prior to registration.  All disease must be assessed and documented 
on the Baseline Tumor Assessment Form (RECIST 1.1). 
 
d. 
Patients must have Zubrod Performance status ≤ 2 (see Section 10.4). 
 
e. 
No other prior malignancy is allowed except for the following:  adequately treated 
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately 
treated Stage I or II cancer from which the patient is currently in complete 
remission, or any other cancer from which the patient has been disease free for 
five years. Patients with history of RAS mutation-positive tumors are not eligible 
regardless of interval from the current study.  Note: Prospective RAS testing is 
not required.  However, if the results of previous RAS testing are known, they 
must be used in assessing eligibility. 
 
 


 
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6.0 
STRATIFICATION FACTORS 
 
This section is not applicable. 
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact Dr. Ribas at 310/206-3928 or Dr. 
Algazi at 415/353-7552.  For dosing principles or questions, please consult SWOG Policy #38 
"Dosing Principles for Patients on Clinical Trials" at http://swog.org (then click on "Policies and 
Manuals" under the "Visitors" menu and choose Policy 38). 
 
NOTE:  GSK2141795 will not be available after September 30, 2018.  At that time, patients 
remaining on protocol treatment may continue with dabrafenib and trametinib alone.  
 
7.1 
Treatment Overview 
 
The study will be conducted in two sequential parts.  A patient may be enrolled to 
either the Phase I Portion or the Phase II Portion, but not both. 
Phase I Dabrafenib plus GSK2141795  (D+G) Details are in Section 7.3 and 
Dabrafenib and Trametinib plus GSK2141795 (D+T+G) Portion – Details are in 
Section 7.4. 
 
Phase II Portion – Details are in Section 7.5. 
 
7.2 
General Concomitant Medication and Supportive Care Guidelines 
 
a. 
The investigator must be informed as soon as possible about any medication 
taken from the time of screening until 30 days after the last dose of study 
treatment. Because there is a potential for interaction of the study drugs with 
other concomitantly administered drugs through the cytochrome P450 system, 
the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies must be recorded in the clinical chart. The minimum requirement is that 
drug name, dose, and the dates of administration are to be recorded. 
Additionally, a complete list of all prior surgical procedures will be recorded in the 
clinical chart.   The Study Chair should be alerted if the patient is taking any 
agent known to affect or with the potential to affect selected CYP450 isoenzymes 
(see Section 18.4).  Appendix 18.6 contains a patient information sheet that can 
be used for this specific protocol and presented to the patient. 
 


 
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Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong inhibitors 
or inducers of CYP3A and CYP2C8 (see list in Section 18.4) may only be used 
under special circumstances (e.g. as a single use for a procedure) while 
treatment with study drug is interrupted as they may alter dabrafenib 
concentrations; consider therapeutic substitutions for these medications. 
 
b. 
Warfarin exposure may be decreased due to enzyme induction when on 
treatment, thus warfarin dosing may need to be adjusted based upon PT/INR.  
Consequently, when discontinuing dabrafenib, warfarin exposure may be 
increased and thus dose monitoring via PT/INR and warfarin dose adjustments 
must be made as clinically appropriate.  Prophylactic low dose warfarin may be 
given to maintain central catheter potency. 
 
c. 
Patients should have a baseline fasting glucose level within the institutional 
upper limit of normal (IULN).  This result should be obtained within 28 days prior 
to registration.  Given the known metabolic toxicities of GSK2141795, patients 
with prior diabetes mellitus or problems in glucose control should have an HgA1c 
≤ 7% within 28 days prior to registration.  The same criterion will be used in 
patients with confirmed diagnosis of diabetes mellitus who have been on a stable 
dietary or therapeutic regimen for this condition in the last three months. 
 
d. 
Subjects should receive full supportive care during the study, including 
transfusions of blood and blood products, and treatment with antibiotics, anti-
emetics, anti-diarrheals, and analgesics, and other care as deemed appropriate, 
and in accordance with their institutional guidelines. 
 
e. 
Radiation skin injury has been reported with concurrent use of dabrafenib and 
radiation.  Any radiation therapy should be completed at least two days prior to 
registration. 
 
7.3 
Treatment - Phase I  Dabrafenib + GSK2141795 (D+G)   
 
a. 
Dose Escalation Scheme for D + G 
 
Effective November 15, 2014, this trial will not proceed to the Phase II study of 
dabrafenib and GSK2141795, in favor of evaluation of triple therapy.  (See 
Section 7.4). 
 
This will be a dose-escalation clinical trial using a standard 3+3 design. There will 
be 2 dose levels. The starting dose level is 1. No patients will be enrolled in the 
next dose level until the toxicity is fully assessed after the completion of 2 cycles 
in at least 3 patients enrolled at the previous dose level. The maximum tolerated 
dose (MTD) is defined as the highest dose studied in which the incidence of 
dose-limiting toxicities (DLT) is < 33%. The cohort of the MTD (or proposed dose 
for Phase II Portion if MTD not reached) will be at least 6 patients. 


 
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Dose escalation scheme for D+G: 
 
Dose Level 
Dabrafenib 
(twice a day) 
GSK2141795 
(once a day) 
1 
150 mg 
50 mg 
2 
150 mg 
75 mg 
2+ 
12/1/15 
12/1/15 
 
NOTE:  The drug regimen will be given on an outpatient basis. A cycle equals 28 
days. 
 
In the case that the PK sampling suggests that there is a drug-drug interaction 
between dabrafenib and GSK2141795 resulting in decreased exposure of one or 
both of the study drugs, a cohort 2+ will be open with dosing increased over 
cohort 2 with goal of reaching the full dose plasma levels of both agents based 
on the prior single agent experience with each of them. 
 
Patients enrolled at a lower dose cohort can have their doses of GSK2141795 
increased to the next cohort level if DLT is < 33% and at least 3 patients have 
gone through the full DLT assessment period of 2 months.  
 
b. 
Dose Determination Rules 
 
1. 
Dose Limiting Toxicity (DLT) is defined in Section 7.3c. 
 
2. 
Only DLTs occurring during Cycles 1 and 2 will be used to guide dosing 
determination of GSK2141795. 
 
3. 
Patients will be considered evaluable for DLT if they fulfill one of the 
following criteria: 
 
• They experience a DLT or 
 
• They received GSK2141795 at the assigned dose for at least 11 days 
during Cycle 1, and at least 28 days combined of dabrafenib over 
Cycles 1 and 2 or  
 
• They received GSK2141795 at the assigned dose for at least 11 days 
during Cycle 1 and at least 50% of dabrafenib during Cycle 1. 
 
Patients who do not meet at least one of these criteria will be considered 
not evaluable for DLT and will be replaced. 


 
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4. 
The following dosing scheme will be used for dose determination: 
 
a. 
Begin at Dose Level 1 (see Dose Escalation Scheme above): 
 
1) Enroll 3 patients and evaluate for toxicity. Enroll additional 
patients as required until 3 evaluable patients have been 
enrolled. 
 
2) If 0 of the initial 3 patients experience a DLT stop enrollment 
at this dose and continue to Dose Level 2. 
 
3) If only 1 of the initial 3 evaluable patients at the current dose 
level experience a DLT, expand enrollment until 6 evaluable 
patients have been enrolled or a second patient experiences 
a DLT. 
 
4) If 1 of 6 patients experiences a DLT, continue to Dose Level 
2. 
 
5) If 2 or more patients experience a DLT, lower dose levels 
may be investigated to find the recommended dose for the 
Phase II Portion or the study may be permanently closed. 
 
b. 
At Dose Level 2 (see Dose Escalation Scheme above): 
 
1) Enroll 3 patients and evaluate for toxicity. Enroll additional 
patients as required until 3 evaluable patients have been 
enrolled. 
 
2) If 0 or 1 patients experience a DLT, expand enrollment until 
6 evaluable patients have been enrolled or a second patient 
experiences a DLT. 
 
3) If 0 or 1 of 6 patients experiences a DLT, Dose Level 2 is the 
MTD. 
 
4) If 2 or more patients experience a DLT, 
 
a) If 6 patients have been enrolled in Dose Level 1, 
Dose Level 1 is the MTD.  
 
b) If 3 patients have been enrolled in Dose Level 1, 
expand enrollment to 6 evaluable patients.  
 
1. If 0 or 1 patients of 6 patients experience a DLT, 
Dose Level 1 is the MTD. 
 
2. If 2 or more patients experience a DLT, lower 
dose levels may be investigated to find the 
recommended dose for the Phase II Portion or 
the study may be permanently closed. 


 
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c. 
Definition of Dose-Limiting Toxicity 
 
Toxicities will be graded according to the NCI Common Terminology Criteria for 
Adverse Events Version 4.0. 
 
Dose-limiting toxicities (DLT) apply only during Cycles 1 and 2 and should be 
drug-related (possible, probable or definite).  The following events are considered 
dose limiting: 
 
1. 
Febrile neutropenia, 
 
2. 
Grade 4 neutrophil count decrease for more than 7 days duration, 
 
3. 
Grade 4 platelet count decrease, 
 
4. 
Grade 3 or 4 skin rash, fevers and hyperglycemia that do not recover 
within 14 days with adequate medical management as described in 
Section 8.0, 
 
5. 
Grade 3 or 4 non-hematologic toxicity that does not recover within 7 days 
with adequate medical management.  
 
7.4 
Treatment - Phase I  Dabrafenib + Trametinib + GSK2141795 (D + T + G)  
   
a. 
Dose Escalation Scheme of D + T + G: 
Phase I portion: The primary objective is to assess the safety of dabrafenib, 
trametinib, and GSK2141795 in combination and to determine the dosing of the 3 
drug combination for the Phase II portion. Dose escalation of dabrafenib, 
trametinib, and GSK2141795 will be initiated after completion of the dabrafenib + 
GSK2141795 phase I dose escalation. This three drug dose escalation will follow 
a standard 3+3 design. There will be 4 dose levels. No patients will be enrolled in 
the next dose level until the toxicity is fully assessed after the completion of 2 
cycles in at least 3 patients enrolled at the previous dose level. The maximum 
tolerated dose (MTD) is defined as the highest dose studied in which the 
incidence of dose-limiting toxicities (DLT) is < 33%. The MTD cohort (or 
proposed dose for Phase II portion if MTD not reached) will include at least 6 
patients. 
Dose escalation scheme for D+T+G 
 
Dose Level 
Dabrafenib  
(mg PO BID) 
Trametinib  
(mg PO daily) 
GSK2141795  
(mg PO daily) 
1 
150 
1.5 
25 
2 
150 
1.5 
50 
3 
150 
1.5 
75 
4 
150 
2 
75 


 
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b. 
Dose Determination Rules 
 
1. 
Dose Limiting Toxicity (DLT) is defined in Section 7.4c. 
 
2. 
Only DLTs occurring during Cycles 1 and 2 will be used to guide dosing 
determination of the study combinations. 
 
3. 
Patients will be considered evaluable for DLT if they fulfill one of the 
following criteria: 
 
• They experience a DLT or 
 
• They received GSK2141795 at the assigned dose for at least 11 days 
during Cycle 1, at least 28 days combined of trametinib over Cycles 1 
and 2, and at least 28 days of dabrafenib over Cycles 1 and 2 or 
 
• They received GSK2141795 at the assigned dose for at least 11 days 
during Cycle 1, at least 50% of trametinib during Cycle 1 and at least 
50% of dabrafenib during Cycle 1. 
. 
Patients who do not meet at least one of these criteria will be considered 
not evaluable for DLT and will be replaced. 
 
4. 
The following dosing scheme will be used for dose determination: 
 
a. 
Begin at Dose Level 1 (see Dose Escalation Scheme above): 
 
1) Enroll 3 patients and evaluate for toxicity. Enroll additional 
patients as required until 3 evaluable patients have been 
enrolled. 
 
2) If 0 of the initial 3 patients experience a DLT stop enrollment 
at this dose and continue to the next higher dose level. If the 
current dose level is Dose Level 4, then expand enrollment 
until 6 evaluable patients have been enrolled or  two patients 
experience a DLT. 
 
3) If 0-1 out of 6 patients experience a DLT on Dose Level 4, 
then Dose Level 4 is the MTD. 
 
4) If only 1 of the initial 3 evaluable patients at the current dose 
level experience a DLT, expand enrollment until 6 evaluable 
patients have been enrolled or a second patient experiences 
a DLT. 
 
5) If 1 of 6 patients experiences a DLT, continue to the next 
highest dose level. If 2 or more patients have already 
experienced a DLT at the next highest level or if the current 
dose level is Dose Level 4 then the current dose level is the 
MTD.  
 
6) If 2 or more patients experience a DLT, stop enrollment at 
the current dose level and continue to the next lowest dose 
level. If 6 patients have already been enrolled at the next 
lowest dose level then that dose level is the MTD. If the 
current dose level is Dose Level 1  lower dose levels may 


 
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be investigated to find the recommended dose for the Phase 
II Portion or the study may be permanently closed. 
 
c. 
Definition of Dose-Limiting Toxicity 
 
Toxicities will be graded according to the NCI Common Terminology Criteria for 
Adverse Events Version 4.0. 
 
Dose-limiting toxicities (DLT) apply only during Cycles 1 and 2 and should be 
drug-related (possible, probable or definite).  The following events are considered 
dose limiting: 
 
1. 
Febrile neutropenia, 
 
2. 
Grade 4 neutrophil count decrease for more than 7 days duration, 
 
3. 
Grade 4 platelet count decrease, 
 
4. 
Grade 3 or 4 skin rash, fevers and hyperglycemia that do not recover 
within 14 days with adequate medical management as described in 
Section 8.0, 
 
5. 
Grade 3 or 4 non-hematologic toxicity that does not recover within 7 days 
with adequate medical management. 
 
7.5 
Treatment - Phase II Portion of the Study 
 
Agent 
Dose 
Route 
Schedule* 
 
 
Dabrafenib 
150 mg 
PO 
Twice a day 
 
Trametinib 
determined in 
PO 
Once a day 
 
Phase I portion 
 
GSK2141795 
determined in 
PO 
Once a day 
 
Phase I portion 
 
*  Note:  One cycle = 28 days 
 
Patients will continue treatment until disease progression or other reason for 
discontinuation of protocol treatment (see Section 7.9). 
 
7.6 
Guidelines for Administration 
 
When dabrafenib, trametinib and GSK2141795 are administered in combination, take the 
once-daily dose of trametinib and GSK2141795 at approximately the same time each day 
with either the morning dose or the evening dose of dabrafenib.  The second dose of 
dabrafenib should be administered approximately 12 hours after the morning dose.  
Study medication should be taken orally with approximately 200 mL of water under 
fasting conditions, either 1 hour before or 2 hours after a meal.   
 
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled. Study drugs may 
be delivered to patients with feeding tube as long the capsules and tablets are not 
modified. 
 


 
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If administration of drug is interrupted or permanently discontinued, administration of the 
other drugs may be continued.   
 
If a subject misses a dose of dabrafenib, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later.  If the next scheduled dose of dabrafenib 
is due in less than 6 hours, the subject should skip the dose and resume dabrafenib 
dosing at the next scheduled dose.  If a subject misses a dose of trametinib or 
GSK2141795, the subject may take the dose immediately if the next dose is scheduled 
for at least 12 hours later. 
 
7.7 
Drug Compliance Documentation 
 
Drug compliance will be recorded by patients on the Intake Calendar (see Appendix 
18.3).  Institutional CRAs will review and ascertain patient adherence with protocol 
therapy at the end of treatment for each cycle.  Calendar should be kept in the patient's 
clinic chart.  Note that the Intake Calendar is provided only as a tool for tracking patient 
compliance.  Sites may utilize institutional pill diaries or other source documentation in 
place of the Intake Calendar at the discretion of the treating physician. 
 
