Clinical trial NCT03232892
Conditions: Non-small Cell Lung Cancer
Keywords: NSCLC NF-1 mutant
Sponsor: University of California, San Francisco
Start date: 2018-02-13; Completion date: 2019-09-11
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

Detailed description:
This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the efficacy and safety of trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors non-synonymous NF1 mutations and are KRAS wildtype. Eligible patients must have documented disease progression either during or after treatment with most recent therapy and may not have received prior treatment with a MEK inhibitor. Patients with activating alterations in EGFR, ALK, and ROS-1 must also have received appropriate TKI treatment. Patients who meet eligibility criteria will receive trametinib monotherapy and followed for the primary endpoint of objective response rate and additional secondary endpoints. A total of 27 patients will be enrolled into the study, with the goals of obtaining 24 evaluable patients. Patients may continue treatment until disease progression or up to 24 months from the time of study entry or until the study is closed. All patients will be followed for 12 months.

Arms: arm 1: Trametinib 2.0mg PO daily in 28-day cycles. A maximum of two trametinib dose level reductions are allowed (1.5mg and 1mg) in the case of adverse reactions.
Interventions: intervention 1: Trametinib
Intervention descriptions: intervention 1: Trametinib 2mg, once daily, PO, 28-day cycles

Protocol documents:
Prot_SAP_001.pdf: 
Phase II trial to evaluate trametinib in patients with 
advanced NF1-mutant non-small cell lung cancer 
Protocol Number: CC # 166521 
Study Drug: Trametinib 
Version Number: 7.0 
Version Date: 06-20-18 
IND Number: Exempt 
Principal Investigator (Sponsor-Investigator) 
Collin Blakely, MD, PhD 
University of California San Francisco 
 
 
 
Statistician 
 
Revision History 
Version 1.0 
02-15-16
Version 2.0 
05-12-16
Version 2.1 
05-19-16
Version 2.2 
06-17-16
Version 3.0 
09-21-16
Version 3.1 
11-22-16
Version 4.0 
01-20-17
Version 5.0 
05-25-17
Version 6.0 
02-15-18
Version 7.0 
06-20-18
Proprietary and Confidential 
The information in this document is considered privileged and confidential, and may not be disclosed to others except 
to the extent necessary to obtain Institutional Review Board approval and informed consent, or as required by Federal 
and State laws.  Persons to whom this information is disclosed should be informed that this information is privileged 
and confidential and that it should not be further disclosed. 
NCT# 03232892


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Protocol Signature Page 
Protocol No.: 166521 
Version Date: 06-20-2018 
 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC). 
2. I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
3. I certify that I, and the study staff, have received the requisite training to conduct this 
research protocol. 
4. I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory  requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5. I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations. 
6. 
 
UCSF Principal Investigator / Study Chair 
Collin Blakely, MD PhD 
Printed Name 
Signature 
Date 
 
 
Participating Site(s) 
 
Site Name: University of 
California, Davis 
Principal Investigator: 
Jonathan Riess, MD 
 
 
Site Name: University of 
California, San Diego 
Principal Investigator: Hatim 
Husain, MD 
 
Signature: 
Signature: 
 
 
 
 
 
 
 
 
 
 
 
 


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Abstract 
 
Title 
Phase II trial to evaluate trametinib in patients with advanced NF1-mutant non- 
small cell lung cancer 
Patient 
population 
Patients with metastatic or unresectable locally advanced non-squamous, non- 
small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF1 
mutation, with progressive disease on at least one prior line of therapy. 
Rationale  for 
Study 
NF1 is a tumor suppressor gene, which encodes a RAS GTPase activating 
protein (GAP), which facilitates the hydrolysis of RAS-GTP to the inactive RAS- 
GDP.7-9 Germline NF1 inactivating mutations are associated with both pediatric 
and adult malignancies.10 Somatic mutations in NF1 have been associated with 
adenocarcinoma of lung,11 malignant melanoma,12 glioblastoma,13 as well as 
myelodysplastic syndrome.10 NF1 loss in melanoma cell lines that were wild- 
type for BRAF/RAS resulted in elevated RAS-GTP levels and MAPK signaling 
activation. Treatment of these cells with the MEK inhibitor trametinib resulted in 
sustained ERK inhibition and suppression of tumor cell proliferation.12 Likewise, 
leukemias have been shown to arise from either germline or somatic loss of 
NF114 and treatment of autochthonous myeloid malignancies driven by 
engineered NF1 loss in the mouse have been shown to be sensitive to MEK 
inhibition in preclinical models.15 
We hypothesize that patients with advanced NSCLC whose tumors harbor non- 
synonymous somatic mutations in NF1 will exhibit tumor dependence upon the 
MAPK signaling pathway and will be sensitive to treatment with the potent and 
selective MEK inhibitor trametinib.16 
Primary 
Objective 
To evaluate the efficacy of trametinib in patients with advanced, non-squamous 
NSCLC who have progressed on at least one prior line of systemic cancer therapy 
(i.e. platinum doublet, anti-PD1/PDL1 or appropriate EGFR, ALK, or ROS-1 
targeted therapy), and whose tumors harbor a non-synonymous mutation in NF1 
and is negative for an activating mutation in KRAS. 
Secondary 
Objectives 
● 
To evaluate secondary measures of clinical efficacy in advanced NSCLC 
patients treated with trametinib. 
● 
To evaluate the safety and tolerability of trametinib using National 
Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.03. 
● 
To describe the pharmacokinetics associated with trametinib. 
● 
To assess tissue and blood-based biomarkers that may be predictive of 
response or primary resistance to trametinib. 
● 
To determine subsets of advanced NSCLC in whom MEK inhibition is 
especially effective. (e.g., specific NF1 mutations). 
 
