Conditions: Cervical Cancer
Keywords: Cervical Cancer Cervical Cervix
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 14
Healthy volunteers: no

Brief summary:
This research study is evaluating the combination of two drugs called GSK1120212 (trametinib) and GSK2141795 as a possible treatment for recurrent or persistent cervical cancer. Trametinib and GSK2141795 are drugs that may stop cancer cells from growing. Trametinib is a MEK inhibitor - it blocks a protein called MEK that is commonly overactive in tumor cells. GSK2141795 is an AKT inhibitor which blocks a pathway in cancer cells that is commonly overactive in tumor cells called the PI3kinase pathway. In this research study, the investigator is looking to see whether the combination of Trametinib and GSK2141795 is useful in treating recurrent and persistent cervical cancer.

Additionally, the investigator is looking to see if participants whose tumors contain a particular genetic make-up will have better response to combination trametinib and GSK2141795. Participants' tumors will be tested for mutations in genes which could make some cancers more susceptible to trametinib and GSK2141795.

Detailed description:
Before the research starts (screening): The participant will be asked to undergo some screening tests or procedures to find out if they can be in the research study. Many of these tests and procedures are likely to be part of regular cancer care and may be done even if it turns out that the participant does not take part in the research study. If the participant has had some of these tests or procedures recently, they may or may not have to be repeated.

* A medical history, which includes questions about the participant's health, current medications, and any allergies.
* Physical exam, including height and weight
* An eye exam, by an eye specialist
* Performance status, the investigator will ask the participant questions about how they are able to carry on with your usual activities.
* Vital signs, including blood pressure, pulse, body temperature and respiratory rate
* An assessment of the participant's tumor by CT (Computerized Tomography) scan or MRI (Magnetic Resonance Imaging), of their chest, stomach area, and pelvis.
* Blood tests (approximately 2-3 tablespoons) including hematology, chemistry, liver function, kidney function, blood sugar levels, blood clotting levels
* Electrocardiogram (EKG), a test to check the participant's heart's rhythm
* Echocardiogram (ECHO), a test to check the participant's heart's structure and function.
* Serum pregnancy test if the participant are capable of becoming pregnant

If the results of the above tests show that the participant is eligible to participate in the research study, the participant will begin the study treatment. If the participant does not meet the eligibility criteria, the participant will not be able to participate in this research study.

If these tests show that the participant is eligible to participate in the research study, the participant will begin the study treatment. If the participant does not meet the eligibility criteria, the participant will not be able to participate in this research study.

Additional research procedures to be performed at the time of screening:

\- Archival tumor testing: During this study, additional tests will be performed on a sample of the participant's original tumor that has been stored in your institution's tissue banks. These tests will be performed on tumor tissue samples from previous biopsies or surgeries for the participant's cancer. The research done on these samples will involve looking at DNA and proteins in the participant's cancer to see if researchers can learn more about the participant's type of cancer and understand how trametinib and GSK2141795 might work on their tumor. Testing of this sample will not require the participant to undergo any additional procedures.

TISSUE COLLECTIONS/OWNERSHIP: Participation in this protocol involves providing specimen(s) of the participant's tissue. Please know that if the investigator leaves the institution, the research and the tissue might remain at the DF/HCC or might be transferred to another institution.

* Additional Blood tests: Approximately 2 tablespoons of blood will be collected for research testing. This testing will involve looking at DNA and proteins in the participant's blood to compare them with those seen in their cancer. This will be drawn before the participant begin taking the study drug. These research sample collections are a required part of this research study. If the participant does not wish to undergo these procedures, the participant may not participate in this research study.
* Optional pre and post tumor biopsies: Before the participant begin receiving the study drug, your doctor will arrange for a procedure where your tumor will be biopsied. Your entire tumor or part of your tumor might be removed (excisional biopsy) or a small sample of the tumor might be removed using a needle (needle biopsy, fine needle aspirate) with guidance under radiographic studies. This will also occur before the participant begins treatment and between 2-4 weeks after treatment has started.

After the screening procedures confirm that the participant is eligible to participate in the research study:

Study Drugs:

If the participant decides to take part in this research study, the participant will be given a study drug diary for each treatment cycle. The participant will be asked to complete a drug diary to record when they took each dose or to give a reason if the participant did not take the study drugs. At the end of each cycle, the participant should return the pill bottles and all of the remaining pills prior to starting the next cycle. The participant will receive a new set of pills and new diary if the participant is to continue the next cycle.

Clinical Exams: During all cycles the participant will have a physical exam, and will be asked questions about their general health and specific questions about any problems that they might having and any medications the participant may be taking.

The participant can expect the following while they are a participant on this study.

At the beginning of each cycle (one cycle equals 28 days):

* Recording of any health problems, including side effects of the study drugs
* List of medications taken since the last visit
* Physical examination (including measurement of vital signs, such as blood pressure, breathing rate, heart rate, temperature and weight)
* Evaluation of the participant's performance status (the ability to carry on daily activities)
* Blood samples (approximately 2-3 tablespoons of blood will be taken) to evaluate the participant's blood counts, electrolytes, liver function, kidney function and blood sugar levels.
* EKG, a test to check the participant's heart's rhythm. This will be performed at the start on each cycle.

Once a week during the first cycle:

* The participant will be called by a member of the study team to record any health problems, including side effects from the study drugs and any changes in medications.
* Blood samples (approximately 1 teaspoon of blood will be taken) to evaluate their blood sugar levels. This can be done at a lab close to home. If the participant's doctor thinks that their blood sugars need further monitoring, the participant may have continued blood samples drawn to check their blood sugar weekly or daily past the first cycle.

Every 2 cycles:

* Blood samples (approximately 1 teaspoon of blood will be taken) to evaluate the participant's HgbA1C, a test that evaluates their blood sugar levels over a period of time. This can be done at a lab close to home.
* CT scan or MRI of your chest, stomach area, and pelvis to see if the participant's cancer is increasing, decreasing, or staying the same size. If the cancer is decreasing, the participant's doctor may schedule the participant for another CT scan in about one month to check it again.
* ECHO, a test to check the participant's heart's structure and function

At the end of the study:

* Recording of any health problems, including any side effects from the study drugs.
* List of medications taken since the last visit
* Physical examination (including measurement of the participant's vital signs, such as blood pressure, breathing rate, heart rate, temperature, and weight.)
* Evaluation of the participant's performance status (their ability to carry on daily activities).
* Blood samples (approximately 2-3 tablespoons of blood will be taken) to evaluate the participant's blood counts, electrolytes, liver function, kidney function, blood sugar level, and HgbA1C.

After the final dose of the study drug:

The investigator would like to keep track of the participant's medical condition for up to 3 years after the participant completes the study. The investigator would like to do this by calling the participant on the telephone or seeing the participant in clinic for evaluation of their status, disease and current therapy. Keeping in touch with the participant and checking their condition routinely helps us look at the long-term effects of the research study.

Arms:
arm 1: GSK1120212 (trametinib) 1.5 mg QD + GSK2141795 50 mg QD in 28 day cycles

Interventions: intervention 1: GSK1120212 (trametinib) intervention 2: GSK2141795
Intervention descriptions: intervention 1: Trametinib dose is 1.5 mg orally once per day intervention 2: The dose of GSK2141795 is 50 mg orally once per day

Protocol document:
Prot_SAP_000.pdf: 
DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
 
 
 
 
 
 
DF/HCC Protocol 13-334 
 
 
 
A Single Arm, Single Stage Phase II Trial of 
GSK1120212 and GSK2141795 in  
Persistent or Recurrent Cervical Cancer 
 
 
 
IND No.: 119567 
 
 
 
Principal Investigator: 
 
Ursula Matulonis, MD 
 
 
 
 
 Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
 
 
Protocol Amendment 2 
Date: July 11, 2017 
 
Previous Protocol Version: 
Original Protocol – August 23, 2013 
 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
ii 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
SUMMARY OF CHANGES 
 
DF/HCC Protocol # 13-334 
 
Current Protocol Version Date: July 11, 2017 
 
Previous Protocol Version Date: January 15, 2014 
 
Section 
Changes 
Pages 1-2 
Updates to participating sites and study team contact information. 
Appendix 
C 
Removal of Appendix C:  DF/HCC Multi-Center Data and Safety Monitoring 
Plan.  Removed because the trial never became a multi-center study. 
Appendix 
G 
OncoPanel information has been added to the protocol. 
 
APPENDIX G:   Laboratory Correlative Studies 
 
Mutational Analysis 
 
OncoPanel 
 
OncoPanel sequencing on archival specimens will be obtained from all 
patients where available.  OncoPanel is a targeted next generation 
sequencing panel selected based on clinical actionability in cancer that is 
designed for the detection of single-nucleotide variants, insertions and 
deletions, copy number alterations, and structural variants.  A validation 
study demonstrated that OncoPanel could successfully identify multiple 
types of genetic alterations, with a sensitivity of 98% for single-nucleotide 
variants, 84% for indels, 86% for copy number variants, and 74% for 
structural variants when compared to appropriate orthogonal detection 
methods, including single-gene assays, mass spectrometry-based genotyping, 
array comparative genomic hybridization, or fluorescence in situ 
hybridization (Garcia 2017).  Where OncoPanel sequencing has already been 
performed on patient samples through DF/HCC protocol 11-104, we will 
plan to access these results to conserve primary patient samples for 
additional analyses. 
 
N/A 
Administrative and editorial changes/updates throughout 
 
 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
PRINCIPAL INVESTIGATOR:  
Ursula Matulonis, MD 
Dana-Farber Cancer Institute 
450 Brookline Ave, YC1421 
Boston, MA 02215 
Phone: 617-632-2334  
Fax: 617-632-3479  
Email: ursula_matulonis@dfci.harvard.edu 
 
COORDINATING CENTER: 
Dana-Farber Cancer Institute 
450 Brookline Avenue 
Boston, MA 02215 
 
PARTICIPATING SITES: 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
 
TRANSLATIONAL INVESTIGATOR:  
Lewis Cantley, PhD 
Cornell Weill Medical College 
New York City, NY 
Email: lewis_cantley@cornell.edu 
 
STATISTICIAN: 
William Barry, PhD 
Dana-Farber Cancer Institute 
11058 Center for Life Sciences, 11007 
Boston, MA 02114 
Phone: 617-632-5134 
Email: bbarry@jimmy.harvard.edu 
 
STUDY COORDINATOR:  
Ariana Peralta 
Dana-Farber Cancer Institute 
450 Brookline Avenue, D117 
Boston, MA 02215 
Phone: 617-632-3743 
Fax:  617-582-7921 
Email:  aperalta2@partners.org 
 
 
 
 
 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
2 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
RESEARCH PROJECT MANAGER:  
Jennifer Curtis 
Dana-Farber Cancer Institute 
450 Brookline Avenue, D117 
Boston, MA 02215 
Phone: 617-582-7183 
Fax:  617-582-7921 
Email: jdcurtis@partners.org 
 
RESEARCH NURSE:  
Christin Whalen, RN 
Dana-Farber Cancer Institute 
450 Brookline Ave, D117 
Boston, MA 02215 
Phone: 617-582-7738  
Fax: 617-582-7921 
Email: christin_whalen@dfci.harvard.edu 
 
INVESTIGATIONAL AGENTS: 
GSK1120212 (IND #102,175)  
GSK2141795 (IND #104,527)
 
 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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This document is confidential. Do not disclose or use except as authorized. 
TABLE OF CONTENTS 
SCHEMA .............................................................................................................................................................. 6 
1. OBJECTIVES................................................................................................................................................ 7 
1.1 Study Design ............................................................................................................................................ 7 
1.2 Primary Objective .................................................................................................................................... 7 
1.3 Secondary Objectives ............................................................................................................................... 7 
2. BACKGROUND ............................................................................................................................................ 7 
2.1 Study Disease: Cervical Cancer .............................................................................................................. 7 
2.2 Investigational Agents: GSK1120212 and GSK2141795 ....................................................................... 9 
2.3 Rationale for This Study ....................................................................................................................... 21 
2.4 Correlative Studies Background ........................................................................................................... 22 
3. PARTICIPANT SELECTION ................................................................................................................... 23 
3.1 Inclusion Criteria .................................................................................................................................. 23 
3.2 Exclusion Criteria ................................................................................................................................. 25 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations ...................................... 27 
4. REGISTRATION PROCEDURES ........................................................................................................... 28 
4.1 General Guidelines for DF/HCC and DF/PCC Institutions ................................................................ 28 
4.2 Registration Process for DF/HCC and DF/PCC Institutions .............................................................. 28 
5. TREATMENT PLAN ................................................................................................................................. 30 
5.1 Pre-Treatment Criteria .......................................................................................................................... 30 
5.2 Agent Administration ............................................................................................................................ 31 
5.3 General Concomitant Medication and Supportive Care Guidelines ................................................... 32 
5.4 Duration of Therapy .............................................................................................................................. 38 
5.5 Duration of Follow Up .......................................................................................................................... 38 
6. EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS ............................... 39 
6.1 Anticipated Toxicities ............................................................................................................................ 39 
6.2 Toxicity Management ............................................................................................................................ 43 
6.3 Dose Modification and Dose Interruption ............................................................................................ 44 
6.4 Dose Adjustment/Stopping Safety Criteria for Other Clinically Significant Toxicities ...................... 59 
7. DRUG FORMULATION AND ADMINISTRATION ............................................................................. 61 
7.1 GSK1120212 (Trametinib) ..................................................................................................................... 61 
7.2 GSK2141795 .......................................................................................................................................... 63 
8. CORRELATIVE/SPECIAL STUDIES ..................................................................................................... 66 
8.1 Hypothesis ............................................................................................................................................. 66 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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8.2 Preliminary Data ................................................................................................................................... 66 
8.3 Study Design .......................................................................................................................................... 66 
8.4 Study Population ................................................................................................................................... 66 
8.5 Methodology .......................................................................................................................................... 66 
8.6 Analytic Plan ......................................................................................................................................... 67 
8.7 Specimen Requirements ........................................................................................................................ 67 
9. STUDY CALENDAR .................................................................................................................................. 69 
10. MEASUREMENT OF EFFECT ................................................................................................................ 72 
10.1 Antitumor Effect– Solid Tumors ......................................................................................................... 72 
10.2 Methods for Evaluation of Measurable Disease ................................................................................ 73 
10.3 Response Criteria ................................................................................................................................ 74 
11. ADVERSE EVENT REPORTING REQUIREMENTS .......................................................................... 78 
11.1 Definitions ........................................................................................................................................... 78 
11.2 Procedures for AE and SAE Recording and Reporting ..................................................................... 79 
11.3 Reporting Requirements ...................................................................................................................... 80 
11.4 Reporting to the Study Sponsor ........................................................................................................... 80 
11.5 Reporting to NCCN and GSK ............................................................................................................. 81 
11.6 Reporting to the Institutional Review Board (IRB) ............................................................................ 82 
11.7 Reporting to the Food and Drug Administration (FDA) ................................................................... 82 
11.8 Reporting to Hospital Risk Management............................................................................................ 83 
11.9 Monitoring of Adverse Events and Period of Observation ................................................................. 83 
12. DATA AND SAFETY MONITORING ..................................................................................................... 84 
12.1 Data Reporting .................................................................................................................................... 84 
12.2 Safety Meetings .................................................................................................................................... 84 
12.3 Monitoring ........................................................................................................................................... 85 
13. REGULATORY CONSIDERATIONS ..................................................................................................... 86 
13.1 Protocol Review and Amendments ...................................................................................................... 86 
13.2 Informed Consent ................................................................................................................................ 86 
13.3 Ethics ................................................................................................................................................... 86 
13.4 Study Documentation .......................................................................................................................... 87 
13.5 Records Retention ................................................................................................................................ 87 
13.6 Multi-center Guidelines ....................................................................................................................... 87 
14. STATISTICAL CONSIDERATIONS ....................................................................................................... 88 
14.1 Study Design/Endpoints ...................................................................................................................... 88 
14.2 Statistical Analysis ............................................................................................................................... 88 


DF/HCC Protocol # 13-334 
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14.3 Sample Size/Accrual Rate ................................................................................................................... 89 
14.4 Reporting and Exclusions ................................................................................................................... 89 
15. PUBLICATION PLAN ............................................................................................................................... 90 
16. REFERENCES ............................................................................................................................................ 91 
17. Appendices ................................................................................................................................................... 95 
APPENDIX A:  Performance Status Criteria .................................................................................................. 96 
APPENDIX B:  New York Heart Association Classification of Heart Failure ............................................. 97 
APPENDIX C:  Participant Drug Diaries for GSK1120212 (trametinib) and GSK2141795 ...................... 98 
PATIENT’S MEDICATION DIARY: GSK1120212 (trametinib) ................................................................. 99 
PATIENT’S MEDICATION DIARY: GSK2141795 .................................................................................... 100 
APPENDIX D:  List of Prohibited Medications ............................................................................................ 101 
APPENDIX E:  List of Cautionary Medications ........................................................................................... 102 
APPENDIX F:  CTCAE v 4.0 Grading of Visual Changes ........................................................................... 104 
APPENDIX G:   Laboratory Correlative Studies .......................................................................................... 105 
APPENDIX I:  Data Collection Forms ........................................................................................................... 109 
APPENDIX J:  PATIENT’S HOME GLUCOSE MONITORING DIARY ................................................ 110 
Appendix K: QT interval on ECG corrected using the Bazett’s formula (QTcB) ...................................... 111 
 
 


DF/HCC Protocol # 13-334 
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Protocol Version Date:  July 11, 2017 
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a:  
Pre- and post-treatment biopsies, as well as the post-progression biopsy, are optional. The 
pre-treatment biopsy will be performed prior to treatment. The post-treatment biopsy will 
be performed between 2-4 weeks after treatment initiation. The post-progression biopsy 
will be performed within 6 weeks of progression. 
 
b: 
Participants will be monitored for toxicity as dictated by CTCAE v4.0.  
 
c: 
From the CT results will be evaluated by RECIST 1.1 criteria. Scans will be performed 
every 2 cycles.  Participants with progressive disease will discontinue the trial. Participants 
with stable disease, partial or complete responses will continue on study and as long as 
toxicities are acceptable.  
 
d: 
Treatment will be discontinued as per Section 5.4, and patients will enter survival follow-
up as per Section 5.5. 
 
e: 
Treatment with GSK1120212 (trametinib) and GSK2141795 as per Section 5. 
SCHEMA 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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This document is confidential. Do not disclose or use except as authorized. 
1. 
OBJECTIVES 
 
1.1 
Study Design 
 
This is an open label, single-arm, single-stage, phase II multicenter trial. 
 
1.2 
Primary Objective 
 
To assess the activity of GSK1120212 (trametinib) and GSK2141795 in combination in 
patients with recurrent or persistent cervical cancer. Activity will be ascertained by 
estimation of best objective tumor response per RECIST version 1.1. 
  
1.3 
Secondary Objectives 
 
• To assess the duration of progression-free (PFS) and overall survival (OS) following 
initiation of therapy with GSK1120212 (trametinib) and GSK2141795  
 
• To determine the nature and degree of toxicity of GSK1120212 (trametinib) and 
GSK2141795 as assessed by version 4.0 of the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) in this cohort of patients.   
 
• To describe the mutation and co-mutation rates of genes in the PI3K and RAS-ERK 
signaling pathways in recurrent cervical cancer using high throughput targeted 
mutational analysis on participant tumor samples. 
  
 
• To explore the association of mutational status with clinical benefit from 
GSK1120212 (trametinib) and GSK2141795.  
 
2. 
BACKGROUND 
 
2.1 
Study Disease: Cervical Cancer 
 
2.1.1 Epidemiology 
 
In the United States, invasive cervical cancer will affect an estimated 12, 710 women this 
year with approximately 4290 resulting deaths [13].  While implementation of screening has 
greatly reduced the burden of this disease in the developed world, it remains a leading cause 
of cancer death globally [14].  Treatment options for persistent, recurrent or metastatic 
cervical cancer remain limited and prognosis is poor [15]. 
  
2.1.2 Treatment 
 
From studies performed primarily by the Gynecology Oncology Group, pelvic radiation 
augmented with platinum based chemotherapy is first line therapy for bulky or advanced 
cervical cancer [16-19]. In the recurrent setting, cisplatin has emerged a favored agent for 
systemic treatment in combination with other cytotoxics with response rates around 25-40% 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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This document is confidential. Do not disclose or use except as authorized. 
[20-24].  Sub-set analysis of these studies has demonstrated that patients with short intervals 
of disease control as well as those with disease that recurs within the irradiated pelvis have 
worse outcomes [25]. Two series within the GOG (127 and 227) have been developed to 
explore the chemotherapeutics and biologics for second line recurrence [26].  From over a 
dozen completed clinical studies in this population, bevacizumab has one of the higher levels 
of activity, resulting in a response rate of 11% and progression free survival rate of just 25% 
at 6 months [27]. There is a great need to identify more active agents in this population.  
 
2.1.3 PI3K and RAS Signaling in Cervical Cancers 
 
As compared to other women’s cancers, there are limited comprehensive data on the rates 
of RAS-ERK and PI3K pathway alterations.  PIK3CA and PTEN mutation have been 
characterized in one published study at a frequency of approximately 10% [9, 28]. 
However, molecular testing of phase I study participants from MD Anderson identified a 
PIK3CA mutation rate of 36% in squamous cervical cancer [29, 30].  At the Dana-
Farber/Harvard Cancer Center (DF/HCC), patients’ tumors are frequently genotyped for 
oncogenic mutations and our preliminary data support this higher rate of PIK3CA 
mutation [31].  K-RAS and H-RAS mutations have also each been reported at 10% and 
22% [9, 29, 32].  In our own study at DFCI, in a group of 80 patients with both squamous 
cell or adenocarcinoma of the cervix, validated mutations were detected in 60.0% (48/80) 
of tumors examined.  The highest mutation rates were PIK3CA (31.3%), KRAS (8.8%), 
and EGFR (3.8%). PIK3CA mutations were found at similar rates in both 
adenocarcinoma and squamous cell carcinomas (25.0% vs. 37.5%, p=0.33). In contrast, 
K-RAS mutations were identified only in adenocarcinoma (17.5% vs. 0%, p=0.01), 
and EGFR mutations were detected exclusively in patients with squamous cell carcinoma 
(0% vs. 7.5%).  We did not see any co-mutations of both KRAS and PIK3CA in any 
samples [31 and submitted manuscript].    
 
Both the RAS- ERK and PI3K pathways have been implicated in resistance to radiation, 
suggesting utility in previously irradiated patients.  PI3K pathway activation, as measured 
by phosphorylated AKT has been shown to be associated with local recurrence after 
radiation [33].  Additionally, cervical patients with K-RAS mutations had poorer 
outcomes after treatment with radiation therapy [32].  
 
PI3K and MEK inhibitors in Cervical Cancer 
 
Multiple therapeutics that target the PI3K pathway are in clinical development including 
PI3K inhibitors, PI3K dual inhibitors (which target both PI3K and mTOR), AKT 
inhibitors, and mTOR inhibitors [34]. A recent report from MD Anderson evaluated 
clinical response to this large class of drugs in phase I trial in patients whose tumors had 
PIK3CA mutation or PTEN loss. Several patients with cervical cancer were among those 
to respond to drugs targeted to the PI3K pathway in these trials [30]. However, these 
responses were not durable suggesting the need for combination therapies. To date, MEK 
inhibition has not been explored for treatment of cervical cancer. 
 
 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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This document is confidential. Do not disclose or use except as authorized. 
2.2 
Investigational Agents: GSK1120212 and GSK2141795 
 
2.2.1 GSK1120212 (trametinib) 
 
Please see GSK1120212 Investigator’s Brochure for additional information on this 
compound (1). 
 
Nonclinical Pharmacology 
 
GSK1120212 is a reversible, highly selective, allosteric inhibitor of mitogen-activated 
extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are critical 
components of the extracellular signal-related kinase (ERK) pathway which is commonly 
hyperactivated in tumor cells. Oncogenic mutations in both BRAF and RAS signal 
through MEK1 and MEK2. GSK1120212 is non-competitive towards ATP and inhibits 
activation of MEK by RAF kinases as well as MEK kinase activity. The specificity of 
GSK1120212 to MEK1 and MEK2 was confirmed against a panel of 183 kinases, 
including MEK5, the closest kinase homolog to MEK1 and MEK2, and no significant 
inhibitory activity was measured [1]. In vitro, 80% of cell lines carrying activating 
mutations of B-Raf and 72% of Ras mutant cancer cell lines were sensitive to 
GSK1120212 in cell proliferation assays, and a majority (83%) of hematopoietic cancers 
from acute or chronic myeloid leukemia (AML or CML, respectively) origins were also 
very sensitive. 
 
Anti-tumor Activity in vitro 
 
Cancer cells expressing high constitutive levels of activated ERK (pERK) tend to be 
more sensitive to GSK1120212 than those with lower levels of pERK, suggesting that 
tumors with B-RAF or RAS mutations and/or high levels of pERK may respond to 
GSK1120212 treatment. In all cell lines, pERK was strongly inhibited following 
treatment with GSK1120212 and was independent of their proliferative response, 
suggesting that pERK inhibition is necessary but not sufficient to inhibit cell 
proliferation. In cell lines that were sensitive to the anti-proliferative activity of 
GSK1120212, the response was associated with arrest in G1 phase of the cell cycle, 
accumulation of p27, and reduction of cyclin D1 and phospho-retinoblastoma protein. 
Induction of apoptosis was demonstrated in some cell lines. Inhibition of pERK and 
inhibition of cancer cell proliferation were fully reversible following compound removal, 
suggesting that sustained exposure to GSK1120212, or potential combination with other 
drugs, may be required for full activity.  
 