7.8 
Full CDUS Reporting Requirements 
 
Because this study contains an investigational drug for which CTEP holds the IND, it falls 
under CTEP requirements for full reporting.  This involves required submission of cycle-
specific toxicity and dose information (see Section 14.4c, the S1221 Treatment Form, 
and the S1221 Adverse Event Form).  A cycle is defined as 28 days. 
 
7.9 
Criteria for Removal from Protocol Treatment 
 
a. 
Progression of disease as defined in Section 10.2d.  However, the patient may 
continue to stay on protocol treatment as long as in the opinion of the treating 
investigator the patient is continuing to clinically benefit from treatment. This may 
be if there are lesions that continue to respond to the therapy despite others 
progressing, or if there is symptomatic relief of symptoms on therapy. 
 
b. 
Symptomatic deterioration (as defined in Section 10.2e). 
 
c. 
Unacceptable toxicity. 
 
d. 
Treatment delay of both protocol drugs for any reason > 8 weeks. 
 
e. 
The patient may withdraw from the study at any time for any reason. 
 
7.10 
Discontinuation of Treatment 
 
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice. 
 
7.11 
Follow-Up Period 
 
All patients will be followed until death or 3 years after registration, whichever occurs first. 
 


 
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8.0 
TOXICITIES TO BE MONITORED AND DOSAGE MODIFICATIONS 
 
8.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 4.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE 
Version 4.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All 
appropriate treatment areas should have access to a copy of the CTCAE Version 4.0. 
 
8.2 
General Dose Modification Considerations 
 
a. 
If multiple toxicities are experienced, dose modifications will be based on the 
toxicity requiring the largest dose reductions. 
 
b. 
No dose escalation or re-escalation is allowed. 
 
8.3 
Dose Modifications for Dabrafenib, Trametinib, and GSK2141795 
 
The table below outlines the dose levels to be used for any necessary dabrafenib, 
trametinib and GSK2141795 dose modifications: 
 
Dose Level 
Dabrafenib Dose/Schedule 
0 
150 mg BID 
-1 
100 mg BID 
-2 
75 mg BID 
-3 
50 mg BID 
 
 
Dose Level 
Trametinib Dose/Schedule 
0 
2 mg QD 
-1 
1.5 mg QD 
-2 
1.0 mg QD 
 
 
Dose Level 
GSK2141795 Dose/Schedule 
0 
 75 mg QD 
-1 
50 mg QD 
-2 
25 mg QD 
 
Dabrafenib, Trametinib, and GSK2141795 Dose Modification Guidelines 
 
If an AE resolves to Grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level.  A dose reduction below 50 mg BID for dabrafenib 
is not allowed.  Dose reduction below 1 mg once daily for trametinib is not allowed.  Dose 
reduction below 25 mg once daily for GSK2141795 is not allowed.  However, if 
dabrafenib, trametinib, or GSK2141795 is permanently discontinued due to an agent 
specific toxicity (see below), the patient will be allowed to continue on the remaining 
agent(s).  
 
Study Chair approval is required to restart study treatment after ≥ 28 days of dose 
interruption. 


 
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The dose modifications may involve one or both agents, and should be based on the 
nature, severity and attributions of the AEs.  General guidelines are provided in Tables 
below, with details stipulated in subsequent sections.  Study Chair should be consulted if 
there are questions about the attribution of AEs and how the doses should be modified. 
 
a. 
Dose Modification for Toxicities Not Specified in Subsequent Sections 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1 
Grade 2 (tolerable) 
• Continue study treatment at same dose level (no 
dose modification). 
• Monitor closely. 
• Provide supportive care according to institutional 
standards. 
Grade 2 (intolerable) 
Grade 3 
• Interrupt study treatment. 
• Monitor closely. 
• Provide supportive care according to institutional 
standards. 
• When toxicity resolves to grade 1 or baseline, 
restart study treatment reduced by one dose 
level. 
• If the grade 2 (intolerable) or grade 3 toxicity 
recurs, interrupt study treatment. 
• When toxicity resolves to grade 1 or baseline, 
restart study treatment reduced by another 
dose level. 
Grade 4 
• Permanently discontinue, or interrupt, study 
treatment. 
• Monitor closely. 
• Provide supportive care according to institutional 
standards. 
• If study treatment was interrupted, restart  study 
treatment reduced by one dose level once 
toxicity resolves to grade 1 or baseline. 
*If the AEs are thought to be due to one of the two agents, resumption of the 
other agents may be considered if the first agent is discontinued due to 
toxicities and treatment interruption is <28days.  CTEP monitor should be 
consulted for resumption of single agent. 
 
b. 
Dose Modification for Pyrexia 
 
• 
Pyrexia is defined as a body temperature equal to or above 38.5○ Celsius or 
101.3○ Fahrenheit  
• 
Pyrexia is an adverse event associated with dabrafenib and is increased in 
frequency and severity in subjects receiving dabrafenib in combination with 
trametinib.  In a minority of cases, pyrexia was accompanied by symptoms 
such as severe chills/rigors, dehydration, hypotension, dizziness or 
weakness and required hospitalization.  


 
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Subjects should be instructed on the importance of immediately reporting 
febrile episodes.  In the event of a fever, the subject should be instructed to 
take anti-pyretics (e.g. ibuprofen or acetaminophen/paracetamol) as 
appropriate to control fever.  The use of oral corticosteroids should be 
considered in those instances in which anti-pyretics are insufficient. 
Monitor. 
• 
serum creatinine and other evidence of renal function during and following 
severe events of pyrexia  
Dose Modification and Management Guidelines for Pyrexiaa 
Event 
Management Guideline 
Dose Modification 
Work up: 
• Clinical evaluation for infection and hypersensitivity, especially if pyrexia is complicated by rigors, 
severe chills, dehydration, etc.  
• Laboratory work-up (should include full-blood-count, electrolytes, creatinine, BUN, CRP, liver-
function tests, blood and urine culture). 
 
Management:  
• Anti-pyretic treatment should be started immediately at the first occurrence.  Anti-pyretic treatment 
may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic medication per 
institutional standards. 
• Oral hydration is encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended if pyrexia is complicated by dehydration/hypotension. 
• In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled 
with anti-pyretic medication, oral corticosteroids should be started. 
• Prophylactic anti-pyretic treatment is recommended after the 2nd event, or after the 1st event if 
complicated by rigors or severe chills. Prophylactic anti-pyretics may be discontinued after three days 
in absence of pyrexia   
1st Eventb: 
• Cinical evaluation for 
infection and  
hypersensitivityc 
• Laboratory work-upc 
• Hydration as requiredd 
 
• Administer anti-pyretic 
treatment if clinically 
indicated and continue 
prophylactic treatmentf 
• Interrupt dabrafenib. 
• Continue trametinib and 
GSK2141795.  
• Upon recovery to baseline, restart 
dabrafenib at the same dose level.  
If fever was associated with 
dehydration or hypotension, 
reduce dabrafenib by one dose 
level. 
 
2nd Event 
• Clinical evaluation for 
infection and 
hypersensitivityc 
• Laboratory work-upc 
• Hydration as requiredd 
• Within 3 days of onset of 
pyrexia: 
− Optimize anti-pyretic 
therapy. 
− Consider oral 
corticosteroids (i.e., 
prednisone 10 mg) for 
at least 5 days or as 
clinically indicated.f 
• Interrupt dabrafenib. 
• Continue trametinib and 
GSK2141795  
• Upon recovery to baseline, restart 
dabrafenib at the same dose level.  
If fever was associated with 
dehydration or hypotension, 
reduce dabrafenib by one dose 
level. 


 
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Dose Modification and Management Guidelines for Pyrexiaa (contd) 
Event 
Management Guideline 
Dose Modification 
Subsequent Events:  
 
• Clinical evaluation for 
infection and 
hypersensitivityc 
• Laboratory work-upc 
• Hydration as requiredd 
• Blood sample for cytokine 
analysise 
• Within 3 days of onset of 
pyrexia: 
− Optimize oral 
corticosteroid dose as 
clinically indicated for 
recalcitrant pyrexia.g 
− If corticosteroids have 
been tapered and 
pyrexia recurs, restart 
steroids. 
− If corticosteroids cannot 
be tapered, consult 
medical monitor. 
• Interrupt dabrafenib. 
• Continue trametinib and 
GSK2141795. 
• Once pyrexia resolves to baseline, 
restart dabrafenib reduced by one 
dose level.h 
• If dabrafenib must be reduced to 
<50 mg BID, permanently 
discontinue dabrafenib. 
h Dabrafenib should be reduced 
by one dose level after three 
episodes of pyrexia which cannot 
be managed by best supportive 
care and increasing doses of oral 
steroids.  Escalation of dabrafenib 
is allowed if no episode of pyrexia 
is observed in the 4 weeks 
subsequent to dose reduction. 
−  
 
 
c. 
Dose Modification for Rash 
 
Rash is a frequent AE observed in patients receiving trametinib, dabrafenib, and 
GSK2141795.  
 
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. 
 
Supportive Care and Dose Modification for Rash 
CTCAE Grade 
Adverse Event Management 
Action and Dose 
Modification 
Supportive care: 
Prevention:   
• 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) 


 
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Supportive Care and Dose Modification for Rash 
CTCAE Grade 
Adverse Event Management 
Action and Dose 
Modification 
Symptom management: 
• Pruritic lesions: cool compresses and oral antihistamine therapies  
• Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide cream  
• Desquamation: thick emollients and mild soap  
• Paronychia: antiseptic bath, local potent corticosteroids in addition to oral antibiotics; if no 
improvement, consult dermatologist or surgeon 
• Infected lesions: appropriate bacterial/fungal culture-driven systemic or topical antibiotics  
*Rash prophylaxis is recommended for the first 6 weeks of study treatment  
a. * Subjects who develop rash/skin toxicities should be seen by a qualified physician and 
should receive evaluation for symptomatic/supportive care management  
Grade 1 
 
• Initiate prophylactic and 
symptomatic treatment 
measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Continue study treatment. 
• If rash does not recover to 
baseline within 2 weeks despite 
best supportive care, reduce 
study treatment by one dose 
level (all agents).3 
Grade 2  
 
• Initiate prophylactic and 
symptomatic treatment 
measures.1 
• Use moderate strength topical 
steroid.2 
• Reassess after 2 weeks. 
• Reduce study treatment 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 study 
treatment until recovery to ≤ 
grade 1. 
• Restart study treatment at 
reduced dose level (all 
agents).3 
Grade ≥3  
 
• Use moderate strength topical 
steroids PLUS oral methyl-
prednisolone dose pack.2 
• Consult dermatologist. 
• Interrupt study treatment until 
rash recovers to ≤ grade 1. 
• Restart study treatment 
reduced by one dose level (all 
agents).3,4 
• If no recovery to ≤ grade 2 
within 28 days, permanently 
discontinue study treatment. 
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 Study Chair is required to restart study treatment after >28 days of 
interruption. 
4.  Study treatment may be escalated to previous dose level if no rash is evident 4 weeks 
after restarting study treatment. 
 
d. 
Dose Modification for palmar-plantar erythrodysesthesia syndrome (PPES) 
 
• 
Lifestyle modification:  avoidance of hot water, traumatic activity, constrictive 
footwear, or excessive friction on the skin and the use of thick cotton socks and 
gloves, and shoes with padded insoles 


 
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• 
Symptomatic treatments:  apply moisturizing creams frequently, topical 
keratolytics (e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, 
fluorouracil 5% cream), clobetasol propionate 0.05% ointment for erythematous 
areas, topical lidocaine 2%, and / or systemic pain medication such as 
nonsteroidal anti-inflammatory drugs, codeine, and pregabalin for pain. 
• 
Dose modification may also be required. – Refer to table for dose modification for 
non-specific AEs 
e. 
Treatment Modification for New Primary/ Recurrent Malignancies:   
 
Cutaneous SCC and New Primary Melanoma 
Dermatologic skin assessments for subjects on treatment should be performed 
before initiation of dabrafenib, then every 2 months through treatment.  (For 
protocols that start after June 2014, it is also recommended that skin exams 
should continue every 2-3 months for 6 months after discontinuation of 
dabrafenib or initiation of another anti-neoplastic therapy.)  Report any new 
primary/recurrent malignancies as SAE through CTEP-AERS.    
 
• 
Cutaneous SCC 
Cases of cuSCC (which include those classified as keratoacanthoma or 
mixed keratoacanthoma subtype) have been observed in subjects 
treated with dabrafenib.  Approximately 70 % of events occurred within 
the first 12 weeks of treatment with a median time to onset of 8 weeks. 
 
These should be surgically removed according to institutional practices.  
Dose modification or interruption of study treatment is not required for 
cuSCC or KA, however cuSCC should be reported as an SAE. In 
addition, a biopsy of the lesion should be taken, where possible, and a 
summary of the results submitted to CTEP through the SAE reporting.   
 
Patients should be instructed to immediately inform their physician if new 
lesions develop.  
 
• 
New Primary Melanoma 
New primary melanomas have been reported in patients treated with 
dabrafenib. These were identified primarily within the first 5 months of 
therapy and did not require treatment modification other than excision.  
New primary melanoma should be reported as SAE through CTEP-
AERS.   
 
Non-Cutaneous Malignancies 
In vitro experiments have demonstrated paradoxical activation of MAP-kinase 
signalling in BRAF wild type cells with RAS mutations when exposed to BRAF 
inhibitors, which may lead to increased risk of non-cutaneous malignancies in 
patients treated with dabrafenib.  Cases of RAS-driven malignancies have been 
seen with BRAF inhibitors.  Patients should be monitored as clinically 
appropriate. 
 
Permanently discontinue dabrafenib in patients who develop RAS mutation-
positive non-cutaneous malignancies.  If used in combination with trametinib, 
trametinib may continue.   
 
Following 
discontinuation 
of 
dabrafenib, 
monitoring 
for 
non-cutaneous 
secondary/recurrent malignancies should continue for up to 6 months or until 
initiation of another anti-neoplastic therapy. 


 
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New non-cutaneous malignancies should be reported as a SAE. A biopsy of the 
new malignancy should be taken, where possible, and submitted for further 
analyses with the results provided to CTEP via SAE reporting.  Testing of these 
biopsies should include RAS mutation analysis and may include analysis of 
genomic alterations, which include but not limited to DNA, RNA and protein 
analysis of these biopsy specimens, and would analyze the biological pathways 
known to be associated with, and relevant to, BRAF-mutant tumor activation. 
 
f. 
Dose Modification for Hemorrhages 
 
Grade 3 
• Hold dabrafenib, trametinib and GSK2141795 for up to 3 weeks 
• If improved, resume the drugs at one dose reduction 
• If no improvement, permanently discontinue dabrafenib or 
dabrafenib-trametinib 
Grade 4 
• Permanently discontinue dabrafenib or dabrafenib-trametinib 
 
 
 
g. 
Dose Modification for Pancreatitis 
 
In the event of abdominal pain or suspected pancreatitis, amylase and lipase 
laboratory samples should be collected for confirmation of the diagnosis.  
Patients should be closely monitored when re-starting dabrafenib after an 
episode of pancreatitis. 
 
h. 
Dabrafenib-Trametinib Dose Modification for Hyperglycemia 
 
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral 
therapy can occur with dabrafenib. Monitor serum glucose levels as clinically 
appropriate during treatment with dabrafenib in subjects with pre-existing 
diabetes or hyperglycemia. Advise patients to report symptoms of severe 
hyperglycemia such as excessive thirst or any increase in the volume or 
frequency of urination.  See Section 8.4a for GSK2141795 dose modification 
instructions. 