 
 
 
 
 
 


Phase II – Trametinib 
Page 3 of 86 
Version date: 06-20-2018 
Protocol CC#: 166521 
 
 
 
Study Design 
This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the 
efficacy and safety of trametinib monotherapy in patients with advanced non- 
squamous NSCLC whose tumors non-synonymous NF1 mutations and are KRAS 
wildtype. Eligible patients must have documented disease progression either 
during or after treatment with platinum doublet chemotherapy or most recent 
therapy and may not have received prior treatment with a MEK inhibitor. Patients 
with activating alterations in EGFR, ALK, and ROS-1 must also have received 
appropriate TKI treatment. Patients who meet eligibility criteria will receive 
trametinib monotherapy and followed for the primary endpoint of objective 
response rate and additional secondary endpoints. 
Number of 
patients 
A total of 27 patients will be enrolled into the study, with the goals of obtaining 
24 evaluable patients. Using a Simon 2-stage design, if we do not observe at 
least 2 responses within the first 15 patients, enrollment will be stopped due to 
lack of efficacy. 
Duration of 
Therapy 
Patients may continue treatment until disease progression or up to 24 months 
from the time of study entry or until the study is closed. 
Duration of 
Follow up 
All patients will be followed for 12 months. 
Duration of 
study 
The study is estimated to reach completion 4 years from the time the study 
opens to accrual. 
 
 
 
 
 
 
 
 


Phase II – Trametinib 
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Protocol CC#: 166521 
 
 
Study Drugs 
Trametinib is a reversible and highly selective allosteric inhibitor of MEK1 and 
MEK2 activation and kinase activity. Trametinib will be administered as 2 mg 
orally once daily. 
Safety 
Assessments 
Safety assessments will be based on events occurring during the on-study period, 
defined as from the first dose of trametinib to 30 days after the last dose of 
trametinib or until resolution for serious adverse events. Safety will be assessed 
by 
reviewing 
adverse 
events 
(AEs), 
laboratory 
evaluations, 
physical 
examination, and imaging or procedures when clinically indicated. Toxicity will 
be graded according to the National Cancer Institute’s Common Terminology 
Criteria for Adverse Events (version 4.03). 
Efficacy 
Assessments 
Efficacy measures will include tumor assessments by CT scans of the chest, 
abdomen, and pelvis with appropriate slice thickness per RECIST Version 1.1. 
Brain imaging (CT/MRI) is  required at baseline and follow-up scans should 
include the brain in patients with baseline brain lesions. All sites of disease 
should be followed and the same imaging methodology should be used 
throughout the study. Tumor assessments will be carried out at screening and 
every 8 weeks ± 1 week from the time of trametinib initiation and thereafter until 
tumor progression. Patients are required to have an end-of-treatment tumor 
scan using the same methodology used at screening unless: 
● 
The patient  has radiographic  evidence  of  disease progression  while  on 
study, or 
● 
It has been < 2 weeks since their last on-study scan 
Patients who discontinue trametinib without progression should continue to be 
scanned per standard of care until disease progression occurs. 


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List of Abbreviations 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCEA 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DCR 
Disease control rate 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DR 
Duration of Response 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCT 
Hematocrit 
HCV 
hepatitis C virus 
HDFCCC 
Helen Diller Family Comprehensive Cancer Center 
HGB 
Hemoglobin 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
 
 
 
 


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List of Abbreviations 
 
 
IV 
Intravenous 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NF1 
Neurofibromatosis type 1 
NSCLC 
non-small cell lung cancer 
ORR 
overall response rate 
OS 
overall survival 
PD 
disease progression 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PFS 
progression Free Survival 
PR 
partial response 
PRC 
Protocol Review Committee (UCSF) 
RBC 
red blood cell (count) 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 


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Table of Contents 
Protocol Signature Page ..................................................................................................................... 1 
Participating Site(s) ............................................................................................................................ 1 
Abstract .............................................................................................................................................. 2 
List of Abbreviations ........................................................................................................................... 6 
Table of Contents ............................................................................................................................... 7 
1.1 
Background on Indication .......................................................................................................... 9 
1.2 
Background on the Compounds ................................................................................................ 9 
1.3 
Rationale for the Proposed Study ....................................................................................... 12 
1.4 
Correlative Studies .................................................................................................................. 14 
1.4.2 Cell-Free DNA ................................................................................................................... 16 
2 
Objectives of the Study ....................................................................................................... 16 
2.1 
Primary .............................................................................................................................. 16 
2.2 
Secondary ............................................................................................................................... 16 
2.3 
Exploratory Objectives, Other Assessments ........................................................................... 16 
2.4 
Endpoints ................................................................................................................................ 17 
3 
Study Design ...................................................................................................................... 17 
3.1 
Characteristics ........................................................................................................................ 17 
3.2 
Number of Subjects ................................................................................................................. 19 
3.3 
Eligibility Criteria ...................................................................................................................... 19 
Table 3.1  Definitions for adequate baseline organ function ............................................................ 21 
3.4 
Duration of Therapy ............................................................................................................ 23 
3.5 
Duration of Follow Up ......................................................................................................... 23 
3.6 
Study Timeline ........................................................................................................................ 23 
4 
Study Drugs ....................................................................................................................... 24 
4.1 
Description, Supply and Storage of Investigational Drugs ...................................................... 24 
4.2 
Drug Accountability ................................................................................................................. 28 
4.3 
Drug Ordering ......................................................................................................................... 28 
4.4 
Packaging and Labeling of Study Drugs ................................................................................. 28 
5 
Treatment Plan ........................................................................................................................ 28 
5.1 
Dosage and Administration ..................................................................................................... 28 
5.2 
Dose Modifications and Dosing Delays ................................................................................... 28 
Table 5.2 
Dose Modifications and Dosing Delays .................................................................. 28 
Table 5.3 Dose Delay and Modification for Events Considered Related to Trametinib ................... 29 
Table 5.4 
Guidelines for Supportive Care of Rash ................................................................. 31 
Table 5.5 
Management and Dose Modification Guidelines for Rash ...................................... 32 
Table 5.6 
Management and Dose Modification Guidelines for Diarrhea ................................ 34 
Table 5.9 
Withholding and Stopping Criteria for QTc-Prolongation ........................................ 38 
Table 5.10 
Management and Dose Modification Guidelines for Pneumonitis .......................... 39 
Table 5.15 ........................................................................................................................................ 43 
 