When GSK1120212 was combined with standard of care drugs against human cancer cell 
lines in vitro, an additive effect was observed for pancreatic cancer with gemcitabine or 
erlotinib and for colon cancer with 5-FU or irinotecan. The combination of GSK1120212 
with rapamycin, ara-C, bexarotene or sorafanib produced an additive effect against most 
AML cell lines tested. In addition, combination of GSK1120212 with an investigational 
phosphoinositide 3-kinase (PI3K) inhibitor, as well as with a Centromer Protein-E 
(CENP-E) inhibitor, was synergistic on inhibition of cell growth in various cancer 


DF/HCC Protocol # 13-334 
Phase II of GSK1120212 and GSK2141795 in Cervical Cancer  
 
Protocol Version Date:  July 11, 2017 
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This document is confidential. Do not disclose or use except as authorized. 
(pancreas, colon, lung) cells. Additionally, the combination of GSK1120212 and a 
CENP-E inhibitor increased caspase activity, indicating enhanced apoptosis in colon 
cancer cell lines. 
While many proliferating human cells are sensitive to GSK1120212 in vitro, 
GSK1120212 did not affect non-dividing normal cells and did not completely inhibit 
bone marrow progenitor cells at concentrations demonstrating anti-proliferative activity 
on very sensitive cancer cell lines. 
 
Anti-tumor Activity in vivo 
 
GSK1120212 was orally bioavailable in mice, and doses as low as 1 mg/kg reached 
blood concentrations that caused sustained reductions of pERK, an accumulation of p27, 
and a decrease of Ki67 in tumor xenografts; brain exposure levels were ~10% of those in 
blood, and no significant pERK inhibition was measured in brain tissue. In mice, 
exposure to GSK1120212 produced dose- and schedule-dependent anti-tumor responses 
correlating with blood levels. Typically, B-RAF--mutant xenografts responded with 
tumor regression while K-RAS-mutant xenografts responded with tumor growth 
inhibition. In vivo combination studies testing GSK1120212 together with various other 
anticancer drugs showed good potential for synergistic effects. 
 
Safety Pharmacology 
 
In a rat neurobehavioral screen, following a single oral dose of GSK1120212 at 650 
mg/m2 to male rats, diarrhea, prone position, blepharoptosis, piloerection, reduced 
spontaneous locomotion and mydriasis were observed between 2 and 24 hours post dose. 
In a respiratory safety pharmacology study in rats, an oral dose of 1 mg/m2 produced a 
mild, transient decrease in body temperature (up to 0.8°C) at 1 hour post dose. There 
were no other effects on ventilatory function, airway resistance or body temperature. 
GSK1120212 inhibited hERG channel repolarization in HEK293 with an IC50 of1.54μM 
(950 ng/mL). In a rabbit left ventricular wedge assay, GSK1120212 had no significant 
effect on QT interval at concentrations up to 30 μM (18450 ng/mL; limit of solubility). 
However, significant decreases in isometric contractile force occurred at concentrations 
of 10 (6150 ng/mL) and 30 μM. GSK1120212 also decreased the Tp-e interval at a 
concentration of 30 μM. A single intravenous infusion of GSK1120212 in dogs at 20 
mg/m2 over 10 minutes (Cmax of 2.5 μM or 1500 ng/mL) produced no changes in 
electrocardiogram (ECG) parameters, blood pressure or heart rate during the 30 minute 
measurement period. In addition, single oral doses up to 1.5 mg/m2 in dogs produced no 
changes in arterial blood pressure, heart rate, body temperature or ECG intervals, 
including QTc. While GSK1120212 affected cardiac electrophysiology in vitro, no 
effects were observed in vivo at doses that were maximally tolerated in dogs. This 
difference in responses is likely related to the very low Cmax (~10 ng/mL total drug) at 
tolerated doses in dogs and the high protein binding (97% in dogs) of GSK1120212. The 
concentrations at which effects were seen in these in vitro studies are significantly higher 
than the free fraction observed in nonclinical toxicology studies or the clinical dose (2 
mg). These results suggest a low risk for cardiovascular effects in the clinic. 
 


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Pharmacokinetics and Product Metabolism in Animals 
 
GSK1120212 exhibited low plasma clearance among nonclinical species (mouse, rat, dog 
and monkey) with varied but generally long half-lives. Oral bioavailability ranged 
between 42% and 100%. Since GSK1120212 is a low solubility, high permeability 
molecule, its absorption is likely limited by solubility and dissolution. Plasma protein 
binding was high in nonclinical species and human (>95%) and blood cell association 
was low. Consistent with high permeability, GSK1120212 had moderate to high volume 
of distribution among the nonclinical species studied and drug related material (DRM) 
was widely distributed into rat tissues. The low concentration of DRM observed in the 
brain up to 8 hours post dose was observed. Although studies showed protracted 
elimination of DRM (consistent with high volume and long half-life), DRM in tissues 
was not detectable by 35 days post dose.  
 
In rats and dogs after repeat oral dosing up to 13 weeks, systemic exposure increased 
approximately dose-proportionally at higher doses or when steady state was reached at 
Week 3. Upon repeat dosing, increases in systemic exposure after Day 1 were observed 
up to Week 3;  however, between Weeks 4 and 13, there was no marked increase in 
systemic exposure for either pre-clinical species. A tendency for higher exposure in 
females than in males was observed in some studies in both rats and dogs. No apparent 
human-specific metabolite was observed in the in vitro cross-species [14C] GSK1120212 
metabolism study. [14C]GSK1120212 was also found to metabolize predominantly via a 
non-cytochrome P450 (CYP) mediated deacetylation with secondary oxidation or 
glucuronidation biotransformation pathways. CYP3A4 was implicated in the in-vitro 
formation of M7, a metabolite mediated by both non-CYP and CYP pathways. The 
relative contribution of CYP3A4 to the total metabolic clearance of GSK1120212 in 
human in vivo is not currently understood and, therefore, the possibility of a metabolic 
drug interaction cannot be eliminated. Elimination of DRM in rat and dog after oral 
administration occurred predominantly via the feces (>60% of dose), with urinary 
excretion (<7% of dose) representing a minor route. 
 
Although GSK1120212 was found to be an in vitro inhibitor of CYP2C8, CYP2C9 and 
2C19, inducer of CYP3A4 and inhibitor of the transporters (OATP1B1, OATP1B3, Pgp 
and BCRP), the low clinical GSK1120212 systemic exposure relative to these in vitro 
inhibition values suggests a low potential for GSK1120212 as a perpetrator in clinical 
drug-drug interaction (DDI). However, drugs with a narrow therapeutic index that are 
substrates of CYP2C8, the CYP with the lowest inhibition IC50, should be used with 
caution. There was no evidence of time-dependent inhibition with any of the CYP 
enzymes investigated. In addition, GSK1120212 was not found to be an in vitro substrate 
of the transporters Pgp and human breast cancer resistance protein (BCRP). 
 
Toxicology 
 
Systemic toxicity of GSK1120212 has been evaluated following oral dosing in rats and 
dogs for up to 13 weeks. In the most sensitive nonclinical species, rat, the principal 
adverse effects seen in oral toxicity studies of up to 13 weeks with daily dosing were skin 


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and stomach erosions, skin ulcerations, which were secondary to reduced proliferation, 
altered phosphate homeostasis that resulted in soft tissue mineralization, hepatocellular 
necrosis, bone marrow degeneration/necrosis and ovarian perturbations. The skin and 
stomach findings and phosphatemia demonstrated reversibility with 4 weeks of recovery. 
The maximum tolerated dose (MTD) in rats in the definitive 13 week study with daily 
dosing was 0.25 mg/m2/day (AUC0-t of 126 ng.h/mL, end of study). Reversible acute 
effects (diarrhea, decreased body weight gain, prone position, blepharoptosis, 
piloerection, reduced spontaneous locomotion and mydriasis) were observed following a 
single high dose of 650 mg/m2 to rats. In dogs, the principal dose-limiting toxicities seen 
oral toxicity studies of up to 13 weeks with daily dosing were related to gastrointestinal 
and hematopoietic perturbations. Inflammatory responses to gastrointestinal erosions 
were observed in dogs and were reversible following a recovery period. In the definitive 
13 week daily oral dosing study in dogs, the No Observed Adverse Effect Level 
(NOAEL) was 0.45 mg/m2/day (AUC0-t of 139 ng.h/mL, end of study). Principal 
adverse effects were consistent with inhibition of cell proliferation and were monitorable 
and generally reversible. GSK1120212 was negative in both in vitro and in vivo 
genotoxicity assays. 
 
Effects in Humans 
 
The effect of GSK1120212 in subjects with a variety of refractory cancers is currently 
under evaluation in 14 clinical studies which are ongoing as of the IB cut-off date. 
GSK1120212 has been administered as monotherapy in 6 of these studies, and as 
combination therapy in the other 8 studies. As of 14 April 2011, 657 subjects with cancer 
have received at least one dose of GSK1120212 in the 13 ongoing Phase I/II/III clinical 
studies. This number does not include subjects from 2 randomized trials 
(MEK113487and MEK114267), from the blinded part of the combination trial 
(BRF113220), and from another combination trial (P3K113794). There are no completed 
clinical trials to date. Preliminary GSK1120212 pharmacokinetics were determined after 
single and repeat dose oral administration of GSK1120212 tablets in subjects with solid 
tumors. GSK1120212 is absorbed rapidly with median Tmax generally occurring within 
1-3 hours after oral administration of GSK1120212 under fasting conditions. Following 
repeat-dosing the mean area under the curve (AUC0-τ) and maximum concentrations 
(Cmax) increased in an approximately dose proportional manner. 
 
GSK1120212 accumulates with repeat dosing with a mean effective half life of 
approximately 5 days. Based on the adverse events (AEs) observed in the dose escalation 
phase of the first time in-human (FTIH) study MEK111054, the maximum tolerated dose 
was established at 3.0 mg once daily (QD), and the recommended Phase II dose (RP2D) 
of GSK1120212 was identified as 2.0 mg QD.  
 
In the 3 monotherapy trials of GSK1120212 for which data are available (MEK111054, 
MEK111759, and MEK113583), 99% to 100% of all 356 subjects in any dose group 
experienced at least one AE, and 26% to 68% of all 356 subjects in any dose group 
experienced at least one SAE. Of the 356 subjects, 4% to 23% permanently discontinued 
study treatment due to AEs. 


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Of the 241 subjects in the 2.0 mg dose group in the 3 monotherapy trials (MEK111054, 
MEK111759, and MEK113583), 99% to 100% of subjects experienced at least one AE, 
and 26% to 71% of all subjects experienced SAEs. Of the 241 subjects, 4% to 23% 
permanently discontinued study treatment due to AEs. 
 
In the 2.0 mg dose group across all 3 monotherapy trials, the most common AEs 
experienced were rash, diarrhea, nausea, fatigue, vomiting, anemia, peripheral edema, 
abdominal pain, constipation, dermatitis acneiform, decreased appetite, pruritus, dyspnea, 
pyrexia, pneumonia, febrile neutropenia, AST increased, ALT increased, and dry skin. In 
the 5 combination therapy trials of GSK1120212 for which data are available 
(MEK112110, MEK112111, MEK113486, open-label parts of BRF113220, 
andTAC113886), 89% to 100% of all 296 subjects in any dose group experienced at least 
one AE, and 21% to 45% of all 388 subjects in any dose group experienced at least one 
SAE. Of these 296 subjects, 4% to 10% permanently discontinued study treatment due to 
AEs. 
 
In the 5 combination trials for which data are available, the most common AEs 
experienced were nausea, fatigue, diarrhea, vomiting, decreased appetite, pyrexia, rash, 
constipation, neutropenia, dry skin, dermatitis acneiform, anemia, mucosal inflammation, 
stomatitis, exfoliative rash, thrombocytopenia, peripheral edema, abdominal pain, cough, 
chills, and AST increased. 
 
2.2.2 GSK2141795 
 
Nonclinical Pharmacology 
 
GSK2141795 is a novel member of the N-alkyl pyrazole class of orally available kinase 
inhibitors and has been shown to be a potent, pan AKT (a serine/threonine protein kinase 
with 3 isforms, AKT1, AKT2 and AKT3) inhibitor, with potency (Ki*) values for human 
AKT1, 2 and 3 kinases being 0.006, 1.4 and 1.5 nM, resp.   GSK2141795 exhibited a 
time-dependent inhibition of AKT with a dissociation half-life of ≤ 20 mins.  In vitro, 
GSK caused a concentration and time dependent reduction in phosphorylation of multiple 
proteins downstream of AKT such as glycogen synthase kinase 3 beta, an insulin-
regulated inhibitor of the mammalian target of rapamycin complex 1 (mTORC1) protein 
kinase (PRAS40), Forkhead gene product (FOXO) and caspase 9.   Treatment of tumor 
cells with GSK2141795 resulted in a concentration-dependent increase in the nuclear 
translocation of the FOXO transcription factor as a functional consequence of reduced 
phosphorylation of FOXO.  GSK2141795 inhibited the proliferation of a range of tumor 
cells from multiple histologies including breast, hematological, colon, ovarian and 
prostate (EC50 < 1 microM).  AKT signaling was inhibited in cell lines both sensitive 
and less sensitive to GSK2141795, suggesting that resistance to GSK2141795 is not due 
to a lack of AKT kinase inhibition. GSK2141795 induced cell cycle arrest at G1 or 
apoptosis in a concentration-dependent manner depending on the cellular context. 
 
In vivo studies conducted in immuno-compromised mice bearing human tumor cell 
line xenografts showed GSK2141795 can inhibit multiple AKT substrates 


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downstream of AKT in a dose- and time-dependent manner. The highest tolerated 
repeat dose in mice (30 mg/kg) caused a small elevation in blood glucose levels 
(~300 mg/dL). In mice, doses 10 mg/kg did not alter blood glucose levels, and repeat 
administration of GSK2141795 at 30 mg/kg elevated blood glucose levels without 
any evidence of a cumulative effect. Elevation in blood glucose was noted between 1 
and 8 hours post dose with GSK2141795 and correlated with the pharmacodynamic 
effect of maximal inhibition of phospho-PRAS40. Additionally, studies have 
suggested that a combination of fasting and low carbohydrate diet in mice can 
minimize AKT inhibitor-induced glucose elevation. Further, co-administration of 
metformin with GSK2141795 appeared to reduce the magnitude of GSK2141795-
induced glucose elevation in mice. Repeat oral administration of GSK2141795 for 3 
weeks inhibited the growth of various tumor xenografts, including BT474 (breast), 
HCC1954 (breast), and SKOV3 (ovarian) in mice. Daily dosing with GSK2141795 
was more efficacious at inhibiting the growth of tumor xenografts than less frequent 
dosing, suggesting the need for repeat administration for maximal anti-tumor effect. 
GSK2141795 was further studied, in vitro and in vivo, in combination with other 
anti-cancer agents. In vitro, GSK2141795 was combined in a 3-day cell proliferation 
study with ofatumumab (an anti-CD20 antibody) against a panel of 10 lymphoma 
cell lines. In 3 lymphoma cell lines that were also sensitive to ofatumumab alone, the 
response after treatment with both GSK2141795 and ofatumumab was additive when 
compared to treatment of either alone. Similarly, GSK2141795 was combined in a 3-
day cell proliferation study with GSK1120212 (a mitogen-activated protein 
kinase/ERK kinase [MEK] inhibitor) against a panel of 26 colon, 15 lung, and 6 
pancreatic cancer cell lines. GSK2141795 and GSK1120212 were synergistic in 
cancer cell lines from colon (19 of 26), lung (4 of 15), and pancreatic (2 of 6). 
In vivo, after daily oral combination treatment of GSK2141795 and lapatinib (a dual 
inhibitor of epidermal growth factor receptor [ErbB-1] and human epidermal growth 
factor receptor 2 [ErbB-2] tyrosine kinases) to mice, the anti-tumor effect on ErbB-2 
overexpressing BT474 breast tumor xenografts (lapatinib sensitive) was additive, but 
the effect on non-ErbB-2 overexpressing MDA-MB-231 breast tumor xenografts (not 
very sensitive to lapatinib) was not improved over either agent alone. Similarly, no 
additive effect was seen with A2780 and SKOV-3 ovarian tumor xenografts after 
GSK2141795 was administered in combination with pazopanib, an angiogenesis 
inhibitor. Combination of GSK2141795 with pazopanib or GSK1363089 (a dual 
inhibitor of mesenchymal epithelial transition factor [MET] and vascular endothelial 
growth factor receptor-2 [VEGFR-2]) showed no advantage over GSK2141795 alone 
in a model of hepatocellular carcinoma using primary human tumor xenografts 
(LIX014). 
 
Combination treatment of GSK2141795 and GSK1120212 (MEK inhibitor) resulted 
in an additive anti-tumor effect in HPAC pancreatic xenograft; however, there was 
no additive effect in Capan-2 pancreatic tumor xenograft. 
 
GSK2141795 did not produce acute neurobehavioral or respiratory effects in rats at 
doses up to 20 mg/kg. In a dog cardiovascular study, there was a mild to moderate, 


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transient increase in mean arterial blood pressure (MAP; up to 20 mmHg) between 3 
and 16 hours following a single oral 5 mg/kg dose (Cmax = 0.41 g/mL) of 
GSK2141795. There was a concurrent increase in pulse pressure (up to 13 mmHg), 
decrease in the QA interval (the time between the Q wave of the ECG and A point of 
the blood pressure waveform); up to 11 msec) and transient decrease in heart rate (up 
to 20 bpm) between 3 and 10 hours after treatment, likely reflecting a compensatory 
baroreflex response to the increased blood pressure. While GSK2141795 was an 
inhibitor of hERG repolarization (IC50 of 3.1 M; 1.36 g/mL) and inhibited cardiac 
sodium and calcium channel repolarization (IC50 of 7.2 M and 8.0 M [3.1 and 3.44 
g/mL], respectively), there were no electrocardiogram (ECG) effects or meaningful 
prolongation of the QTc interval in an in vitro rabbit wedge assay. There were also 
no ECG effects or meaningful QTc prolongation in dogs in vivo. Given the high 
protein binding (>98% in dog and human plasma), the low Cmax concentrations at 
tolerated doses in animals and the absence of effects on the QT interval in dogs, there 
is a low risk for QTc prolongation in humans. 
 
Pharmacokinetics and Product Metabolism in Animals 
 
Nonclinical pharmacokinetic studies with GSK2141795 were conducted in the 
mouse, rat, dog, and monkey. In these species, oral bioavailability of GSK2141795 
was moderate to high (≥40%), blood clearance was low to moderate (20% to 50% of 
liver blood flow) and volume of distribution was high (>6 times total body water). In 
toxicity studies in rats and dogs, systemic exposure generally increased dose-
proportionally, with no consistent marked gender differences. 
 
In vitro, GSK2141795 was moderately to highly bound (93% to >95%) to plasma 
proteins in nonclinical species and human, and had minimal to moderate association 
(0.99 to 1.64) with blood cells. GSK2141795 was a human P-glycoprotein (Pgp) and 
mouse breast cancer resistance protein (Bcrp 1) substrate and did not inhibit Pgp-
mediated digoxin transport. GSK2141795 had moderate passive permeability (60 
nm/sec) and low to moderate absorptive membrane permeabilities (3.0 to 11 nm/sec). 
GSK2141795 inhibited human organic anion transporting polypeptide (OATP) 
1B1(IC50 of 16 µM) and 1B3 (IC50 of 21 µM) and BCRP-mediated transport of 
cimetidine (up to 50% of control at 3 µM). In a tissue distribution study following 
single oral administration of [14C] GSK2141795, consistent with its high volume of 
distribution, radioactivity was widely distributed into tissues, and most tissue 
concentrations were higher than those observed in blood. Concentrations of 
radioactivity generally declined over time, and by 7 days post dose, the levels of 
radioactivity were below the limit of quantification (BLQ) in most tissues. 
Radioactivity was still quantifiable at 35 days post dose in the uveal tract, suggesting 
the potential for the selective association of drug-related material with melanin. 
 
In rats and dogs following single oral administration of [14C] GSK21417, the major 
route of elimination of drug-related material was via the feces, while urinary 
excretion constituted a minor route in both species. 
 


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In vitro intrinsic clearance for GSK2141795 was low in hepatocytes and microsomes 
from the mouse, rat, dog, monkey, and human. In rat and human hepatocytes, the 
metabolism of GSK2141795 occurred by mono-oxygenation, glucuronidation, 
oxidative deamination, and N-demethylation; there were no apparent human-specific 
metabolites, and cytochrome P450 (CYP) 3A4 was the primary enzyme responsible 
for the oxidative metabolism. No stereo-conversion to the R-enantiomer was 
observed in vitro, and no rearrangement to an acyl migrated isomer of parent was 
observed either in vitro or following oral administration to mice. In vitro, 
GSK2141795 demonstrated the potential for oxidative bioactivation. In vitro study 
results suggest that GSK2141795 has the potential to be a perpetrator in drug-drug 
interactions with substrates of CYP enzymes (notably CYP2C8 and CYP3A4) or the 
BCRP transporter, and to be a victim of drug-drug interactions upon co-
administration with CYP3A4, Pgp, and BCRP inhibitors or potent inducers. 
 
Toxicology 
 
Systemic toxicity of GSK2141795 has been evaluated following oral dosing in rats 
and dogs for up to 4 weeks. The principal dose-limiting toxicities seen involved the 
gastrointestinal (GI) and hematopoietic systems. In rats, morbidity with marked 
clinical effects (severe body weight loss) was seen acutely following a single dose of 
100 mg/kg or as early as 4 days of repeat daily dosing at 20 mg/kg/day. In dogs, 
morbidity was seen after a single dose of 150 mg/kg or repeat doses of 5 mg/kg/day 
for up to 7 days. Emesis, often frequent, frothy, mucoid, and blood tinged, together 
with loose watery feces, dominated the clinical picture. At lower doses administered 
for up to 4 weeks, GI effects and clinical signs were less severe but did contribute to 
a declining clinical condition. Microscopic lesions in the stomach, large intestine, 
and oral cavity were characterized by focal and multifocal erosions and ulcers with 
inflammation, hemorrhage, and submucosal edema. These findings likely resulted 
from a direct irritant effect at high doses along with a pharmacodynamic effect on the 
intestinal mucosa. 
 
Hematopoietic toxicity manifested in rats as bone marrow hypocellularity with an 
accompanying lymphopenia. The GI and hematopoietic effects had reversed, or were 
improving, by the end of the 2 week recovery period. In one dog given a non-
tolerated dose, a vascular lesion in the lung, consisting of focal medial degeneration 
and necrosis, was observed. Localized inflammation and reactive fibrosis of the 
splenic capsule was seen in rats. The relationship to treatment of either of these 
findings is unknown. Consistent with GSK2141795 inhibition of the AKT signaling 
pathway, mild to marked dose-dependent increases in plasma insulin were observed 
in rats and dogs. The insulin levels became persistently elevated following repeat 
dosing and reversed following cessation of treatment. There were no consistent 
changes in plasma glucose levels. Additional effects consistent with the 
pharmacologic action of GSK2141795 included decreased lymphoid cellularity in the 
thymus, peripheral lymph nodes and spleen with decreased circulating lymphocytes, 
particularly in rats. Lymph node involvement was more widespread in dogs where it 
persisted through the recovery period. 


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The maximum tolerated dose (MTD) of GSK2141795 in rats following daily dosing 
for 4 weeks was 10 mg/kg/day (AUC0-t of 9.27 g.h/mL and Cmax of 0.644 g/mL). The 
MTD in dogs was 2 mg/kg/day (AUC0-t of 4.50 g.h/mL and Cmax of 0.298 g/mL). A 
no observed adverse effect level (NOAEL) was not determined in rats or dogs, 
although effects at the low doses in these studies were generally mild, seen in 
individual animals and reversible. In addition, GSK2141795 is not likely to present a 
genotoxic hazard to humans. 
 
Effects and pharmacokinetics in Humans 
 
There are 3 clinical studies for GSK2141795. PCS112689 is a first-time-in-human 
(FTIH), dose-escalation study in subjects with cancer to characterize the safety, 
pharmacokinetic, and pharmacodynamic profiles of GSK2141795. Enrollment is 
complete as the primary objective was met and 2 subjects remain on study as of the 
data cut-off date. PCS113124 is an open-label, multiple-dose, dose-escalation study 
designed to explore the potential dose response relationship between the 
pharmacokinetics of GSK2141795 and [18F] FDG PET pharmacodynamic markers of 
glucose metabolism in tumor tissue. The study enrolled a total of 12 subjects in order 
to meet the study’s primary objective without necessitating enrolment of the 
estimated maximum number of subjects indicated in the protocol which allowed for 
replacement of any non-evaluable subjects. PCS113124 is clinically complete and 
the clinical study report is in progress. TAC113886 is an ongoing dose-escalation, 
open-label study to determine the recommended Phase II dose and regimen for the 
combination of the orally administered MEK inhibitor GSK1120212 and the orally 
administered AKT kinase inhibitor GSK2141795. 
 
Single-dose (Day 1) PK parameters of GSK2141795 were evaluated in the first-time-in-
human (FTIH) study (PCS112689).  Preliminary data indicated that plasma 
concentrations for GSK2141795 were measurable for all subjects over the 72 hours after 
a single dose over the dose range tested (10 mg to 150 mg).  In addition, drug 
concentrations were measurable on Day 8, suggesting that GSK2141795 can still be 
found in the plasma at least 1 week after a single dose of study drug over the dose range 
tested (75 mg to 100 mg). While the exposures for the 100 mg and 150 mg doses were 
similar following a single dose, drug exposure following multiple doses was 
approximately in proportion to dose.  GSK2141795 accumulated 2.5- to 8.4-fold with 
repeat daily dosing.  Mean area under the concentration-time curve (AUC(0-24)) and 
maximum plasma concentration (Cmax) values generally increased in a dose-proportional 
manner, although there was variability among subjects.  Median time to reach peak 
concentration (Tmax) across doses was 3 hours and ranged from 0 to 4 hours.  The mean 
value for the effective half-life of elimination (t½, eff) across subjects was 3.0 days and 
ranged from approximately 1.3 to 5.5 days. 
 