 
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i. 
Dose Modification for Renal Insufficiency 
 
Prior to start of study treatment, concomitant medications should be reviewed for 
the potential risk of inducing nephrotoxicity and modified if clinically possible. 
 
Dose Modification for Renal Insufficiency 
Serum Creatinine Level 
Management Guideline 
Action and Dose 
Modification 
Serum creatinine 
increase 
>0.2 mg/dL (18 mcmol/L) 
BUT 
≤0.5 mg/dL (44 mcmol/L) 
above baseline 
• Recheck serum creatinine within 1 
week. 
• Serum creatinine increase >1 week:  
contact CTEP Medical Monitor. If 
elevation persists beyond 4 weeks, 
recommend evaluation (consider 
renal biopsy) for etiology; consider 
nephrology consultation. 
• If pyrexia is present, treat pyrexia as 
per guidelines.a 
Continue study 
treatment at the same 
dose level. 
Serum creatinine 
increase 
>0.5 mg/dL (44 mcmol/L) 
OR 
>2 mg/dL (>177 mcmol/L) 
• Monitor serum creatinine ≥2-times 
per week. 
• Hospitalization may be necessary if 
serum creatinine cannot be 
monitored frequently. 
• If pyrexia is present, treat pyrexia 
per guidelines. 
• Consult nephrologist if clinically 
indicated. 
• Perform renal biopsy if clinically 
indicated, for example: 
− Renal insufficiency persists 
despite volume repletion. 
− Patient has new rash or signs of 
hypersensitivity (such as 
elevated eosinophil count). 
• Interrupt study 
treatment until 
serum creatinine 
recovers to 
baseline. 
• Restart study 
treatment.b 
  
a  NSAIDs can induce renal insufficiency, especially in patients with dehydration; 
;encourage oral fluids or consider IV fluids as clinically indicated. See guidelines for 
pyrexia Section 6.1.2. 
b  Investigator may restart at either the same or a reduced dose level.  Escalation of 
study treatment to previous dose level is allowed if another episode of renal insufficiency 
does not occur after 4 weeks of dose reduction.  Consultation with the Study Chair is 
required before restarting study treatment if there is evidence of thrombotic 
microangiopathy. 
 
j. 
Dose Modification for Reduced Left Ventricular Ejection Fraction 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in 
patients receiving trametinib.  Therefore, ECHO/MUGA must be performed in 
regular intervals outlined in the Study Calendar.  The same procedure (either 
ECHO or MUGA, although ECHO is preferred) should be performed at baseline 
and at follow-up visit(s).   


 
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Treatment Modification and Management Guidelines for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Dose Modification 
Asymptomatic 
 
Absolute decrease of >10% 
in LVEF compared to 
baseline and ejection 
fraction below the 
institution’s LLN. 
• Interrupt trametinib.  Dabrafenib may continue  
• repeat ECHO within 2 weeks.a 
• If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline): 
− Consult with the Study Chair and request 
approval for restart. 
− Restart trametinib at reduced doses by one 
dose level. 
− Repeat ECHO 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 
− Continuation of dabrafenib and GSK214175 
may be considered after consultation with 
Study Chair. 
− Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution. 
Symptomaticb 
 
• Grade 3:  resting LVEF 39-
20% or >20% absolute 
reduction from baseline 
• Grade 4:  Resting LVEF 
≤20%. 
• Permanently discontinue trametinib.  Report 
as SAE 
• Hold dabrafenib and GSK2141795 until 
LVEF improves.  Consult Study Chair for 
resumption of  dabrafenib and GSK2141795 
• Consult with cardiologist. 
• Repeat ECHO after 2, 4, 8, 12, and 16 weeks 
or until resolution. 
a If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b Symptoms may include:  dyspnea, orthopenea, and other signs and symptoms of pulmonary 
congestion and edema. 
 
k. 
Dose Modification for Hypertension 
 
Increases in blood pressure (BP) have been observed in patients receiving 
dabrafenib plus 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. 


 
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• 
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. 
• 
Visits to monitor increased blood pressure can be scheduled independently 
from the per-protocol visits outlined in the study calendar.  Ideally, 
subsequent blood pressure assessments should be performed within 1 week. 
• 
Persistent hypertension is defined as an increase of systolic BP (SBP) >140 
mmHg and/or diastolic BP (DBP) >90 mmHg in three consecutive visits with 
blood pressure assessments from two readings. 
• 
Asympomatic hypertension is defined as an increase of SBP >140 mmHg 
and/or diastolic BP (DBP) >90 mmHg in the absence of headache, light-
headedness, vertigo, tinnitus, episodes of fainting, or other symptoms 
indicative of hypertension. 
 
Treatment Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
(Scenario A) 
• Asymptomatic and 
persistenta SBP of ≥140 
and < 160 mmHg, or DBP 
≥ 90 and < 100 mmHg 
OR 
• Clinically significant 
increase in DBP of 20 
mmHg (but DBP still 
below 100 mmHg) 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-
controlledb BP.   
• If BP is not well-controlled within 
2 weeks, consider referral to a 
specialist and go to scenario (B). 
• Continue study 
treatment. 
 
(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 study 
treatment if clinically 
indicated. 
• Once BP is well-
controlledb, restart 
study treatment 
reduced  by one dose 
levelc  
 
(Scenario C) 
• Symptomaticd 
hypertension  
OR 
• Persistent SBP ≥160 
mmHg, or DBP 
≥100 mmHg, despite 
antihypertensive 
medication and dose 
reduction of study 
treatment 
• Adjust current or initiate new 
antihypertensive medication(s). 
• Titrate antihypertensive 
medication(s) during the next 2 
weeks to achieve well-controlled 
BP. 
• Referral to a specialist for further 
evaluation and follow-up is 
recommended. 
• Interrupt study 
treatment 
• Once BP is well 
controlled, restart 
study treatment  
reduced by one dose 
levelc. 
 


 
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Treatment Modification for Hypertension 
Event 
Management Guideline 
Dose Modification 
(Scenario D) 
Refractory hypertension 
unresponsive to above 
interventions or 
hypertensive crisis. 
Continue follow-up per protocol. 
• Permanently 
discontinue study 
treatment. 
 
a. Hypertension detected in two separate readings during up to three consecutive visits 
b. Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in 
two separate readings during up to three consecutive visits. 
c. Escalation of trametinib to previous dose level can be considered if BPs remain well-
controlled for 4 weeks after restarting of trametinib.  Approval from Study Chair is 
required. 
d. Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., 
headache, light-headedness, vertigo, tinnitus, episodes of fainting) that resolve after 
the blood pressure is controlled within the normal range 
 
l. 
Dose Modification for QTc Prolongation and Valvular Changes 
 
Dose Modification  for QTc Prolongation 
QTc Prolongationa 
Action and Dose Modification 
• QTcB ≥501 msec 
 
• 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 agents that prolong 
QTc. 
• If the event resolves, restart study treatment at current dose 
levelb. 
• If the event does not resolve, permanently discontinue 
study treatment. Consider evaluation with cardiologist. 
• If the event recurs, permanently discontinue study 
treatment. Consider evaluation with cardiologist. 
Abbreviations:  msec = milliseconds; QTcB = QT interval on electrocardiogram corrected 
using the 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 CTEP medical monitor agree that the subject 
will benefit from further treatment. 
 


 
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Dose modifications for valvular changes 
Asymptomatic, moderate 
regurgitation or stenosis by 
ECHO (Grade 2 
mitral/tricuspid/aortic valvular 
toxicity per CTC AE v4.0) 
• Hold study therapy.  Repeat ECHO within 1 week, and 
every 1-2 weeks for 4 weeks. 
• If abnormality recovers within 4 weeks, resume study 
therapy with one dose level reduction.  For such 
subjects, continue ECHO monitoring 2 and 4 weeks 
after rechallenge, then every 4 weeks for 12 weeks and 
then per protocol. 
• If no recovery by 4 weeks, discontinue the study drug.  
Follow up with echocardiogram as above 
Grade 3 or 4 (symptomatic, 
severe regurgitation/stenosis 
by imaging, with symptoms 
controlled by medical 
intervention)  
• 
Permanently discontinue GSK2118436. 
• 
Continue echocardiogram every 4 weeks for 16 
weeks or until resolution.     
Resumption of the study agent may be considered in patients who were benefiting and 
have recovered from the valvular toxicities, but would require approval by the study 
sponsor (CTEP) and study chair) 
 
m. 
Dabrafenib or Dabrafenib-Trametinib Dose Modification for Diarrhea 
 
Episodes of diarrhea have been observed in patients receiving dabrafenib, 
trametinib, or both therapies in combination.  Other, frequent causes for diarrhea 
including concomitant medications (e.g., stool softeners, laxatives, antacids, 
etc.), infections caused by C. difficile or other pathogens, partial bowel 
obstruction, etc., should be clinically excluded. 
 
 
Dabrafenib or Dabrafenib-Trametinib Treatment Modification and Management 
Guidelines for Diarrhea 
CTCAE Grade 
Management Guideline 
tion and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 1  
or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, BRAT-diet 
(banana, rice, apples, toast) 
recommended. 
• Hydration:  8-10 large glasses of clear 
liquids per day (e.g., Gatorade or broth). 
• Loperamide3:  Initially 4 mg, followed by 
2 mg every 4 hours or after every 
unformed stool; maximum 16 mg/day.  
Continue until diarrhea-free for 12 hours. 
• Diarrhea >24 hours:  Loperamide 2 mg 
every 2 hours; maximum 16 mg/day.  
Consider adding oral antibiotics. 
• Diarrhea >48 hous:  Loperamide 2 mg 
every 2 hours; maximum 16 mg/day.  
Add budesonide or other second-line 
therapies (octreotide, or tincture of 
opium) and oral antibiotics. 
• Continue study treatment. 
• If diarrhea is grade 2 for > 
48 hours, interrupt study 
treatment until diarrhea 
resolves to grade ≤1. 
• Restart study treatment at 
the same dose level. 
 


 
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Dabrafenib or Dabrafenib-Trametinib Treatment Modification and Management 
Guidelines for Diarrhea 
CTCAE Grade 
Management Guideline 
tion 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 treatment 
until diarrhea resolves to ≤ 
grade 1. 
• Restart study treatment  
reduced by one dose 
level.4 
• If 3 dose reductions of 
study treatment are 
clinically indicated, 
permanently discontinue 
study treatment. 
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 study treatment  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. 
 
n. 
Dose Modification for Visual Changes 
 
Episodes of visual changes have been observed in patients receiving dabrafenib, 
trametinib, or the combination of both therapies.  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. 
 
Uveitis and iritis have been associated with dabrafenib, while RPED and RVO have been 
associated with trametinib therapy.  Monitor patients for visual signs and symptoms (such 
as change in vision, photophobia, and eye pain) during therapy. 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]).  For 
events of visual changes regardless of severity but for which an ophthalmic examination 
is conducted, a blood sample for PK analysis is encouraged when feasible, and the blood 
sample should be drawn as close as possible to the time of the event. 
 
The ophthalmology exam will include best corrected visual acuity, visual field 
examination, tonometry, slit lamp biomicroscopic examination of the anterior segment 
(with special attention to inflammation) and the posterior segment, and dilated indirect 
fundoscopy with special attention to retinal abnormalities.  Optical coherence tomography 
is strongly recommended at scheduled visits and if retinal abnormalities are suspected.  
Other types of ancillary testing including color 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 table below. 
 
Treatment Modification for Visual Changes  
CTCAE Grade 
Management Guideline 
Action and 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. Dabrafenib may be 
continued. 
• If RPED and RVO excluded, 
continue (or restart) trametinib at 
same dose level 
•  
• If Uveitis/Iritis, refer to table below 
for Iritis/Uveitis 
• If RPED suspected or diagnosed, 
refer to RPED dose modification 
table below; report as SAE if 
diagnosed. 
• If RVO diagnosed:  Permanently 
discontinue trametinib and report 
as SAE. 
Grade 2 and 
Grade 3 
 
• Consult ophthalmologist 
immediately. 
 
• Hold trametinib.  Dabrafenib and 
GSK2141795 may be continued. 
• If RPED and RVO excluded, restart 
trametinib at same dose level 
• If Uveitis/Iritis, refer to table below 
for Uveitis/Iritis 
• If RPED diagnosed, see RPED dose 
modification table below; report as 
SAE. 
• If RVO diagnosed:  Permanently 
discontinue trametinib and report 
as SAE. 
Grade 4 
 
• Consult ophthalmologist 
immediately. 
 
• Interrupt trametinib.  Dabrafenib and 
GSK2141795 may be continued. 
• If RPED and RVO excluded, may 
consider restarting trametinib at 
same or reduced dose after 
discussion with study medical 
monitor. 
• If Uveitis/Iritis, refer to table below 
• If RVO or RPED diagnosed, 
permanently discontinue 
trametinib and report as SAE. 
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. 


 
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Dose Modification for RPED 
Event 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; 
clinical or diagnostic observations 
only) 
• Continue trametinib with retinal evaluation monthly 
until resolution.  If RPED worsens, follow 
instructions below. 
• Dabrafenib and GSK2141795 treatment is not 
affected 
Grade 2-3 RPED (Symptomatic 
with mild to moderate decrease in 
visual acuity; limiting instrumental 
ADL) 
• Interrupt trametinib.  Continue dabrafenib and 
GSK2141795 
• 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 
 
 
Dabrafenib or Dabrafenib-Trametinib Dose Modification for Uveitis and Iritis 
CTCAE Grade 
Action and Dose Modification 
Uveitis and Iritis 
• Continue study treatment 
• Control ocular inflammation with local therapies  
• If not improved to grade ≤1 within 1 week, interrupt 
dabrafenib until resolution of ocular inflammation 
and then restart dabrafenib reduced by one dose 
level 
• If no recovery within 4 weeks, permanently 
discontinue dabrafenib.  Trametinib may continue. 
 
o. 
Dose Modification for Pneumonitis 
 
Pneumonitis has been observed in patients receiving trametinib in combination 
with dabrafenib.  To reduce the risk of pneumonitis, patients will be monitored 
closely for symptoms, evaluated with imaging and functional tests when 
appropriate. 
 
 


 
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CTCAE Grade 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 


 
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p. 
Dose Modification for Liver Chemistry Changes 
 
Dabrafenib or Dabrafenib-Trametinib Dose Modification for Liver Chemistry Changes 
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 treatment. 
• 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 and 
dabrafenib. 
 
1. ALT ≥3xULN and bilirubin ≥2x 
ULN  or >35% direct bilirubin1, 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 
Study Chair.   
• 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). 
If applicable, provide details on required follow up 
assessments (e.g., follow up for overall survival or 
disease recurrence or progression).  
 
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 hours  
• Monitor subjects weekly until LFTs return to 
normal/baseline or stabilize. 
ASSESSMENT and WORKUP: 
• Viral hepatitis serology.4 
• If possible, obtain blood sample for PK analysis.5 
• Serum CPK and LDH. 
• Fractionate bilirubin, if total bilirubin ≥2x ULN. 
•  


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


 
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q. 
Dose Modification for Venous Thromembolism (VTE) 
 
Event 
Dabrafenib 
Trametinib 
(When Used in Combination) 
Uncomplicated 
DVT or PE 
Do not modify the 
dose. 
 