 
 
 
 


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6 
Study Procedures and Observations ...................................................................................... 45 
6.1 
Schedule of Procedures and Observations............................................................................. 45 
Table 6.1 
Schedule of Study Procedures and Assessments .................................................. 49 
6.2 
Usage of Concurrent/Concomitant Medications ..................................................................... 52 
6.3 
Dietary Restrictions ................................................................................................................. 52 
6.4 
Prohibited Medications ............................................................................................................ 52 
7 
Reporting and Documentation of Results ............................................................................... 53 
7.1 
Evaluation of Efficacy (or Activity) ........................................................................................... 53 
Table 7.1 
Response Criteria ................................................................................................... 55 
7.2 
Evaluation of Safety ............................................................................................................ 56 
7.3 
Definitions of Adverse Events ................................................................................................. 56 
7.4 
Recording of an Adverse Event .............................................................................................. 57 
7.5 
Follow-up of Adverse Events .................................................................................................. 59 
7.6 
Adverse Events Monitoring ..................................................................................................... 59 
7.7 
Expedited Reporting.................................................................................... 60_Toc506966742 
8 
Statistical Considerations and Evaluation of Results .............................................................. 62 
8.1 
Study Endpoints ...................................................................................................................... 62 
8.2 
Determination of Sample Size and Accrual Rate .................................................................... 62 
8.3 
Analyses Plans ........................................................................................................................ 63 
8.4 
Evaluation of Safety ............................................................................................................ 66 
9 
Study Management ................................................................................................................. 66 
9.1 
Pre-study Documentation ........................................................................................................ 66 
9.2 
Institutional Review Board Approval........................................................................................ 67 
9.3 
Informed Consent.................................................................................................................... 67 
9.4 
Changes in the Protocol .......................................................................................................... 67 
9.5 
Handling and Documentation of Clinical Supplies .................................................................. 67 
9.6 
Case Report Forms (CRFs) .................................................................................................... 68 
9.7 
Oversight and Monitoring Plan ............................................................................................ 68 
9.8 
Multicenter communication ..................................................................................................... 68 
9.9 
Coordinating Center Documentation of Distribution ................................................................ 69 
9.10 Regulatory Documentation ...................................................................................................... 69 
10 
Protection of Human Subjects ................................................................................................. 70 
10.1 Protection from Unnecessary Harm ........................................................................................ 70 
10.2 Protection of Privacy ............................................................................................................... 70 
References ....................................................................................................................................... 71 
Appendices ....................................................................................................................................... 73 
Appendix 2 Performance Status Criteria .......................................................................................... 74 
Appendix 3 UCSF Policy/Procedure for Required Regulatory Documents for a UCSF Investigator- 
Initiated Oncology Clinical Trials with an Investigator held Investigational New Drug (IND) .73 
Appendix 4  Data Safety Monitoring Plan for a Multicenter Study (Phase II or III study)  
 
..........................................................................................................................................79 
Appendix 5  Prohibited Medications ................................................................................................. 82 
Appendix 6  Specimen Collection .................................................................................................... 84 


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1 
Introduction 
1.1 
Background on Indication 
 
The RTK-RAS-MAPK pathway is central in the initiation and maintenance of non-small cell lung 
cancer (NSCLC). Canonical mutations in KRAS, EGFR or fusions in ALK, ROS1, or NRTK1 are 
present in about 50% of NSCLC of the adenocarcinoma subtype.24 In two studies of 
approximately 400 NSCLC patients by The Cancer Genome Atlas (TCGA) Research Network, 
the frequency of mutations in NF1 became apparent.1,25 These mutations are typically mutually 
exclusive from KRAS, EGFR, or BRAF mutations (Figure 1.1). 
 
We hypothesize that patients with advanced non-squamous NSCLC whose tumors harbor re- 
current non-synonymous somatic mutations in NF1 will exhibit tumor dependence upon the 
MAPK signaling pathway and will be sensitive to treatment with the potent and selective MEK 
inhibitor trametinib.16 
 
 
 
 
1.2 
Background on the Compounds 
1.2.1 Non-clinical pharmacology 
 
Trametinib (GSK1120212) is a selective MEK1 and MEK2 inhibitor with selective activity 
towards BRAF and RAS mutant cancer cell lines and hematopoietic cancer cells from acute 
myeloid leukemia (AML) and chronic myeloid leukemia (CML) origins. Trametinib inhibited the 
proliferation of most of the BRAF mutant melanoma cell lines tested (22 of 25) and it effectively 
inhibited the growth of BRAF mutant melanoma xenografts in vivo alone or in combination with 
dabrafenib. It causes inhibition of ERK phosphorylation leading to Gap-1 (G1) cell cycle arrest 
and tumor xenograft growth. 
 