As of the safety cut-off date of 06-May-2012, a total of 151 subjects had enrolled and 
were administered at least 1 dose of GSK2141795 in these 3 studies combined. The 
most common adverse events (AEs) reported were primarily GI and metabolism and 


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nutritional disorders, (including nausea, vomiting, and diarrhea) and metabolism and 
nutritional disorders (primarily hypoglycemia and hyperglycemia). Dose limiting 
toxicities for the monotherapy are primarily related to glucose metabolism 
(hypoglycemia and hyperglycemia) and also include rash and mucositis. When 
administered in combination with the MEK inhibitor GSK1120212 (trametinib), the 
most common AEs are similar as in the case of GSK2141795 monotherapy, however 
the frequency and severity are increased. In particular, GI and dermatological 
toxicities are the most frequent overall and the most frequent serious adverse events 
in TAC113866 were reported in the GI disorders (e.g., nausea, vomiting, diarrhea, 
stomatitis) and Investigations system organ class (SOC).  Preliminary responses have 
been seen for the combination of GSK2141795 and GSK1120212 (e.g., in highly 
pretreated triple negative breast cancer, endometrial cancer, ocular melanoma and a 
KRAS-mutant cancer of unknown primary origin). However, at this early stage in 
development, an assessment of clinical efficacy is premature.  The effect of 
GSK2141795 in subjects with a variety of refractory cancers is currently under evaluation 
in 3 GSK-sponsored clinical studies as of 06 May 2012.  In addition to this study, which 
explores GSK2141795 administered in combination with GSK1120212, two other studies 
administer GSK2141795 as monotherapy.  As of the cut-off date, a total of 151 subjects 
with cancer have received at least one dose of GSK2141795. 
 
The investigator should refer to the GSK2141795 Clinical Investigator’s Brochure for 
detailed information regarding ongoing clinical studies, pharmacokinetics, as well as 
observed safety and efficacy findings. 
 
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of 
Single Agent GSK2141795  
 
The MTD of single-agent GSK2141795 is 75 mg once-daily as determined by the FTIH 
study.  The RP2D of single-agent GSK2141795 has not been determined. 
 
2.2.3 Data on Preclinical Combination and Preliminary Clinical Safety Data from 
TAC113886, Phase I of combined GSK1120212 with GSK2141795 
 
Pre-clinical combination studies were performed in vitro on colon (n=25), pancreas (n=6), 
and lung (n=15) cell lines.  A fixed ratio of GSK1120212 (0.25 M) to GSK2141795 
(10 M) with 3-fold serial dilutions was used in a 3-day proliferation assay.  The 
combination effect was determined by excess over highest single agent (EOHSA), BLISS, 
and Combination Index (Cl) (<1).  Results indicated synergy in 14 colon, 7 lung, and 2 
pancreas cell lines; modest synergy in 7 each colon and lung, and 2 pancreas cell lines; 
additive in 3 colon, 1 lung, and 2 pancreas cell lines; and none in one colon cell line.  
Synergy was seen in one colon and one lung cell line at concentrations greater and equal to 
0.003 M (1.9 ng/mL) GSK1120212 and 0.124 M (53 ng/mL) GSK2141795.  Human 
steady-state plasma trough concentrations, not correcting for protein binding, similar to the 
in vitro values would be obtained at doses of 0.5 mg (GSK1120212) and 20 mg 
(GSK2141795).  Different values were required for other tumor types. 
 


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Clinical Experience with the Combination of Trametinib and GSK2141795 
 
Twenty-three patients with advanced solid tumors received the combination using a zone-
based escalation procedure enabling evaluation of multiple combination doses in parallel 
cohorts (Kurzrock et al., 2011).  While the RP2D for single agent for single agent 
trametinib and GSK2141795 are 2 mg/d and 75 mg/d, dose reductions were required for 
the combination.  DLTs include grade 2 AST and ALT elevation, and grade 3 chest pain 
with sustained ventricular tachycardia; all DLTs were reversible with drug interruption.  
The most common AEs (≥10%) included nausea (26%), AST elevation (22%; grade 3/4, 
9%), fatigue (22%) and rash (22%).  Three MTDs were defined for variable dose ratios:  
2 mg trametinib + 25 mg GSK2141795; 0.5 mg trametinib + 75 mg GSK2141795; and 
1.5 mg trametinib + 50 mg GSK2141795.  Three of 13 evaluable patients (unselected) 
had tumor shrinkage of 8% (ovarian), 16% (endometrial), and 17% (ovarian) after 8 
weeks on study.  The dose regime of 1.5 mg trametinib + 50 mg GSK2141795 will be 
considered for further development.  Additional trials to explore alternate schedules (e.g., 
intermittent) and pharmacodynamic markers are ongoing. 
 
Rationale for the Selection of a Continuous Dosing Schedule 
 
Combination studies were performed in vitro on colon (n=25), pancreas (n=6), and lung 
(n=15) cell lines.  A fixed ratio of GSK1120212 (0.25 M) to GSK2141795 (10 M) 
with 3-fold serial dilutions was used in a 3-day proliferation assay.  The combination 
effect was determined by excess over highest single agent (EOHSA), BLISS, and 
Combination Index (Cl) (<1).  Results indicated synergy in 14 colon, 7 lung, and 2 
pancreas cell lines; modest synergy in 7 each colon and lung, and 2 pancreas cell lines; 
additive in 3 colon, 1 lung, and 2 pancreas cell lines; and none in one colon cell line.  
Synergy was seen in one colon and one lung cell line at concentrations greater and equal 
to 0.003 M (1.9 ng/mL) GSK1120212 and 0.124 M (53 ng/mL) GSK2141795.  
Human steady-state plasma trough concentrations, not correcting for protein binding, 
similar to the in vitro values would be obtained at doses of 0.5 mg (GSK1120212) and 
20 mg (GSK2141795).  Different values were required for other tumor types. 
 
 
 
 


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2.2.4 AKT Inhibitors Dosed in Combination with MEK Inhibitors: Rationale for 
Treatment of Cervical Cancer   
 
PI3K and RAS-ERK Signaling 
 
Receptor Tyrosine Kinases (RTK) regulate cell growth, proliferation, and differentiation 
through downstream signals, including the PI3K and the RAS-RAF-MEK-ERK pathways 
[4] (see figure below).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI3K enzymes are activated transfer phosphate groups to the inositol ring of 
phosphatidylinositol to produce the signaling molecule phosphatidylinositol 3,4,5tri-
phosphate (PIP3)[5].  Alterations in the PI3K pathway are important in both the 
development and maintenance of cancer [6]. There are many underlying mechanisms for 
PI3K pathway activation in cancer, including receptor tyrosine kinase activation or 
amplification; mutation, deletion, or silencing of negative regulators of the PI3K pathway 
(such as PTEN) and activation or amplification of downstream kinase mediators [6]. RAS 
proteins are small GTPases and upon stimulation of an RTK initiates protein kinase 
cascade through RAF, MEK, and ERK protein kinases [7]. RAS proteins also interact 
with and signal through PI3K [8]. Specific oncogenic mutations in RAS (K-RAS, N-RAS 
and H-RAS) as well B-RAF are common some specific solid tumors [9].  Importantly, 
there is mounting evidence  that the PI3K and RAS-ERK  pathways have some redundant 
functions, that there are multiple negative feedback loops between theses pathways and 
that these interactions may be important for both primary and secondary resistance to 
inhibitors of either of these pathways in isolation [9].   
 


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Rationale for Dual Inhibition of PI3K and RAS- ERK Pathways 
 
Pre-clinical and translational studies support the use of inhibitors of PI3kinase pathway 
and MEK inhibitors together given the redundancy of the pathways and negative 
feedback loops.  Mouse models of K-RAS driven tumors do not response to either PI3K 
or MEK inhibition alone, but respond to the combination [10].  Interestingly the different 
isoforms of RAS ( H-RAS, N-RAS) can have differential signaling through PI3K or 
RAF, suggesting the need for both inhibitors to cease all downstream signaling [8].  PI3K 
inhibition in patients can result in the activation of several RKTs that can signal through 
RAS-ERK. In a clinical study of breast cancer, ERK was activated after two weeks of 
treatment with a rapalog, RAD001 [11]. These data have resulted in the exploration of 
combination of PI3K and MEK inhibitors in patients.  Importantly, Phase I studies of 
PI3K and MEK inhibitors in combination have shown activity in patients with 
gynecologic malignancies [12]. 
 
PI3K/AKT pathway interacts extensively with the RAF/MEK/ERK pathway.   The 
PI3K/AKT pathway also influences the response of K-RAS mutant cancers to MEK 
inhibitors, as evidenced by the observation that B-RAF mutant cancers are highly 
sensitive to MEK inhibition whereas RAS mutant cancers have varied responses.  
Activating PIK3CA mutations and loss of PTEN function, both of which can lead to 
activation of AKT signaling, lead to resistance to MEK inhibitors.  In tumors with 
coexisting KRAS and PI3KCA mutations, down-regulation of PI3KCA resensitizes 
tumors to MEK pathway inhibition.  In addition, dual inhibition of the PI3K/AKT and 
RAF/MEK/ERK pathways also seems to be required for complete inhibition of 
downstream mTOR effector pathway. 
 
2.3 
Rationale for This Study 
 
1. Pre-clinical and translational studies support the use of PI3K/AKT and MEK 
inhibitors together given the redundancy of the pathways and negative feedback 
loops.  Mouse models of K-RAS driven tumors do not response to either PI3K or 
MEK inhibition alone, but respond to the combination [10].  Interestingly the 
different isoforms of RAS (H-RAS, N-RAS) can have differential signaling through 
PI3K or RAF, suggesting the need for both inhibitors to cease all downstream 
signaling [8].  PI3K pathway inhibition in patients can result in the activation of 
several RKTs that can signal through RAS-ERK. 
 
2. Mutations in both RAS and PI3kinase have been found, with RAS mutations found 
only in adenocarcinomas and PI3kinase mutations found in both squamous cell and 
adenocarcinomas. 
 
3. Phase I studies of PI3K and MEK inhibitors in combination have shown activity in 
patients with gynecologic malignancies [12]. 
 
4. Cervical cancer is the 2nd most common cause of cancer death in the world.   Very 
few options exist for patients with recurrent cervical cancer, and chemotherapy has 


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little activity in this cancer at the time of recurrence.  Newer options are needed for 
these patients. 
 
2.4 
Correlative Studies Background 
 
The successful implementation of personalized medicine with targeted therapies 
continues to be fraught with unexpected pitfalls, decreasing the speed at which agents can 
be directed to patients that will benefit.  The failure to understand the basic biology of 
therapeutic targets frequently results in the failure of targeted therapeutics to fulfill their 
promise.  The key road block remains an inability to design and implement biomarker 
driven trials that match patients to targeted therapies most likely to inhibit their own 
tumor. 
 
As compared to other women’s cancers, there are limited comprehensive data on the rates 
of RAS-ERK and PI3K pathway alterations in cervical cancer.  The translation 
component of this study is designed in part to help alleviate this knowledge deficit.   
PIK3CA and PTEN loss have been characterized in one published study at a frequency of 
approximately 10% [9, 28]. However, molecular testing of phase I study participants 
from MD Anderson identified a PIK3CA mutation rate of 36% in squamous cervical 
cancer [29, 30].  At the Dana-Farber/Harvard Cancer Center (DFHCC), patients’ tumors 
are frequently genotyped for oncogenic mutations and our preliminary data support this 
higher rate of PIK3CA mutation [31]. K-RAS and H-RAS mutations have also each been 
reported at 10% and 22% [9, 29, 32].The co-mutation rates of PIK3CA and RAS are 
unknown but studies to explore this are ongoing at the DFHCC in archived samples.  
 
To complete the translational research objectives listed above, primary tumor and blood 
will be collected from all women who consent to participate in the trial. Additionally 
patients with tumors that are accessible tumors for in-office biopsies (i.e. vaginal 
recurrences) will be given the option of undergoing pre-treatment and post-treatment 
biopsies. These tissues will be snap frozen tissue and amenable to phospho-protein 
analysis thereby allowing investigation of negative feedback loops within the RTK-RAS- 
ERK and PI3K pathways. The details of these procedures are noted in Appendix H.  
 
 
 


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3. 
PARTICIPANT SELECTION 
 
3.1 
Inclusion Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to 
participate in the study: 
 
3.1.1 Participants must have histologically or cytologically confirmed cervical cancer which is 
now recurrent or metastatic and is refractory to curative therapy or established treatments.  
Histologic or cytologic confirmation of the original primary tumor is required. All 
histologic types of cervical origin are permitted.  
 
3.1.2 All patients must have measurable disease as defined by RECIST 1.1. Measurable disease 
is defined as at least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded).  Each lesion must be  10 mm when measured by spiral 
CT, MRI or caliper measurement by clinical exam; or  20 mm with conventional 
techniques.  Lymph nodes must be > 15 mm in short axis when measured by CT or MRI. 
 
3.1.3 Prior Therapy: 
 
• Patients must have had one prior chemotherapeutic regimen for management of 
cervical carcinoma.  Initial treatment may include chemotherapy, chemotherapy and 
radiation therapy, and/or chemotherapy as consolidation/maintenance therapy.  
Chemotherapy administered in conjunction with primary radiation as a radio-
sensitizer will not be counted as a systemic chemotherapy regimen. 
 
• Patients are allowed to receive, but are not required to receive, one additional prior 
treatment regimen (including a single chemotherapeutic, a combination of 
chemotherapeutics, or biologic drugs such as bevacizumab) for management of their 
recurrent or persistent disease.  
 
• Patients must have NOT received any class of drugs targeted to the PI3K pathway 
(such has PI3K inhibitors or mTOR inhibitors) or RAS-ERK pathway for 
management of recurrent or persistent disease.  
 
3.1.4 Age > 18 years. Because no dosing or adverse event data are currently available on the use 
of GSK1120212 and GSK2141795 in participants < 18 years of age, children are excluded 
from this study. Cervical cancer is very rare in the pediatric population.   
 
3.1.5 Life expectancy of greater than 3 months. 
 
3.1.6 ECOG performance status < 2 (see Appendix A).   
 
3.1.7 Participants must have normal organ and marrow function as defined below: 
 
• Absolute Neutrophil Count (ANC) > 1,500/mcL 


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• Platelets > 100,000/mcL 
• Hemoglobin > 9.0/dL 
• PT/INR and PTT < 1.5 × institutional ULN 
• AST (SGOT) and ALT (SGPT) < 2.5 × institutional ULN  
• Total bilirubin within normal institutional limits (isolated bilirubin > 1.5 × 
institutional ULN is acceptable if bilirubin is fractionated and direct bilirubin 
<35%) 
• Albumin > 2.5 g/dL 
• Creatinine < institutional ULN or creatinine clearance > 50 mL/min/1.73 m2 for 
subjects with creatinine levels above institutional normal or ≥ 50 mL/min 24-
hour creatinine clearance 
• Left ventricular ejection fraction (LVEF) ≥ institutional LLN by ECHO or 
MUGA 
• Fasting Blood Glucose within institutional normal limits (see Exclusion 
Criterion 3.26)    
 
3.1.8 Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue from the 
original or most recent biopsy for mutational analysis. Availability must be confirmed prior 
to enrollment. 
 
3.1.9 Blood pressure well controlled and must have systolic < 140 mmHg and diastolic < 90 
mmHg.   
 
3.1.10 The effects of GSK1120212 (trametinib) and GSK2141795 on the developing human fetus 
at the recommended therapeutic dose are unknown.  For this reason, women of 
childbearing potential must agree to use two forms of contraception (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study 
participation.  Should a patient become pregnant or suspect she is pregnant while she is 
participating in this study, she should inform the treating physician immediately. 
 
3.1.11 Toxicities of prior therapy (excepting alopecia) should be resolved to < grade 1 per the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4.0.   
 
3.1.12 GSK1120212 (trametinib) and GSK2141795 are oral medications. Patients must be able to 
tolerate oral medications and not have gastrointestinal illnesses that would preclude 
absorption of GSK1120212 and GSK2141795. 
 
 
3.1.13 Ability to understand and willingness to sign a written informed consent document. 
 
 


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3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible 
for admission into the study. 
 
3.2.1 Participants who have had chemotherapy within 3 weeks (6 weeks for nitrosoureas or 
mitomycin C,) or radiation therapy within 2 weeks prior to entering the study or those who 
have not recovered to < grade 1 (except alopecia) from adverse events (as per the 
revised NCI CTCAE version 4) due to agents administered more than 3 weeks earlier.  
 
3.2.2 Participants may not be receiving any other investigational agents nor have participated in 
an investigational trial within the past 4 weeks (or five half-lives whichever is shorter; with 
a minimum of 14 days from the last dose). 
 
3.2.3 Presence of active GI disease or other condition that could affect gastrointestinal absorption 
(e.g. malabsorption syndrome) or predispose a subject to GI ulceration.  Subjects with prior 
Whipple procedure are eligible. 
 
3.2.4 Evidence of mucosal of internal bleeding 
 
3.2.5 Any major surgery within the last 4 weeks 
 
3.2.6 Participants with fasting blood glucose values that are > institutional ULN.   In addition, 
patients with Type 1 diabetes will also be excluded; however, patients with Type 2 diabetes 
will be allowed if diagnosed ≥6 months prior to enrollment, and if presenting with regular 
hemoglobin A1C (HbA1C) ≤8% at screening. 
 
3.2.7 Participants with metastases are excluded if their brain metastases are: 
 
• Symptomatic, 
• Treated (e.g., surgery, radiation therapy) but not clinically and radiographically 
stable one month after therapy (as assessed by at least two distinct contrast 
enhanced MRI or CT scans over at least a one month period), 
OR 
• Asymptomatic and untreated but > 1 cm in the longest dimension  
 
3.2.8 Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression. 
Should participants develop brain metastases while on trial and have clinical benefit from 
GSK1120212 and GSK2141795 otherwise, participants may continue on drug after clinical 
management of the brain metastases with the permission of the principal investigator. 
GSK1120212 and GSK2141795 should be restarted between 2 and 6 weeks after the last 
radiation treatment.  
 
3.2.9 Pregnant women are excluded from this study because of the potential for teratogenic or 
abortifacient effects. Because there is an unknown but potential risk of adverse events in 
nursing infants secondary to treatment of the mother with GSK1120212 and GSK2141795 


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breastfeeding should be discontinued if the mother is treated with GSK1120212 and 
GSK2141795. 
 
3.2.10 Individuals with a history of a different malignancy are ineligible except for the following 
circumstances: 
• Individuals with a history of other malignancies are eligible if they have been disease-
free for at least 3 years or are deemed by the investigator to be at low risk for 
recurrence of that malignancy. 
• Individuals with the following cancers are eligible if diagnosed and treated within the 
past 3 years: breast cancer in situ and basal cell or squamous cell carcinoma of the 
skin, stage I colon carcinoma confined to a polyp. 
 
3.2.11 Any serious and/or unstable pre-existing medical disorder (aside from malignancy 
exception above), psychiatric disorder, or other conditions that could interfere with 
subject’s safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the Investigator. 
 
3.2.12 Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C 
Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection 
which will be allowed) as these individuals are at increased risk of lethal infections when 
treated with marrow-suppressive therapy. Appropriate studies will be undertaken in 
participants receiving combination antiretroviral therapy when indicated. 
 
3.2.13 Required, chronic, use of drugs that are strong inhibitors or inducers of p450 CYP3A4 (see 
Appendix E for a table of these agents).  
 
3.2.14 Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to GSK1120212 and GSK2141795, or excipients or to dimethyl 
sulfoxide (DMSO). 
 
3.2.15 Participants may not use natural herbal products or remedies not approved by the FDA 
while participating in this study 
 
3.2.16 History of interstitial lung disease or pneumonitis. 
  
3.2.17 Presence of cardiac metastases 
 
3.2.18 Subject with intra-cardiac defibrillators or pacemaker.  
 
3.2.19 History of retinal vein occlusion (RVO).  
 
3.2.20 History or evidence of cardiovascular risk including any of the following: 
 
• QTcF ≥ 480 msec (≥ 500 msec for subject with bundle branch block)  


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• History or evidence of current clinically significant uncontrolled arrhythmias. 
Exception:  Subjects with controlled atrial fibrillation for >30 days prior to 
randomization are eligible. 
• History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
randomization. 
• History or evidence of current ≥ Class II congestive heart failure as defined by 
New York Heart Association (NYHA; Appendix B). 
 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Only women will be included into this study because only women will develop cervical 
cancer.   
 
Women of all racial and ethnic groups are eligible for this trial. 
  
 
 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
5 
 
5 
Not Hispanic or Latino 
30 
 
30 
Ethnic Category: Total of all subjects 
35 
0 
35 
Racial Category 
 
American Indian or Alaskan Native 
0 
 
0 
Asian 
1 
 
1 
Black or African American 
5 
 
5 
Native Hawaiian or other Pacific Islander 
0 
 
0 
White 
29 
 
29 
Racial Category: Total of all subjects 
35 
0 
35 


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4. 
REGISTRATION PROCEDURES 
   
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance 
Office for Clinical Trials (QACT) central registration system. Registration must 
occur prior to the initiation of therapy. Any participant not registered to the protocol 
before treatment begins will be considered ineligible and registration will be denied.  
 
An investigator will confirm eligibility criteria and a member of the study team will 
complete the QACT protocol-specific eligibility checklist.   
Following registration, participants may begin protocol treatment. Issues that would 
cause treatment delays should be discussed with the Overall Principal Investigator 
(PI). If a participant does not receive protocol therapy following registration, the 
participant’s registration on the study may be canceled. Notify the QACT Registrar 
of registration cancellations as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 
5:00 PM Eastern Standard Time. In emergency situations when a participant must begin 
treatment during off-hours or holidays, call the QACT registration line at 617-632-3761 
and follow the instructions for registering participants after hours. 
   
The registration procedures are as follows: 
 
1. Obtain written informed consent from the participant prior to the performance of 
any study related procedures or assessments. 
 
2.  Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. 
To be eligible for registration to the protocol, the participant must meet all 
inclusion and exclusion criterion as described in the protocol and reflected on 
the eligibility checklist. 
  
 
Reminder: Confirm that a Formalin Fixed Paraffin Embedded (FFPE) tissue 
sample is available. Registration to both treatment and ancillary studies will not be 
completed if eligibility requirements are not met for all study aspects of the trial.  
  
3. Fax the eligibility checklist and all pages of the consent form to the QACT at 
617-632-2295. 
  
4. Send FFPE block via overnight post to the following address:  
 
Ariana Peralta 
Dana-Farber Cancer Institute 
450 Brookline Avenue, D117 


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Boston, MA 02215 
Telephone: 617-632-3743 
Email: aperalta2@partners.org 
 
5. The QACT Registrar will (a) review the eligibility checklist, (b) register the 
participant on the protocol, and (c) randomize the participant when applicable. 
  
6. An email confirmation of the registration and will be sent to the Overall PI, study 
coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration. 
  
 
 
 


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5. 
TREATMENT PLAN  
 
Treatment will be administered on an outpatient basis.  Reported adverse events and 
potential risks for GSK1120212 (trametinib) and GSK2126458 are described in Section 6 
(Anticipated Toxicities and Dosing Delays/Dose Modification). No investigational or 
commercial agents or therapies other than those described below may be administered 
with the intent to treat the participant’s malignancy (see Section 5.3).  
 
Each cycle will be 28 days.  The starting doses of agents are:  GSK1120212 (trametinib) 
1.5 mg QD + GSK2141795 50 mg QD.  Participants should plan to take GSK1120212 
(trametinib) and GSK2141795 at the same time each day within a 1-2 hour window. 
GSK1120212 (trametinib) and GSK2141795 should be taken orally, with approximately 
9 oz. of water. Participants must not eat grapefruit or drink grapefruit juice while taking 
study medications. Participants must not crush, chew or dissolve study medications. 
Participants will be expected to fast for 1 hour before and 2 hours after dosing of either 
study treatment.  If a participant vomits after taking either study treatment, the subject 
should be instructed not to retake the dose and should take the next scheduled dose.  
Participants will have up to 2 hours from the scheduled dosing time to take study drugs.  
If it is beyond 2 hours, the dose will be skipped. The patient will be required to maintain 
a medication diary of each dose of each medication as included in Appendix D.  
Participants will be instructed in the use of the medication diary, and will return it to 
clinic staff at the end of each cycle.  Participants should record doses as they are taken 
and not batch entries at a later time. 
 
5.1 
Pre-Treatment Criteria 
 
5.1.1 Cycle 1, Day 1 
 
• Participants must continue to meet all eligibility criteria listed in protocol sections 
3.1 and 3.2.  For clarity, laboratory criteria are listed in the table below 
• Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit of normal by 
ECHO or MUGA 
• Toxicities of prior therapy (except alopecia) should be resolved to < grade 1 
• ECOG performance status < 2 
• No evidence of life-threatening medical problems 
 
5.1.2 Subsequent Cycles, Day 1 
 
• Participants must meet the laboratory criteria listed in the table below 
• ECOG performance status < 2 
• All toxicities of previous cycles must have resolved to ≤ grade 2 
• No evidence of life-threatening medical problems 
 
 
 


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Laboratory Pre-Treatment Criteria 
 
Cycle 1, Day 1 
Subsequent Cycles, Day 1 
Absolute Neutrophil Count (ANC) 
> 1,500 / mcL 
> 1,000 / mcL 
Platelets 
> 100,000 / mcL 
> 75,000 / mcL 
Hemoglobin 
> 9.0 mg/dL 
Total Bilirubin 
Within normal 
institutional limits 
N/A 
ALT/SGPT and AST/SGOT 
< 2.5 × institutional upper limit of normal 
Albumin 
> 2.5 g/dL 
N/A 
Serum Creatinine 
< institutional upper limits of normal or creatinine clearance > 
50 mL/min/1.73 m2 for subjects with creatinine levels above 
institutional normal 
Fasting Glucose 
Within normal institutional limits 
5.2 
Agent Administration  
 
5.2.1 GSK1120212 (Trametinib) 
  
GSK1120212 will be given orally at 1.5 mg PO once per day in continuous 28 day cycle. 
Dose modification may be made for toxicities as noted in Section 6.   Participants should 
plan to take GSK1120212 (trametinib) at the same time each day within a 1-2 hour 
window with 8 oz of water.  Participants will be expected to fast for 1 hour before and 
2 hours after dosing of either study treatment.  If a participant vomits after taking either 
study treatment, the participant should be instructed not to retake the dose and should 
take the next scheduled dose.  If a dose is forgotten, the participant should not “make up” 
a dose as per section 5. GSK1120212 (trametinib) will be dispensed at the start of each 
cycle.  Participants will be provided with a pill diary (Appendix D), instructed in its use, 
and asked to bring it with them to each appointment. 
 