Withhold trametinib for up to 3 
weeks. 
• If improved to Grade 0-1, resume 
at a lower dose level. 
• If not improved, permanently 
discontinue. 
Life Threatening 
PE 
Permanently 
discontinue 
dabrafenib 
Permanently discontinue trametinib. 
 
8.4 
Dose Modifications for GSK2141795 
 
a. 
GSK2141795 Dose Modification for Hypo- or Hyperglycemia 
 
Management and Dose Modification Guidelines for Hypo- or Hyperglycemia 
Criteria 
Management Guidelines 
Study Drug 
Modification 
(For management purposes, refer to mild, moderate and severe intensity criteria; 
however for eCRF reporting use NCI-CTCAE version 4.0 Grades 1-5) 
Mild 
Fasting blood glucose 
> 150mg/dL 
Monitor fasting and 
preprandial glucose. 
Continue study drug 
Moderate to Severe 
Fasting blood glucose 
<70 mg/dL OR any 
blood glucose > 
250mg/dL 
 
• If a blood glucose >250 
mg/dL, monitor for 
ketoacidosis as clinically 
indicated. 
• When managing 
hyperglycemia associated 
with GSK2141795, be 
aware that the action of 
insulin or other 
antihyperglycemic agents 
(e.g., sulfonylureas, 
biguanides, etc.) may be 
substantially blocked by the 
study agent.  However the 
action of antihyperglycemic 
agents would be restored 
as GSK2141795 is 
cleared.  The patient 
should be observed closely 
for rebound hypoglycaemia 
as GSK2141795 is held/or 
discontinued.   
• Intravenous insulin 
treatment is recommended. 
Hold GSK2141795 and 
notifyinvestigator 
immediately.  
 
Continue dabrafenib 
and trametinib. 
 
The investigator 
should discuss 
intervention and 
possible resumption of 
GSK2141795 with the 
Study Chair. 


 
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8.5 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact Dr. Ribas at 310/206-3928 
or Dr. Algazi at 415/353-7552. 
 
8.6 
Adverse Event Reporting 
 
Toxicities (including suspected reactions) that meet the expedited reporting criteria as 
outlined in Section 16.1 of the protocol must be reported to the Operations Office, Study 
Chair and NCI via CTEP-AERS, and to the IRB per local IRB requirements. 
 
9.0 
STUDY CALENDAR 
 
 
 


 
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9.1 
Study Calendar – Phase I D+G Portion 
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time of 
Progression 
Post-
Progression 
Follow-Up Ψ 
REQUIRED 
STUDIES 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
H & P 
X 
X 
  
X 
 
X 
  
X 
  
X 
 
  
  
X 
X 
X 
Wt & PS 
X 
X 
  
X  
 
 X 
  
X 
  
 X 
 
  
  
  
  
X 
Baseline 
Abnormality 
Assessment 
X 
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
Tox Notation 
  
X 
  
 X 
 
 X 
  
X 
  
 X 
 
  
  
X≠ 
X≠ 
X≠ 
Eye Exam√√ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Derm Exam** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X** 
X** 
X** 
Disease 
Assessment ¥ 
X 
  
  
  
 
  
  
 
  
 X 
 
  
  
X 
X 
  
Review Intake 
Calendar 
  
  
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
  
LAB ∏ 
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
CBC/ 
Diff/PLT /Hg 
X 
X 
  
X 
 
 X 
  
X 
  
 X 
 
  
  
  
  
X 
Serum Bilirubin 
X 
X 
  
X 
 
 X 
  
X 
  
 X 
 
  
  
  
  
X 
AST & ALT 
X 
X 
  
X  
 
 X 
  
X 
  
X 
 
  
  
  
  
X 
Serum 
Creat or CrCl 
X 
X 
  
X  
 
 X 
  
X 
  
 X 
 
  
  
  
  
X 
Serum Glucose 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Serum albumin 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
Amylase/Lipase+ 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
PT/INR, PTT ∆ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH Ω 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test 
(women of child 
bearing potential) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Section 9.1 Study Calendar continues on next page.  Click here for footnotes. 


 
 
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9.1 
Study Calendar – Phase I D+G Portion (contd.) 
 
 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time of 
Progression 
Post-
Progression 
Follow-Up 
Ψ 
REQUIRED 
STUDIES 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
X-RAYS & 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain CT or MRI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CT or MRI ¥ 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X£ 
X 
 
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
Xπ 
 
 
 
Xπ 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for PK  ∝ 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Paraffin-Embedded 
Tissue/Slides (Fresh 
Frozen Tissue if 
Available) 
X 
 
 
XΦ 
 
 
 
 
 
 
 
 
 
 
X 
 
Plasma and buffy 
Coat ® 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dabrafenib  ∑ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
GSK2141795  ⌐ 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Click here for footnotes. 
 


  
 
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NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
Footnotes: 
 
¥ 
For the first two years after registration, disease assessments must be performed after every two cycles of treatment using the same method 
as baseline and must be documented on the Follow-Up Tumor Assessment Form (RECIST 1.1). A response must be confirmed by a second 
determination at least 4 weeks after a complete or partial response has been noted. After two years (measured from time of registration), the 
frequency of disease assessment, CT, and MRI may be reduced to once every 12 weeks. 
√√ Ophthalmic exam must be performed at baseline.  Follow-up exams should be performed as clinically indicated. 
** Dermatology exams are required every 2 months throughout treatment, and every 2 months through 6 months after discontinuation of 
dabrafenib or until the start of another anti-neoplastic therapy. 
π 
On treatment echocardiogram (or MUGA) should be obtained every 2 months for all patients in the Phase I portion. 
∏ Patients known to be HIV + must not be on antiviral agents and must have CD34 counts ≥ 500 mm3 (see Section 5.1t). 
Δ 
See Sections 5.1u and 7.2b. 
Β 
Protocol treatment assessments will continue on this schedule until any one of the criteria in Section 7.8 is met. 
£ 
Once off protocol treatment, disease assessments must be performed every 8 weeks until disease progression. After two years (measured 
from time of registration), the frequency of disease assessments, CT and MRI may be reduced to once every 12 weeks.  
Ψ After disease progression (see Section 10.2), follow-up for survival status must be performed every 3 months for the first year, then every 6 
months for a total of 3 years from the date of registration or death, whichever is first. 
≠ 
Assessments should continue until resolution of all acute adverse events.  Patients with AEs at progression should be followed at frequencies 
appropriate for the nature and duration of the events, until the AE has resolved or is deemed irreversible. 
∑ 
To be taken twice daily. 
⌐ 
To be taken once a day. 
Ω For melanoma patients only. 
∝ 
Required at baseline and prior to dosing on Days 15 and 29. Three patients treated within the second cohort of the Phase I Portion (D+G) will 
have more extensive PK sampling at baseline, pre-dose and +1, +2, +4, and +8 hours on Day 15, and pre-dose Day 29. 
Φ Optional biopsy between Day 15-28. 
® Plasma and buffy coat must be submitted at baseline, before the start of Cycle 3 and at the time of progression. 
+ 
As clinically indicated to evaluate adverse events (i.e., abdominal pain, pancreatitis, etc). 
 
 
 


 
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9.2 
Study Calendar – Phase I D+T +G Portion  
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time 
of 
Progression 
Post- 
Progression 
Follow-Up Ψ 
REQUIRED 
STUDIES 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
 
 
 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
 
H & P 
X 
X 
  
X 
 
X 
  
X 
  
X 
 
  
  
X 
X 
X 
Wt & PS 
X 
X 
  
X  
 
 X 
  
X 
  
 X 
 
  
  
  
X 
X 
Baseline 
Abnormality 
Assessment 
X 
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
Tox Notation 
  
X 
  
 X 
 
 X 
  
X 
  
 X 
 
  
  
X≠ 
X≠ 
X≠ 
Eye Exam√√ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Derm Exam** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X** 
X** 
X** 
Disease 
Assessment ¥ 
X 
  
  
  
 
  
  
 
  
 X 
 
  
  
X 
X 
  
Review 
Intake 
Calendar 
  
  
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
 
LAB ∏ 
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
 
CBC/ 
Diff/PLT /Hg 
X 
X 
  
X 
 
 X 
  
X 
  
 X 
 
  
  
  
 
X 
Serum Bilirubin 
X 
X 
  
X 
 
 X 
  
X 
  
 X 
 
  
  
  
 
X 
AST & ALT 
X 
X 
  
X  
 
 X 
  
X 
  
X 
 
  
  
  
 
X 
Serum 
Creat or CrCl 
X 
X 
  
X  
 
 X 
  
X 
  
 X 
 
  
  
  
 
X 
Serum Glucose 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
  
Serum albumin 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
  
Amylase/ 
Lipase + 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
PT/INR, PTT ∆ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LDH Ω 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test 
(women of child 
bearing 
potential) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Section 9.2 Study Calendar continues on next page.  Click here for footnotes. 


 
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9.2 
Study Calendar – Phase I D+T +G Portion (contd.) 
 
 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time 
of 
Progression  
Post- 
Progression 
Follow-Up Ψ 
REQUIRED 
STUDIES 
 
 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
X-RAYS & 
SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brain CT or MRI  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CT or MRI ¥ 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X£ 
X 
 
ECHO or 
MUGA 
X 
 
 
 
 
 
  
 
 
Xπ 
 
 
 
X π 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Blood for PK  ∝ 
X 
 
 
X 
 
X 
  
 
 
 
 
 
 
 
 
 
Paraffin-
Embedded 
Tissue/Slides 
(Fresh Frozen 
Tissue if 
Available) 
X 
 
 
XΦ 
 
 
  
 
 
 
 
 
 
 
X 
 
Plasma and 
Buffy Coat ® 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
TREATMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dabrafenib  ∑ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Trametinib ⌐ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
GSK2141795  ⌐ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Click here for footnotes. 
 


 
S1221 
 
Page 70 
 
Version Date 8/21/17 
 
 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
Footnotes: 
 
¥ 
For the first two years after registration, disease assessments must be performed after every two cycles of treatment using the same method 
as baseline and must be documented on the Follow-Up Tumor Assessment Form (RECIST 1.1). A response must be confirmed by a second 
determination at least 4 weeks after a complete or partial response has been noted. After two years (measured from time of registration), the 
frequency of disease assessments, CT and MRI may be reduced to once every 12 weeks. 
√√ Ophthalmic exam must be performed at baseline.  Follow-up exams as clinically indicated. 
** Dermatology exams are required every 2 months throughout treatment, and every 2 months through 6 months after discontinuation of 
dabrafenib or until the start of another anti-neoplastic therapy. 
π 
On treatment echocardiogram should be obtained every 2 months for all patients in the Phase I portion. 
∏ Patients known to be HIV + must not be on antiviral agents and must have CD34 counts ≥ 500 mm3 (see Section 5.1t). 
Δ 
See Sections 5.1u and 7.2b. 
Β 
Protocol treatment assessments will continue on this schedule until any one of the criteria in Section 7.8 is met. 
£ 
Once off protocol treatment, disease assessments must be performed every 8 weeks until disease progression. After two years (measured 
from time of registration), the frequency of disease assessments, CT and MRI may be reduced to once every 12 weeks. 
Ψ After disease progression (see Section 10.2), follow-up for survival status must be performed every 3 months for the first year, then every 6 
months for a total of 3 years from the date of registration or death, whichever is first. 
≠ 
Assessments should continue until resolution of all acute adverse events.  Patients with AEs at progression should be followed at frequencies 
appropriate for the nature and duration of the events, until the AE has resolved or is deemed irreversible. 
∑ 
To be taken twice daily. 
⌐ 
To be taken once a day. 
Ω For melanoma patients only. 
∝ 
Required at baseline and prior to dosing on Days 15 and 29. Three patients treated within the second cohort of the Phase I Portion (D+G) will 
have more extensive PK sampling at baseline, pre-dose and +1, +2, +4, and +8 hours on Day 15, and pre-dose Day 29. 
Φ Optional biopsy between Day 15-28. 
® Plasma and buffy coat be submitted at baseline, before the start of Cycle 3 and at the time of progression. 
+ 
As clinically indicated to evaluate adverse events (i.e., abdominal pain, pancreatitis, etc). 
 
 
 
 
 


 
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9.3 
Study Calendar – Phase II D+T+G 
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time of 
Progression 
Post-
Progression 
Follow Up Ψ   
REQUIRED 
STUDIES 
 
 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
PHYSICAL 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
H & P  
X 
X 
  
  
 
X 
  
 
  
X  
 
  
  
X 
X 
X 
Wt & PS 
X 
X 
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
X 
Baseline 
Abnormality 
Assessment 
X 
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
Tox Notation 
  
X 
  
  
 
 X 
  
 
  
 X 
 
  
  
X≠ 
X≠ 
X≠ 
Disease 
Assessment ¥ 
X 
  
  
  
 
  
  
 
  
 X 
 
  
  
X£ 
X 
  
Eye Exam √√ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dermatology 
Exam** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X** 
X** 
X** 
Review Intake Cal 
 
  
  
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
  
LAB ∏ 
  
  
  
  
 
  
  
 
  
  
 
  
  
  
  
  
CBC/Diff/PLT/Hg 
X 
X 
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
X 
Serum Bili 
X 
X 
  
  
 
 X 
  
 
  
 X 
 
  
  
  
  
X 
AST & ALT 
X 
X 
  
  
 
 X 
  
 
  
X  
 
  
  
  
  
X 
Serum Cr or CrCl 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
Serum Glucose 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Serum Albumin 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Amylase /Lipase + 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
PT/INR, PTT  ∆ 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
LDH  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy 
test (women of 
child bearing 
potential) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Section 9.3 Study Calendar continues on next page.  Click here for footnotes. 


 
 
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Page 72 
 
 
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9.3 
Study Calendar – Phase II D+T+G (contd.) 
 
 
 
Cycle 1 
Cycle 2 
Cycle 3 + β 
Follow-Up 
Prior to 
Progression 
At Time of 
Progression 
Post-
Progression 
Follow Up 
Ψ 
REQUIRED 
STUDIES 
  
 
 
PRE- 
STUDY 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
Wk 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
X-RAYS & 
SCANS 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CT or MRI Scan of 
the brain 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
CT or MRI ¥ 
X 
  
  
  
  
  
  
 
  
X  
  
  
  
X£ 
X 
  
ECHO or MUGA 
X 
 
 
 
 
 
 
 
 
X𝜋𝜋 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPECIMEN 
SUBMISSION 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Paraffin-Embedded 
Tissue/Slides 
(Fresh Frozen 
Tissue 
If Available) 
X 
  
  
XΦ 
  
  
  
  
  
  
  
  
  
  
X 
  
Plasma and Buffy 
Coat ® 
X 
  
  
  
 
  
  
 
 
X 
 
  
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
TREATMENT 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dabrafenib  ∑ 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Trametinib ⌐ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
GSK2141795  ⌐ 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
Click here for footnotes. 


 
 
S1221 
 
 
Page 73 
 
 
Version Date 8/21/17 
 
 
 
 
 
NOTE:  Forms are found on the protocol abstract page of the SWOG website (www.swog.org).  Forms submission guidelines are found in Section 
14.0. 
 