There were no clinically relevant findings in single dose safety pharmacology studies in rats and 
dogs evaluating the cardiovascular, respiratory and central nervous systems conducted with 
trametinib. Left ventricular ejection fraction decrease is a common adverse event in patients 
taking trametinib. Mice given trametinib at ≥ 0.25 mg/kg/day for 3 weeks (3-times the clinical 
area under the plasma concentration-time curve [AUC] at steady state) had decreased 
ventricular function, lower heart rates and lower heart weight in the absence of cardiac 
histopathology. Importantly, there was no diminution of dobutamine-induced contractility. An in 
vitro investigative study demonstrated that the echocardiography effects were not likely to be 
due to acute myocardial toxicity or inhibition of mitochondrial function. 
 
 
 
 
Figure 1: Mutations in BRAF and NF1 are mutually exclusive from EGFR or KRAS mutations in lung 
adenocarcinoma (Source: Cancer Genome Atlas Research Network1) 


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1.2.2 Pharmacokinetics and Product Metabolism in Animals 
 
The nonclinical pharmacokinetics (PK) of trametinib were similar across the species (mouse, 
rat, dog and monkey). Low plasma clearance relative to liver blood flow and generally long half- 
lives (t1/2) likely contribute to the accumulation upon repeat dosing which is consistent with 
observations in humans. Upon achieving steady-state, by 7 days for mice and by 3 weeks for 
rats and dogs (based on sparse sampling study design), the exposure of trametinib generally 
increased dose proportionally, which is consistent with observations in humans (steady state 
appeared to be achieved by Day 15). 
 
The volume of distribution of trametinib was generally greater than total body water for all 
species, consistent with the observed wide distribution to tissues in the rat. There was no 
selective association of drug-related material with melanin containing tissues. Plasma protein 
binding was high in nonclinical species and humans (>95%). In vitro blood cell association in 
humans was concentration dependent with a high blood to plasma ratio (ranged from 3 to 8) at 
the clinically relevant trametinib concentrations of 1 and 10 ng/mL. Nonclinical species, 
including rats and dogs, showed protracted elimination of DRM (Drug Related Material) 
consistent with a high volume of distribution, long half-life, and the PK data of trametinib in 
subjects with solid tumors. 
 
Absorption and systemic availability in nonclinical species and humans was moderate to high 
(>40% to approximately 100%). The fecal route of elimination was the major excretory pathway 
in humans, rats, dogs, and mice. Trametinib has a high passive permeability and is not an in 
vitro substrate for human P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), multi- 
drug resistance protein 2 (MRP2) and multidrug and toxin extrusion protein 1 (MATE1). 
Therefore, the risk for an effect of other drugs on trametinib via these mechanisms is low. 
Trametinib is a weak in vitro substrate of the efflux transporter bile salt export pump (BSEP). 
The current literature suggests that BSEP mostly transports endogenous bile salts26 and is 
unlikely to play a major role in drug disposition and hence poses a low risk in drug-drug 
interactions.27 In humans, trametinib is eliminated predominantly by hydrolytic deacetylation, 
either deacetylation alone (M5) or in combination with mono-oxygenation M7). The enzymes 
involved are likely hydrolytic enzymes, such as esterases or amidases that are not generally 
associated with drug interaction risks. 
 
For the nonclinical species (rat and dog), trametinib was the major circulating component (> 60% 
of DRM) in plasma at all sampling time points. In humans, trametinib partitions in red blood cells 
and the majority of the circulating radioactivity is present as trametinib in blood (78-95% of 
DRM). Three minor metabolites M5, M6 and M7 were identified with the deacetylated metabolite 
(M5), which was shown to have similar in vitro pharmacological activity as parent, accounting for 
≤11% of plasma (rat and dog) or blood DRM (human). In an earlier investigation of plasma 
metabolites in humans following repeat dosing, the metabolites do not appear to accumulate to 
the same degree as parent. Qualitatively, all of the major metabolites of trametinib observed in 
humans have been detected in the nonclinical species. 
 
Based on in vitro studies, trametinib is not an inhibitor of cytochrome P450 enzymes including 
CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Although trametinib was found to be an in 
vitro inhibitor of CYP2C8, CYP2C9 and 2C19, inducer of CYP3A4 and inhibitor of the organic 
anion transporting polypeptide (OATP) transporters (OATP1B1, OATP1B3), Pgp, BCRP, 
organic anion transporter (OAT)1, OAT3, organic cation transporter 2 (OCT2), and MATE1), its 
low efficacious dose, and low clinical systemic concentration (22.2 ng/mL or 0.04 M at 2 mg) 


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relative to the in vitro inhibition/induction potency suggests an overall low potential for drug-drug 
interactions. 
 
1.2.3 Pharmacokinetics in humans 
 
Trametinib pharmacokinetics were determined after single- and repeat-dose oral administration 
of trametinib tablets in subjects with solid tumors. Trametinib is absorbed rapidly with median 
time to maximum plasma concentration (tmax) generally occurring 1.50 hours after single oral 
administration of trametinib under fasting conditions. The absolute oral bioavailability of a single 
trametinib 2.0 mg tablet is moderate to high (72%) relative to a co-administered intravenous (IV) 
microdose. Single-dose administration of trametinib with a high-fat, high-calorie meal resulted in 
a 70% decrease in Cmax, a 24% decrease in area under the concentration-time curve from time 
zero (predose) to last time point (AUC[0-t]) and a 10% decrease in AUC extrapolated to infinity 
(AUC [0-
]) compared to fasted conditions. 
 