5.2.2 GSK2141795  
 
GSK2141795 will be given orally at 50 mg once PO daily continuously in 28 day cycles.  
 
Based on nonclinical data and increasing clinical experience, it is possible that 
GSK2141795 may be a direct gastrointestinal mucosal irritant such that subjects with GI 
dysmotility or GERD may be predisposed to symptoms of dyspepsia.  Therefore, in an 
effort to decrease this discomfort, we have the following recommendations: 
 
• A small snack followed by a 1hr fast prior to taking GSK2141795.  Water is allowed 
during this fasting period 


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• If possible; take each GSK2141795 capsule approximately 5 minutes apart with 
divided amounts of fluid (4-8 oz with each capsule for a total of at least 12 oz). 
• Remain upright for 30min after taking the last capsule of GSK2141795 
• Fast for 2hr after ingestion of the last capsule of GSK2141795. Water is allowed 
during this fasting period 
• In more severe cases, consider sucralfate and/or Gaviscon as supportive care to be 
taken at least 2hr after ingestion of the last capsule of GSK2141795, so as to avoid 
any potential drug-drug interactions.  
 
If the recommendations above are not sufficient to resolve the symptoms, the investigator 
should consider additional investigations such as upper endoscopy or barium 
radiography.  When co-administration is scheduled, GSK1120212 (trametinib) and 
GSK2141795 should be administered at the same time. 
 
Dose modification may be made for toxicities as noted in Section 6.   Participants should 
plan to take GSK2141795 at the same time each day within a 1-2 hour window.  
Participants should plan to take GSK2141795 at the same time each day within a 1-2 
hour window.  Participants should take GSK2141795 with 8 oz of water.  Participants 
will be expected to fast for 1 hour before and 2 hours after dosing of either study 
treatment.  If a participant vomits after taking either study treatment, the participant 
should be instructed not to retake the dose and should take the next scheduled dose. If it 
is greater than 2 hours from the scheduled dosing, the participant will miss the dose and 
take the next scheduled dose of study drug. Missed doses will not be made up. 
GSK2141795 will be dispensed at the start of each cycle.  Participants will be provided 
with a pill diary (Appendix D), instructed in its use, and asked to bring it with them to 
each appointment.  
 
5.2.3 Other Procedures  
 
Tumor Biopsies 
 
Participants with tumor accessible for an in-office biopsy (e.g a skin or vaginal lesion) 
will be offered the option of undergoing paired tumor biopsies. The initial biopsy will be 
performed after the patient has signed consent and has been registered for the study prior 
to administration of any drug.  The second biopsy will be planned for week 2 following 
initiation of treatment, although this may be delayed until week 3 or week 4 if necessary 
due to scheduling considerations. 
 
Participants who derive clinical benefit from the drug will be offered a biopsy at the time 
of progression, should they have disease that is safely accessible.  Participants will be 
consented for this procedure.  This biopsy should be performed within 6 weeks after 
progression. 
 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
 
The following medications are prohibited: 


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1. Other anti-cancer therapy while on treatment in this study.  
 
NOTE: megestrol (Megace) if used as appetite stimulant is allowed and palliative 
radiation therapy can be permitted with the approval of the principal investigator. 
 
2. Use of other investigational drugs within 28 days (or five half-lives whichever is 
shorter; with a minimum of 14 days from the last dose) preceding the first dose of 
GSK1120212 and GSK2141795during the study. 
 
3. All medications in Appendix E are prohibited and those listed in Appendix F are to be 
used with caution. 
 
4. Concurrent treatment with bisphosphonates is permitted; however, treatment must be 
initiated prior to the first dose of study therapy. Prophylactic use of bisphosphonates 
in subjects without bone disease is not permitted, except for the treatment of 
osteoporosis. 
 
5. Subjects should abstain from taking any herbal and dietary supplements within 5 half 
lives (or 14 days if the drug is a potential enzyme inducer) prior to the first dose of 
either study drug until completion of the follow-up visit. 
   
Because the composition, pharmacokinetics and metabolism of many herbal 
supplements are unknown, the concurrent use of all herbal supplements is prohibited 
during the study (including but not limited to St. John’s wort, kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, or 
ginseng).  
 
The investigator should contact the study PI before initiating treatment with any 
herbal preparation. 
6. Growth factor support is allowed only with the permission of the principal 
investigator. 
 
7. Oral steroids should be used with caution and subjects monitored for steroid-induced 
hyperglycemia.  Short courses (up to a maximum of 14 days) of oral corticosteroids 
intended to treat study treatment related rash or diarrhea are allowed.  Budenoside is 
recommended for supportive care of diarrhea. Subjects will be instructed to inform 
the investigator before taking any of these or any other medications.  Investigators (or 
his/her appropriate designee) will be expected to review concomitant medications 
with the subject at each clinical visit. 
 
Drugs to be used with Caution with GSK1120212 and GSK2141795 are listed in 
Appendix F (the interactions with p450 for GSK2141795 in the in vitro studies are at 
much higher concentrations than with GSK1120212).  
 
 
 


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Drugs that Inhibit or Induce Cytochrome P450 
 
In vitro studies suggest that the metabolism of GSK1120212 is mediated predominantly 
by non-CYP-mediated process and possibly by CYP3A4. Therefore, drugs that potently 
inhibit or induce CYP3A4 should be administered with caution as they may alter 
exposure to GSK1120212 and GSK2141795.  Appendix F provides a list of possible 
medications including but not limited to those drug substances that may alter 
GSK1120212 elimination. Participants who require the chronic administration of strong 
CYP3A4 inhibitors or inducers should not be enrolled on study (see section 3.2) . Should 
a clinical situation arise in which a trial participant requires the intermittent use of strong 
inhibitor of inducer of the CYP3A4, alert the principal investigator.  
 
GSK1120212 may be an inhibitor of CYP2C8 in vivo.  Caution should be exercised 
when dosing GSK1120212 concurrently with medications with narrow therapeutic 
windows that are substrates of CYP2C8.  Refer to Appendix F for list of medications 
which exposure may be increased by co-administration with GSK1120212. 
 
GSK1120212 (as victim): In vitro studies suggest that the metabolism of GSK1120212 
may be mediated by non-cytochrome P450 processes and potentially by CYP3A4.  As 
there are currently no known marketed drugs that cause clinically relevant inhibition of 
non-CYP enzymes, low drug interaction risk from the non-CYP enzymes is expected.  
The contribution of the CYP3A4 pathway to the elimination of GSK1120212 in human in 
vivo is presently unknown.  Drugs that potently inhibit or induce CYP3A4 should be 
administered with caution as they might increase or decrease exposure to GSK1120212. 
 
GSK1120212 (as perpetrator): Although in vitro data indicate that GSK1120212 is a 
potential inhibitor of CYP2C8 (IC50 0.34 M), CYP2C9 (IC50 4.1 M) and CYP2C19 
(IC50 5 M), the anticipated GSK1120212 clinical concentration Cmax of 0.1 M is below 
these in vitro IC50 values.  The drug-drug interaction risk for substrates of CYP2C9 and 
CYP2C19 is, therefore, expected to be low.  However, drugs with a narrow therapeutic 
index that are substrates of CYP2C8 should be used with caution.  The CYP3A4 
induction risk for GSK1120212 is also expected to be low for the same reason; the EC50 
value of 1.7 M is > 10-fold higher than the anticipated clinical Cmax values of both 
drugs. 
 
GSK2141795 (as victim): In vitro data indicate that GSK2141795 is a CYP3A4 
substrate.  Drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 
exposure in subjects, and will either be prohibited or used with caution in the study.  
Drugs which are strong inducers of CYP3A and may result in lower exposures of 
GSK2141795 will also be prohibited.   
 
GSK2141795 (as perpetrator) also appears to be a moderate in vitro inhibitor of 
CYP2C8 (IC50 3 M) and CYP3A4 (IC50 11 M).  Drugs that are substrates of CYP3A4 
or CYP2C8 with a narrow therapeutic index may be prohibited.  Drugs that are sensitive 
substrates of CYP3A4 or CYP2C8 should be used with caution. 
 


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Transporter Liability 
 
GSK1120212 (as victim) is neither a substrate for human P-gp nor human BCRP, and is, 
therefore, unlikely to pose a risk of being a victim of drug-drug interactions upon 
co-administration with P-gp or BCRP inhibitors. 
 
GSK1120212 (as perpetrator) inhibited OATP1B1 (IC50 of 1.3 M) and OATP1B3 
(IC50 of 0.94 M), and inhibited human BCRP mediated transport of cimetidine (IC50 of 
1.1 M).  Since these IC50 values are higher than the anticipated GSK1120212 clinical 
concentration Cmax of 0.1 M, the risk is expected to be low.  Co-administration of drugs 
that are sensitive to OATP1B1, OATP1B3, and BCRP substrates will be will be used 
with caution. 
 
GSK2141795 (as victim) is a human p-glycoprotein (P-gp, ABCB1) and breast cancer 
resistant protein (BCRP, ABCG2) substrate.  It has not been determined if GSK2141795 
is a substrate for OATP. 
  
GSK2141795 (as perpetrator) is also a potential inhibitor of BCRP (IC50 of ~1.9 M).  
It is a weak inhibitor of OATP1B1 (IC50 of ~16 M).  Drugs that are inhibitors of P-gp 
and BCRP should be used with caution.  Co-administration of drugs that are sensitive 
BCRP substrates, such as topotecan, will be prohibited. 
 
Drug-Drug interactions of GSK2141795 and GSK1120212 Combination 
 
Potential Drug-drug Interactions 
 
In vitro data indicate that GSK2141795 is a CYP3A4 substrate.  Drugs that potently 
inhibit CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should 
either be prohibited or used with caution.  Drugs which are strong inducers of CYP3A 
and may result in lower exposures of GSK2141795 should also be prohibited.  
GSK2141795 also appears to be a moderate in vitro inhibitor of CYP2C8 (50% inhibitory 
concentration [IC50] 3 mcM) and CYP3A4 (IC50 11 mcM).  Drugs that are substrates of 
CYP3A4 or CYP2C8 with a narrow therapeutic index may be prohibited.  Drugs that are 
sensitive substrates of CYP3A4 or CYP2C8 should be used with caution. 
 
 
 


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


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USE WITH CAUTION – Drugs that may have their concentrations altered by trametinib or 
GSK2141795 
repaglinide, rosiglitazone, pioglitazone 
Antidiabetics 
alfentanil, fentanyl 
Analgesics 
Quinidine 
Antiarrhythmics   
Cilostazole 
Anticoagulants and Antiplatelets 
Astemizole 
Antihistamines 
diergotamine, ergotamine, eletriptan 
Antimigraine agents 
Pimozide 
Antipsychotics 
Buspirone 
Anxiolytics 
Felodipine 
Calcium Channel Blockers 
sildenafil, tadalafil, vardenafil 
Erectile Dysfunction agents 
cerivastatin,ovastatin, simvastatin, atorvastatin 
HMG-CoA Reductase Inhibitors 
alprazolam, diazepam, midazolam, triazolam 
Hypnotics and Sedatives 
cyclosporine, sirolimus, tacrolimus 
Immunosuppressive agents 
Cisapride 
Prokinetic agents 
cyclosporine, torsemide, chloroquine, zopiclone 
Miscellaneous 
Eperenone 
Selective Aldosterone Blockers 
chloroquine, zopiclone 
Thiazolidinediones 
 
The likelihood of drug-drug interactions between GSK1120212 and GSK2141795 is low 
because the in vitro IC50 values for inhibition and EC50 values for induction of CYP450 
enzymes are 3- to 100-fold higher than the anticipated clinical Cmax values for either drug.  
Further, pharmacokinetic analyses comparing steady state exposures with those following 
single doses will be assessed for both treatments to address this question. 
 
Use of repaglinide, rosiglitazone and/or pioglitazone is permitted only after consultation 
with the Medical Monitor. 
 
Oral steroids should be used with caution and subjects monitored for steroid-induced 
hyperglycemia.  Short courses (up to a maximum of 14 days) of oral corticosteroids 
intended to treat study treatment related rash or diarrhea are allowed.  Budenoside is 
recommended for supportive care of diarrhea.  Subjects will be instructed to inform the 
investigator before taking any of these or any other medications.  Investigators (or their 
appropriate designee) will be expected to review concomitant medications with the 
subject at each clinical visit. 
 
Subjects should abstain from taking any herbal and dietary supplements within 5 half 
lives (or 14 days if the drug is a potential enzyme inducer) prior to the first dose of either 
study drug until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor there is little concern for a potential drug-drug interaction with 
the study drug(s).  These herbal medications include, but are not limited to, St. John’s 
wort, kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, and ginseng.  The investigator should contact a Medical Monitor 
before initiating treatment with any herbal preparation. 
 
 
 


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5.4 
Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression 
and tolerance. In the absence of treatment delays due to adverse events, treatment may 
continue indefinitely or until one of the following criteria applies: 
 
• Disease progression, 
• Intercurrent illness that prevents further administration of treatment, 
• Unacceptable adverse event(s), 
• Participant decides to withdraw from the study,  
• Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
• Pregnancy, or 
• General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the opinion of the treating investigator. 
 
5.5 
Duration of Follow Up  
 
Participants will be followed for 3 years after removal from study or until death, 
whichever occurs first. Participants removed from study for unacceptable adverse events 
will be followed until resolution or stabilization of the adverse event.  Date and cause of 
death should be provided for participants who become deceased within the 3-year interval 
following removal from the study.  Should a participant become pregnant while on trial, 
the patient will be withdrawn from the study. However, the outcome of the pregnancy 
and the newborn’s health, if the pregnancy is carried to term, will be monitored. 
  
 
 


DF/HCC Protocol # 13-334 
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6. 
EXPECTED TOXICITIES AND DOSING DELAYS/DOSE MODIFICATIONS  
 
Dose delays and modifications will be made using the following recommendations. 
Toxicity assessments will be performed using the revised NCI CTCAE version 4. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4, which 
can be downloaded at: http://ctep.cancer.gov.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, 
appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, 
etc.). 
 
All adverse events experienced by participants will be collected from the time of the first 
dose of study treatment, through the study and until the final study visit. Participants 
continuing to experience toxicity at the off study visit may be contacted for additional 
assessments until the toxicity has resolved or is deemed irreversible. 
 
Dose Level 
Trametinib Dose 
GSK2141795 Dose  
0 
→  Starting Dose 
1.5 mg PO every day 
50 mg PO every day 
-1 
1.0 mg PO every day 
25 mg PO every day 
 
 
NOTE: AEs occurring in participants treated with GSK2141795 + trametinib may be 
related to 1) overlapping toxicities between the two agents (e.g., rash and diarrhea); 2) 
toxicities typically associated with trametinib (e.g., visual disturbance) or GSK2141795 
(e.g., hyperglycemia or hypoglycemia).  However, toxicities associated with individual 
agents may be potentiated in the combination, or unanticipated AEs may occur.   
 
The dose modifications may involve one or both agents, and should be based on the nature, 
severity and attributions of the AEs.   
 
6.1 
Anticipated Toxicities 
 
 
A list of the adverse events and potential risks associated with the agents administered in 
this study appear below and will determine whether dose delays and modifications will 
be made or whether the event requires expedited reporting in addition to routine 
reporting. 
 
Risk has been assessed based on nonclinical toxicological studies and clinical experience 
of in-class compounds, along with preliminary data from the ongoing single-agent FTIH 
studies with GSK1120212 and GSK2141795.  Procedures to minimize or monitor 
potential risks are listed below. 
 


DF/HCC Protocol # 13-334 
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6.1.1 Predicted Overlapping Toxicities  
 
Gastrointestinal (GI) Toxicity: Interim medical history, continuous assessment of AEs, 
physical examination, and clinical laboratory assessments will be used to identify and 
assess toxicity in the GI tract.  Supportive therapy will be provided according to standard 
medical practice.  Treatment will be discontinued for clinically significant toxicity. 
 
Rash:  Subjects will be followed closely for signs and symptoms of rash and aggressive 
supportive care is recommended.  Guidelines for rash prophylaxis and for rash treatment 
management have been provided in Section 6.3.1 (table titled “Dose Modification 
Guidelines and Management for Rash”).  Treatment will be dose reduced or discontinued for 
clinically significant toxicity not adequately controlled by supportive care measures. 
 
6.1.2 GSK2141795 Safety Profile and Management  
 
Based on available adverse event (AE) data from 151 subjects dosed as of the data cut-off 
date of May 6, 2012, the most common toxicities of GSK2141795 monotherapy or in 
combination with trametinib are gastrointestinal (GI)-related (diarrhea, nausea, and 
vomiting) and fatigue (Investigator’s Brochure, 2012).  Hyperglycemia, hypoglycemia, 
mucositis, and rash are also commonly observed.  In addition, three cases of 
hypothyroidism have been noted. 
 
Interim medical history, continuous assessment of AEs, physical examination, and 
clinical laboratory assessments will be used to identify and assess toxicity in the GI tract.  
Supportive therapy will be provided according to standard medical practice.  Treatment 
will be discontinued for clinically significant toxicity. 
 
Diarrhea:  This is the most frequent drug-related AE in participants receiving 
GSK2141795.  Most diarrhea events reported were Grade 1 and 2.  Based on current data, 
the majority of cases of diarrhea occur within the first 3 to 4 weeks of starting the drug.  
In most cases, diarrhea resolves with interruption of GSK2141795 dosing and 
implementation of supportive treatment.  Based on preliminary data, re-challenge with a 
reduced dose of GSK2141795 is tolerated.  Early diarrhea management for subjects 
taking GSK2141795 is critical and must be initiated as soon as the first episode of 
diarrhea has occurred.  Supportive care interventions should include dietary 
modifications, anti-diarrheal medications, and supplementary intravenous hydration as 
needed. 
 
Mucosal Inflammation:  Mucositis has been observed as a dose-limiting toxicity (DLT). 
 
Early intervention for signs and symptoms of mucosal inflammation is recommended and 
encouraged.  Based on preliminary data, dose interruption followed by dose reduction on 
re-challenge can ameliorate symptoms.  Supportive care interventions should include 
good oral hygiene, adequate pain control, prevention of superinfection, and maintenance 
of adequate of hydration with supplementary intravenous hydration as needed. 
 


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Rash:  Rash may or may not be associated with pruritus.  Preliminary data suggest that 
drug interruption and dose reduction upon re-challenge ameliorate the symptoms.  Rash 
management should focus on symptom relief and maintenance of an intact integument. 
Dermatology consult is recommended when clinically appropriate.  Topical steroid 
creams have been found to provide some relief from symptoms.  Treatment will be dose 
reduced or discontinued for clinically significant toxicity not adequately controlled by 
supportive care measures. 
 
Hyperglycemia:  Hyperglycemia occurred in participants receiving ≥75 mg/day with the 
majority of events occurring at doses exceeding the maximum tolerated dose (MTD) of 
75 mg/day.  Treatment-related grade 3 or grade 4 events were observed at 75 mg, 100 
mg, and 150 mg daily doses.  The frequency and severity of hyperglycemia AEs is 
reduced at the 75mg/day dose as compared with higher doses.  It is not clear if oral anti-
hyperglycemic drugs are useful to ameliorate the hyperglycemia, although both 
intravenous and sliding scale insulin have been helpful. 
 
To reduce the risk of hyperglycemia, participants with abnormal fasting glucose values at 
screening will be excluded.  In addition, participants with Type 1 diabetes will also be 
excluded; however, participants with Type 2 diabetes will be allowed if diagnosed ≥6 
months prior to enrollment, and if presenting with regular hemoglobin A1C (HbA1C) 
≤8% at screening.  Participants will have glucose and insulin monitored during the study.  
If hyperglycemia is observed, supportive therapy will be provided according to standard 
medical practice.  Treatment will be dose reduced or discontinued for clinically 
significant toxicity that cannot be adequately managed medically. 
 
Hypoglycemia:  Asymptomatic hypoglycemia occurred in participants receiving ≥75 
mg/day.  Treatment-related grade 3 or grade 4 events were observed at 75 mg and 100 
mg daily doses.  The mechanism of hypoglycemia is currently unknown.  Careful 
monitoring of glucose levels and encouragement of adequate oral intake are 
recommended. 
 
Thyroid Events:  Reversible minimal to mild hypertrophy of follicular cells was seen in 
the thyroid glands of dogs given 5 mg/kg/day for 4 weeks.  The relationship to 
GSK2141795 and clinical significance are unknown, although three cases of drug-related 
hypothyroidism have been reported.  Continued monitoring for thyroid function (thyroid-
stimulating hormone laboratory testing) will be incorporated in all clinical protocols.  
Supportive therapy will be provided according to standard medical practice, and 
treatment will be discontinued if necessary. 
 
Other Glandular Events:  In both rats and dogs, several glandular structures (salivary, 
nasal, mammary, and Brunner’s glands) had reversible reductions in secretory content 
and/or apoptosis of individual acinar cells.  The mechanism for this finding is not 
understood, although it may result in dry mouth, a toxicity that has been reported in some 
participants.  Frequent monitoring with medical history, physical examination, and 
clinical laboratory assessments will be done.  If clinically significant toxicity is observed, 


DF/HCC Protocol # 13-334 
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supportive therapy will be provided according to standard medical practice, and treatment 
will be discontinued if necessary. 
 
6.1.3 Other Toxicities Based on Clinical Experience 
 
Ocular Events (GSK1120212):  To reduce the risk of ocular toxicity, subjects with a 
history of retinal vein occlusion (RVO) or central serous retinopathy (CSR), predisposing 
factors for RVO or CSR, or predisposing retinal pathology as described by 
ophthalmologic exams will be excluded.  Ophthalmologic exams will be performed at 
baseline and as clinically warranted.  Aggressive management and evaluation of all 
ocular symptoms, as well as specific ocular toxicity stopping criteria, will be 
implemented.   
 
Metabolic Toxicity:  To reduce the risk of hyperglycemia, subjects with abnormal 
fasting glucose values at screening will be excluded.  In addition, subjects with Type 1 
diabetes will also be excluded; however subjects with Type 2 diabetes will be permitted 
in Part 2 of the study only if they meet the specified entry criterion.  If hyperglycemia is 
observed, supportive therapy will be provided according to standard medical practice.  
Treatment will be dose reduced or discontinued for clinically significant toxicity that 
cannot be adequately managed medically. 
  
Cardiac toxicity (GSK1120212):  To monitor cardiac function, echocardiogram 
(ECHO) exams and electrocardiograms (ECGs) will be performed at baseline, regular 
intervals, and as clinically warranted during study treatment.  Specific cardiac toxicity 
stopping criteria will be implemented and treatment will be discontinued for clinically 
significant toxicity. 
 
6.1.4 Other Potential Toxicities Based on Nonclinical Data 
 
Hematologic Toxicity: Complete blood counts (CBC) will be measured frequently 
during therapy to monitor for hematologic toxicity.  Supportive therapy will be provided 
according to standard medical practice and treatment will be discontinued for clinically 
significant toxicity. 
 
Glandular Abnormalities: Frequent monitoring with medical history, physical 
examination and clinical laboratory assessments.  If clinically significant toxicity is 
observed, supportive therapy will be provided according to standard medical practice and 
treatment will be discontinued if necessary. 
 
Thyroid Abnormalities:  Thyroid stimulating hormone (TSH) will be measured 
frequently during therapy to monitor for thyroid dysfunction.  Supportive therapy will be 
provided according to standard medical practice and treatment will be discontinued for 
clinically significant toxicity. 
 
 
 


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6.1.5 Adverse Events List for GSK1120212 
 
The most commonly reported AE’s in Phase I studies of GSK1120212 are listed below.   
Other SAE’s that attributed to GSK1120212 but less common include: hepatic 
encephalopathy, chorioterinopathy, pneumatosis intestinalis, retinal hemorrhage, myopathy 
and pulmonary hypertension.  
 
Most Commonly Reported Adverse Events for trametinib (GSK1120212) 
in Phase I Studies 
rash 
dyspnea 
diarrhea  
pyrexia  
nausea 
pneumonia  
fatigue 
febrile neutropenia  
vomiting  
AST increased  
anemia  
ALT increased 
peripheral edema 
dry skin 
abdominal pain  
thrombocytopenia 
constipation  
peripheral edema 
dermatitis acneiform  
cough 
decreased appetite  
chills 
pruritus  
 
 
6.1.6 Adverse Events List for GSK 2141795 
 
The most commonly reported adverse events in Phase I studies of GSK2141795 are listed 
below. 
    
Most Commonly Reported Adverse Events for GSK2141795 
fatigue 
pyrexia  
nausea 
back pain 
diarrhea 
mucositis 
decreased appetite 
hypoglycemia 
blood glucose increased/hyperglycemia 
hypertension 
vomiting 
liver enzyme elevation 
dyspnea 
dehydration 
constipation  
pruritus 
rash 
edema 
cough 
 
  
6.2 
Toxicity Management 
 
The following section outlines specific management guidelines for the following 
toxicities: overdose (6.2.1), rash (6.2.2), diarrhea (6.2.3), hypertension (6.2.4), and other 
toxicities in 6.2.5 including QTc alterations, hypocalcemia and hypercalcemia, 


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pneumonitis, left ventricular changes, liver chemistry changes, visual changes, and all 
other toxicities. 
 
6.2.1 Overdose 
 
There is no specific guidance available regarding overdose due to the lack of clinical 
experience.  In case of an acute overdose, it is recommended that activated charcoal be 
administered orally to reduce the absorption of GSK1120212 and GSK2141795. 
 
6.3 
Dose Modification and Dose Interruption 
 
6.3.1 Dose Modification and Management Guidelines for Rash  
 
Two types of rashes may be seen with the GSK1120212 (trametinib) + GSK2141795 
combination: 
 
1. Acneiform, typically associated with MEK inhibitor therapy (trametinib). 
 
2. Maculopapular, often associated with pruritus (GSK2141795). 
 
If the diagnosis is unclear, a biopsy and photographs should be obtained as well as a 
dermatology consult.  In addition, if the investigator thinks the rash is not consistent with 
a MEK inhibitor-associated acneiform rash and is  Grade 2, a skin punch biopsy should 
be performed.     
 