Footnotes: 
 
¥ 
Disease assessments must be performed after every two cycles of treatment using the same method as baseline and must be documented on 
the Follow-Up Tumor Assessment Form (RECIST 1.1). A response must be confirmed by a second determination at least 4 weeks after a 
complete or partial response has been noted. 
√√ Ophthalmic exam must be performed at baseline.  Follow-up exams are to be performed as clinically indicated. 
** Dermatology exams are required every 2 months throughout treatment, and every 2 months through 6 months after discontinuation of 
dabrafenib or until the start of another anti-neoplastic therapy. 
π 
On treatment echocardiogram should be obtained every 2 months for all patients. 
∏ Patients known to be HIV + must not be on antiviral agents and must have CD34 counts ≥ 500 mm3 (see Section 5.1t). 
Δ 
See Sections 5.1u and 7.2b. 
Β 
Protocol treatment assessments will continue on this schedule until any one of the criteria in Section 7.8 is met. 
£ 
Once off protocol treatment, disease assessments must be performed every 8 weeks until disease progression. 
Ψ After disease progression (see Section 10.2), follow-up for survival status must be performed every 3 months for the first year, then every 6 
months for a total of 3 years from the date of registration or death, whichever is first. 
≠ 
Assessments should continue until resolution of all acute adverse events.  Patients with AEs at progression should be followed at frequencies 
appropriate for the nature and duration of the events, until the AE has resolved or is deemed irreversible. 
∑ 
To be taken twice daily. 
⌐ 
To be taken once a day. 
Ω For melanoma patients only. 
∝ 
Required at baseline and prior to dosing on Days 15 and 29. Three patients treated within the second cohort of the Phase I Portion (D+T+G) 
will have more extensive PK sampling at baseline, pre-dose and +1, +2, +4, and +8 hours on Day 15, and pre-dose Day 29. 
Φ Optional biopsy between Day 15-28. 
® Plasma and buffy coat must be submitted at baseline, before the start of Cycle 3 and at the time of progression. 
+ 
As clinically indicated to evaluate adverse events (i.e., abdominal pain, pancreatitis, etc). 
 
 
 
 


 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
10.1 
Measurability of Lesions 
 
a. 
Measurable disease: Measurable disease is defined differently for lymph nodes 
compared with other disease and will be addressed in a separate section below. 
 
1. 
Lesions that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 2.0 cm  by chest x-ray, by ≥ 1.0 
cm  with CT or MRI scans, or ≥ 1.0 cm with calipers by clinical exam. All 
tumor measurements must be recorded in decimal fractions of 
centimeters (or millimeters). 
 
The defined measurability of lesions on CT scan is based on the 
assumption that CT slice thickness is 0.5 cm or less.  If CT scans have 
slice thickness greater than 0.5 cm, the minimum size for a measurable 
lesion should be twice the slice thickness. 
 
2. 
Malignant lymph nodes are to be considered pathologically enlarged and 
measurable if it measures ≥ 1.5 cm in SHORT AXIS (greatest diameter 
perpendicular to the long axis of the lymph node) when assessed by 
scan (CT scan slice recommended being no greater than 0.5 cm). 
 
b. 
Non-measurable disease:  All other lesions (or sites of disease), including small 
lesions (longest diameter < 1.0 cm or pathologic lymph nodes with ≥ 1.0 cm to < 
1.5 cm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered non-measurable as are previously 
radiated lesions that have not progressed. 
 
c. 
Notes on measurability 
 
1. 
For CT and MRIs, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to 
prior scans.  Body scans should by performed with breath-hold scanning 
techniques, if possible. 
 
2. 
PET-CT:  At present, the low dose or attenuation correction CT portion of 
a PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT, then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with 
conventional CT. 
 
3. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and 
should not be used as a method of measurement. 
 
4. 
Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable 
nor non-measurable) since they are, by definition simple cysts. 
 
5. 
If a target lesion becomes very small some radiologists indicate that it is 
too small to measure.  If the lesion is actually still present, a default 
measurement of 0.5 cm should be applied.  If the radiologist believes the 
lesion has gone, a default measurement of 0.0cm should be recorded. 


 
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10.2 
Objective Status at Each Disease Evaluation 
 
Objective Status is to be recorded at each evaluation.  All measurable lesions up to a 
maximum of 2 lesions per organ 5 lesions in total, representative of all involved organs, 
should be identified as target lesions at baseline.  All other lesions (or sites of disease) 
including any measurable lesions over and above the 5 target lesions should be identified 
as non-target lesions.  Measurements must be provided for target measurable lesions, 
while presence or absence must be noted for non-target measurable and non-
measurable disease. 
 
For studies that use disease progression as an endpoint, whole body scanning at specific 
intervals is necessary to determine that progression is NOT present outside of the 
“target” areas.  Therefore, in these studies it is not acceptable to image only the “target” 
areas of the body in follow-up scans.  For study-specific imaging requirements, see the 
Study Calendar in Section 9.0. 
 
a. 
Complete Response (CR):  Complete disappearance of all target and non-
target lesions (with the exception of lymph nodes mentioned below).  No new 
lesions.  No disease related symptoms.  Any lymph nodes (whether target or 
non-target) must have reduction in short axis to < 1.0 cm.  All disease must be 
assessed using the same technique as baseline. 
 
b. 
Partial Response (PR):  Applies only to patients with at least one measurable 
lesion.  Greater than or equal to 30% decrease under baseline of the sum of 
appropriate diameters of all target measurable lesions.  No unequivocal 
progression of non-measurable disease.  No new lesions.  All target measurable 
lesions must be assessed using the same techniques as baseline. 
 
c. 
Stable:  Does not qualify for CR, PR, Progression or Symptomatic Deterioration.  
All target measurable lesions must be assessed using the same techniques as 
baseline. 
 
d. 
Progression:  One or more of the following must occur:  20% increase in the 
sum of appropriate diameters of target measurable lesions over smallest sum 
observed (over baseline if no decrease during therapy) using the same 
techniques as baseline, as well as an absolute increase of at least 0.5 cm.  
Unequivocal progression of non-measurable disease in the opinion of the treating 
physician (an explanation must be provided).  Appearance of any new lesion/site.  
Death due to disease without prior documentation of progression and without 
symptomatic deterioration (see Section 10.2e). 
 
 
Notes regarding new lesions:  FDG-PET imaging can complement regular scans 
in identifying new lesions according to the following algorithm. 
 
1. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is 
a sign of progression based on a new lesion. 
 
2. 
No FDG-PET at baseline and a positive FDG-PET at follow-up 
corresponding to a potential new site of disease must have a 
confirmation by anatomical assessment (e.g., CT, MRI, x-ray) as new 
site of disease to be considered progressive disease.  In such a case, 
the date of progressive disease will be the date of the initial abnormal 
FDG-PET. 
 
e. 
Symptomatic deterioration:  Global deterioration of health status requiring 
discontinuation of treatment without objective evidence of progression.  Efforts 
should be made to obtain objective evidence of progression after discontinuation. 


 
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f. 
Assessment inadequate, objective status unknown.  Progression or 
symptomatic deterioration has not been documented, and one or more target 
measurable lesions have not been assessed or inconsistent assessment 
methods were used. 
 
g. 
Objective status notes: 
 
1. 
Non-measurable and non-target measurable disease do not affect 
Objective Status in determination of CR (must be absent--a patient who 
otherwise has a CR, but who has non-measurable or non-target 
measurable disease present or not assessed, will be classified as having 
a PR).  However, non-measurable and non-target lesions are included in 
determination of progression (if new sites of disease develop or if 
unequivocal progression occurs in the opinion of the treating physician). 
 
2. 
An objective status of PR or stable cannot follow one of CR.  Stable can 
follow PR only in the rare case that tumor increases too little to qualify as 
progression, but enough that a previously documented 30% decrease no 
longer holds. 
 
3. 
In cases for which initial flare reaction is possible (hypercalcemia, 
increased bone pain, erythema of skin lesions), objective status is not 
progression unless either symptoms persist beyond 4 weeks or there is 
additional evidence of progression. 
 
4. 
Lesions that appear to increase in size due to presence of necrotic tissue 
will not be considered to have progressed. 
 
5. 
For bone disease documented on bone scan only, increased uptake 
does not constitute unequivocal progression.  However, increase in the 
soft tissue component of a lesion as measured by CT or MRI would 
constitute progression. 
 
6. 
Appearance of new pleural effusions does not constitute unequivocal 
progression unless cytologically proven of neoplastic origin, since some 
effusions are a toxicity related to therapy or other medical conditions.  
Increase in the size of an existing effusion does not constitute 
unequivocal progression, since the fluid status of the patient could alter 
the size of the effusion. 
 
7. 
If CR determination depends on a lesion for which the status is unclear 
by the required tests, it is recommended the residual lesion be 
investigated with biopsy or fine needle aspirate. 
 
10.3 
Best Response 
 
This is calculated from the sequence of objective statuses. 
 
a. 
CR:  Two or more objective statuses of CR a minimum of four weeks apart 
documented before progression or symptomatic deterioration. 
 
b. 
PR:  Two or more objective statuses of PR or better a minimum of four weeks 
apart documented before progression or symptomatic deterioration, but not 
qualifying as CR. 
 
c. 
Unconfirmed CR:  One objective status of CR documented before progression or 
symptomatic deterioration but not qualifying as CR or PR. 
 


 
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d. 
Unconfirmed PR:  One objective status of PR documented before progression or 
symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. 
 
e. 
Stable/no response:  At least one objective status of stable/no response 
documented at least 6 weeks after registration and before progression or 
symptomatic deterioration, but not qualifying as anything else above. 
 
f. 
Increasing disease:  Objective status of progression within 12 weeks of 
registration, not qualifying as anything else above. 
 
g. 
Symptomatic deterioration:  Objective status of symptomatic deterioration within 
12 weeks of registration, not qualifying as anything else above. 
 
Inadequate assessment, response unknown:  Progression or symptomatic deterioration 
greater than 12 weeks after registration and no other response category applies. 
 
10.4 
Performance Status 
 
Patients will be graded according to the Zubrod Performance Status Scale. 
 
POINT 
DESCRIPTION 
 
0 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
1 
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. 
 
2 
Ambulatory and capable of self-care but unable to carry out any 
work activities; up and about more than 50% of waking hours. 
 
3 
Capable of limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
4 
Completely disabled; cannot carry on any self-care; totally 
confined to bed or chair. 
 
10.5 
Progression-Free Survival 
 
From date of registration to date of first documentation of progression or symptomatic 
deterioration (see Section 10.2e), or death due to any cause.  Patients last known to be 
alive without report of progression are censored at date of last contact. 
 
10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be 
alive are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Accrual Goals 
 
This study will initially be open to limited institutions, with an expected accrual of 3-12 
patients in the D+G Phase I Portion and 6-18 patients in the D+T+G Phase I Portion.  
The Phase II Portion of the trial will be open Group-wide and will require 10-33 eligible 
patients. Assuming that 10% of patients enrolled will be ineligible or not evaluable, 


 
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approximately 70 patients will be required. Based on data from previous studies in similar 
patient populations the estimated accrual rate is 2-3 patients per month. 
 
11.2 
Evaluation of Dabrafenib + GSK2141795 (D+G) 
 
a. 
Analysis of Phase I Portion 
 
Section 7.3 provides the details of the study design for the Phase I Portion of the 
study. The Phase I Portion will be a limited dose-escalation. 
 
The primary objective of the Phase I Portion will be to determine the maximum 
tolerated dose (MTD) of GSK2141795 and dabrafenib in patients with BRAF 
mutant locally advanced or metastatic cancer.  The regimen will be considered 
safe and the MTD determined if the dose-limiting toxicity rate is ≤ 33%. 
 
Prior to implementation of the Phase II Portion, a temporary closure will occur in 
order to assess dose and to evaluate the safety profile more fully. 
 
b. 
Analysis of Phase II Portion 
 
Note:  Effective November 15, 2014, this trial will not proceed to the Phase II 
study of dabrafenib and GSK2141795, but will be moving to an evaluation of 
triple therapy. 
 
The study will be conducted in two sequential parts.  Patients enrolled to the 
Phase I Portion will not be included in the analysis of the Phase II Portion. 
 
The primary objective of the Phase II Portion of this study is to evaluate the 
objective response rate (confirmed and unconfirmed, complete and partial 
responses) of GSK2141795 used in combination with dabrafenib in patients with 
Stage IV or unresectable Stage III melanoma who have acquired resistance to 
BRAF inhibitor-based therapy. Resistance to BRAF inhibitor-based therapy will 
be defined as progressive disease by RECIST 1.1 criteria while receiving therapy 
with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in combination with a 
MEK inhibitor). This may be innate resistance (patients who never achieved a 
tumor response while on BRAF inhibitor therapy) or acquired resistance 
(progression after having a tumor response to BRAF inhibitor therapy). 
 
It is assumed that this regimen will not be of further interest if the true response 
rate is less than 5% (null) and that a true response rate of 25% or more would be 
of considerable interest for further investigation (alternative). 
 
Parallel patient enrollment will be implemented for two strata (prior therapy with 
BRAF-inhibitor only versus prior therapy with both a BRAF-inhibitor and a MEK-
inhibitor), and a two-stage design will proceed separately for each stratum as 
follows:  In the first step, 9 eligible patients will be accrued.  If necessary, the 
study may be temporarily closed while response data matures.  If zero responses 
are observed, the study will be closed with the conclusion that this regimen does 
not warrant further study.  If at least one response is observed, an additional 15 
eligible patients will be accrued.  Three or more responses out of 24 will be 
considered evidence that this regimen warrants further study, provided other 
factors such as overall survival and adverse events also appear favorable.  This 
design has 90% power with a one-sided alpha of 10%. 
 
 


 
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11.3 
Evaluation of Dabrafenib + Trametinib + GSK2141795 (D+T+G) 
 
a 
Analysis of Phase I Portion 
 
Section 7.4 provides the details of the study design for the Phase I Portion of the 
study. The Phase I Portion will be a limited dose-escalation. 
 
The primary objective of the Phase I Portion will be to determine the maximum 
tolerated dose (MTD) of GSK2141795, dabrafenib and trametinib in patients with 
BRAF mutant locally advanced or metastatic cancer.  The regimen will be 
considered safe and the MTD determined if the dose-limiting toxicity rate is ≤ 
33%. 
 
Prior to implementation of the Phase II Portion, a temporary closure will occur in 
order to assess dose and to evaluate the safety profile more fully. 
 
 
b 
Analysis of Phase II Portion  
 
The study will be conducted in two sequential parts.  Patients enrolled to the 
Phase I Portion will not be included in the analysis of the Phase II Portion. 
 
 
The primary objective of this portion study is to evaluate the objective response 
rate (confirmed and unconfirmed, complete and partial responses) of 
GSK2141795 used in combination with dabrafenib and trametinib in patients with 
Stage IV or unresectable Stage III melanoma who have acquired resistance to 
BRAF inhibitor-based therapy. Resistance to BRAF inhibitor-based therapy will 
be defined as progressive disease by RECIST 1.1 criteria while receiving therapy 
with a BRAF inhibitor (vemurafenib or dabrafenib, alone or in combination with a 
MEK inhibitor). This may be innate resistance (patients who never achieved a 
tumor response while on BRAF inhibitor therapy) or acquired resistance 
(progression after having a tumor response to BRAF inhibitor therapy).  
 
It is assumed that this regimen will not be of further interest if the true response 
rate is less than 15% (null) and that a true response rate of 35% or more would 
be of considerable interest for further investigation (alternative).  
 
A two-stage design will be used for patient accrual.  In the first step, 10 eligible 
patients will be accrued. If necessary, the study may be temporarily closed while 
response data matures. If 0-1 responses are observed, the study will be closed 
with the conclusion that this regimen does not warrant further study in the Group 
A population. If at least 2 responses are observed, an additional 23 eligible 
patients will be accrued. Eight or more responses out of 33 will be considered 
evidence that this regimen warrants further study, provided other factors such as 
overall survival and adverse events also appear favorable. This design has 87% 
power with a one-sided alpha of 0.9%. 
 