Following repeat-dosing the mean area under the curve from 0 hours to the time of next dosing 
(AUC[0-
]) and Cmax increased in an approximately dose proportional manner. Trametinib 
accumulates with repeat dosing with a mean accumulation ratio at the recommended dose of 2 
mg once daily of 5.97 and a terminal half-life of 5.3 days determined after single dose 
administration. Steady state appears to be achieved by Day 15, with little difference in pre-dose 
(trough) concentration at the end of the dosing interval (C ), Cmax and area under the 
concentration-time curve from time zero (pre-dose) to 24 hrs (AUC[0-24]) between Days 15 and 
21. 
 
Trametinib is a low extraction ratio drug based on plasma IV clearance of 3.21 L/hr, which 
represents approximately 1% of liver blood flow. Trametinib has a high volume of distribution 
(Vd) of 1060 L determined following an IV microdose. 
 
Fecal excretion is the major route of elimination after [14C] trametinib oral dose, accounting for 
>80% of excreted radioactivity recovered (or 39.2% and 35.0% of the radioactive dose in 2 
subjects) while urinary excretion accounted for <19% of excreted radioactivity recovered (<10% 
of the radioactive dose). Following a single dose of [14C]-trametinib, approximately 50% of 
circulating radioactivity is represented as the parent compound. However, based on metabolite 
profiling after repeat dosing of trametinib, ≥75% of drug-related material in plasma is the parent 
compound. 
 
In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other drugs and 
that the PK of trametinib is unlikely to be affected by other drugs. Trametinib is metabolized 
predominantly via deacetylation which is likely mediated by hydrolytic esterases which are not 
generally associated with drug interaction risk, nor is it a substrate of Pgp or BCRP. 
 
 
1.2.4 Trametinib Efficacy 
 
Efficacy results from the MEK114267 (melanoma) study and the supporting studies 
MEK113583 (melanoma), MEK111054 (solid tumors or lymphoma), and MEK114653 
(non-small cell lung carcinoma; NSCLC) indicated: 


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● 
Substantial evidence of effectiveness in unresectable BRAF V600 mutation positive 
melanoma as evidenced by prolongation of progression-free survival (PFS) and overall 
survival (OS). Updated long term results from MEK114267 study also consolidated the 
OS benefit of trametinib treatment over chemotherapy in this patient population. 
● 
The clinical activity of trametinib observed in melanoma subjects whose tumors harbor 
BRAF V600K mutations is comparable to the activity seen in BRAF V600E mutations 
● 
Comprehensive efficacy data to support the recommended dose of trametinib of 2 mg 
once daily for all subjects 
● 
The efficacy of trametinib in melanoma across all demographic (e.g., age, gender) and 
prognostic factors (e.g., tumor stage, Eastern Cooperative Oncology Group Performance 
Status [ECOG PS], lactate dehydrogenase (LDH) levels, history of brain metastases). 
 
1.2.5 Safety 
 
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, and the RP2D of trametinib was identified as 2.0 mg once daily. 
 
In the 11 monotherapy studies of trametinib for which data are available (MEK111054, 
MEK111759, MEK113583, MEK113708, MEK113709, MEK114267, MEK114375, MEK115064, 
MEK114653, MEK114655, and MEK115892), all studies except MEK113708 had AEs. 
 
In the studies with AEs, 50% to 100% of all subjects in any dose group had at least 1 AE, and 
0% to 70% of all subjects in any dose group had at least 1 serious adverse event (SAE). Of the 
studies with discontinuations or withdrawals, 3% to 26% of subjects receiving trametinib 
permanently discontinued study treatment or withdrew due to AEs. 
 
Of the > 700 subjects (including crossover subjects) in the 2.0 mg dose group, in 8 
monotherapy studies with AEs (MEK111054, MEK111759, MEK113583, MEK113709, 
MEK114267, MEK115064, MEK114655, and MEK114653), 50% to 100% of subjects had at 
least 1 AE, and 0% to 70% of all subjects had SAEs. Of the studies with discontinuations or 
withdrawals (MEK111054, MEK113583, MEK114267, MEK114653, and MEK111759), 3% to 
24% in the 2.0 mg does group permanently discontinued study treatment or withdrew from the 
study due to AEs. Data from studies with the combination of trametinib and dabrafenib 
(GSK2118436) are included in another IB [GlaxoSmithKline Document Number 
2011N126811_02]. In the 2.0 mg dose group across all completed monotherapy studies with 
AEs, the most common AEs had were rash, diarrhea, fatigue, edema peripheral, nausea, 
dermatitis acneiform, vomiting, constipation, anemia, pruritus, alopecia, hypertension, 
decreased appetite, dyspnea and dry skin. 
1.3 
Rationale for the Proposed Study 
Recent genomic studies, including the Cancer Genome Atlas (TCGA), have identified >140 
different recurrent somatic mutations in neurofibromin-1 (NF1) in human NSCLC17,18. These 
NF1-mutants are present in ~10% of NSCLC patients and often occur in the absence of another 
known genetic driver event, suggesting a potential driver role for mutant NF117,18; thus, NF1- 
mutant NSCLC comprises an emerging distinct genetic subtype of NSCLC and the largest 
population of NF1-mutant patients across all tumor types. NF1 is a tumor suppressor that is 
genetically inactivated in several tumor types including melanoma, glioblastoma, certain 


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leukemias, and the hereditary syndrome neurofibromatosis12,19-23.  NF1 is a GTPase activating 
protein (GAP) for RAS GTPases, which require GTP binding to signal to downstream effector 
pathways such as the RAF-MEK-ERK cascade20. NF1 enhances the intrinsic rate of GTP 
hydrolysis of RAS, thereby switching RAS off. Loss of NF1 activity enhances RAS-GTP levels to 
promote RAF-MEK-ERK signaling, cellular proliferation and growth, and oncogenesis12,20,23. 
 