In general, topical and oral antibiotics (doxycycline or minocycline) play a larger 
role in management of the MEK inhibitor acneiform rash, while topical and oral 
steroids are more relevant to the management of the AKT inhibitor maculopapular 
rash. 
 
Rash prophylaxis is recommended for the first 6 weeks of study treatment. 
 
Subjects should contact the investigator immediately upon onset of a rash. Full 
supportive care should be provided to subjects who experience a rash while on study. 
 
The following information is a guideline. The investigator’s best medical judgment 
should determine medical intervention for rash. 
 
General Considerations in Rash Management 
 
• Encourage subjects to avoid unnecessary exposure to sunlight. 
• Employ a proactive approach (i.e., prophylactic treatment; see below for 
recommendations). 
• If subject develops rash, verify treatment intervention and follow steps outlined below 
 
 


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Prophylactic Treatment (during the first 6 weeks of treatment) 
 
The exact prophylactic regimen should be based on the investigator’s experience; 
however, the following regimen is recommended: 
 
• Broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with a skin 
protection factor (SPF) >15. 
• Thick, alcohol-free emollient cream (e.g. glycerine and cetomacrogol cream) on dry 
areas of the body. 
 
Reactive Rash Management 
 
It is strongly recommended that subjects who develop rash or skin toxicities receive 
evaluations for management of the specific side effect. 
 
• Upon the first signs of rash, mild strength topical steroid (e.g. hydrocortisone 1% 
cream) with escalation to higher strength and/or oral steroid as detailed below. 
• Upon the first signs of papulopustular (acneiform) rash consider doxycycline (100 mg 
BID) or minocycline (100 mg BID). 
• For pruritic lesions, the use of cool compresses and oral antihistamine agents may be 
helpful. Hypoallergenic moisturizers and emollients for dry skin (5% to10% urea in 
cetomacrogel cream or soft paraffin) may also provide symptomatic relief for 
pruritus. 
• For fissuring, the use of Monsel’s solution, silver nitrate, or zinc oxide cream is 
advised. 
• For desquamation, thick emollients and mild soap are recommended. 
• For paronychia, antiseptic bath and local potent corticosteroids in addition to oral 
antibiotics are recommended and, if no improvement is seen, a dermatology or 
surgery consultation is recommended. 
• For infected lesions, bacterial and fungal culturing followed by the appropriate 
culture-driven systemic or topical antibiotics is indicated. 
• For subjects who had study drug reduced because of rash, re-escalation may be 
considered if toxicity does not recur with a re-challenge at a lower dose. 
• Consider the following algorithm (Table below) in a stepwise manner. 
 
 
Rash Management Guidelines 
Rash Grading 
Management of Rash 
Study Drug(s) Dose Adjustment 
Grade 1 
Initiate Reactive Rash Management 
regimen 
Reassess after 2 weeks; if rash worsens 
or does not improve, proceed to step 2 
Continue current dose. 


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Rash Management Guidelines 
Rash Grading 
Management of Rash 
Study Drug(s) Dose Adjustment 
Grade 2 
Initiate Reactive Rash Management 
regimen if not already started, but 
using moderate strength topical 
steroids.* 
 
Reassess after 2 weeks; if rash worsens 
or does not improve, proceed to step 3 
Continue current dose. 
>Grade 3 
Initiate Reactive Rash Management 
regimen if not already started, but 
using moderate strength topical 
steroids PLUS methyprednisolone dose 
pack. 
 
For papulopustular (acneiform) rash 
consider doxycycline 100 mg bid or 
minocycline 100 mg bid. 
 
Consider obtaining dermatology 
consultation. Manage rash per 
dermatologist’s recommendation. 
Hold study treatment until rash improves to < 
Grade 2 (or resolves), then reduce dose of 
study medications by at least 25% and monitor 
for change in rash severity*. 
Reassess after 2 weeks; if rash worsens or 
does not improve, discontinue treatment. 
 
*For first occurrence of Grade 3 rash: 
restarting at the original dose may be 
considered after instituting optimal rash 
management. 
 
6.3.2 Dose Modification and Management Guidelines for Diarrhea 
 
Episodes of diarrhea have occurred in patients receiving trametinib (Investigator’s 
Brochure, 2012a).  Other frequent causes of diarrhea including concomitant medications 
(e.g., stool softeners, laxatives, antacids, etc.), infections by Clostridium difficile or other 
pathogens, or partial bowel obstruction should be excluded. 
 
Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Uncomplicated 
Diarrhea,1 
Grade 1 or 2 
• Diet:  Stop all lactose containing 
products; eat small meals, BRAT-diet 
(bananas, rice, apples, toast) 
recommended. 
• Hydration:  8-10 large glasses of clear 
liquids per day (e.g., Gatorade or 
broth). 
• Loperamide3:  Initially 4 mg, followed 
by 2 mg every 4 hours or after every 
unformed stool; maximum 16 
mg/day.  Continue until diarrhea-free 
for 12 hours. 
• Diarrhea >24 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Consider adding oral 
antibiotics. 
• Continue treatment. 
• If diarrhea is grade 2 for > 48 h, interrupt 
GSK2141795 and trametinib (for up to 3 
weeks) until diarrhea resolves to grade ≤1. 
• Restart treatment at the same dose level 
• If treatment delay is > 21 days, discontinue 
both agents.  (Resumption of trametinib or 
GSK2141795 alone may be considered 
based on toxicity-benefit consideration and 
after consultation with PI). 


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Management and Dose Modification Guidelines for Diarrhea 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
• Diarrhea >48 hours:  Loperamide 
2 mg every 2 hours; maximum 16 
mg/day.  Add budesonide or other 
second-line therapies (octreotide, or 
tincture of opium) and oral 
antibiotics. 
Uncomplicated 
Diarrhea,1 
Grade 3 or 4 
 
and 
 
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 BOTH agents until diarrhea 
resolves to ≤ grade 1. 
• Restart with trametinib or GSK2141795 
reduced by one dose level (for the 
combination, reduce both agents by one 
level).4 
• If more than one dose reduction of study 
treatment is clinically indicated, 
permanently discontinue treatment. 
• If treatment delay is >21 days, discontinue 
treatment. (resumption of trametinib or 
GSK2141795 alone may be considered based 
on toxicity-benefit consideration and after 
consultation with PI) 
1.   Uncomplicated diarrhea defined by the absence of symptoms such as cramping, nausea/vomiting, ≥ 
grade 2, decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or 
dehydration requiring intravenous fluid substitution. 
2.   Complicated diarrhea defined by the presence of symptoms such as cramping, nausea/vomiting, ≥ 
grade 2, decreased performance status, pyrexia, sepsis, neutropenia ≥ grade 3, frank bleeding, and/or 
dehydration requiring intravenous fluid substitution. 
3.   Loperamide should be made available prior to start of study treatment so loperamide administration 
can begin at the first signs of diarrhea. 
4.   Escalation of trametinib and/or  GSK2141795 to previous dose level(s) is allowed after consultation 
with the PI and in the absence of another episode of complicated or severe diarrhea in the 4 weeks 
subsequent to dose reduction. 
 
 
 
 
 


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6.3.3 GSK2141795 Dose Modification and Management Guidelines for Hypo- or 
Hyperglycemia 
 
Hyperglycemia has been associated with treatment with GSK2141795. 
 
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 
hypoglycemia as GSK2141795 is 
held/or discontinued.   
• Intravenous insulin treatment is 
recommended. 
Hold GSK2141795 and notify 
investigator immediately.  The 
investigator should discuss 
intervention and possible 
resumption of GSK2141795 with the 
PI. 
 
 


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6.3.4 Dose Modification and Monitoring Guidelines for LVEF Decrease 
 
Decreases of the left ventricular ejection fraction (LVEF) have been observed in patients 
receiving trametinib.  GSK2141795 dose is to be modified the same as for trametinib.  
ECHOs must be performed in regular intervals outlined in the Study Calendar.  The same 
procedure (either ECHO or MUGA, although ECHO is preferred) should be performed at 
baseline and at follow-up visit(s). 
 
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinical Assessment 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose 
Modification 
Asymptomatic 
 
Absolute decrease of >10% in LVEF 
compared to baseline and ejection 
fraction below the institution’s LLN. 
• Hold trametinib and GSK2141795. 
• Repeat ECHO in 2 weeksa 
• If the LVEF recovers within 4 
weeks (defined as LVEF ≥ LLN and 
absolute decrease ≤10% 
compared to baseline)  
o Consult with the GSK medical 
monitor and request approval 
for restart  
o Restart treatment with 
trametinib reduced dose by 
one dose levelb 
o Repeat ECHO/MUGA 2, 4, 8 
and 12 weeks after re-start; 
continue in intervals of 12 
weeks thereafter  
• If  LVEF does not recover within 4 
weeks 
o Consult with cardiologist 
o Permanently discontinue 
trametinib 
o Repeat ECHO/MUGA after 2, 4, 
8, 12, and 16 weeks or until 
resolution 
o Consult with principal 
investigator and GSK medical 
monitorc 
Symptomaticc 
 
• Grade 3:  resting LVEF 39-20% or >20% 
absolute reduction from baseline 
• Grade 4:  Resting LVEF ≤ 20%. 
 
• Permanently discontinue 
trametinib and GSK2141795 
• Report as SAE 
• Consult with cardiologist 
• Repeat ECHO after 2, 4, 8, 12 and 
16 weeks or until resolution. 
a  If ECHO/MUGA does not show LVEF recovery after 2 weeks, repeat ECHO/MUGA 2 weeks later. 
b  Escalation of trametinib to previous dose level can be considered if LVEF remains stable for 4 weeks 
after restarting of trametinib.  Approval from GSK Medical Monitor is required. 
c  Symptoms may include:  dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion 
and edema. 
 


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If LVEF recovers (defined as greater than or equal to LLN AND absolute decrease is less 
than or equal to 10% compared to baseline) at any time during the next 4 weeks, after 
consultation with the PI, both trametinib and GSK141795 can be restarted at a reduced 
dose. Monitoring LVEF will be performed 2 and 4 weeks after re-challenge, and every 4 
weeks thereafter for 12 weeks and then by protocol 
 
Copies of all cardiology consultations performed on subjects who experience a > 10% 
decrease in LVEF from baseline and whose cardiac ejection fraction is below the 
institution’s LLN may also be required by GSK for review.  
 
6.3.5 Dose Modification and Monitoring Guidelines for Liver Chemistry Changes 
 
Liver chemistry stopping criteria are defined as follows: 
 
When any of the liver chemistry stopping criteria are met, immediately discontinue 
trametinib and GSK2141795, perform liver event follow-up assessments, and monitor the 
patient until liver chemistries resolve, stabilize, or return to baseline values. 
 
• ALT ≥ 3 × institutional ULN and bilirubin ≥2x institutional ULN (>35% direct 
bilirubin) (or ALT ≥3x institutional ULN and international normalized ratio [INR] 
>1.5x institutional ULN, if INR measured).  NOTE:  If serum bilirubin fractionation 
is not immediately available, treatment should be discontinued if ALT ≥ 3 × 
institutional ULN and bilirubin ≥2x institutional ULN.  Serum bilirubin fractionation 
should be performed if testing is available.  If testing is unavailable, record presence 
of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations 
and suggesting liver injury. 
• ALT ≥ 5 × institutional ULN. 
• ALT ≥ 3 × institutional ULN if associated with the appearance or worsening of 
symptoms of hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, or eosinophilia. 
• ALT ≥ 3 × institutional ULN persisting for ≥4 weeks. 
• ALT ≥ 3 × institutional ULN and cannot be monitored weekly for 4 weeks. 
 
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of investigational product and 
the follow-up period, and are in alignment with the FDA premarketing clinical liver 
safety guidance 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf).  These procedures do not apply if subjects develop liver 
chemistry abnormalities as a result of progressive disease: 
 
• Immediately withdraw the subject from study treatments. 
  
• Notify NCCN within 24 hours of learning of the abnormality to confirm the subject’s 
study treatment cessation and follow-up. 
 


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• Complete the “Safety Follow-Up Procedures” listed below. 
 
• Complete the liver event case report forms.  If the event also meets the criteria of an 
SAE (see Section 11.1.2), the SAE data collection tool will be completed separately 
with the relevant details. 
 
• Upon completion of the safety follow-up, investigator to decide whether to 
permanently withdraw the subject from the study.  Approval by the study PI for 
restarting IP can be considered where the subject is receiving compelling benefit and 
no effective alternative therapy is available OR liver chemistries have a clear 
underlying cause (e.g. biliary obstruction, hypotension) and liver chemistries have 
improved to normal or within 1.5x baseline and ALT < 3x institutional ULN).  
Subjects approved by the study PI for restarting IP must return twice a week for 
liver chemistries until stable, and then resume routine lab monitoring as per protocol.   
 
Restarting IP:  If requested by the investigator, drug restart /rechallenge following liver 
events that are possibly related to investigational product may be considered only for 
subjects who are already receiving compelling benefit from a critical or life-saving drug 
for whom there is no alternative treatment.  In these cases, approval by the study PI for 
restart may be approved when the following conditions are satisfied: 
 
• Ethics Committee or Institutional Review Board approval of drug restart/rechallenge 
must be obtained before IP can be administered. 
• If the restart/rechallenge is approved by the study PI in writing, the subject must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death. 
• The subject must also provide signed informed consent specifically for the IP 
restart/rechallenge.  Documentation of informed consent must be recorded in the 
study chart. 
• Study drug must be administered at the dose specified by the study PI. 
 
Safety Follow-Up Procedures for subjects with ALT  3x institutional ULN and  2 × 
value at Screening: 
 
• Make every reasonable attempt to have subjects return to the clinic within 24 to 
72 hours for repeat liver chemistries, additional testing. 
• Monitor subjects at least weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 
Safety Follow-Up Procedures for subjects with ALT  3 × institutional ULN and 
bilirubin  2 × institutional ULN (or ALT  3 × institutional ULN and INR1 > 1.5): 
 
• This event is considered an SAE (see Section 11.1.2). Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 


DF/HCC Protocol # 13-334 
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bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury). 
• Make every reasonable attempt to have subjects return to the clinic within 24 hours 
for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended). 
• Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 
In addition, for all subjects with no evidence of malignant involvement of the liver 
and ALT   3 × institutional ULN, every attempt must be made to also obtain the 
following: 
• Obtain viral hepatitis serology testing including: 
o Hepatitis A IgM antibody. 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM).  
o Hepatitis C RNA.  
o Cytomegalovirus IgM antibody. 
o Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing). 
o Hepatitis E IgM antibody   
• Blood sample for analysis of serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH). 
• Fractionate bilirubin, if total bilirubin 2x institutional ULN. 
• Assess eosinophilia. 
• Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, fatigue, decreased appetite, nausea, vomiting, abdominal pain, 
jaundice, fever, or rash as relevant on the AE eCRF. 
• Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins on the Concomitant Medications 
eCRF. 
• Record alcohol use on the Liver Events eCRF. 
 
The following are required for subjects with ALT 3x institutional ULN and total 
bilirubin  2x institutional ULN (>35% direct bilirubin; bilirubin fractionation required) 
or INR > 1.5x institutional ULN, without evidence of biliary obstruction or progressive 
disease, but are optional for other abnormal liver chemistries: 
 
• Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies. 
• Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution 
to liver injury, detectable by HPLC assay more than 1 week following acetaminophen 
use) [41] 
• Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody. 


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• Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
• The Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests 
are performed. 
 
6.3.6 Dose Modification, Monitoring, and Management of Hypertension 
 
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided below. 
 
Monitoring of Hypertension 
 
All blood pressure assessments should be performed under optimal conditions i.e. after (i) 
subject has been seated with back support, ensuring that legs are uncrossed and flat on the 
floor, (ii) subject is relaxed comfortably for at least 5 minutes, (ii) preparatory steps 
including removal of any restrictive clothing over the cuff area and selection of the right 
cuff size have been ensured, (iii) the arm is supported so that the middle of the cuff is at 
the heart level, and (iv) the subject remains quiet during the measurement. In subjects 
with an initial blood pressure reading within the hypertensive range, a second reading 
should be taken at least 1 minute later, with the 2 readings averaged to obtain a final 
blood pressure measurement. 
  
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) 
> 140 mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in up to three 
subsequent visits with blood pressure assessments from two readings under the optimal 
conditions described above.  Visits to monitor increased blood pressure should be 
scheduled independently from the per-protocol visits outlined in the time-and-events 
schedule; ideally, subsequent blood pressure assessments should be performed within one 
week.  
 
Asymptomatic hypertension is defined as an increase of SBP > 140 mm Hg and/or DBP 
> 90 mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of 
fainting, or other symptoms indicative of hypertension which would disappear after the 
blood pressure is controlled within the normal range. 
 
Dose Modification and Management of Hypertension 
 
• Hypertension is typically associated with trametinib.  Please follow guidelines for 
trametinib. 
• GSK2141795 may continue when trametinib is on hold if AEs are < grade 2. 
• If hypertension is grade 3-4, GSK2141795 should be held when trametinib is held.  
Once hypertension has resolved to grade 1 or baseline, GSK2141795 may resume at 
the same dose. 
• If GSK2141795795 has been held for >21 days, a discussion with the PI is required 
before resuming treatment with the agent. 
 


DF/HCC Protocol # 13-334 
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For subjects experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for the 
clinical management of hypertension are described in the table below: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Management of Hypertension 
Scenario A: 
 
• Asymptomatic and persistenta SBP of  140 
and < 160 mm Hg, or DBP  90 and <100 mm 
Hg 
 
or 
 
• Clinically significant increase in DBP of 
20 mm Hg (but still below 100 mmHg) 
Step 1: Continue GSK1120212 (trametinib) at the 
current dose.  
Step 2: Adjust current or initiate new antihypertensive 
medication(s). 
Step 3: Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-controlledb 
blood pressure (BP). If BP is not well-controlled within 
2 weeks, consider referral to a specialist and go to 
scenario B. 
Scenario B: 
 
• Asymptomatic SBP 160 mmHg, or DBP 
100 mmHg 
 
or 
 
• Failure to achieve well-controlled BP within 
2 weeks in scenario A 
Step 1: Interrupt GSK1120212 (trametinib), if clinically 
indicated. 
Step 2:  Adjust current or initiate new antihypertensive 
medication(s).  
Step 3: Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-controlled 
BP.  
Step 4: Once BP is well-controlledb, restart 
GSK1120212 reduced by one dose levelc  
Scenario C.  
 
• Symptomaticd hypertension 
 
or 
 
• Persistent SBP  160 mm Hg, or DBP 
 100 mm Hg, despite modification of 
antihypertensive medication(s) and dose 
reduction of trametinib 
Step 1: Interrupt GSK1120212(trametinib)  
Step 2: Adjust current or initiate new antihypertensive 
medication(s).  
Step 3: Titrate antihypertensive medication(s) during 
next 2 weeks as indicated to achieve well-controlled 
BP.  Referral to a specialist for further evaluation and 
follow-up is also recommended. 
Step 4: Once BP is well-controlled, restart GSK1120212 
(trametinib) reduced by one dose levelc  
Scenario D: 
 
Refractory hypertension unresponsive to 
above interventions. 
Permanently discontinue GSK1120212 (trametinib) and 
continue follow-up per protocol. 
a. hypertension detected in two separate readings during up to three subsequent visits 
b. Well-controlled blood pressure defined as SBP  140 mmHg and DBP  90 mmHg in two separate 
readings during up to three subsequent 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 GSK Medical Monitor 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. 


DF/HCC Protocol # 13-334 
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6.3.7 Dose Modification and Monitoring for QTc Prolongation 
 
Guidelines for dose modification and stopping criteria due to QTC-prolongation are 
provided in the table below. Refer to Appendix I for QTcB prolongation correction 
guidance. 
 
Dose Modification and Monitoring for QTc Prolongation 
QTc Prolongationa Criteria 
Management Guidelines 
• QTcF > 501 msec (Grade 3 or 4 QTc 
prolongation) 
 
or 
 
• uncorrected QT > 600 msec 
 
or 
 
• QTcF > 530 msec for subjects with bundle 
branch block 
• Hold study drug(s) until QTcB prolongation resolves to 
Grade 1 or baseline 
 
• Recommend testing of serum potassium, calcium, 
phosphorus, and magnesium. If abnormal, correct per 
routine clinical practice to within normal limits 
 
• Review concomitant medication usage for a 
prolonged QTc 
 
• Restart study drug(s) at the current dose levelb 
 
• If the event recurs, permanently discontinue study 
treatment 
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 GSK medical monitor agree that the subject will benefit from further treatment. 
 
 
 
 


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6.3.8 Dose Modification and Monitoring for Pneumonitis 
 
• Pneumonitis is typically associated with trametinib.  Please follow guidelines for 
trametinib. 
• GSK2141795 may continue when trametinib is on hold if AEs are < grade 2. 
• If pneumonitis is grade 3-4, GSK2141795 should be held when trametinib is held.  
Once pneumonitis has resolved to grade 1 or baseline, GSK2141795 may resume at 
the same dose. 
• If GSK2141795795 has been held for >21 days, a discussion with the PI is required 
before resuming treatment with the agent. 
 
Dose Modification and Monitoring for Pneumonitis 
Criteria 
Management Guidelines 
For all grades, obtain high resolution chest CT if possible. 
Grade 1 
Consider evaluation by pulmonologist.  Consider room air O2 saturation at rest via 
pulse oximetry reading (x2, 5 mins apart).  Repeat evaluations every 8-12 weeks 
until return to within normal limits (WNL).  Continue study drug(s) at current 
dose(s). 
Grade 2 
For Grade 2 or higher respiratory symptoms (i.e cough, dyspnea, hypoxia, etc.) 
consider evaluation by pulmonologist.  Consider pulmonary function tests 
including: spirometry, DLCO, and room air O2 saturation at rest via pulse oximetry 
reading (x2, 5 mins apart).  Repeat evaluations every 8-12 weeks until return to 
WNL.  Consider a bronchoscopy with biopsy and/or bronchoalveolar lavage (BAL). 
 
Treat only if symptomatic.  Consider corticosteroids if symptoms are troublesome 
and infective origin is ruled out.  Taper as medically indicated. 
 
Hold study drug(s) until recovery to < Grade 1, then reduce dose by at least 25%.   
Discontinue study drug(s) if no recovery to < Grade 1 within 4 weeks.  May 
consider escalation to pre-event dose(s). 
Grade 3 or 4 
Evaluation by pulmonologist.  Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at rest via pulse oximetry reading (x 
2, 5 mins apart).  Repeat evaluations at least every 8 weeks until return to WNL.  
Bronchoscopy with biopsy and/or BAL is recommended. 
 
Consider corticosteroids if infective origin is ruled out. Taper as medically 
indicated.  
 
(Grade 3) Hold study drug(s) until recovery to < Grade 1. Discontinue study drug(s) 
if no recovery to < Grade 1 within 4 weeks. May consider restarting study drug(s) 
at a reduced dose(s). Monitor if there is clinical benefit. 
 
(Grade 4) Discontinue study drug(s) 
 
 
 
 


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6.3.9 Dose Modification and Monitoring for Mucositis 
 
Dose Modification and Monitoring for Mucositis 
Criteria 
Management Guidelines 
Grade 1 or 2 
Encourage oral hygiene. Offer topical supportive anesthetics.  
Encourage adequate hydration. 
Grade 3 or 4 
As above, plus systemic opiate administration as needed. Consider 
IV hydration and hospital admission as appropriate. Temporarily 
discontinue study drug(s). 
 
 
6.3.10 Dose Modifications, Monitoring, and Stopping Rules for Visual Disturbance 
 
Episodes of visual changes have been observed in subjects receiving trametinib, and 
ocular adverse events are known to be related to trametinib. 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), monitor closely but ophthalmic 
examination can be deferred. Special attention should be given to retinal findings (e.g. 
retinal pigment epithelial detachment (RPED), retinal vein abnormalities (e.g. branch or 
central retinal vein occlusions (RVO)), or optic nerve swelling. 
 
Guidelines regarding management and dose reduction for visual changes and/or 
ophthalmic examination findings considered to be related to study treatment are provided 
in the tables below: 
 
Table 6.3.10 A:  Management and Dose Modification Guidelines for Visual 
Changes and/or Ophthalmic Examination Findings 
Table 6.3.10 B:  NCI-CTCAE v 4.0: “Eye Disorders - Other, specify” 
Table 6.3.10 C:  Recommended dose modifications for trametinib for retinal 
pigment epithelial detachments (RPED) 
Table 6.3.10 D:  NCI-CTCAE v 4.0: “Retinopathy” 
 
Ophthalmologic Exam 
 
At certain time points in the trial and if visual changes develop, an eye exam is indicated. 
(Refer to Table 6.3.10 A for visual changes stopping criteria).  The exam will include 
best corrected visual acuity, visual field examination, tonometry, slit lamp 
biomicroscopic examination, and indirect fundoscopy, with special attention to retinal 
abnormalities.  Optical coherence tomography is recommended at scheduled visits and if 
retinal abnormalities are suspected. Other types of ancillary testing including visual field 
examination, fundus photography, and fluorescein angiography may also be indicated as 
determined by clinical exam. 
 
 
 


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Table 6.3.10 A:  
Management and Dose Modification Guidelines for Visual Changes 
and/or Ophthalmic Examination Findings 
CTCAE Gradea 
Adverse Event Management 
Action and Dose Modification 
  
Grade 1b 
• Consult ophthalmologist 
within 7 days of onset 
• If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED, and RVO can be 
excluded by retina specialist/ophthalmologist. 
• If RPED and RVO excluded, continue (or 
restart) trametinib at same dose level 
• If RPED suspected or confirmed: see RPED dose 
modification table below; report as SAE. 
• If RVO diagnosed:  Permanently discontinue 
trametinib and report as SAE. 
 