 
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11.4 
Analysis of Secondary Endpoints 
 
The Phase II Portion will include estimating overall survival, progression-free survival, 
and toxicity rates.  Assuming 33 eligible patients are enrolled, this will be sufficient to 
estimate overall survival, progression-free survival, and toxicity rates to within ± 17% 
(95% confidence interval). Assuming 33 eligible patients overall, any toxicity with at least 
a 5% chance of occurring has a 82% chance of being observed at least once.  In 
addition, to assess safety and feasibility in both the Phase I and Phase II Portions of the 
trial, descriptive statistics will be presented for the number of patients requiring dose 
reduction, interruption or discontinuation and the percentage of dose delivery. 
 
11.5 
Analysis of Translational Medicine Component 
 
This analysis will include those patients enrolled to the Phase I or II Portion of the study 
with adequate specimens.  Every attempt will be made for pre-study collection of blood 
and tissue specimens.  Blood and tissue specimens from accessible metastatic lesions 
will be requested from two other time points:  1) after start on therapy (approximately Day 
15-30), and 2) at the time of progression on this study. 
 
For the pre-study time point, for each of the categorical markers listed in Section 18.2, we 
will estimate the prevalence of the marker in this patient population.  For binary markers, 
the prevalence will be able to be estimated and exact binomial confidence interval will be 
calculated.  The association between these categorical markers and clinical outcomes 
will be explored in a preliminary manner, using Fisher’s exact test to compare response 
and a logrank test to compare Kaplan-Meier estimates of OS and PFS between marker 
positive and marker negative groups. 
 
For the quantitative markers in the previous section, we will estimate median and range 
values in this patient population.  The association between quantitative markers and 
clinical outcomes will be explored in a preliminary manner, using the Wilcoxon-rank sum  


 
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test to assess response and Cox regression to assess PFS and OS.  In addition, we may 
explore dichotomizing the patients into two groups by splitting at the median (or other 
cutpoints may be explored) and applying the methods specified above for the categorical 
markers. 
 
For patients with samples at more than one time we will examine changes in marker 
status over time.  This analysis will be very exploratory. 
 
For patients enrolled on the Phase I Portion, PK sampling steady state should be taken at 
baseline, pre-dose Day 15 and pre-dose Day 29.  In addition, three patients treated within 
the second cohort of each of the Phase I Portions (D+G and D+T+G) will have more 
extensive PK sampling at baseline, pre-dose and +1, +2, +4, and +8 hours on Day 15, 
and pre-dose Day 29. 
 
11.6 
Data and Safety Monitoring 
 
See Section 15.0, description of conference calls for safety monitoring of the Phase I 
Portion and selection of the recommended Phase II dose. 
 
There is no formal data and safety monitoring committee for single arm Phase II studies. 
Toxicity and accrual monitoring are done routinely by the Study Chair, study Statistician 
and the Disease Committee Chair.  Endpoint monitoring is done by the study Statistician 
and Study Chair.  Accrual reports are generated weekly, and formal toxicity reports are 
generated every 6 months.  In addition, the Statistical Center, Adverse Event Chair at the 
Operations Office, SAE Physician Reviewer, and Study Chair monitor toxicities on an 
ongoing basis. 
 
 
12.0 
DISCIPLINE REVIEW 
 
This study will not utilize discipline review. 
 
 
13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Patients must be registered prior to initiation of treatment (no more than eight working 
days prior to planned start of treatment).  If enrolling a patient onto the Phase I portion, 
sites must order S1221 PK kit immediately after registration (see Section 18.6).  The 
SWOG patient ID number must be provided on the S1221 PK Kit Request Form. Allow up 
to five working days for the PK kit to arrive.  
 
13.2 
Slot Reservation 
 
Patients planning to enroll on this study must first have a slot reserved in advance of the 
registration, even if the site plans to enroll right away.  All site staff will use OPEN to 
create a slot reservation. OPEN is a web-based application and can be accessed at 
https://open.ctsu.org, or from the OPEN tab on the CTSU members’ side of the website 
at https://www.ctsu.org, or from the OPEN Patient Registration link on the SWOG CRA 
Workbench. Please refer to the ‘Slot Reservation Quick Reference Site User Guide’ 
within the OPEN tab on the CTSU members’ website under ‘Training and Demonstration 
Materials’ for detailed instructions. 
 


 
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The individual making the slot reservation for the patient must be prepared to provide 
answers to the following questions: 
 
a.   
Institution CTEP ID 
 
b.   
Protocol Number 
 
c.   
Registration Step 
 
d.   
Patient Initials 
 
e.    
Patient’s Date of Birth 
 
f.   
ZIP Code 
 
g.   
Gender (select one): 
• 
Female Gender 
• 
Male Gender 
 
Slot reservations expire within 28 calendar days. A warning e-mail will be sent 48 hours 
before the expiration date. The reservation can be renewed any time before it expires as 
long as at least 1 slot is still available. After it expires, a new slot reservation must be 
created for the patient before they can be enrolled to this trial. Reservations may also be 
withdrawn at any time. If you withdraw a reservation, please notify the Statistical Center 
at melanomaquestion@crab.org. 
 
13.3 
OPEN Registration Requirements 
 
The individual registering the patient must have completed the appropriate SWOG 
Registration Worksheet.  The completed form must be referred to during the registration 
but should not be submitted as part of the patient data. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
 
b. 
Protocol Number 
 
c. 
Registration Step 
 
d. 
Treating Investigator 
 
e. 
Credit Investigator 
 
f. 
Patient Initials 
 
g. 
Patient’s Date of Birth 
 
h. 
Patient SSN (SSN is desired, but optional.  Do not enter invalid numbers.) 
 
i. 
Country of Residence 
 
j. 
ZIP Code 
 
k. 
Gender (select one): 
• 
Female Gender 
• 
Male Gender 


 
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l. 
Ethnicity (select one): 
• 
Hispanic or Latino 
• 
Not Hispanic or Latino 
• 
Unknown 
 
m. 
Method of Payment (select one): 
• 
Private Insurance 
• 
Medicare 
• 
Medicare and Private Insurance 
• 
Medicaid 
• 
Medicaid and Medicare 
• 
Military or Veterans Sponsored NOS 
• 
Military Sponsored (Including Champus & Tricare) 
• 
Veterans Sponsored 
• 
Self Pay (No Insurance) 
• 
No Means of Payment (No Insurance) 
• 
Other 
• 
Unknown 
 
n. 
Race (select all that apply): 
• 
American Indian or Alaska Native 
• 
Asian 
• 
Black or African American 
• 
Native Hawaiian or other Pacific Islander 
• 
White 
• 
Unknown 
 
13.4 
Registration Procedures 
 
a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is a web-based 
application and can be accessed at https://open.ctsu.org, or from the OPEN tab 
on the CTSU members’ side of the website at https://www.ctsu.org, or from the 
OPEN Patient Registration link on the SWOG CRA Workbench. 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
• 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff 
should refer to Section 5.0 to verify eligibility. 
 
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
Access requirements for OPEN: 
 
• 
Site staff will need to be registered with CTEP and have a valid and active 
CTEP-IAM account.  This is the same account (user ID and password) used 
for the CTSU members' web site. 
 
• 
To perform registrations on SWOG protocols you must have an equivalent 
'Registrar' role on the SWOG roster.  Role assignments are handled through 
SWOG. 
 
Note:  The OPEN system will provide the site with a printable confirmation of 
registration and treatment information.  Please print this confirmation for your 
records. 


 
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d. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org.  
For any additional questions contact the CTSU Help Desk at 1-888-823-5923 or 
ctsucontact@westat.com. 
 
13.5 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients 
registered, whether or not assigned treatment is administered, including patients deemed 
to be ineligible.  Patients for whom documentation is inadequate to determine eligibility 
will generally be deemed ineligible. 
 
14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the SWOG website 
(www.swog.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see Section 14.3a for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Data Collection  
 
Data collection for this study will be done exclusively through the Medidata Rave 
clinical data management system.  Access to the trial in Rave is granted through 
the iMedidata application to all persons with the appropriate roles assigned in 
Regulatory Support System (RSS).  To access Rave via iMedidata, the site user 
must have an active CTEP-IAM account (check at < https://eapps-
ctep.nci.nih.gov/iam/index.jsp >) and the appropriate Rave role (Rave CRA, 
Read-Only, Site Investigator) on either the LPO or participating organization 
roster at the enrolling site. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave 
roles assigned on the appropriate roster will be sent a study invitation e-mail from 
iMedidata.  To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM user name and 
password, and click on the “accept” link in the upper right-corner of the iMedidata 
page.  Please note, site users will not be able to access the study in Rave until all 
required Medidata and study specific trainings are completed.  Trainings will be 
in the form of electronic learnings (eLearnings), and can be accessed by clicking 
on the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time 
of initial site registration approval for the study in RSS will also receive a 


 
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 separate invitation from iMedidata to activate their account.  Account activation 
instructions are located on the CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study Invitation Acceptance).  
Additional information on iMedidata/Rave is available on the CTSU members’ 
website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU 
Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com.  
 
b. 
You may also access Rave® via the SWOG CRA Workbench.  Go to the SWOG 
web site (http://swog.org) and logon to the Members Area using your SWOG 
Roster ID Number and password. After you have logged on, click on 
Workbenches, then CRA Workbench to access the home page for the CRA 
Workbench and follow the link to Rave® provided in the left-hand navigation 
panel. 
 
To access the CRA Workbench the following must be done (in order): 
 
1. 
You are entered into the SWOG Roster and issued a SWOG Roster ID 
Number, 
2. 
You are associated as an investigator or CRA/RN at the institution where 
the patient is being treated or followed, 
 
3. 
Your Web User Administrator has added you as a web user and has 
given you the appropriate system permissions to view data for that 
institution. 
 
For assistance with points 1 and 2 call the Operations Office at 210/614-8808.  
For point 3, contact your local Web User Administrator (refer to the "Who is my 
Web User Administrator?" function on the swog.org Members logon page). 
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
14.4 
Data Submission Overview and Timepoints 
 
a. 
WITHIN 7 DAYS OF REGISTRATION FOR ALL PATIENTS SUBMIT: 
 
S1221 Onstudy Form 
 
Baseline Tumor Assessment Form (RECIST 1.1) 
 
S1221 Baseline Abnormalities Form 
 
Radiology reports from all scans performed to assess disease at baseline 
 
Pathology report from a CLIA certified lab documenting BRAF mutation status 
 
ALSO SUBMIT WITHIN 7 DAYS OF REGISTRATION FOR PATIENTS 
ENROLLED ON THE PHASE II PORTION: 
 
Pathology report documenting histologic confirmation of malignant melanoma. 


 
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b. 
SUBMIT WITHIN 14 DAYS AFTER REGISTRATION: 
 
Pre-study specimens as outlined in Section 15.4. 
 
c. 
WITHIN 7 DAYS AFTER COMPLETION OF EVERY CYCLE (1 CYCLE = 28 
DAYS), SUBMIT: 
 
S1221 Treatment Form  
 
S1221 Adverse Event Form (Submit every 14 days during Cycles 1 and 2 of 
Phase I Portion, see Section 15.1 for Rapid Reporting requirements): 
 
d. 
WITHIN 7 DAYS AFTER EVERY TUMOR ASSESSMENT (INCLUDING BOTH 
ON 
TREATMENT 
AND 
OFF 
TREATMENT 
PRIOR 
TO 
DISEASE 
PROGRESSION) (see Section 9.0 for Disease Assessment Schedule) SUBMIT: 
 
Follow-Up Tumor Assessment Form 
 
Radiology reports from all scans performed to assess disease.  Physician must 
note tumor measurement in patient records. 
 
e. 
WITHIN 14 DAYS OF PROGRESSION SUBMIT: 
 
NOTE: 
 
IF 
PATIENT 
REMAINS 
ON 
TREATMENT 
FOLLOWING 
PROGRESSION (SEE SECTION 7.9a, CONTINUE TO SUBMIT THE S1221 
ADVERSE EVENT FORM AND S1221 TREATMENT FORM AFTER EVERY 
CYCLE OF TREATMENT AS OUTLINED IN SECTION 14.4c). 
 
Follow-Up Tumor Assessment Form (RECIST 1.1) 
 
Radiology reports from all scans performed to assess disease. Physician must 
note tumor measurement in patient records. 
 
S1221 Treatment Form and S1221 Adverse Event Form (if the patient was still 
on protocol treatment) or  
 
Follow-Up Form (if patient was off treatment) documenting date, site and method 
for determining progression. 
 
f. 
WITHIN 14 DAYS OF DISCONTINUATION OF TREATMENT SUBMIT: 
 
Off Treatment Notice 
 
S1221 Treatment Form 
 
S1221 Adverse Event Form. 
 
g. 
AFTER OFF TREATMENT, SUBMIT EVERY 3 MONTHS FOR 1 YEAR AND 6 
MONTHS UP TO 3 YEARS FROM DATE OF REGISTRATION: 
 
Follow-Up Form 
 
Late Effects Form (if prior to treatment for progression or relapse or a second 
primary, and prior to non-protocol treatment, the patient experiences any severe 
[Grade ≥ 3] long term toxicity that has not been previously reported). 


 
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h. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH SUBMIT:  
 
Notice of Death and all of the items listed in Section 14.4f (if the patient was 
still on protocol treatment) or Follow-Up Form (if the patient was off protocol 
treatment) documenting death information. 
 
 
15.0 
SPECIAL INSTRUCTIONS 
 
15.1 
Phase I Portion:  Rapid Reporting 
 
RAPID REPORTING OF TREATMENT-RELATED DOSE-LIMITING TOXICITIES FOR 
PHASE I PORTION OF TRIAL 
 
Participation in the Phase I Portion of the trial requires that Adverse Events be reported 
every 14 days for patients who have initiated treatment. 
 
Institutional participation in the Phase I Portion of the trial requires the identification of a 
contact CRA and back-up CRA.  Prior to registration of the first patient, each 
institution must provide the contact and back-up CRA names, e-mail addresses, 
and phone numbers to the SWOG Data Operations Center.  Institutions will be 
responsible for keeping this information up-to-date and must notify the study Data 
Coordinator (Jennie Barrett; jennieb@crab.org; 206/652-2267) of any changes. 
 
The contact CRA and back-up CRA will receive weekly e-mails including a list of the 
Adverse Event and Treatment forms that are overdue, currently due, or due in the next 
week.  These e-mails will include a reply-to address and phone number to contact the 
Data Operations Center when questions arise. 
 
15.2 
Phase I Portion:  Mandatory Conference Calls 
 
A mandatory conference call for study teams with active patients will take place twice a 
month.  The call will update participants on the current status of the trial and will include 
representatives from the study team, investigators from all participating institutions and 
representatives from GSK.  At this time any serious toxicities encountered will be discussed 
and appropriate action taken.  In between these regularly scheduled conference calls, 
investigators will be informed of important study decisions via e-mail. 
 
15.3 
Phase I Portion:  Mandatory Pharmacokinetic (PK) Sampling  
 
a 
Pharmacokinetic (PK) kits will not be provided for this submission; sites will use 
institutional supplies.  NOTE: Kits are no longer being supplied by the SWOG 
Biospecimen Repository. 
 
b. 
In all Phase I Portion patients PK sampling will be obtained at baseline, pre-dose 
Day 15, and pre-dose Day 29. 
 
At each time point, collect 3 mL whole blood PK sample into a properly labeled 2 mL 
K2EDTA evacuated blood collection tube. Record the date and time each sample is 
collected. 
 