There are currently no FDA-approved targeted therapy options for patients with advanced non- 
squamous NSCLC whose tumors harbor  NF1 mutations and have failed treatment with first-line 
platinum-containing cytotoxic chemotherapy or appropriate EGFR, ALK, or ROS-1 targeted 
therapies. After progression on first-line platinum doublet chemotherapy or second-line 
immunotherapy, single-agent cytotoxic chemotherapy in the second or third-line setting has 
limited efficacy28. . This highlights the ongoing unmet need for patients with advanced NSCLC 
with NF1 mutations. 
 
 
 
 
 
 
NF1 is a tumor suppressor gene, which encodes a RAS GTPase activating protein (GAP), 
which facilitates the hydrolysis of RAS-GTP to the inactive RAS-GDP.7-9 Germline NF1 
inactivating mutations are associated with both pediatric and adult malignancies.10 Somatic 
mutations in NF1 have been associated with adenocarcinoma of lung,11 malignant melanoma,12 
glioblastoma,13 as well as myelodysplastic syndrome.10 NF1 loss in melanoma cell lines that 
were wild-type for BRAF/RAS resulted in elevated RAS-GTP levels and MAPK signaling 
activation. Treatment of these cells with the MEK inhibitor trametinib resulted in sustained ERK 
inhibition and suppression of tumor cell proliferation.12 Likewise, leukemias have been shown to 
arise from either germline or somatic loss of NF114 and treatment of autochthonous myeloid 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1.4. Relative sensitivity of NF1-mutant patient-derived lung adenocarcinoma
cell line to the MEK inhibitor trametinib. (A) Detection of cell-free DNA by Guardant 360
assay in a patient with known, metastatic NF1-mutant lung adenocarcinoma (A) Western
blot showing a decrease in ERK phosphorylation upon trametinib treatment of cell lines
derived from the patient’s tumor. (B) Cell viability assay showing a ~ 50 % reduction in cell
viability upon trametinib treatment of NF1 mutant lung adenocarcinoma cells. 


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malignancies driven by engineered NF1 loss in the mouse have been shown to be sensitive to 
MEK inhibition in preclinical models.15 
 
We have generating a non-small cell lung cancer cell line from a patient whose only know 
somatic mutations were in TP53 E349* and NF1 S1759C.  Notably, the frequency of these 
mutations detectable by cell-free DNA from the patients’ blood have increased as the lung 
cancer progressed radiographically (Figure 1.4A).  MEK activity, as determined by ERK 
phosphorylation is rapidly decreased upon treatment of these cells with trametinib (Figure 1.4B). 
Meanwhile, cell viability decreases by ~50 % upon trametinib treatment (Figure 1.4C). 
With demonstrated activity against and NF1 mutant melanoma12 and myeloid malignancy31 and 
lung adenocarcinoma preclinical models (Figure 1.4), we hypothesize that trametinib will 
provide an effective and tolerable therapy for patients with NF1-mutant NSCLC. The goals of  
the current study are to determine the anti-tumor efficacy and safety of oral single-agent 
trametinib in patients with NF1 mutated advanced non-squamous NSCLC after failure of at least 
one prior line of chemotherapy including a platinum doublet, and appropriate treatment with an 
EGFR, ALK, or ROS-1 inhibitor in patients whose tumors harbor activating alterations in those 
genes. 
1.4 
Correlative Studies 
1.4.1 Whole exome and transcriptome sequencing. 
 
 
We will use whole exome and transcriptome deep sequencing (WES; RNAseq) in the pre- 
treatment, on treatment, and post-resistance samples to uncover somatic genetic alterations 
(mutations and copy number alterations) and transcriptional events associated with clinical 
resistance (either de novo or acquired), using our methods and with a minimum depth of WES 
coverage of 100X to capture events occurring down to ~1% frequency. This approach will 
enable identification and/or validation of RNA signatures of potential resistance events, such as 
ERK1/2 transcriptional output. The analysis of samples from patients with de novo resistance 
and of matched paired tumor samples acquired from individual patients before treatment and at 
acquired resistance (based on standard radiographic assessment in the trial, such as RECIST 
criteria) will be prioritized for study to facilitate the clinical correlation of the genetic findings with 
bona fide clinical resistance. Orthogonal validation of specific findings will be done using 
individualized assays in the clinical specimens (e.g. direct sequencing, SNP arrays, 
fluorescence in situ hybridization for DNA alterations; q-RT-PCR, IHC for RNA and protein 
abundance changes) and associated circulating free DNA, where feasible. 
1.4.2 IHC for phospho-ERK and downstream effectors: 
 
 
We will evaluate whether trametinib effectively shuts down the MEK signaling axis by 
performing IHC analysis on pre-treatment and on-treatment biopsy specimens.  YAP-TAZ 
signaling will also be evaluated, given that its upregulation is associated with resistance to 
MAPK pathway inhibitors32. 
1.4.3 Patient-derived xenografts and organoids 
 
 
When possible, patient derived xenografts or organoids will be generated from patient biopsy 
specimens. Alterations discovered in the clinical specimen analysis will be functionally studied 
using our standard cell-based assays. We will test if activation or suppression of the candidate 
resistance gene (as indicated by whether the gene is increased or decreased in resistance) 


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promotes MEK inhibitor resistance, in vitro and in vivo in tumor  xenograft and organoid studies. 
 