 Grade 2 and 
 Grade 3 
• Consult ophthalmologist 
immediately 
• Interrupt trametinib  
• If RPED and RVO excluded and ophthalmic 
findings are consistent with an alternative 
suspected trametinib-related ocular adverse 
event (e.g., optic neuropathy), and signs and 
symptoms resolve to baseline, resume 
trametinib at a lower dose (reduced by 0.5 
mg) or discontinue trametinib in patients 
taking 1 mg daily. 
• If RPED and RVO excluded and ophthalmic 
findings are NOT consistent with an alternative 
suspected trametinib-related ocular adverse 
event (e.g., optic neuropathy), restart 
trametinib at same dose level 
• 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  
• If RVO or RPED then permanently discontinue 
trametinib and report as SAE 
• If RPED and RVO excluded and ophthalmic 
findings are consistent with an alternative 
suspected trametinib-related ocular adverse 
event (e.g. optic neuropathy), then 
permanently discontinue trametinib and 
report as SAE 
• If RPED and RVO excluded, and ophthalmic 
findings are NOT consistent with an alternative 
suspected trametinib-related ocular adverse 
event, interrupt treatment with trametinib and 
report as an SAE.  If signs and symptoms 
resolve to baseline, may consider restarting 
trametinib at same or reduced dose 
a. Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify,’ as detailed in Table 6.3.10 B, below 
b. 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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Table 6.3.10 B: NCI-CTCAE v 4.0: ‘Eye Disorders - Other, specify’ 
Grade 
Description 
1 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) 
3 
Severe or medically significant but not immediately sight-threatening; 
hospitalization or prolongation of existing hospitalization indicated; disabling; 
limiting self care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 
or worse) in the affected eye 
 
 
Table 6.3.10 C: Recommended dose modifications for trametinib for retinal pigment 
epithelial detachments (RPED)a 
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only) 
• Continue treatment with retinal evaluation monthly 
until resolution. If RPED worsens follow instructions 
below and withhold trametinib for up to 3 weeks 
Grade 2-3 RPED (Symptomatic with 
Mild to moderate decrease in visual acuity; 
limiting instrumental ADL 
• Withhold trametinib for up to 3 weeks 
 
Grade 2-3 RPED that improves to Grade 0-1 
within 3 weeks  
• If improved within 3 weeks, resume trametinib at a 
lower dose (reduced by 0.5 mg) or discontinue 
trametinib in patients taking trametinib 1 mg daily 
Grade 2-3 RPED that does not improve to at 
least Grade 1 within 3 weeks  
• Permanently discontinue trametinib 
a. Refers to CTCAE Version 4.0 ‘Retinopathy,’ as detailed in Table 6.3.10 D, below 
 
 
Table 6.3.10 D: NCI-CTCAE v 4.0: ‘Retinopathy’ 
Grade 
Description 
1 
Asymptomatic; clinical or diagnostic observations only 
2 
Symptomatic with moderate decrease in visual acuity (20/40 or better); limiting 
instrumental ADL 
3 
Symptomatic with marked decrease in visual acuity (worse than 20/40); disabling; 
limiting self care ADL 
4 
Blindness (20/200 or worse) in the affected eye 
 
6.4 
Dose Adjustment/Stopping Safety Criteria for Other Clinically Significant Toxicities 
 
Dose modification guidelines are outlined in the table below for clinically significant 
toxicities, including hematologic toxicities, that are deemed related to study 
medication(s) but are not addressed above.   If a given toxicity is considered by the 


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investigator to be related to a single investigational drug and not both, then dose 
modification may occur only with the drug associated with a specific toxicity or event of 
clinical concern. 
Dose Modification Guidelines for GSK1120212 (trametinib) and/or GSK2141795 
Toxicity Gradea  
Dose Modification of GSK1120212 (trametinib)  and/or GSK2141795 
Grade 1 
Continue at current dose level.  Consider supportive care 
recommendations.  
Grade 2 
Consider withholding dose until toxicity resolves to Grade 1 or 
baseline.  Upon resolution, then restart at current dose level.  Consider 
supportive care recommendations. 
Grade 3 
Withhold dose until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, then consider dose reducing by next lower dose level. 
Consider supportive care recommendations.  
Grade 4 
Permanently discontinue study medications. 
a. Considered related to study drug. 
 
6.4.1 Management of Fever and Neutropenia 
 
Participants who develop fever and neutropenia will be managed via standard medical 
practice and American Society of Clinical Oncology and NCCN guidelines.  Participants 
will need to recover from fever and active infectious issues prior to resuming therapy.  Use 
of growth factors may be considered after discussion with the primary investigator. 
 
6.4.2 Additional Toxicities 
 
Other toxicities are possible on this trial.  Participants developing drug-associated grade 3 
or 4 non-hematological toxicities or grade 4 hematological toxicities that do not resolve 
or improve to grade 1 within 21 days will be removed from protocol.  Participants whose 
toxicity has resolved to baseline or Grade 1 and whose therapy has been discontinued for 
fewer than 21 days may resume therapy with 1 level of dose reduction. 
 
 


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7. 
DRUG FORMULATION AND ADMINISTRATION  
 
7.1 
GSK1120212 (Trametinib) 
 
Please refer to the Investigator’s Brochure for GSK1120212 information in addition to the 
information below. 
 
7.1.1 Description 
 
Chemical Structure:  
GSK1120212 polycyclic, nitrogen containing heterocycle 
also possessing aromatic halide and amide functionality, and 
is a dimethyl sulfoxide solvate. The biochemical structure has 
been unambiguously identified. 
 
Other Names:  
GSK1120212B, trametinib 
 
Classification:  
MEK 1/2 inhibitor 
 
Approximate Solubility:   
Almost insoluble in water (<0.0001 mg/mL at 25°C). 
Aqueous solubility is not affected by pH in the range 2-10. 
 
Mode of Action:   
The RAS-ERK pathway is downstream of EGFR, HER2, 
IGF1R, and cMet, and is a suspected driver of tumor 
progression in many cancers. GSK 1120212 inhibits MEK, a 
kinase within the RAS-ERK cascade.  
 
Description:   
MEK 1/2 inhibitor 
 
7.1.2 Form 
 
How Supplied:  GSK1120212B Tablets are supplied as 0.5 mg and 2 mg (as free base) 
tablets for oral administration. GSK1120212B Tablets, 0.5 mg (as free base) are white or 
yellow, modified oval, biconvex, film-coated tablets. GSK1120212B Tablets, 2 mg (as free 
base) are pink, round, biconvex, film-coated tablets. 
 
GSK1120212B Tablets are packaged into a high density polyethylene (HDPE) bottle that 
contains desiccant with a child-resistant closure that includes an induction seal liner. The 
HDPE bottle may be enclosed in a paperboard carton. The carton is required for white 0.25 
mg, 0.5 mg, and 1 mg tablets and optional for yellow 0.5 mg tablets and pink 2 mg tablets. 
 
List of Excipients 
 
Tablet Core:  
Mannitol, Microcrystalline cellulose, Hypromellose, 
Croscarmellose sodium, Magnesium stearate (non-animal), 
Colloidal silicon dioxide, Sodium lauryl sulfate 
 


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Aqueous Film Coating:  
Opadry White OY-S-28876 (all strengths except 2 mg) 
containing hypromellose, titanium dioxide, polyethylene glycol; 
Opadry Pink YS-1-14762-A (2 mg only) containing 
hypromellose, titanium dioxide, polyethylene glycol, polysorbate 
80, iron oxide red; Opadry Yellow 03B120006 (0.5 mg only) 
containing hypromellose, titanium dioxide, polyethylene glycol, 
iron oxide yellow 
 
7.1.3 Storage and Stability 
 
The recommended storage conditions, and expiry date where required, are stated on the 
product label. Under normal conditions of handling and administration, GSK1120212 is 
not expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request. 
 
7.1.4 Compatibility 
 
Potential Drug Interactions:   No clinical drug interaction studies have been performed 
with GSK1120212.  GSK1120212 may induce of inhibitor of 
major P450 enzymes CYP34A and 2C9.  
 
7.1.5 Availability 
 
GSK1120212 is an investigational agent and will be supplied to investigators by the 
GSK.  
 
7.1.6 Administration 
 
Route of Administration:  
Oral 
 
Method of Administration:  
Take GSK1120212 with 8 oz of water.  
 
7.1.7 Patient Care Implications 
 
In acute overdose, use activated charcoal to reduce the absorption of GSK1120212.  If 
additional measures are needed, consider emptying the stomach.  Administer specific 
medical therapy as clinically appropriate. 
 
7.1.8 Ordering 
 
GSK1120212 may be requested by the Principal Investigators (or their authorized 
designee) at each participating institution from GlaxoSmithKline.  
 
 


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7.1.9 Accountability 
 
The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at http://ctep.cancer.gov/protocolDevelopment  
for the “Policy and Guidelines for Accountability and Storage of Investigational Agents” 
or to obtain a copy of the drug accountability form.) 
 
7.1.10 Destruction and Return 
 
At the end of the study, unused supplies of GSK1120212 should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
7.2 
GSK2141795  
 
Please refer to the Investigator’s Brochure for GSK2141795 information in addition to 
the information below. 
 
7.2.1 Description 
 
Chemical Structure:  
GSK2141795   
 
Other Names:  
GSK2141795 
 
Classification:  
AKT inhibitor 
 
Approximate Solubility:   
GSK2141795 is very slightly soluble in water (0.18 mg/ml) at 
room temperature.  > 11 mg/mL in Simulated Gastric Fluid at 
370C.  Solubility decreases as pH increases. 
 
Mode of Action:   
The PI3K pathway is downstream of EGFR, HER2, IGF1R, 
and cMet, and is a suspected driver of tumor progression in 
many cancers.  GSK2141795 inhibits AKT.     
 
Description:   
AKT inhibitor 
 
7.2.2 Form 
 
How Supplied:  Four strengths of GSK2141795C are supplied as capsules for oral 
administration equivalent to 1 mg (orange/white, opaque size 4 gelatin capsules with thick 
and thin bars printed in black ink), 5 mg (blue/white, opaque size 3 gelatin capsules with 
thick and thin bars printed in black ink), 5 mg (white opaque body and cap, size 3 gelatin 
capsules), 25 mg (Swedish orange, opaque size 2 gelatin capsules), 100 mg (purple/white, 
opaque size 1 gelatin capsules with thick and thin bars printed in black ink) or 100 mg 


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(white opaque body and cap, size 1 gelatin capsules). 
 
The capsules are packaged in white high density polyethylene bottles with white plastic, 
induction-seal, child-resistant caps. 
 
7.2.3 Storage and Stability 
 
The recommended storage conditions, and expiry date where required, are stated on the 
product label.  Patients can have the drug at room temperature during travel from the 
clinic to home.  The drug should be kept refrigerated once the patient arrives at home.  
Advise the subjects to notify the study staff if the drug is left at room temperature for 
long periods of time. 
 
7.2.4 Compatibility 
 
Potential Drug Interactions: 
No clinical drug interaction studies have been performed 
with GSK2141795.   
 
7.2.5 Availability 
 
GSK2141795 is an investigational agent and will be supplied to investigators by 
GlaxoSmithKline.  
 
7.2.6 Administration 
 
Route of Administration:  
Oral 
 
Method of Administration:  
GSK2121795 should be taken orally, with approximately 
200 mL of water.  Participants will be expected to fast for 1 
hour before and 2 hours after dosing of either study 
treatment.  If a participant vomits after taking either study 
treatment, the participant should be instructed not to retake 
the dose and should take the next scheduled dose.  
 
7.2.7 Patient Care Implications 
 
In acute overdose, use activated charcoal to reduce the absorption of GSK2141795.  If 
additional measures are needed, consider emptying the stomach.  Administer specific 
medical therapy as clinically appropriate. 
 
7.2.8 Ordering 
 
GSK2121795 may be requested by the Principal Investigators (or their authorized 
designee) at each participating institution from GlaxoSmithKline. 
 
7.2.9 Accountability 


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The investigator, or a responsible party designated by the investigator, must maintain a 
careful record of the inventory and disposition of the agent (investigational or free of 
charge) using the NCI Drug Accountability Record or another comparable drug 
accountability form. (See the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment for the “Policy and Guidelines for 
Accountability and Storage of Investigational Agents” or to obtain a copy of the drug 
accountability form.) 
 
7.2.10 Destruction and Return 
 
At the end of the study, unused supplies of GSK2141795 should be destroyed 
according to institutional policies. Destruction will be documented in the Drug 
Accountability Record Form. 
 
 
 


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8. 
CORRELATIVE/SPECIAL STUDIES 
  
8.1 
Hypothesis  
 
The further development and study of molecular targeted therapy has revealed that in 
many cases, the genetic makeup of the tumor can be used to predict response or 
resistance to treatment with a given therapeutic. The pre-clinical studies of PI3K pathway 
and MEK inhibitors, suggest that these drugs will have differential effects on tumors 
harboring different genetic aberrations [35, 36]. The hypothesis of these studies is that 
cervical cancers harbor high rates of mutations in both PI3K and RAS pathways and that 
these mutations may make them more susceptible to agents that target these pathways. 
 
8.2 
Preliminary Data  
 
Isolated mutational analyses of PIK3CA, K-RAS and H-RAS genes from cervical cancers 
from different clinical cohorts have identified mutational rates of 10-33%, 10% and 9-
22% respectively [9, 29, 32].   Parallel mutational analysis of these genes has not been 
reported and, as such, it is unknown if co-mutation occurs (as it does commonly in 
endometrial cancer) [37]. These studies are underway at the DF/HCC.  
 
8.3 
Study Design 
  
Tumor specimens from archived specimens will be required for all participants in the 
clinical study.  Tissue will be requested from either the original hysterectomy specimen 
or from biopsies at recurrence.  A single vial of whole blood will also be collected for 
isolation of control germline DNA. Dependent upon the amount of DNA available, 
targeted mutation detection, targeted gene sequencing or targeting SNP analysis will be 
performed (see methodology below). Correlative studies of RAS isoform mutation and 
PIK3CA mutation to clinical benefit will be performed (see Appendix H for details). 
Optional pre and post- treatment biopsies will be requested from participants whose 
tumors are amenable to an in-office biopsy (e.g. vaginal recurrence or cervical 
recurrence). Participants who derive benefit from GSK1120212 and GSK2126458 and 
whose tumors are amenable to an in-office biopsy will be offered optional biopsies at the 
time of progression. These samples will be amenable to more detailed protein evaluation 
including pharmacodynamic studies and exploration of mechanisms of resistance. These 
studies will be exploratory in nature (see analytic plan). 
  
8.4 
Study Population 
 
Tumors tissue will be sought from all participants in the clinical study. 
  
8.5 
Methodology 
  
Unlike other gynecologic malignancies, surgery is not necessarily performed on all 
patients and hysterectomy tissues, which can be ample, will not be available for all 
participants.  As such, correlative studies will need to be designed with the presumption 


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that material will be available from biopsies at recurrence, which have limited tissue.  
Technology advances now allow for parallel sequencing of multiple targets, from small 
amounts of DNA (50-500ng) For this study, we propose to evaluate the PI3K and RAS-
ERK pathway in detail with the use of either next generation targeted sequencing, 
mutation detection with sequenome technology, or SNP hybridization analysis for 
mutation and copy number analysis (all described in Appendix H). The decision of which 
assay to use will depend upon amount of DNA available as well as proven validity of 
each assay at the time of sample processing as these technologies are being rapidly 
improved. For example, targeted DNA sequencing could offer the discovery of new gene 
mutations as well as some information about copy number.  However, it may be more 
susceptible to false positives. It is expected that there will be advanced in the precision 
and experience with all of these assays by the time these samples are studied 
(approximately 2 years from now).  Pre-and post- treatment as well as progression 
samples will be collected both in formalin as well as flash frozen. Formalin samples will 
be paraffin embedded.  These samples will be H and E stained for histological evaluation. 
IHC or RPPA will performed on frozen samples. 
  
8.6 
Analytic Plan  
 
Molecular correlative analyses will be conducted and all patient outcomes: response, 
PFS, OS and toxicity will be compared between the PIK3CA and RAS-isoform mutated 
and WT groups using the statistical methodologies specified above; estimating the 
proportion of participants harboring mutations in both genes is also of interest, as is 
comparing their outcomes to those in the remainder of the cohort. These analyses are 
considered exploratory and will not be adjusted for multiple comparisons.  
 
8.7 
Specimen Requirements 
 
Participation in the laboratory correlative study component of this study is mandatory for 
all participants.  Additional details regarding correlative studies are outlined in Appendix H 
and the lab manual.  The participating institution will collect and submit the patient’s 
specimens as outlined below: 
 
Required Specimen 
Collection Time Point 
Specific Instructions 
Archival Formalin-Fixed 
Paraffin-Embedded (FFPE) 
Tumor 
Required for Study 
Eligibility 
Collected prior to initiating 
study treatment 
1st choice: block 
2nd choice: 25 unstained 
sections (10- 5 μm and 15- 10 
μm) 
Pre-treatment Whole 
Blood  
Collected prior to initiating 
study treatment  
Blood drawn into two (2) 
EDTA tubes, 7-10 mL blood 
into each tube 


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Required Specimen 
Collection Time Point 
Specific Instructions 
Pre-treatment Plasma 
Collected prior to initiating 
study treatment  
7-10 mL drawn into 
appropriate plasma 
separator tube 
Snap Frozen Primary 
Tumor1 
Collected prior to initiating 
study treatment 
N/A 
Pre-treatment Biopsy2 
Collected after screening 
and prior to initiating study 
treatment 
Minimum 3 cores: 
1 FFPE 
2 snap frozen 
Post-treatment Biopsy3 
Collected at Cycle 1 
between Days 8-154, after 
initiation of study 
treatment  
Minimum 3 cores: 
1 FFPE 
2 snap frozen 
Post-progression Biopsy5 
Collected within 6 weeks of 
progression  
Minimum 3 cores: 
1 FFPE 
2 snap frozen 
1 If available from the participating institution’s tissue banks 
2 Optional in participants with accessible, biopsiable lesions 
3 Only in participants who had an initial pre-treatment biopsy.  Post-treatment biopsy 
will not be required in participants who have had a complete response or whose 
tumor has responded such that lesions are no longer biopsiable. 
4 Can be collected at any point during Cycle 1 between Days 8-15, preferred. If unable 
to collect during Days 8-15 for scheduling reasons, it will be acceptable to perform the 
biopsy between Days 15-28 of Cycle 1. 
5 Optional in participants with accessible, biopsiable lesions 
 
Shipping instructions for frozen samples will be clarified at a later time point. 
 
Sites should send ambient FFPE biopsy samples directly to the Clinical Research 
Coordinator at the following address: 
 
Ariana Peralta 
Dana-Farber Cancer Institute 
450 Brookline Avenue, D117 
Boston, MA 02215 
Telephone: 617-632-3743 
Email: aperalta2@partners.org 
 
 
 


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9. 
STUDY CALENDAR 
 
Baseline evaluations should be conducted within 14 days prior to start of protocol therapy. Scans must be done ≤ 28 days prior to the start of 
therapy. All assessments must be performed prior to administration of any study medication. All study assessments should be administered within +/- 
3 days of the protocol-specified date, unless otherwise noted.  Study assessments not required after an indicated timepoint should be performed as 
clinically indicated in the future. In the event that the participant's condition is deteriorating, laboratory evaluations should be repeated within 48 
hours prior to initiation of the next cycle of therapy. One treatment cycle is 28 days in duration.  
 
Study Assessments a 
Screen b 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles c  
Even Cycles 
Off-Treatment 
Visit d 
Day 1 
Day 8 
Day 
15 
Day 22 
Day 1 
Day 1 
Day 1 
Day 1 
Between 
Days 22 - 28 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical History / 
Interim History 
X 
X 
X e 
X 
X e 
X 
X 
X 
X 
 
X 
Physical Exam f 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
ECOG Performance 
Status 
X 
X g 
 
X 
 
X 
X 
X 
X 
 
X 
Vital Signs w 
X 
X 
 
X 
 
X 
X 
X 
X 
 
X 
Height and Weight v 
X 
X g 
 
 
 
X 
X 
X 
X 
 
X 
Hematology h 
X 
X g 
X e 
X 
X e 
X 
X 
X 
X 
 
X 
Clinical Chemistry i 
X 
X g 
X e 
X 
X e 
X 
X 
X 
X 
 
X 
Fasting Blood Glucose y 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Coagulation j 
X 
X g 
 
 
 
 
 
 
 
 
 
Creatinine Clearance 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test k 
X 
 
 
 
 
 
 
X v 
 
 
X 
Fasting Lipid Panel 
X 
 
 
 
 
 
 
X v 
 
 
X 
Hemoglobin A1C 
X 
 
 
 
 
 
 
X v 
 
 
X 
TSH 
X 
 
 
 
 
 
 
X v 
 
 
X 
1,5-anhydroglucitol 
(1,5-AG) l 
X 
 
 
X 
 
X l 
X l 
X l 
 
 
 
12-Lead ECG m 
X 
X 
 
X 
 
 
 
 
X 
 
X 
ECHO or MUGA n 
X 
 
 
 
 
X u 
 
 
 
 
X 


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Study Assessments a 
Screen b 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Subsequent 
Cycles c  
Even Cycles 
Off-Treatment 
Visit d 
Day 1 
Day 8 
Day 
15 
Day 22 
Day 1 
Day 1 
Day 1 
Day 1 
Between 
Days 22 - 28 
Ophthalmic Exam o 
X 
 
 
 
 
 
 
 
 
 
 
Disease Assessment r 
X 
 
 
 
 
 
 
 
 
X 
X 
Brain Imaging s 
X 
 
 
 
 
 
 
 
 
X 
 
Chest Imaging 
(X-ray or CT) t 
X 
 
 
 
 
 
 
 
 
X 
X 
Trametinib and 
GSK2141795 Dosing 
 
X (Continuous daily dosing)  ----------------------------------------------------------------------------------  X 
 
Circulating Free 
Tumor DNA p 
 
X g 
 
 
 
 
 
 
 
 
X 
Archival Tumor Tissue p 
X 
 
 
 
 
 
 
 
 
 
 
Biopsies q 
X 
 
X 
 
 
 
 
 
 
 
X 
Concomitant 
Medications 
X 
X (Continuous)  ------------------------------------------------------------------------------------------------------------------------  X 
Adverse Events 
 
X (Continuous)  ------------------------------------------------------------------------------------------------------------------------  X  
a. Assessments should be done prior to administration of study drug(s), unless otherwise specified. 
b. Within 14 days before first dose with the following exceptions: 
• LVEF assessment can occur within 45 days of first dose 
• disease assessment can occur within 28 days of first dose 
c. If clinically indicated, assessments during subsequent cycles can occur more frequently. 
d. Final study visit should occur 21 days (7 days) after last dose of study drug. 
e. Medical history and interim history for Cycle 1 Day 8 and Day 22 can be obtained through a phone call to the participant. Hematology and clinical chemistry 
can be obtained locally. 
f. Physical exams should be completed as follows: 
•  Screening physical exam should include: the evaluation of the head, eyes, ears, nose, and throat, cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal and neurological systems. 
• After screening, targeted physical examinations should be limited to systems of primary relevance and those systems associated with symptoms. 
g. If completed within 72 hours prior to dosing, this assessment does not need to be repeated. 
h. Hematology should include: red blood cell count, total white blood cell count, hemoglobin, hematocrit, platelet count, WBC differential (absolute) 
i. Clinical chemistry should include: sodium, BUN, creatinine, bicarbonate, chloride, calcium, LDH, phosphorus, GGT, magnesium, potassium, total protein, 
albumin, SGOT (AST), SGPT (ALT), alkaline phosphatase, total bilirubin 
j. Coagulation should include: prothrombin time (PT)/international normalized ratio (INR) and activated partial thromboplastin time (aPTT). 
k. Perform only in women of child-bearing potential.  A serum pregnancy test should be performed at screening; subsequent pregnancy tests may be either 


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serum or urine. 
l. Should be collected pre-dose while the participant is on treatment. If 1,5-AG test is not available in a given country, the analyte is not required to be 
performed in that country. 
m. A single 12-lead ECG should be performed at screening, prior to dosing on Day 1 and Day 15 of Cycle 1, and prior to dosing on Day 1 of each subsequent 
cycle. 
n. Either an ECHO or MUGA should be performed to assess LVEF at screening, Cycle 2 Day 1, then every 12 weeks, at the final study visit, and as 
symptomatically warranted 
o. Ophthalmic exam will include indirect and direct fundoscopy, visual acuity (corrected), visual field examination, tonometry, and color fundus photos.  
Additional ophthalmic exams will be performed if symptomatically warranted. 
p. Refer to the Lab Manual and Section 8.7 of the protocol. 
q. Pre-treatment biopsy to be collected after screening and prior to initiation of study treatment. Post-treatment biopsy to be collected at Cycle 1 at any point 
during Days 8 – 14 (preferred); collected during Days 15-28 are also acceptable. Post-progression biopsy to be collected within 6 weeks of progression. Refer 
to Section 8.7. 
r. CT or MRI in between Days 22-28 of every even cycle. The same radiographic procedure used for screening should be used throughout the study. A 
confirmatory disease assessment should be performed no fewer than 4 weeks (28 days) after the criteria for response (PR or CR) are first met.  If subject 
was withdrawn due to radiographic progression of disease (PD), disease assessments do not need to be repeated at the final study visit. 
s. Head CT with contrast or brain MRI imaging required only for subjects with brain metastases present at screening. 
t. Chest imaging required only for subjects with chest metastases present at screening.  If a patient develops pneumonitis while on study, a high-resolution 
chest CT should be obtained, if feasible. 
u. Repeat every 12 weeks from the time point marked with footnote “u.” 
v. Height to be measured at baseline only. 
w. Vital signs should include: BP, HR, Temperature. 
y. Fasting blood glucose levels should be obtained weekly during Cycle 1 (locally, along with Clinical Chemistry). If > grade 2 hyperglycemia occurs, initiate 
daily home glucose monitoring, until FBS resolves to < grade 1. Daily glucose monitoring should be recorded by the participant in the Home Glucose 
Monitoring Diary (Appendix K). Please refer to Section 6.3.3. 
 


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10. 
MEASUREMENT OF EFFECT  
 
For the purposes of this study, participants should be reevaluated at the end of every 2 
cycles (+/- 1 week) and should be completed prior to the participant initiating the next 
cycle. In addition to a baseline scan, confirmatory scans should also be obtained at least 4 
weeks following initial documentation of an objective response. 
 