Immediately after collection, gently invert (DO NOT SHAKE) the evacuated blood 
collection tube 8-10 times to mix the K2EDTA anticoagulant with the whole blood, 
 blood samples should remain at room temperature prior to centrifugation and 
should be processed within 30 minutes of collection. Centrifuge the sample at 2500 
to 3000 rpm for 10 to 15 minutes at room temperature to achieve a clear plasma 
layer over the red cells. The speed and time may be varied according to the make 
and model of centrifuge used.  Immediately transfer plasma into two (2)  


 
 
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corresponding pre-labeled 1.8 mL NUNC tubes (each containing approximately 
0.75 mL of plasma) and store at - 20°C until shipped.  The Covance Bioanalytical 
study number for S1221 is 8290125.  The GSK study number is BRA117182.  
Please include either the GSK or Covance study number along with the SWOG 
protocol number in all correspondence. 
 
PK samples will be shipped to: 
 
Lab #207: 
Covance BioanalyticalLaboratory Services Inc.  
Sample Management-bioanalytical (Rm 131D 1S) 
3301 Kinsman Boulevard 
Madison, WI 53704 -2523  
Attn: Principal Investigator: John banach  
Tel 608/310-2939 
E-mail: John.Banach@covance.com 
 
Covance require an electronic manifest to be sent with each PK shipment. By 
logging your shipment in the SWOG Specimen Tracking system, an electronic 
manifest will be automatically emailed to Covance for you. 
 
c.   
During each of the Phase I portions (D+G and D+T+G) a more intense PK 
sampling schedule will be followed for three patients of cohort 2, or as an 
extension to cohort 1 if it is identified as the MTD, (and additional ones if 
needed to further define potential drug-drug interactions).  These patients will 
have PK sampling at baseline, pre-dose and +1, +2, +4, +8 hours on Day 15, 
and pre-dose Day 29.  
 
15.4 
Phase I & II Portions:  Mandatory Specimen Submission for Translational Medicine 
 
Specimens for Translational Medicine Studies and Banking submitted to the SWOG 
Specimen Repository – Solid Tissue, Myeloma and Lymphoma Division, Lab #201 
(required for patients): 
 
a. 
Specimens must be submitted at the following times (see Section 9.0): 
 
1. 
Submit entire block of paraffin-embedded tissue (and if available entire 
fresh-frozen tumor) or 20 unstained slides (if site cannot send tissue 
block) at baseline, at anytime during Days 15-28 of Cycle 1 (optional), 
and at time of progression. 
 
2. 
Submit four separate purple-top EDTA tubes each containing four ml of 
whole blood at baseline, prior to the start of Cycle 3 and at time of 
progression.  Follow guidelines on the SWOG Specimen Webpage for 
collecting, processing and shipping buffy coat and plasma specimens.  
Batch ship frozen plasma and buffy coat specimens to the SWOG 
Specimen Repository. 
 
b. 
Specimen collection and submission instructions can be accessed on the SWOG 
Specimen Submission webpage  
 
(http://swog.org/Members/ClinicalTrials/Specimens/STSpecimens.asp),  
or via the link on the S1221 protocol abstract page on the SWOG website 
(www.swog.org). 
 
c. 
Avoid refrigerated storage overnight before liquid nitrogen immersions; instead 
the tissue must be completely immersed in RNALater and then liquid nitrogen 
immediately after biopsy and must be maintained cryopreserved.  The specimens 
must be shipped in dry ice. 
 
d. 
Specimen collection kits are not being provided for this submission; sites will 
use institutional supplies. 


 
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16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent 
 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
 
This study must be approved by an appropriate institutional review committee as defined by 
Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) 
and the Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code 
of Federal Regulations 45 CFR 46). 
 
Drug Accountability 
 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
 
The agents supplied by CTEP, DCTD, NCI used in this protocol are provided to the NCI under a 
Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical Company 
(hereinafter referred to as “Collaborator”) 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 in this study: 
 
1. 
Agent may not be used for any purpose outside the scope of this protocol, nor can Agent 
be transferred or licensed to any party not participating in the clinical study.  Collaborator 
data for Agent are confidential and proprietary to the Collaborator and shall be 
maintained as such by the investigators.  The protocol documents for studies utilizing 
Agents contain confidential information and should not be shared or distributed without  
the permission of the NCI.  If a copy of this protocol is requested by a patient or patient’s 
family member participating on the study, the individual should sign a confidentiality 
agreement. A suitable model agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination with 
another investigational Agent, 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. 


 
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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 CFR 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 the 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 the 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 the Collaborator(s) 
intellectual property rights, are protected.  Copies of abstracts must be provided to CTEP 
for forwarding to the Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings.  Press releases and other 
media presentation must also be forwarded to CTEP prior to release.  Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
E-mail:  ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No publication, 
manuscript or other form of public disclosure shall contain any of the Collaborator's 
confidential/proprietary information. 
 
Monitoring 
 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  
Cumulative CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are 
due January 31, April 30, July 31 and October 31. 


 
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Confidentiality 
 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
16.1 
Adverse Event Reporting Requirements 
 
a. 
Purpose 
 
Adverse event data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as 
well as those who will enroll in future studies using similar agents. Adverse 
events are reported in a routine manner at scheduled times during a trial. 
(Directions for routine reporting are provided in Section 14.0.) Additionally, 
certain adverse events must be reported in an expedited manner to allow for 
more timely monitoring of patient safety and care. The following guidelines 
prescribe expedited adverse event reporting for this protocol. See also Appendix 
18.1 for general and background information about expedited reporting. 
 
b. 
Reporting method 
 
This study requires that expedited adverse events be reported using the Cancer 
Therapy Evaluation Program (CTEP) Adverse Event Reporting System (CTEP-
AERS). 
CTEP’s 
guidelines 
for 
CTEP-AERS 
can 
be 
found 
at 
http://ctep.cancer.gov.  A CTEP-AERS report must be submitted to the SWOG 
Operations office electronically via the CTEP-AERS web-based application 
located at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.
htm 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 16.1) via CTEP-
AERS.  
 
When the adverse event requires expedited reporting, submit the report within 
the number of calendar days of learning of the event specified in Table 16.1. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection.   
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
d. 
Other recipients of adverse event reports 
 
The SWOG Operations Office will forward reports and documentation to the 
appropriate regulatory agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 


 
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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 16.1.  The investigational agent(s) used in Phase I and Phase II of this study 
are dabrafenib and GSK2141795 If there is any question about the reportability of 
an adverse event or if on-line CTEP-AERS cannot be used, please telephone or 
email the SAE Specialist at the Operations Office, 210/614-8808 or adr@swog.org, 
before preparing the report. 


 
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Table 16.1 Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1  Dabrafenib, Trametinib, and GSK2141795 (Phase I and Phase II) 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 
312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization       
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization       
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR or Section 
16.1f. 
 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
 
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
May 5, 2011 


 
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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Phase I and Early Phase II Studies Utilizing an Agent under 
a CTEP IND: 
 
Group-specific instructions:  Submission of the on-line CTEP-AERS report 
plus any necessary amendments generally completes the reporting 
requirements In addition, you may be asked to submit supporting clinical data 
to the SWOG Operations Offices in order to complete the evaluation of the 
event.  If requested, the supporting data should be sent within 5 calendar 
days by fax to 210-614-0006.  Supporting clinical data submitted should 
include: 
 
• 
Printed copy of the first page of the CTEP-AERS Report. 
• 
Copies of clinical source documentation of the event. 
• 
If applicable, and they have not yet been submitted to the SWOG Data 
Operations Center copies of Off Treatment Notice and/or Notice of Death. 
g. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a 
previous 
malignancy 
(e.g., 
treatment 
with 
investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
 
CTEP requires all secondary malignancies that occur following 
treatment with an agent under an NCI IND to 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. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/d
ocs/aeguidelines.pdf. 
 
2. 
Supporting documentation should be submitted to CTEP in 
accordance with instructions provided by the CTEP-AERS system.  A 
copy of the report and the following supporting documentation must 
also be submitted to SWOG Operations Office within 30 days: 
 
• 
a copy of the pathology report confirming the AML/ALL /MDS 
diagnosis 
• 
(if available) a copy of the cytogenetics report   
 
SWOG 
ATTN: SAE Program 
4201 Medical Drive, Suite 250 
San Antonio, Texas 78229 
 
NOTE: If a patient has been enrolled in more than one NCI-
sponsored study, the report must be submitted for the most recent 
trial.


 
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h.  
Reporting Pregnancy, Fetal Death, and Death Neonatal 
 
1. 
Pregnancy Study participants who become pregnant while on study; that 
pregnancy should be reported in an expedited manner via CTEP-AERS 
as Grade 3 “Pregnancy, puerperium and perinatal conditions – 
Other (pregnancy)” under the Pregnancy, puerperium and perinatal 
conditions SOC.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Fetal Death Fetal Death defined in CTCAE as “A disorder characterized 
by death in utero; failure of the product of conception to show evidence 
of respiration, heartbeat, or definite movement of a voluntary muscle 
after expulsion from the uterus, without possibility of resuscitation” 
should be reported expeditiously as Grade 4 “pregnancy, puerperium 
and perinatal conditions – Other (pregnancy loss)” under the 
Pregnancy, puerperium and perinatal conditions SOC.   
 
3. 
Death Neonatal  Neonatal death, defined in CTCAE as “A disorder 
characterized by cessation of life occurring during the first 28 days of life” 
that is felt by the investigator to be at least possibly due to the 
investigational agent/intervention should be reported expeditiously.   
 
A neonatal death should be reported expeditiously as Grade 4 “General 
disorders and administration – Other (neonatal loss)” under the 
General disorders and administration SOC. 
 
Fetal death and neonatal death should NOT be reported as a Grade 5 event.  If 
reported as such, the CTEP-AERS interprets this as a death of the patient being 
treated. 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed 
and faxed with any additional medical information to 301-230-0159.  The 
potential risk of exposure of the fetus to the investigational agent(s) or 
chemotherapy agent(s) should be documented in the “Description of Event” 
section of the CTEP-AERS report. 
 
The Pregnancy Information Form is available at: 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm    
 
 
 


 
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17.0 
BIBLIOGRAPHY 
 
1. 
Flaherty, K. T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. 
Med. 363, 809–819, 2010. 
 
2. 
Sosman, J. A. et al. Survival in BRAF V600-mutant advanced melanoma treated with 
vemurafenib. N. Engl. J. Med. 366, 707–714, 2012. 
 
3. 
Chapman, P. B. et al. Improved survival with vemurafenib in melanoma with BRAF V600E 
mutation. N. Engl. J. Med. 364, 2507–2516, 2011. 
 
4. 
Hauschild, A. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, 
phase 3 randomised controlled trial. Lancet 380, 358–365, 2012. 
 
5. 
Falchook, G. S. et al. Dabrafenib in patients with melanoma, untreated brain metastases, and 
other solid tumours: a phase 1 dose-escalation trial. Lancet 379, 1893–1901, 2012. 
 
6. 
Long, G. V. et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma 
metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 13, 
1087–1095,2012. 
 
7. 
Bollag, G. et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant 
melanoma. Nature 467, 596–599, 2010. 
 
8. 
Gorre, M. E. et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene 
mutation or amplification. Science 293, 876–880, 2001. 
 
9. 
Pao, W. et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated 
with a second mutation in the EGFR kinase domain. PLoS Med. 2, e73, 2005. 
 
10. 
Shi, H. et al. Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-
mediated acquired B-RAF inhibitor resistance. Nat. Commun. 3, 724, 2012. 
 
11. 
Poulikakos, P. I. et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced 
BRAF(V600E). Nature 480, 387–390, 2011. 
 
12. 
Nazarian, R. et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS 
upregulation. Nature 468, 973–977, 2010. 
 
13. 
Wagle, N. et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor 
genomic profiling. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 29, 3085–3096, 2011. 
 
14. 
Shi, H. et al. Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer 
resistance to BRAF inhibitors. Cancer Discov. 2, 414–424, 2012. 
 
15. 
Johannessen, C. M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway 
reactivation. Nature 468, 968–972, 2010. 
 
16. 
Shi, H. et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor 
therapy. Cancer Discov. 4, 80–93, 2014. 
 
17. 
Flaherty, K. T. et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 
mutations. N. Engl. J. Med. 367, 1694–1703, 2012. 


 
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18. 
Long, G. V. et al. COMBI-d: A randomized, double-blinded, Phase III study comparing the 
combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line 
therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive 
cutaneous melanoma. J. Clin. Oncol. 32:5s, 2014. 
 
19. 
Shi, H., Kong, X., Ribas, A. & Lo, R. S. Combinatorial treatments that overcome PDGFRβ-driven 
resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 71, 5067–5074, 2011. 
 
20. 
Villanueva, J. et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in 
melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18, 683–695, 
2010. 
 
21. 
Wilson, Fridly, Yan et al. Widespread potential for growth-factor-driven resistance to anticancer kinase 
inhibitors.  Nature 26;487(7408):505-9, 2012. 
 
22. 
Straussman, Morikawa, Shee, et al. Tumor microenvironment contributes to RAF-inhibitor 
resistance through HGF secretion. Nature 26;487(7408):500-4, 2012. 
 
23. 
Jiang, C. C. et al. MEK-independent survival of B-RAFV600E melanoma cells selected for 
resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin. Cancer Res. Off. J. Am. 
Assoc. Cancer Res. 17, 721–730, 2011. 
 
24. 
Atefi, M. et al. Reversing melanoma cross-resistance to BRAF and MEK inhibitors by co-targeting 
the AKT/mTOR pathway. PloS One 6, e28973, 2011. 
 
25. 
Paraiso, K. H. T. et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through 
the suppression of BIM expression. Cancer Res. 71, 2750–2760, 2011. 
 
26. 
Kurzrock, R. et al. Phase I dose-escalation of the oral MEK1/2 inhibitor GSK1120212 (GSK212) 
dosed in combination with the oral AKT inhibitor GSK2141795 (GSK795). J. Clin. Oncol. 29: 2011 
(suppl; abstr 3085), 2011. 
 
27. 
Sosman, J. A. et al. BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor 
(MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive 
metastatic melanoma (MM). J. Clin. Oncol. 31, 2013. 
 
28. 
Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with 
BRAF inhibitors. N. Engl. J. Med. 366, 207–215, 2012. 
 
29. 
Søndergaard, J. N. et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation 
to the specific Raf inhibitor PLX4032. J. Transl. Med. 8, 39, 2010. 
 
30. 
Lo, R. S. Combinatorial therapies to overcome B-RAF inhibitor resistance in melanomas. 
Pharmacogenomics 13, 125–128, 2012. 
 


 
 
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18.0 
APPENDIX 
 
18.1 
Determination of Expedited Adverse Event Reporting Requirements  
 
18.2 
Translational Medicine  
 
18.3 
Intake Calendar 
 
18.4 
Strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, Bcrp and possibly 2C8/9 and 2C19 
 
18.5 
New York Heart Association Classifications 
 
18.6 
Information on Possible Drug Interactions 
 
18.7 
Patient Information – Wallet Card 
 
18.8 
Instructions for Patients for Storage of Trametinib Tablets 
 


 
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18.1 
Determination of Expedited Adverse Event Reporting Requirements 
 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies as well as those who 
will enroll in future studies using similar agents. Adverse events are reported in a routine 
manner at scheduled times during a trial. (Directions for routine reporting are provided in 
Section 14.0.) Additionally, certain adverse events must be reported in an expedited 
manner to allow for more timely monitoring of patient safety and care. Expedited adverse 
event reporting principles and general guidelines follow; specific guidelines for expedited 
adverse event reporting on this protocol are found in Section 16.1. 
 