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1.4.2 Cell-Free DNA 
 
Blood samples for circulating tumor DNA (ctDNA) will be collected pre-treatment and post- 
resistance tissue biopsy to identify mechanisms of resistance. Concordance of ctDNA with  pre- 
and post- tissue biopsy will be assessed. 20ml of whole blood for ctDNA analysis will be 
collected at the time of pre-treatment biopsy, monthly until tumor progression, and at the time of 
post-resistance biopsy to monitor dynamic changes in the quantity of ctDNA for the specific NF1 
mutations. The rate of ctDNA clearance of the specific NF1 mutations will be serially tracked  
and will be compared to radiologic change on CT scans. Acquired somatic mutations in, NF1 or 
off-target genes qualitatively evaluated to identify second site mutations that may confer 
resistance to therapy. 
 
2 
Objectives of the Study 
2.1 
Primary 
To evaluate the efficacy of trametinib in patients with advanced, non-squamous NSCLC who 
have progressed on at least one prior systemic anti-cancer therapy (i.e. platinum doublet 
chemotherapy, anti-PD1 or anti-PDL1 immunotherapy, or appropriate EGFR, ALK, and 
ROS-1 targeted therapy) and whose tumors harbor a non- synonymous mutation in NF1 
and is negative for activating mutations in KRAS. 
2.2 
Secondary 
● 
To evaluate secondary measures of clinical efficacy in advanced NSCLC patients 
treated with trametinib. 
● 
To evaluate the safety and tolerability of trametinib using National Cancer Institute 
Common Toxicity Criteria (NCI-CTC) version 4.03. 
 
2.3 
Exploratory Objectives, Other Assessments 
● 
Determine whether specific mutations in NF1 identified in pretreatment tumor samples 
correlate with response and/or resistance to trametinib. 
● 
To identify biomarkers of clinical benefit and mechanisms of resistance (de novo 
resistance, incomplete response, and acquired resistance) to trametinib therapy in NF1 
mutant NSCLC. 
● 
Assess circulating tumor DNA (ctDNA) for biomarkers of response and/or resistance to 
trametinib. 


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2.4 
Endpoints 
2.4.1 Primary Endpoints 
 
● 
Objective Response Rate (ORR) according to RECIST Version 1.1 criteria as 
determined by investigator assessment. The ORR is defined as the best overall 
response recorded from the start of the treatment until disease progression or 
recurrence from the start of treatment. 
 
2.4.2 Secondary Endpoints 
 
● 
Efficacy: DR, DCR, PFS, and OS according to RECIST Version 1.1 criteria as 
determined by investigator assessment. 
● 
The DR for CR and PR will be measured from the date that the best response if first 
recorded until the date that PD is documented. For patients who continue treatment 
post progression, the date of PD documentation will be used for analysis. 
● 
DCR will be defined as the percentage of patients who have achieved CR, PR, or SD 
for at least 12 weeks. 
● 
PFS will be calculated as 1+ the number of days from the first dose of study drugs to 
documented radiographic progression or death due to any cause over a period of 1 
year. For patients who continue treatment post-progression, the date of radiographic 
progression will be used for PFS analysis. 
● 
OS will be calculated as 1+ the number of days from the first dose of study drugs to 
death due to any cause over a period of 1 year. 
 
● 
Safety and tolerability: 
● 
All treatment-emergent AEs 
● 
Treatment-emergent AEs by CTCAE grade 
● 
Grade 3 or greater treatment-emergent AEs 
● 
Treatment-related, treatment-emergent AEs 
● 
Dose-limiting toxicity AEs 
● 
Serious treatment-emergent AEs 
● 
Treatment-emergent AEs with an outcome of death 
● 
Treatment-emergent AEs leading to discontinuation of trametinib. 
● 
Treatment-emergent AEs resulting in interruption or reduction or delay of trametinib. 
2.4.3 Exploratory Endpoints 
 
● 
Specific mutations in NF1 identified in pretreatment tumor samples correlated with 
response and/or resistance to trametinib. 
● 
Circulating cell free DNA (cfDNA) biomarkers associated with response and/or 
resistance to trametinib. 
● 
RNA and DNA changes in samples during therapy and at progression. 
3 
Study Design 
3.1 
Characteristics 
   This is a Phase II, open-label, multicenter clinical trial evaluating the efficacy and safety of  
 


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trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors harbor 
 
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a non-synonymous NF1 mutation and are wildtype for activating mutations in KRAS. Eligible 
patients must have documented disease progression either during or after treatment with 
appropriate EGFR, ALK, or ROS-1 inhibitors (in patients with EGFR activating mutations, or 
ALK or ROS-1 fusions) and platinum doublet chemotherapy (or inability to tolerate) or most 
recent therapy and must not have received prior treatment with a MEK inhibitor. 
 
 
Figure 3.1. Study schema 
 
Patients will receive trametinib monotherapy in 28-day cycles. The primary outcome is objective 
response rate. 
3.2 
Number of Subjects 
A total of 27 patients will be enrolled in the study, with the goal of obtaining 24 evaluable 
patients. This will provide 80% power to detect a 30% ORR with trametinib compared to the null 
hypothesis of a 10% ORR. Using a Simon 2-stage design, if we do not observe at least 2 
responses within the first 15 patients, enrollment will be stopped due to lack of efficacy. 
 
3.3 
Eligibility Criteria 
Patients must have baseline evaluations performed prior to the first dose of study drug and must 
meet all inclusion and exclusion criteria.  In addition, the patient must be thoroughly informed 
about all aspects of the study, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 


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from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified. 
 