10.1 
Antitumor Effect– Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 2 
cycles (+/- 1 week), which should be completed prior to the participant initiating the next 
cycle. In addition to a baseline scan, confirmatory scans should also be obtained at least 4 
weeks following initial documentation of objective response.  The next scheduled 
restaging scan may be used as the confirmatory scan. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
(Eisenhauer et al, 2009) guideline version 1.1.  Changes in the diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST criteria. 
 
10.1.1 Definitions 
 
Evaluable for toxicity. All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response. Only those participants who have received at least one 
cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression or 
die due to disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
10.1.2 Disease Parameters 
 
Measurable Disease 
Measurable disease is the presence of at least one (1) lesion that can be accurately 
measured in at least one dimension with longest diameter > 20 millimeters (mm) using 
conventional techniques (CT, MRI, x-ray) or  > 10 mm with spiral CT scan. Measurable 
lesions must be at least 2 times the slice thickness in mm. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 
 
Lesions situated in a previously irradiated area will be considered measurable if there is 
objective evidence of progression of the lesion prior to study enrollment.  Lesions in 
previously irradiated areas must be clearly identified as such. 
 
Malignant lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be > 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be 


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no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm 
or pathological lymph nodes with > 10 to < 15mm short axis, are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses 
identified by physical exam that are not measurable by reproducible imaging techniques, 
and cystic lesions are all considered non-measurable. 
 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Lesions must be accurately measured in 1 dimension with a 
minimum size of 10 mm by CT or MRI (slice thickness no greater than 5 mm), 20 mm by 
chest x-ray. Nodes must have a short axis > 15 mm. The short axis should be included in 
the sum of the lesions in the calculation of response. Nodes that shrink to < 10 mm are 
considered normal. Target lesions should be selected on the basis of their size, be 
representative of all the involved organs, and should be lesions that can be followed with 
reproducible repeated measurements.  
 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 
considered target lesions if the soft tissue component meets the definition of 
measurability as defined above. Cystic lesions thought to represent cystic metastases can 
be considered as target lesions. However, if non-cystic lesions are present, these are 
preferred for selection as target lesions. Lesions in previously irradiated areas or areas 
subject to other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression of that lesion.  
 
Non-target Lesions 
All other lesions, including small lesions < 10 mm or pathological lymph nodes 
measuring > 10 mm to < 15 mm in short axis, as well as truly non-measurable lesions, 
which include leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses identified by physical exam that are not measurable by reproducible imaging 
techniques.  
10.2 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, 
or digital measurement tool. All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 


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evaluation is preferred to evaluation by clinical examination when both methods have 
been used to assess the anti-tumor effect of a treatment. 
 
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung; however, CT is preferable. 
 
Conventional CT and MRI 
These techniques should be performed with cuts of 10 mm or less in slice thickness 
contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction 
algorithm. This applies to tumors of the chest, abdomen, and pelvis. Head and neck 
tumors and those of extremities usually require specific protocols.  MRI is also 
acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
version 1.1 guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior scans.  
Body scans should be performed with breath-hold scanning techniques, if possible. 
10.3 
Response Criteria  
 
10.3.1 Evaluation of Target Lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph node must have reduction in 
short axis to < 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference 
the baseline sum diameters. 
 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference 
the smallest sum on study with at least a 5 mm absolute increase in the sum of all lesions. 
The appearance of one or more new lesions* denotes disease progression.  
 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
 


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Unknown (UN): 
Assessment of target lesions cannot be made due to insufficient or unevaluable data. In 
this case, a concise explanation must be given. 
 
Note: If tumor response data is missing for target lesions, the overall assessment must be 
UN unless there is new disease that would result in an overall assessment of PD. 
However, if there is missing or unevaluable data for non-target lesions, but data is 
available for all target lesions, the overall response for that time point will be assigned 
based on the sum LD of all target lesions. Additionally, the assessment of CR cannot be 
made if there is missing or unevaluable data for non-target lesions. In this case, the 
overall assessment would be PR. 
 
*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a new 
lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if it 
truly represents new disease and if PD is confirmed, progression should be declared using 
the date of the initial scan on which the lesion was discovered.  
 
10.3.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in size 
(< 10 mm short axis).  
 
Note: If tumor markers are initially above the upper normal limit, they must normalize 
for a subject to be considered in complete clinical response. 
 
Incomplete Response/Stable Disease (SD):  
Persistence of one or more non-target lesions and/or maintenance of tumor marker level 
above the normal limits. 
 
Progressive Disease (PD):  
Appearance of one or more new lesions* (new lesions must be > slice thickness) and/or 
unequivocal progression of existing non-target lesions. 
 
Overall level of substantial worsening that merits discontinuation of therapy. A useful 
test that can be applied when assessing non-targets for unequivocal progression is to 
consider if the increase in overall disease burden based on the change in non-measurable 
disease is comparable in magnitude to the increase that would be required to declare PD 
for measurable disease. 
 
Unknown (UN):  
Assessment of non-target lesions cannot be made due to insufficient or unevaluable data. 
In this case, a concise explanation must be given. 


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*Definition of New Lesion: The finding of a new lesion should be unequivocal (i.e. not 
due to difference in scanning technique, imaging modality, or findings thought to 
represent something other than tumor (ex: new bone lesions may be healing or flare of 
pre-existing lesions).  However, a lesion identified on a follow-up scan in an anatomical 
location that was not scanned at baseline is considered new and will indicate PD. If a new 
lesion is equivocal (because of small size, etc.), follow-up evaluation will clarify if it 
truly represents new disease and if PD is confirmed, progression should be declared using 
the date of the initial scan on which the lesion was discovered.  
 
10.3.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The participant's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
For Participants with Measurable Disease (i.e., Target Disease) 
Target Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response for when 
Confirmation is Required: 
CR 
CR 
No 
CR 
> 4 wks confirmation 
CR 
Non-CR/Non-PD 
No 
PR 
> 4 wks confirmation 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/Not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/Not 
evaluated 
No 
SD 
Documented at least 
once > 4 wks from baseline 
PD 
Any 
Yes or No 
PD 
No prior SD, PR or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted 
as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as "symptomatic deterioration". Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
 


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10.3.4 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrence or PD is objectively documented, taking as reference for PD 
the smallest measurements recorded since the treatment started. 
 
Duration of overall complete response: The duration of overall CR is measured from 
the time measurement criteria are first met for CR until the first date that recurrent 
disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started. 
 
10.3.5 Progression-Free Survival 
 
Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to 
time of objective disease progression.  
 
10.3.6 Response Review 
 
Radiology assessments for DF/HCC sites will be provided by the DF/HCC tumormetrics 
core.  Assessment for other participating sites should be performed per local protocols.  
All complete or partial responses should be confirmed by the DF/HCC tumormetrics core.  
Please see Appendix I for procedures for submission of materials for DF/HCC 
tumormetrics review from non-DF/HCC participating institutions. 
 
 
 


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11. 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Definitions 
 
11.1.1 Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not considered to 
be related to the study.  
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
Please see Section 6.1, “Anticipated Toxicities” for specific information about expected 
toxicities for both study agents.  
 
11.1.2 Serious Adverse Event (SAE) 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless 
of causality that:  
 
• Results in death. 
• Is life-threatening. Life-threatening means that the person was at immediate risk 
of death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 
24-hour hospitalization or prolonged a hospitalization beyond the expected length 
of stay). Hospitalization admissions and/or surgical operations scheduled to occur 
during the study period, but planned prior to study entry are not considered SAEs 
if the illness or disease existed before the person was enrolled in the trial, 
provided that it did not deteriorate in an unexpected manner during the trial (e.g., 
surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect. 
• Is an important medical event when, based upon appropriate medical judgment, 
it may jeopardize the participant and require medical or surgical intervention to 
prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
• Newly diagnosed cancer (not the cancer under treatment). 
• Overdose. 
 
Events not considered to be serious adverse events are hospitalizations for: 
 


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• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
• elective or pre-planned treatment for a pre-existing condition that did not worsen 
• emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
• respite care 
 
11.1.3 Expectedness 
 
Adverse events can be 'Expected' or 'Unexpected.'  
 
Expected Adverse Event 
 
Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered 
expected when it appears in the current adverse event list, the Investigator’s Brochure, 
the package insert or is included in the informed consent document as a potential risk.   
 
Refer to Section 6.1 for a listing of expected adverse events associated with the study 
agents. 
 
Unexpected Adverse Event 
 
 
For the purposes of this study, an adverse event is considered unexpected when it varies 
in nature, intensity or frequency from information provided in the current adverse event 
list, the Investigator’s Brochure, the package insert or when it is not included in the 
informed consent document as a potential risk.  
  
11.1.4 Attribution 
 
Attribution is the relationship between an adverse event or serious adverse event and the 
study treatment. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated – The AE is clearly NOT related to the study treatment. 
 
11.2 
Procedures for AE and SAE Recording and Reporting 
 
Participating investigators will assess the occurrence of AEs and SAEs at all participant 
evaluation time points during the study.  
 
All AEs and SAEs whether reported by the participant, discovered during questioning, 
directly observed, or detected by physical examination, laboratory test or other means, 


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will be recorded in the participant’s medical record and on the appropriate study-specific 
case report forms.  
 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 4. The 
CTCAE version 4 can be downloaded from the CTEP website at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
11.3 
Reporting Requirements 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, 
each participating investigator is required to abide by the reporting requirements set by 
the DF/HCC. The study must be conducted in compliance with FDA regulations, local 
safety reporting requirements, and reporting requirements of the principal investigator.  
 
Each investigative site will be responsible to report SAEs that occur at that institution to 
their respective IRB. It is the responsibility of each participating investigator to report 
serious adverse events to the study sponsor and/or others as described below.  
 
11.4 
Reporting to the Study Sponsor 
 
11.4.1 Serious Adverse Event Reporting 
 
All serious adverse events that occur after the initial dose of study treatment, during 
treatment, or within 30 days of the last dose of treatment must be reported to the DF/HCC 
Overall Principal Investigator on the local institutional SAE form. This includes events 
meeting the criteria outlined in Section 11.1.2, as well as the following: 
 
• Grade 2 (moderate) and Grade 3 (severe) events that are unexpected and at least 
possibly related/associated with the intervention. 
 
• All Grade 4 (life-threatening or disabling) events that are unexpected or not 
specifically listed in the protocol as not requiring reporting. 
 
• All Grade 5 (fatal) events while the participant is enrolled and actively 
participating in the trial OR when the event occurs within 30 days of the last study 
intervention.  
 
Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
Participating investigators must report each serious adverse event to the DF/HCC Overall 
Principal Investigator within 1 business day of learning of the occurrence. In the event 
that the participating investigator does not become aware of the serious adverse event 
immediately (e.g., participant sought treatment elsewhere), the participating investigator 
is to report the event within 1 business day after learning of it and document the time of 


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his or her first awareness of the adverse event. Report serious adverse events by facsimile 
(preferred), email, or telephone to: 
 
Ursula Matulonis, MD   
Phone: 617 632-2334  
Fax: 617-582-7921 
Pager: 617-632-3352 
Email: umatulonis@partners.org 
 
Within the following 24-48 hours, the participating investigator must provide follow-up 
information on the serious adverse event. Follow-up information should describe whether 
the event has resolved or continues, if and how the event was treated, and whether the 
participant will continue or discontinue study participation. 
 
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting 
requirements set by the DF/HCC. This applies to any medical event equivalent to an 
unexpected grade 2 or 3 with a possible, probable or definite attribution, unexpected 
grade 4 toxicities, and grade 5 (death) regardless of study phase or attribution. 
 
11.4.2 Non-Serious Adverse Event Reporting  
 
Non-serious adverse events will be reported to the DF/HCC Overall Principal 
Investigator on the toxicity Case Report Forms. 
   
11.5 
Reporting to NCCN and GSK  
 
In addition to complying with all applicable regulatory reporting laws and regulations, 
the DF/HCC Overall Principal Investigator will report the following information to 
NCCN and Grantor in writing via fax within one business day of the occurrence, 
referencing the applicable Protocol number that is assigned by Grantor upon approval of 
the Study. Such reports shall be directed to the following contacts at NCCN and GSK:  
 
NCCN: 
GSK: 
Email: ORPReports@nccn.org  
Michael Arbushites and Jeremey Levin 
 
 
Fax:  610-200-1767 or 
 
 
Email:  Michael.2.arbushites@gsk.com 
 
 
 
and Jeremey.2.levin@gsk.com 
Reports include: 
(a) 
 All SAEs; 
(b) 
Reports of pregnancy exposure (pregnancy encompasses the entire course of 
pregnancy and delivery, perinatal and neonatal outcomes, even if there were no 
abnormal findings; both maternal and paternal exposure is collected); 
(c) 
 Reports of lactation exposure; 
(d) 
Overdose (with or without an SAE); 
(e) 
Abuse (use for non-clinical reasons with or without an SAE); 
(f) 
Inadvertent or accidental exposure; and 
(g) 
Follow-up information regarding any of the above.   


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The Investigator should include his or her assessment of the causal relationship between 
each SAE and the Grantor product in the form faxed to Grantor and NCCN. 
 
11.6 
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the 
DFCI Office for Human Research Studies (OHRS). 
 
Other investigative at external sites will report SAEs to their respective IRB according to 
the local IRB’s policies and procedures in reporting adverse events. A copy of the 
submitted institutional SAE form should be forwarded to the Overall PI within the 
timeframes detailed in the table below.   
 
DF/HCC Reportable AEs 
Attribution 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE 
Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar 
days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar 
days 
 
5 calendar days# 
 
5 calendar 
days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be 
reported. 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of 
the last intervention, the AE should be reported within 24 business hours of learning of the event. 
 
Other investigators must submit SAE reports to the Overall PI via this contact 
information: 
Ursula Matulonis, MD 
Phone: 617 632-2334  
Fax:  617-582-7921 
Pager: 617-632-3352 
Email:  umatulonis@partners.org 
 
The Overall PI will submit SAE reports from outside institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
11.7 
Reporting to the Food and Drug Administration (FDA) 
 
The DF/HCC Overall Principal Investigator, as holder of the IND, will be responsible for 
all communication with the FDA. The DF/HCC Overall Principal Investigator will report 
to the FDA, regardless of the site of occurrence, any adverse event that is serious, 
unexpected and reasonably related (i.e., possible, probable, definite) to the investigational 
agents. 
 


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Unexpected fatal or life-threatening experiences associated with the use of the 
investigational agents will be reported to FDA as soon as possible but in no event later 
than 7 calendar days after initial receipt of the information. 
 
All other serious unexpected experiences associated with the use of the investigational 
agents will be reported to FDA as soon as possible but in no event later than 15 calendar 
days after initial receipt of the information. 
 
 
 
Events will be reported to the FDA using Form FDA 3500A (Mandatory Reporting Form 
for investigational agents) by sending the paper report via overnight, traceable delivery 
service. Forms are available at http://www.fda.gov/medwatch/getforms.htm 
 
11.8 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject 
safety reports or sentinel events that require reporting according to institutional policy. 
 
11.9 
Monitoring of Adverse Events and Period of Observation 
 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last study 
intervention should be followed to their resolution, or until the participating investigator 
assesses them as stable, or the participating investigator determines the event to be 
irreversible, or the participant is lost to follow-up. The presence and resolution of AEs 
and SAEs (with dates) should be documented on the appropriate case report form and 
recorded in the participant’s medical record to facilitate source data verification.  
 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or autopsy 
report).  
 
Participants should be instructed to report any serious post-study event(s) that might 
reasonably be related to participation in this study. Participating investigators should 
notify the DF/HCC Overall Principal Investigator and their respective IRB of any 
unanticipated death or adverse event occurring after a participant has discontinued or 
terminated study participation that may reasonably be related to the study.   
 
 


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12. 
DATA AND SAFETY MONITORING 
 
12.1 
Data Reporting 
 
12.1.1 Method  
 
The QACT will collect, manage, and monitor data for this study.  
 
12.1.2 Data Submission  
 
The schedule for completion and submission of case report forms (paper or electronic) to 
the QACT is as follows: 
 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration with QACT 
On Study Form 
Within 14 days of registration 
Baseline Assessment Form 
Within 14 days of registration 
Treatment Form 
Within 10 days of the last day of the cycle 
Adverse Event Report Form 
Within 10 days of the last day of the cycle 
Response Assessment Form 
Within 10 days of the completion of the cycle 
required for response evaluation 
Off Treatment/Off Study Form 
Within 14 days of completing treatment or being 
taken off study for any reason 
Follow up/Survival Form 
Within 14 days of the protocol defined follow up 
visit date or call 
 
12.2 
Safety Meetings  
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor 
toxicity and accrual data from this trial. The committee is composed of clinical specialists 
with experience in oncology and who have no direct relationship with the study. 
Information that raises any questions about participant safety will be addressed with the 
Principal Investigator and study team. 
 
The DSMC will meet quarterly and/or more often if required to review toxicity and 
accrual data.  Information to be provided to the committee may include:  up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or 
higher unexpected adverse events that have been reported; summary of all deaths 
occurring within 30 days for Phase I or II protocols; for gene transfer protocols, summary 
of all deaths while being treated and during active follow-up; any response information; 


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audit results, and a summary provided by the study team. Other information (e.g. scans, 
laboratory values) will be provided upon request.  
12.3 
Monitoring  
Involvement in this study as a participating investigator implies acceptance of potential 
audits or inspections, including source data verification, by representatives designated by 
the DF/HCC Overall Principal Investigator (or Protocol Chair) or DF/HCC. The purpose 
of these audits or inspections is to examine study-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported in accordance with the protocol, institutional policy, and any 
applicable regulatory requirements.  
All data will be monitored for timeliness of submission, completeness, and adherence to 
protocol requirements. Monitoring will begin at the time of participant registration and 
will continue during protocol performance and completion. Please see Section 5.0 of the 
Data and Safety Monitoring Plan (Appendix C) for monitoring details. 
 
 


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13. 
REGULATORY CONSIDERATIONS 
13.1 
Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information 
related to the study (e.g., advertisements used to recruit participants) and any other 
necessary documents must be submitted, reviewed and approved by a properly 
constituted IRB governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be 
approved by the IRB prior to implementation. Any changes in study conduct must be 
reported to the IRB. The DF/HCC Overall Principal Investigator (or Protocol Chair) will 
disseminate protocol amendment information to all participating investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing.  
13.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing 
sufficient information for participants to make an informed decision about their 
participation in this study. The formal consent of a participant, using the IRB approved 
consent form, must be obtained before the participant is involved in any study-related 
procedure. The consent form must be signed and dated by the participant or the 
participant’s legally authorized representative, and by the person obtaining the consent. 
The participant must be given a copy of the signed and dated consent document. The 
original signed copy of the consent document must be retained in the medical record or 
research file.  
13.3 
Ethics  
 
This study is to be conducted according to the following considerations, which 
represent good and sound research practice: 
 
• US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• State laws 
• DF/HCC research policies and procedures        
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-
cru/policies-and-procedures/ 


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It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB according to the local reporting policy.  
13.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the study for each research 
participant. This information enables the study to be fully documented and the study data 
to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not 
limited to hospital records, clinical charts, laboratory and pharmacy records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  
 
13.5 
Records Retention 
 
All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or institutional policies.  
 
13.6 
Multi-center Guidelines 
 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard 
Cancer Center. The specific responsibilities of the DF/HCC Overall Principal 
Investigator (or Protocol Chair), Coordinating Center, and Participating Institutions are 
presented in the Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety 
Monitoring Plan (see Appendix C) 
 
• The DF/HCC Overall Principal Investigator/Coordinating Center is responsible 
for distributing all IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site.  
• Except in very unusual circumstances, each participating institution will order 
the agents directly from the supplier. A participating site may order the 
agents only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center.  
 
 


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14. 
STATISTICAL CONSIDERATIONS  
 
14.1 
Study Design/Endpoints 
 
14.1.1 Study Design 
 
This is an open label single-arm single-stage phase II multicenter trial. 
 
14.1.2 Primary Objective 
 
To assess the activity of GSK1120212 and GSK2141795 in combination in patients with 
recurrent or persistent cervical cancer. Activity will be ascertained by estimation of best 
objective tumor response per RECIST version 1.1.  
    
14.1.3 Secondary Objectives 
 
• To assess the duration of progression-free and overall survival following initiation of 
therapy with GSK1120212 and GSK2141795  
 
• To determine the nature and degree of toxicity of GSK1120212 and GSK2141795 as 
assessed by version 4 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) in this cohort of patients.   
 
• To describe the mutation and co-mutation rates of genes in the PI3K and RAS-ERK 
signaling pathways in recurrent cervical cancer using high throughput targeted 
mutational analysis on participant tumor samples. 
  
 
• To explore the association of mutational status with clinical benefit from 
GSK1120212 and GSK2141795.  
 
14.2 
Statistical Analysis 
 
The primary objective of this study is estimation of the best objective response rate (CR + 
PR) per RECIST 1.1. With the planned accrual of 35 participants to this single-arm trial, 
there is 91% power to detect an improvement in response rate from 0.07 to 0.22 using a 
one-sided 0.09-level exact binomial test. Therefore, the null hypothesis will be rejected if 
5 or more participants respond to combination therapy with GSK1120212 and 
GSK2141795. The null hypothesis of 0.07 is based on a weighted average of the 
observed response rates from the 11 cohorts enrolled to GOG 127 and 227 series.  
 
Secondary objectives include progression-free and overall survival, both of which will be 
estimated by the Kaplan-Meier method. PFS is defined as the time from registration to 
the study until documented disease progression or death without progression, whichever 
occurs first. Participants not experiencing a PFS event will be censored at the last date of 
documented disease evaluation. Overall survival is defined as the time from study 
registration to the time of death from any cause, with follow-up censored at the last date 


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known to be alive. Cox’s proportional hazards models will be fitted to explore significant 
predictors of event-time endpoints.  
 
Toxicity data will be tabulated and compared between any groups of interest using 
Fisher’s exact tests, and will be routinely monitored, analyzed and reviewed by the 
DF/HCC DSMC.  
 
Molecular correlative analyses will be conducted and all patient outcomes: response, 
PFS, OS and toxicity will be compared between the PIK3CA and RAS-isoform mutated 
and WT groups using the statistical methodologies specified above; estimating the 
proportion of participants harboring mutations in both genes is also of interest, as is 
comparing their outcomes to those in the remainder of the cohort. These analyses are 
considered exploratory and will not be adjusted for multiple comparisons.  
 
14.3 
Sample Size/Accrual Rate 
 
The planned sample size is a maximum of 35 participants.  The estimated monthly 
accrual rate is 2 participants.  Participants will be followed for a maximum of 3 years. 
14.4 
Reporting and Exclusions 
 
14.4.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment. 
 
14.4.2 Evaluation of Response 
 
All participants included in the study must be assessed for response to treatment, even if 
there are major protocol treatment deviations or if they are ineligible. Each participant 
should be assigned one of the following categories: 1) complete response, 2) partial 
response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 
6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not 
assessable, insufficient data). By arbitrary convention, category 9 usually designates the 
"unknown" status of any type of data in a clinical database. 
 
All participants who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable 
for response.  Participants in response categories 5-9 will not be considered evaluable but 
will remain within the intention to treat analysis.   
Participants who develop brain metastasis on study, but continue on study after definitive 
treatment of their cranial disease, will be considered to have had progressive disease at 
the point of the diagnosis of the initial brain metastasis.  
 
All conclusions should be based on all evaluable participants. Subanalyses may then be 
performed on the basis of a subset of participants, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, early 
discontinuation of treatment, major protocol violations, etc.). However, these subanalyses 
may not serve as the basis for drawing conclusions concerning treatment efficacy, and the 


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reasons for excluding participants from the analysis should be clearly reported. The 95% 
confidence intervals should also be provided. 
 
15. 
PUBLICATION PLAN 
Publication guidelines exist within the DF/HCC Gynecologic Oncology Program.  The 
study principal investigator will be responsible for collection of data, interpretation of 
data, monitoring of toxicities, and publication of abstracts and final manuscripts.  The 
principal investigator chooses the different authorship slots per the DF/HCC gynecologic 
oncology program guidelines. 
The results should be made public within 24 months of the end of data collection. The 
NCCN research agreement stipulates that the initial publication will be submitted to a 
peer-reviewed journal six months after the Trial’s conclusion as defined by data lock or 
termination of the study.   


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16. 
REFERENCES  
  
1. GSK1120212 Investigator's Brochure 
 
2. Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. Antitumor activities of JTP-
74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in 
vitro and in vivo.Int J Oncol. 2011 Jul;39(1):23-31. 
 
3. GSK2141795 Investigator's Brochure 
 
4. Mendoza MC, Er EE, Blenis J.  The Ras-ERK and PI3K-mTOR pathways: cross-talk 
and compensation.  Trends Biochem Sci. 2011 Jun;36(6):320-8. 
 
5. Engelman, J.A., J. Luo, and L.C. Cantley, The evolution of phosphatidylinositol 3-
kinases as regulators of growth and metabolism. Nat Rev Genet, 2006. 7(8): p. 606-
19. 
 
6. Yuan, T.L. and L.C. Cantley, PI3K pathway alterations in cancer: variations on a 
theme. Oncogene, 2008. 27(41): p. 5497-510. 
 
7. Downward, J., Targeting RAS signalling pathways in cancer therapy. Nat Rev 
Cancer, 2003.  3(1): p. 11-22. 
 
8. Yan, J., et al., Ras isoforms vary in their ability to activate Raf-1 and 
phosphoinositide 3-kinase. J Biol Chem, 1998. 273(37): p. 24052-6. 
 
9. Forbes, S.A., et al., COSMIC (the Catalogue of Somatic Mutations in Cancer): a 
resource to investigate acquired mutations in human cancer. Nucleic Acids Res, 2010. 
38(Database issue): p. D652-7. 
 
10. Engelman, J.A., et al., Effective use of PI3K and MEK inhibitors to treat mutant Kras 
G12D and PIK3CA H1047R murine lung cancers. Nat Med, 2008. 14(12): p. 1351-6. 
 
11. Carracedo, A., et al., Inhibition of mTORC1 leads to MAPK pathway activation 
through a PI3K-dependent feedback loop in human cancer. J Clin Invest, 2008. 
118(9): p. 3065-74. 
 