All serious adverse events determined to be reportable to the Institutional Review Board 
responsible for the oversight of the patient must be reported according to local policy and 
procedures.  Documentation of this reporting should be maintained for possible 
inspection during quality assurance audits. 
 
Steps to determine if an adverse event is to be reported in an expedited manner 
(This includes all events that occur while on treatment or within 30 days of the last dose 
of protocol treatment.) 
 
Step 1: Determine whether the patient has received an investigational agent, commercial 
agent, or a combination of investigational and commercial agents. 
 
An investigational agent is a protocol drug administered under an Investigational New 
Drug Submission (IND). In some instances, the investigational agent may be available 
commercially, but is actually being tested for indications not included in the approved 
package label.  
 
Commercial agents are those agents not provided under an IND but obtained instead 
from a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules 
apply.   
 
• 
Concurrent administration: When an investigational agent(s) is used in 
combination with a commercial agent(s), the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration:   When a study includes an investigational agent(s) 
and a commercial agent(s) on the same study arm with sequential administration 
all expedited reporting of adverse events should follow the guidelines for the type 
of agent being given.  For example, if the patient begins the study on the 
investigational agent(s), then all expedited reporting of adverse events should 
follow guidelines for the investigational agent(s).  Once the patient begins 
receiving the commercial agent(s) then all expedited reporting of adverse events 
should follow the guidelines for commercial agent(s).   
 
Step 2: Identify the type of event using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE). The CTCAE provides descriptive terminology and a grading 
scale for each adverse event listed. A copy of the CTCAE can be downloaded from the 
CTEP home page (http://ctep.cancer.gov). Additionally, if assistance is needed, the NCI 
has an Index to the CTCAE that provides help for classifying and locating terms.  
 
Step 3:  Grade the event using the NCI CTCAE version specified in the protocol for 
reporting serious adverse events. 


 
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Step 4: Determine if the adverse event is Expected or an Exception to Expedited 
Reporting.  Expected events are those that have been previously identified as resulting 
from administration of the agent and are listed in one of the following:   
 
• 
The current NCI SPEER (Specific Protocol Exceptions to Expedited Reporting) 
for treatments using agents provided under an NCI-held IND, or an equivalent 
listing for treatments using agents provided under a Non-CTEP-held IND; located 
in Section 3.0 of the protocol. 
• 
For treatments using commercial agents, the current CAEPR (Comprehensive 
Adverse Event and Potential Risks), ASAEL (Agent Specific Adverse Event List), 
or other list of expected toxicities located in Section 3.0 of the protocol, or the 
drug package insert.   
• 
Exception to Expedited reporting located in Section 16.1f of the protocol. 
 
An adverse event is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in one of the areas 
outlined above. 
 
Step 5:  Determine whether the adverse event involved hospitalization or a prolongation 
of hospitalization (≥ 24 hours). 
 
Step 6:  Additionally, for commercial drugs, determine whether the adverse event is 
related to the protocol therapy. Attribution categories are as follows: Unrelated, Unlikely, 
Possible, Probable, and Definite.  Consult the appropriate table for expedited reporting 
criteria for commercial agent(s). 
 
NOTE:   Any event that occurs more than 30 days after the last dose of study agent and 
is attributed (possible, probable, or definite) to the study agent(s) must be reported 
according to the instructions above and as outlined in the appropriate table in Section 
16.1. 


 
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18.2 
Translational Medicine 
 
Pre-study (after failing frontline BRAF inhibitor therapy) blood and tissue specimens will 
be required. Blood and tissue specimens will be requested from two other time points: 1) 
prior to starting first line BRAF inhibitor therapy (initial diagnosis) and 2) at the time of 
progression on this study.   
 
Studies will be done in blood, formalin-fixed paraffin embedded (FFPE) tissues, and if 
available in fresh cryopreserved tissues. 
 
From FFPE the following studies will be done: 
-       NRAS, MEK1/2, PI3K and AKT1 mutations by Sanger sequencing 
-       Mutant BRAF amplification by genomic DNA (gDNA) Q-PCR 
-       pERK and pAKT by IHC 
-       PDGFRβ, EGFR, cKIT, cMET by IHC 
-       HGF by IHC 
 
From blood, the following studies will be done: 
-       Growth factor (HGF) levels 
-       Extraction of gDNA for validation of somatic alterations in collected tumors 
 
From fresh frozen tissue (when available), the following studies will be done: 
-       NRAS, MEK1/2, PI3K and AKT1 mutations by Sanger sequencing (if available and if 
any assay above fails or the results of which is equivocal) 
-       Mutant BRAF amplification by genomic DNA (gDNA) Q-PCR (if available and if any 
assay above fails or the results of which is equivocal) 
-       Mutant BRAF truncation by cDNA Q-PCR 
-       RTK (PDGFRβ, EGFR, cKIT, cMET) by cDNA Q-PCR 
 
Phosphorylation of receptor tyrosine kinases (RTKs) may be analyzed by a reverse 
phase protein array assay. 
 
In cases a fresh tissue sample of sufficient size is available, whole-exome sequencing 
and RNA-Seq will be attempted, with parallel testing of peripheral blood cells.  Fresh 
tissues cryoperserved in RNALater are expected to provide more reliable cDNA Q-PCR 
assay performance.  Highly pigmented tissues will be processed by an established 
protocol to reduce melanin in gDNA and RNA/cDNA during sample processing. 
 
 
 
 
 
 


 
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18.3 
Intake Calendar 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sunday 
Monday 
Tuesday 
Wednesday 
Thursday 
Friday 
Saturday 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient Signature:  
 
SWOG Patient ID________  Patient Initials (L, F, M) ________ SWOG Study #__________
 
 
 
Institution/Affiliate _______________________  Physician _____________________________ 
Instructions for the participant: 
 
This is a monthly calendar on which you are to record the number of tablets/pills/capsules you 
take each day.  Be sure you have enough calendars to last until your next appointment.  If you 
develop any side effects from the tablets/pills/capsules, mark this on the calendar on the day 
you note the effect.  Bring your calendars with you each time you have an appointment. 
 
If you have questions contact: ____________________ Telephone: _____________________ 
 
Your next appointment is: _______________________ 
Special instructions: 
 
Month: 
 
Year: 
 


 
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18.4 
Strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, Bcrp and possibly 2C8/9 and 2C19 
 
Prohibited Medications 
 
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be 
decreased 
Class/Therapeutic 
Area 
Drugs/Agents 
Antibiotics 
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin  
Miscellaneous 
bosentan, St. John’s wort 
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may 
be increased 
Class/Therapeutic 
Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  
 
The following medications should be used with caution as their concentrations may be altered by 
dabrafenib or they may alter dabrafenib concentrations: 
• 
Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may alter 
concentrations of dabrafenib. 
• 
Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using midazolam  
(CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  Dabrafenib is an in vitro 
inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, UDP-glucuronyl 
transferases, and transporters may also be affected.  Co-administration of dabrafenib and 
medications which are affected by the induction of these enzymes (including warfarin) 
and transporters may result in loss of efficacy.  If co-administration of these medications 
is necessary, investigators should monitor subjects for loss of efficacy or consider 
substitutions of these medications. A partial list of these medications is provided in Table 
1 and in the SPM. 
• 
Dabrafenib solubility is pH-dependent with decreased solubility at higher pH.  Drugs such 
as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH may 
decrease the solubility of dabrafenib and reduce its bioavailability.  No clinical study has 
been conducted to evaluate the effect of pH on dabrafenib pharmacokinetics. In an ad-
hoc analysis, no differences in Cmax and AUC were noted between subjects who reported 
taking pH-elevating products relative to other subjects.  Due to the theoretical risk that 
pH-elevating agents may decrease oral bioavailability and exposure to dabrafenib, these 
medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib. 


 
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• 
A list of medications that should be used with caution are listed in the table below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 1 Medications to be used with Caution 
USE WITH CAUTION:  Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased 
Class/Therapeutic Area 
Moderate CYP3A and CYP2C8 Inhibitors 
Antiarrhythmics 
Diltiazem, verapamil 
Antibiotic 
Erythromycin 
Antifungal 
Fluconazole 
Miscellaneous 
Aprepitant 
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss 
of efficacy.  Monitor subjects for loss of efficacy or substitute with another medication. 
Class/Therapeutic Area 
CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19 Substrates 
that May be Affected by Induction  
Analgesics 
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, 
oxycodone 
Antiarrhythmics 
Disopyramide, dronedarone, mexiletine, propafenone, quinidine 
Antibiotics 
Chloramphenicol, doxycycline, erythromycin, moxifloxacin  
Anticoagulants/ Antiplatelets 
Cilostazole, warfarin 
Anticonvulsants 
Divalproex, lamotrigine, valproate, zonisamide 
Antidepressants and 
Antipsychotics 
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, 
mirtazapine, pimozide, quetiapine, trazodone, amitriptyline, 
clomipramine, imipramine 
Antidiabetics 
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, 
repaglinide, rosiglitazone 
Antifungals 
Caspofungin, fluconazole, terbinafine 
Antihistamines 
Astemizole, chlorpheniramine, ebastine 
Antihypertensives 
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil 
Antimigraine Agents 
Diergotamine, eletriptan, ergotamine 
Corticosteroids 
Dexamethasone, methylprednisolone, oral budesonide 
Erectile Dysfunction Agents 
Sildenafil, tadalafil, vardenafil 
HMG-CoA Reductase 
Inhibitors 
Atorvastatin, lovastatin, simvastatin 
Hypnotics and Sedatives 
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone 
Immunosuppressants 
Everolimus, sirolimus, tacrolimus 
Miscellaneous 
Aprepitant, cisapride, darifenacin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone 
Selective Aldosterone 
Blockers 
Eplerenone 
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used with 
caution when administered with dabrafenib.. 
pH altering agents 
dexlansoprazole. esomeprazole, famotidine, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, ranitidine 
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A. 


 
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* Therapeutic level dosing of warfarin can be used with approval by the medical monitor and close 
monitoring of PT/INR by the site.  Exposure may be decreased due to enzyme induction when on 
treatment, thus warfarin dosing may need to be adjusted based upon PT/INR.  Consequently, 
when discontinuing dabrafenib, warfarin exposure may be increased and thus close monitoring via 
PT/INR and warfarin dose adjustments must be made as clinically appropriate.  Prophylactic low 
dose warfarin may be given to maintain central catheter patency. 
 
Because the list of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/main-table/; 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.  Section 18.6 is a 
patient information sheet that can be used for this specific protocol and presented to the 
patient. 


 
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18.5 
New York Heart Association Classifications 
 
 
 
 
Need for 
Physical Ability 
 
Class 
Cardiac Symptoms 
Limitations 
Additional Rest* 
To Work** 
 
 
I 
None 
None 
None 
Full Time 
 
II 
Only moderate 
Slight 
Usually only slight 
Usually full time 
 
 
 
or occasional 
 
III 
Defined, with less 
Marked 
Usually moderate 
Usually part time 
 
than ordinary 
 
activity 
 
IV 
May be present 
Extreme 
Marked 
Unable to work 
 
even at rest, & any 
 
activity increases 
 
discomfort 
 
 
 
 
 
* 
To control or relieve symptoms, as determined by the patient, rather than as advised by 
the physician. 
 
** 
At accustomed occupation or usual tasks.  
 


 
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18.6 
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 agents dabrafenib, 
trametinib, and GSK2141795.  This clinical trial is sponsored by the National Cancer 
Institute.  This form is addressed to the patient, but includes important information for 
others who care for this patient.  
 
Drug Interactions: 
Dabrafenib, trametinib, and 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:  
 
Liver Enzyme Interactions: 
Dabrafenib, trametinib, and GSK2141795 interact with certain specific enzymes in your 
liver. 
 
• 
The enzymes in question are CYP450 3A4, 2C8, 2C9, 2C19, 2B6, P-gp, BCRP and 
OATP1B1. Dabrafenib, trametinib, and GSK2141795 levels are affected by some of 
these enzymes and can alter the levels of other medicines you take. 
 
• 
Dabrafenib, trametinib, and 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. 
 
• 
Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of one or more of the drugs, while substances that decrease the 
enzyme’s activity (“inhibitors”) could result in high levels of the drugs, increasing the 
chance of harmful side effects.  Dabrafenib mesylate should not be taken with any 
other drugs that are strong inducers or inhibitors of CYP 3A4 or 2C8.  Prohibited 
medications include azole antifungals, some antiepileptic drugs, some antibiotics 
and some immunosuppressants.  Please check with the study investigator before 
prescribing or dispensing strong inhibitors/inducers of CYP 3A4 or 2C8. 
Mild/moderate inhibitors/inducers should be used with caution. 
 


 
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• 
Dabrafenib mesylate is considered an inducer of CYP 3A4, 2B6 and possibly 2C8/9 
and 2C19, meaning that it can decrease the levels of other drugs that are processed 
by these enzymes.  This can lead to harmful side effects and/or reduce the 
effectiveness of those medications. 
 
• 
GSK2141795 is a moderate inhibitor of CYP 2C8 and 3A4.  Drugs that are 
substrates of these CYP 2C8 and 3A4 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 protein 
(BCRP).  It is also an inhibitor of BCRP and OATP1B1.  Administration of sensitive 
BCRP substrates should be prohibited, such as topotecan. 
 
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 prohibited medicines that are considered strong inducers/inhibitors or 
substrates of CYP 3A4, CYP, 2C8, P-gp, or BCRP. 
 
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 3 grams a day if 
you are an adult or 2.4 grams a day if you are older than 65 years of age. Read 
labels carefully! Acetaminophen is an ingredient in many medicines for pain, flu, and 
cold. 
 
Speak to your doctor about any medications you think may contain 
acetaminophen in order to find a dose that is safe for you. 
 
• 
If you take herbal medicine regularly: You should not take St. John’s wort while you 
are taking dabrafenib mesylate. 
 
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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18.7 
Information on Possible Drug Interactions – Patient Wallet Card 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG 
INTERACTIONS  
You are enrolled on a clinical trial using the 
experimental agents dabrafenib mesylate, 
trametinib DMSO, and GSK2141795.  This 
clinical trial is sponsored by the NCI. 
Dabrafenib mesylate 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. 
Dabrafenib mesylate interacts with a specific 
liver enzymes 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 prohibited 
medicines that are considered “strong 
inducers/inhibitors or substrates of CYP 
3A4 and 2C8.” 
 GSK2141795 is a moderate inhibitor of 
CYP 2C8 and 3A4. Drugs that are 
substrates of these CYP 2C8 and 3A4 
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. 
 
 Before prescribing new medicines, your 
regular prescribers should go to 
http://medicine.iupui.edu/clinpharm/ddis/ta
ble.aspxfor 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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18.8 
Instructions for Patients for Storage of Trametinib Tablets 
 
Patient Storage Instructions: 
 
- 
Study drug can be transported home in the bottle(s) that were dispensed to the 
patient at room temperature.  Avoid exposing the bottle(s) to prolonged temperature 
extremes (i.e. do not leave bottle(s) in a hot car while doing errands) 
 
- 
At home, store the study drug in the refrigerator, 2°C – 8°C (36°F - 46°F).  Do not 
freeze the bottles. 
 
- 
Keep the tablets in the original bottle(s).  Do not remove tablets from the bottle(s) and 
put them in a pill box or daily dispenser. 
 
- 
Keep desiccant cylinder in the bottles in order to keep tablets dry.