12. G. Shapiro, P.L., E. L. Kwak, J. M. Cleary, L. Musib, C. Jones, A. de Crespigny, M. 
Belvin, M. McKenzie, M. R. Gates, I. T. Chan, J. C. Bendell. Clinical combination of 
the MEK inhibitor GDC-0973 and the PI3K inhibitor GDC-0941: A first-in-human 
phase Ib study testing daily and intermittent dosing schedules in patients with 
advanced solid tumors. in ASCO. 2011. Chicago: J Clin Oncol. 
 
13. Siegel, R., et al., Cancer statistics, 2011: the impact of eliminating socioeconomic and 
racial disparities on premature cancer deaths. CA Cancer J Clin, 2011. 61(4): p. 212-
36. 
 


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14. Jemal, A., et al., Global cancer statistics. CA Cancer J Clin, 2011. 61(2): p. 69-90. 
 
15. Long, H.J., 3rd, Management of metastatic cervical cancer: review of the literature. J 
Clin Oncol, 2007. 25(20): p. 2966-74. 
 
16. Keys, H.M., et al., Cisplatin, radiation, and adjuvant hysterectomy compared with 
radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J 
Med, 1999.  340(15): p. 1154-61. 
 
17. Morris, M., et al., Pelvic radiation with concurrent chemotherapy compared with 
pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med, 1999. 
340(15): p. 1137-43 
 
18. Rose, P.G., et al., Concurrent cisplatin-based radiotherapy and chemotherapy for 
locally advanced cervical cancer. N Engl J Med, 1999. 340(15): p. 1144-53. 
 
19. Peters, W.A., 3rd, et al., Concurrent chemotherapy and pelvic radiation therapy 
compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery 
in high-risk early-stage cancer of the cervix. J Clin Oncol, 2000. 18(8): p. 1606-13. 
 
20. Omura, G.A., et al., Randomized trial of cisplatin versus cisplatin plus mitolactol 
versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a 
Gynecologic Oncology Group study. J Clin Oncol, 1997. 15(1): p. 165-71. 
 
21. Brewer, C.A., et al., Cisplatin plus gemcitabine in previously treated squamous cell 
carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. 
Gynecol Oncol 2006. 100(2): p. 385-8. 
 
22. Moore, D.H., et al., Phase III study of cisplatin with or without paclitaxel in stage 
IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic 
oncology group study. J Clin Oncol, 2004. 22(15): p. 3113-9. 
 
23. Long, H.J., 3rd, et al., Randomized phase III trial of cisplatin with or without 
topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J 
Clin Oncol, 2005. 23(21): p. 4626-33. 
 
24. Thigpen, T., et al., Cis-platinum in treatment of advanced or recurrent squamous cell 
carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. 
Cancer, 1981.  48(4): p. 899-903. 
 
25. Moore, D.H., et al., Prognostic factors for response to cisplatin-based chemotherapy 
in advanced cervical carcinoma: a Gynecologic Oncology Group Study. Gynecol 
Oncol, 2010.  116(1): p. 44-9. 
 
26. Tewari, K.S. and B.J. Monk, Recent achievements and future developments in 
advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group. 
Semin Oncol, 2009.  36(2): p. 170-80. 
 


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27. Monk, B.J., et al., Phase II trial of bevacizumab in the treatment of persistent or 
recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group 
study. J Clin Oncol, 2009. 27(7): p. 1069-74. 
 
28. Bertelsen, B.I., et al., Molecular analysis of the PI3K-AKT pathway in uterine 
cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J 
Cancer, 2006. 118(8): p. 1877-83. 
 
29. Janku, F., et al., PIK3CA mutations frequently coexist with RAS and BRAF 
mutations in patients with advanced cancers. PLoS One, 2011. 6(7): p. e22769. 
 
30. Janku, F., et al., PIK3CA mutations in patients with advanced cancers treated with 
PI3K/AKT/mTOR axis inhibitors. Mol Cancer Ther, 2011. 10(3): p. 558-65. 
 
31. Wright AA, MS Hirsch, N Wagle, BE Howitt, E Palescandolo, LE MacConaill, P 
Van Hummelen, M Shoni, WC Hahn, UA Matulonis.  KRAS and EGFR mutations to 
distinguish adenocarcinomas and squamous cell carcinomas of the cervix.  J Clin 
Oncol 30, 2012 (suppl; abstr) 5011.   
 
32. Wegman, P., C. Ahlin, and B. Sorbe, Genetic alterations in the K-Ras gene influence 
the prognosis in patients with cervical cancer treated by radiotherapy. Int J Gynecol 
Cancer, 2011. 21(1): p. 86-91. 
 
33. Kim, T.J., et al., Increased expression of pAKT is associated with radiation resistance 
in cervical cancer. Br J Cancer, 2006. 94(11): p. 1678-82. 
 
34. Courtney, K.D., R.B. Corcoran, and J.A. Engelman, The PI3K pathway as drug target 
in human cancer. J Clin Oncol, 2010. 28(6): p. 1075-83. 
 
35. Bollag, G., et al., Clinical efficacy of a RAF inhibitor needs broad target blockade in 
BRAF-mutant melanoma. Nature, 2010. 467(7315): p. 596-9. 
 
36. She, Q.B., et al., Breast tumor cells with PI3K mutation or HER2 amplification are 
selectively addicted to Akt signaling. PLoS One, 2008. 3(8): p. e3065. 
 
37. Cheung, L.W., et al., High Frequency of PIK3R1 and PIK3R2 Mutations in 
Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein 
Stability. Cancer Discov, 2011. 1(2): p. 170-185. 
 
38. Wagle, N., et al., Dissecting therapeutic resistance to RAF inhibition in melanoma by 
tumor genomic profiling. J Clin Oncol, 2011. 29(22): p. 3085-96. 
 
39. Thomas, R.K., et al., High-throughput oncogene mutation profiling in human cancer. 
Nat Genet, 2007. 39(3): p. 347-51. 
 
40. Wang, Y., et al., High quality copy number and genotype data from FFPE samples 
using Molecular Inversion Probe (MIP) microarrays. BMC Med Genomics, 2009. 2: 
p. 8. 


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41. Davern TJ 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, Lalani E, 
Munoz S, Shakil AO, Lee WM; Acute Liver Failure Study Group.  Measurement of 
serum acetaminophen-protein adducts in patients with acute liver failure. 
Gastroenterology. 2006 Mar;130 (3):687-94.  
 
 
 
 


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17. 
APPENDICES 
 
 
 


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APPENDIX A:  Performance Status Criteria 
 
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary 
nature (e.g., light housework, office work). 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 


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APPENDIX B:  New York Heart Association Classification of Heart Failure 
 
 
Class 
Patient symptoms 
Class I (Mild) 
No limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea (shortness of breath). 
Class II (Mild) 
Slight limitation of physical activity. Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation, or dyspnea 
Class III (Moderate) 
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea. 
Class IV (Severe) 
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased 
 
 


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APPENDIX C:  Participant Drug Diaries for GSK1120212 (trametinib) and GSK2141795 
 
 


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PATIENT’S MEDICATION DIARY: GSK1120212 (trametinib) 
Instructions:  
1.  Complete one form for each cycle of treatment. 
2.  Take _____ (number) _____mg (dosage) tablet(s) of GSK1120212 (trametinib) daily within 1-2 hours.  You 
must fast for 1 hour before and 2 hours after taking study medication. If a dose is forgotten or vomited, do not 
make up the dose. Take with 9 oz of water. Do not eat grapefruit, drink grapefruit juice while taking 
medications. Do not crush, chew, or dissolve study medications. 
3.  Record the date, the number 0.5 mg tablets that you took, and when you took them. Do not batch entries at a 
later time. You have up to 2 hours from your scheduled dosing time to take the study medications. If it is 
beyond 2 hours, you must skip the dose.  
4.  If you have any comments or notice any side effects please record them in the comments column.  
5.  Please bring this form and the bottles of trametinib tablets when you return for each appointment.  
 
Today’s Date: _____________________ 
Agents:  GSK1120212 (trametinib)  
Patient Name: _____________________ (initials acceptable)  
Patient Study ID:  _____________________ 
Date 
Day 
Time 
# of 0.5 mg tablets taken of trametinib 
Comments 
 
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Patient’s Signature: _________________________________________ 
Date: 
____________________Physician’s Office will complete this section: 
1.       Date patient started protocol treatment: 
  
2.       Date patient was removed from study:  
  
3.       Patient’s planned total daily dose:  
  
4.       Total number of tablets taken this month:  
  
5.       Physician or Research Nurse Signature:  
  
Protocol # 13-334 


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PATIENT’S MEDICATION DIARY: GSK2141795 
Instructions:  
1.  Complete one form for each cycle of treatment. GSK2141795 must be stored in your refrigerator. 
2.  Take _____ (number) _____mg (dosage) capsule(s) of GSK2141795 daily within 1-2 hours. You must fast for 1 
hour before and 2 hours after taking study medication. If a dose is forgotten or vomited, do not make up the 
dose. Take with 9 oz of water. Do not eat grapefruit, drink grapefruit juice while taking medications.  Do not 
crush, chew or dissolve study medications. 
3. 
Record the date, the number of 25 mg capsules you took, and when you took them.  Do not batch entries at a 
later time. You have up to 2 hours from your scheduled dosing time to take the study medications. If it is 
beyond 2 hours, you must skip the dose. 
4.  If you have any comments or notice any side effects please record them in the comments column.  
5.  Please bring this form and the bottles of GSK2141795 capsules when you return for each appointment.  
 
Today’s Date:  _____________________ 
Agents:  GSK2141795 
Patient Name: _____________________ (initials acceptable)  
Patient Study ID: _____________________ 
Date 
Day 
Time 
# of 25 mg capsules taken of GSK2141795 
Comments 
 
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Patient’s Signature: _____________________________________________ 
Date: ____________________ 
Physician’s Office will complete this section: 
1.       Date patient started protocol treatment: 
  
2.       Date patient was removed from study:  
  
3.       Patient’s planned total daily dose:  
  
4.       Total number of capsules taken this month:  
  
5.       Physician or Research Nurse Signature:  
  
Protocol # 13-334 


DF/HCC Protocol # 13-334 
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APPENDIX D:  List of Prohibited Medications 
 
The following medications, including but not limited to, are prohibited during the study: 
 
PROHIBITED – highly sensitive and/or low therapeutic index CYP3A/CYP2C8/BCRP/ 
CYP3A4 substrates since concentrations of these drugs may be increased 
CYP3A Substrate 
Therapeutic Area 
Cisapride 
Hypnotics and Sedatives 
Pimozide 
Antidepressant, Antipsychotics, Antianxiety 
agents 
Astemizole 
Antihistamine 
BCRP Substrate 
rosuvastatin, sulfasalazine 
HMG-CoA Reductase Inhibitors, 
gastrointestinal agents 
PROHIBITED – strong inducers/inhibitors of CYP3A4 
Strong CYP3A4 Inhibitor/Inducer 
Therapeutic Area 
clarithromycin, telithromycin, rifamycin 
class agents (e.g., rifampin, rifabutin, 
rifapentine), troleandomycin 
Antibiotics 
itraconazole, ketoconazole 
Antifungals 
Nefazodone 
Antidepressants 
atazanzvir, delaviridine, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, 
nevirapine
Antivirals 
carbamazepine, phenobarbital, phenytoin Anticonvulsants 
 
 


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APPENDIX E:  List of Cautionary Medications 
 
Medications, including but not limited to the following, that may alter the concentrations of 
GSK1120212 or GSK2141795 or have their elimination altered by GSK1120212 or 
GSK2141795 should be administered WITH CAUTION. 
   
USE WITH CAUTION – Drugs Potentially Affecting GSK1120212 or GSK2141795 
concentrations 
Drug 
Therapeutic Area 
quinidine, diltiazem, verapamil 
Antiarrhythmics:   
fluvoxamine, fluoxetine, 
Antidepressants: 
aprepitant, cimetidine 
Antiemetics 
fluconazole, terbinafine,  voriconazole 
Antifungals 
ciprofloxacin, erythromycin, isoniazid 
Anti-infectives 
mibefradil, diltiazem, verapamil 
Calcium Channel Blockers 
aprepitant,oxandrolone, tizanidine, 
Miscellaneous 
USE WITH CAUTION – Drugs that may inhibit P-gp and BCRP 
Drug 
Therapeutic Area 
valspoda 
Miscellaneous 
atorvastatin, 
HMG-CoA Reductase Inhibitors 
carvedilol 
Congestive Heart Failure 
methadone 
Analgesic 
meperidine 
Narcotic 
omeprazole 
Proton Pump Inhibitor 
USE WITH CAUTION – Drugs that may have their concentrations altered by GSK1120212 or 
GSK2141795 
repaglinide, rosiglitazone, pioglitazone 
Antidiabetics 
alfentanil, fentanyl 
Analgesics 
quinidine 
Antiarrhythmics   
cilostazole 
Anticoagulants and Antiplatelets 
astemizole 
Antihistamines 
diergotamine, ergotamine, eletriptan 
Antimigraine agents 
pimozide 
Antipsychotics 
buspirone 
Anxiolytics 
felodipine 
Calcium Channel Blockers 
sildenafil, tadalafil, vardenafil 
Erectile Dysfunction agents 
cerivastatin,ovastatin, simvastatin, 
HMG-CoA Reductase Inhibitors 


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alprazolam, diazepam, midazolam, triazolam 
Hypnotics and Sedatives 
cyclosporine, sirolimus, tacrolimus 
Immunosuppressive agents 
cisapride 
Prokinetic agents 
cyclosporine, torsemide, chloroquine, 
Miscellaneous 
eperenone 
Selective Aldosterone Blockers 
chloroquine, zopiclone 
Thiazolidnediones 
 
Use of repaglinide, rosiglitazone and/or pioglitazone is permitted only after approval of the study 
PI. 
 
Oral steroids should be used with caution and subjects monitored for steroid-induced 
hyperglycemia.  Short courses (up to a maximum of 14 days) of oral corticosteroids intended to 
treat study treatment related rash or diarrhea are allowed.  Budenoside is recommended for 
supportive care of diarrhea. Subjects will be instructed to inform the investigator before taking 
any of these or any other medications.  Investigators (or his/her appropriate designee) will be 
expected to review concomitant medications with the subject at each clinical visit. 


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APPENDIX F:  CTCAE v 4.0 Grading of Visual Changes 
 
 
Visual Changes - Grading Based on NCI-CTCAE v 4.0 
 
Grade 
Description 
1 
Asymptomatic or symptomatic but not limiting ADL; clinical or diagnostic 
observations only; intervention not indicated 
2 
 Symptomatic with moderate decrease in visual acuity (20/40 or better);  limiting 
instrumental ADL;  local or noninvasive intervention indicated (e.g., topical or 
oral agents) 
3 
Symptomatic with marked decrease in visual acuity  or marked visual field defect 
(worse than 20/40 but better than 20/200 in the affected eye); Severe pain or 
medically significant but not immediately sight-threatening; operative 
intervention indicated; disabling; limiting self care ADL 
4 
Sight-threatening consequences; urgent intervention indicated; blindness 
(20/200 or worse) in the affected eye 
 
 
Ophthalmologic Exam 
 
Subjects are required to have a standard ophthalmic exam performed by an ophthalmologist at 
baseline and as clinically warranted per protocol’s guidance (Refer to Section 6.3.9 for visual 
changes stopping criteria).  The exam will include indirect fundoscopic examination, visual 
acuity (corrected), visual field examination, tonometry, and direct fundoscopy, with special 
attention to retinal abnormality that are predisposing factors for RVO or CSR.   
 
For participants with clinical suspicion of RVO or CSR, fluorescein angiography and/or optical 
coherence tomography are highly recommended. 
 
 


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APPENDIX G:   Laboratory Correlative Studies 
 
Mutational Analysis 
 
OncoPanel 
 
OncoPanel sequencing on archival specimens will be obtained from all patients where 
available.  OncoPanel is a targeted next generation sequencing panel selected based on clinical 
actionability in cancer that is designed for the detection of single-nucleotide variants, insertions 
and deletions, copy number alterations, and structural variants.  A validation study demonstrated 
that OncoPanel could successfully identify multiple types of genetic alterations, with a 
sensitivity of 98% for single-nucleotide variants, 84% for indels, 86% for copy number variants, 
and 74% for structural variants when compared to appropriate orthogonal detection methods, 
including single-gene assays, mass spectrometry-based genotyping, array comparative genomic 
hybridization, or fluorescence in situ hybridization (Garcia 2017).  Where OncoPanel sequencing 
has already been performed on patient samples through DF/HCC protocol 11-104, we will plan 
to access these results to conserve primary patient samples for additional analyses. 
 
Targeted Sequencing [38] 
 
Samples will be analyzed by next generation sequencing on a 2.1Mb subset of the genome with 
relevance in cancer development. 300ng genomic DNA will be randomly sheared to 250bp 
average fragments and ligated to sequence adaptors that contain sequencing primers and sample 
specific barcodes. Using Agilent’s Sureselect hybrid capture technology the exonic sequences of 
646 genes will be enriched for each samples and up to 12 samples with unique barcodes are 
pooled and subsequently sequenced on a Hiseq2000 sequencer from Illumina. We will sequence 
2x 100bp of each sample in a pair-end mode until an average coverage of around 300x. After 
sequencing, variant sequences will be determined using cancer-specific variant discovery tools 
(GATK), including MuTect for Somatic base substitutions and Somatic Indel Detector for 
insertions and deletions. 
 
Mutation Detection 
 
OncoMap is a high throughput sequencing assay using Sequenom technology that has been 
developed by investigators at Dana-Farber Cancer Institute and the Broad Institute, with the goal 
of being able to interrogate for known cancer mutations from formalin-fixed paraffin-embedded 
(FFPE) tissues as well as from fresh tissue [36] this assay, a series of primers have been designed 
that enable mutation detection (e.g., point mutations and small deletions or insertions) in a 
multiplexed fashion. Using publicly available resources such as COSMIC (www.sanger.ac.uk), 
as well as internal sequencing databases generated at the Broad Institute, an expanded cancer 
gene mutation assay collection has been generated. In total, an expanded iPLEX assay collection 
has been compiled that includes approximately 1138 functioning, non-redundant mutations in 
114 oncogenes and selected tumor suppressor genes. Whole genome amplification (WGA) will 
be performed using the phi-29 DNA polymerase strand-displacement method using the 
GenomePlex Complete Whole Genome Amplification kit (Sigma). For each sample, a PCR 
reaction is performed to assess DNA quality. Specifically, we amplify three fragments of 100 bp, 
150 bp, and 200 bp respectively derived from chromosomes 14, 17 and 21. Two of the three 


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fragments must be amplified to pass this quality assurance step.  
 
Samples will be run on the mass spectrometry based genotyping platform and analyzed 
according to current standardized protocols [39]. Control samples with known oncogenic 
mutations will be included in each plate. In addition, induction of experimental artifacts by WGA 
will be assessed by examining the status of 24 SNPs using a 100K SNP array (Affymetrix). If we 
identify ≥3 SNP discrepancies between the SNPs found in pre- and post-WGA samples, then this 
sample is not used for further analysis. Typer Analyzer v3.4 (Sequenom), which identifies 
mutations based on an algorithm that was initially developed to detect germline SNPs, will be 
used to identify oncogenic mutations.  
 
Each mutation identified by this approach will be validated using two methods. First, 
confirmatory evaluations will be performed using a different platform (homogeneous Mass 
EXTEND®, hem). Next, direct sequencing will be performed from the genomic DNA. Based on 
prior experience, the amount and quality of DNA isolated for this analysis is sufficient to 
perform these validation studies. 
 
SNP Hybridization for Copy Number Analysis or Somatic Mutation [40]  
 
This assay tagged nucleotide probes designed to target the candidate region within genomic 
DNA.  Hybridized probes are then selected for in an exonuclease reaction, amplified and 
hybridized to an array with the tagged sequences, supplying both qualitative and quantitative 
data on point mutations and, when applied to contiguous probes, genomic copy number.  This 
assay uses as little as 50 ng of DNA per reaction and is successful with the use of DNA derived 
from FFPE samples.   In collaboration with Affymetrix, the SU2C Dream Team Studying “PI3K 
signaling in Women’s Cancers” has designed a chip specifically for detecting mutations and 
copy number alterations in 200 genes that are commonly molecularly altered in breast, ovarian, 
and endometrial cancers. Given the focus on specific genes within the whole genome, the density 
of coverage can be increased, allowing for a more sensitive copy number analysis.  This chip has 
300, 000 probes to identify mutation and copy number alteration in these 200 genes.   
 
Protein Expression Analysis 
 
IHC 
 
Pre-treatment snap frozen core biopsy, post-treatment snap frozen core biopsy, and post-
progression snap frozen core biopsy specimens will be directly shipped to pathology core, where 
specimens will be freshly sectioned for IHC expression analyses.  IHC staining will be 
conducted for pAKT, pS6K, pPRAS40, and pERK.  For pAKT and pS6K, nuclear and 
cytoplasmic staining will be assessed and if both are present the specimen will be scored as 
positive; otherwise the specimen will be scored as negative.  If there is not sufficient material to 
perform all assays, the order of priority will be pAKT, pERK, pPRAS40. 
 
RPPA 
 
RPPA is high-throughput antibody-based technique used to compare protein levels in different 
samples.  Using standard methods protein will be extracted from the collected tissues described 
above.  They will be processed by the core proteomic facility at MD Anderson. In brief, lysates 


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will be serially diluted, denatured, printed on nitrocellulose-coated slides and probed with 
validated antibodies that recognize signaling molecules or their activated forms. Signals will be 
captured by tyramide dye deposition (CSA System, DAKO).  Data will be collected and 
analyzed using quantification software specifically developed for this approach The RPPA 
platform contains 127 protein antibodies involved in cancer growth (26).  To identify protein 
changes associated with drug resistance, data will be analyzed by K-means analysis and principle 
component analysis.  
 
Copy Number Analysis 
 
Should there be ample material DNA will be extracted from FFPE primary tumor sections for 
copy number analysis.  Copy number alterations will be determined in aliquots of tumor DNA by 
array comparative genome hybridization (aCGH) using one of several platforms.  The platforms 
currently available to us are the Agilent 1M CGH microarray, the Affymetrix MIP chip, and a 
custom Agilent CGH array.  These platforms vary in breadth of coverage and sample 
requirements.  At the time of research testing, contemporary metrics will be compared and based 
on sample availability, one of these or similar platforms will be employed.  A minimum of 50ng 
of DNA is required for the MIP chips, 500ng of DNA is required for the custom Agilent array, 
and at least 1ug of DNA is required for the 1M Agilent array. 
 
PTEN Assay 
 
Unstained sections of formalin-fixed, paraffin-embedded primary tumor and biopsies will be 
collected for analysis of PTEN by immunohistochemistry.    Five micrometer thick unstained 
slides of archival FFPE tumor will be used for IHC expression analyses. Tumor expression of 
PTEN will be assessed by immunohistochemistry at the BWH.   Loss of PTEN will be evaluated 
in a CLIA certified laboratory at the BWH by immunostaining for PTEN in a validated 
immunohistochemistry assay with the rabbit monoclonal antibody 138G6 (Cell Signaling, Cat 
No 9559).  Results scored as follows. Complete absence of or minimal (<10% of tumor cells) 
staining in the tumor cells in the presence of internal positive control (stromal cells, 
lymphocytes) will be interpreted as PTEN loss. Cases will be scored as being PTEN positive or 
retained if all or majority of the tumor shows positive staining. Cases with patchy PTEN staining 
will be interpreted as showing mixed staining.   
 


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 APPENDIX H:   
DF/HCC Tumor Imaging Metrics Core (TIMC) Submission 
Procedures for non-DF/HCC Sites 
 
All participants with measurable disease with partial or complete responses on trial should have 
their responses confirmed by the DF/HCC Tumor Imaging Metrics Core (TIMC).  For 
participants with responses, the following materials should be submitted to the Dana-Farber 
Cancer Institute: 
 
• Baseline CT/MRI study on CD 
• CT/MRI documenting response on CD 
• CT/MRI confirming response on CD 
• Radiology reports from baseline CT/MRI and CT/MRIs in which response was 
documented and confirmed. 
 
All materials should be sent to the Clinical Research Coordinator at the following address: 
 
Ariana Peralta 
Dana-Farber Cancer Institute 
450 Brookline Ave, D117 
Dana-Farber Cancer Institute 
Boston, MA 02215 
Telephone: 617-632-3743 
Email: aperalta2@partners.org 


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APPENDIX I:  Data Collection Forms 
 
Data collection will occur through the use of the Electronic Data Capture (EDC) system through 
Phase Forward Inform.  
 
Sites should identify the appropriate data management personnel.  An EDC team member from 
DFCI will contact each site to provide information regarding training on the EDC as well as 
EDC site access to identified personnel.  Site members at each site will need to complete online 
training prior to obtaining access to the electronic system. 
 
 


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APPENDIX J:  PATIENT’S HOME GLUCOSE MONITORING DIARY 
 
Instructions:  
1.  Take home glucose readings as instructed by your study doctor or study nurse. 
2.  Record date, time, and value of glucose reading below. 
 
Patient Name_____________________ (initials acceptable)  
Patient Study ID _____________________ 
 
 
AM Reading 
PM Reading 
 
AM Reading 
PM Reading 
Date 
Day 
Time 
Glucose 
Value 
Time 
Glucose 
Value 
Date 
Day 
Time 
Glucose 
Value 
Time 
Glucose 
Value 
 
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Patient’s Signature: __________________________________ 
Date: _______________ 
 
 
Physician’s Office will complete this section: 
Physician or Research Nurse Signature: _____________________________  Date: ____________ 
 
 
Protocol # 13-334 


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Appendix K: QT interval on ECG corrected using the Bazett’s formula (QTcB) 
 
Bazett's formula used to correct QT interval for heart rate is: 
 
 
 
Where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset of one 
QRS complex to the onset of the next QRS complex, measured in seconds, often derived from 
the heart rate (HR) as 60/HR, and QT is the QT interval measured in milliseconds.   
 
Reference 
 
Bazett HC.  An analysis of the time-relations of electrocardiograms.  Heart 1920; 7: 353-370. 
 
RR
QT
QTcB =