3.3.1 Inclusion Criteria 
 
1. Histologically or cytologically confirmed metastatic or unresectable locally advanced, 
non-squamous, NSCLC. 
2. Documented non-synonymous somatic mutation in NF1 in any tumor specimen or cell- 
free DNA assay by CLIA-approved laboratory. 
3. Received at least one prior line of cancer therapy for the treatment of NSCLC. This 
should include at least one of the following: platinum (carboplatin or cisplatin) doublet 
chemotherapy (acceptable combinations include: paclitaxel, docetaxel, abraxane, 
pemetrexed, gemcitabine, vinorelbine, or etoposide), anti-PD1/PDL1 therapy 
(pembrolizumab, nivolumab, or atezolizumab), or appropriate targeted therapy in 
patients with activating EGFR (osimertinib, erlotinib, gefitinib, or afatinib), ALK (alectinib, 
crizotinib, ceritinib, brigatinib, or loralatinib), or ROS-1 (crizotininb or entrectinib) 
alterations.  Therapy may be given as monotherapy or in combination with other 
cancer therapy (e.g. bevacizumab, ipilumimab) 
4. Patients with a known activating mutation in EGFR (Exon 19 deletion, G719A, S768I, 
V769L, T790M, L833F, L858R, L861Q), must have progressed or been intolerant to 
treatment with a first-line EGFR TKI (erlotinib, afatinib, gefitinib or osimertinib).  Patients 
whose tumors were found to have an EGFR  T790M mutation must also have 
progressed or been intolerable to treatment with  osimertinib. 
5. Patients with a known ALK-rearrangement must have progressed or been intolerant to 
treatment with at least one ALK TKI: crizotinib, ceritinib, alectinib, brigatinib, or 
loralatinib. 
6. Patients with a known ROS-1- rearrangement must have progressed or been 
intolerant to treatment with crizotinib or entrectinib. 
7. Patients with PDL1 level of ≥ 50%, who do not have an ALK-rearrangement or 
EGFR-mutation, must have progressed or been intolerant to treatment with anti- 
PD1/PDL1 therapy (pembrolizumab, nivolumab, or atezolizumab). 
8. Documented disease progression or intolerance to treatment either during or after 
treatment with most recent therapy. 
9. Willingness to undergo research biopsy. 
10. Measurable disease defined by RECIST 1.1 criteria. 
11. Life expectancy of at least 3 months. 
12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
13. Age ≥ 18 years. 
14. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy, radiotherapy 
or surgical procedures to NCI CTCAE Version 4.03 grade 1. 
15. Adequate baseline organ function defined in Table 3.1. 
 
 
 
 
 
 


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Table 3.1  Definitions for adequate baseline organ function 
 
System 
Laboratory Values 
Hematologic 
Absolute neutrophil count 
1.2 × 109/L 
Hemoglobin 
9 g/dL 
Platelets 
100 × 109/L 
PT/INR and PTT 
≤ 1.5 x ULN 
Hepatic 
Albumin 
2.5 g/dL 
Total bilirubin 
1.5 x ULN 
AST and ALT 
2.5× ULN 
Renal 
Creatinine or 
1.5 ULN 
Calculated creatinine 
clearancea 
50 mL/min 
Cardiac 
Left Ventricular Ejection 
fraction (LVEF) 
≥ LLN by ECHO or MUGAb 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio; 
PT = prothrombin time; PTT= partial thromboplastin time; ULN = upper limit of normal; LLN = lower limit of 
normal 
a. 
Calculated by the Cockcroft-Gault formula. 
b. 
Same method as used at baseline must be use throughout the study 
 
16. Women of childbearing potential must have a negative serum or urine pregnancy test 
within 3 days prior to study enrollment. The effects of trametinib on the developing 
human fetus are unknown. For this reason and because animal studies with trametinib 
have shown reproductive toxicity, women of child-bearing potential and men must agree 
to use effective methods of contraception (hormonal or barrier method of birth control) 
prior to study entry, for the duration of study participation, and for 4 months following 
discontinuation of trametinib. Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately. Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of study drug administration. 
 
17. Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels. 
 
18. All prior treatment- related toxicities must be CTCAE (Version 4.03) ≤ Grade 1 (except 
alopecia) at the time of randomization 
19. Ability to understand a written informed consent document, and the willingness to sign it. 


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3.3.2 Exclusion Criteria 
 
Patients eligible must not meet any of the following criteria: 
 
1. Known mutation in KRAS at position G12, G13, or Q61. 
 
2. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression. Treated brain metastases are allowed as long as they are stable for at 
least 28 days post-treatment. 
3. Pregnant women are excluded from this study because trametinib is a MEK inhibitor with 
the potential for teratogenic or abortifacient effects. Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the mother 
with trametinib, breastfeeding should be discontinued if the mother is treated with 
trametinib. 
 
4. History of another malignancy. 
Exception:  Subjects who have been disease-free for 3 years, or subjects with a history of 
completely resected non-melanoma skin cancer and/or subjects with indolent second 
malignancies are eligible. 
 
5. 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. 
6. The subject has received cytotoxic chemotherapy, molecular targeted therapy, or 
immunotherapy within 21 days before the first dose of study drug (trametinib). 
 
7. Prior treatment with MEK inhibitor. 
 
8. History of interstitial lung disease or pneumonitis. 
9. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO). 
10. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic 
therapy, or immunotherapy within 21 days prior to study enrollment and/or daily or 
weekly chemotherapy without the potential for delayed toxicity within 14 days prior to 
study enrollment. 
11. History of retinal vein occlusion (RVO). 
12. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C 
Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV 
infection will be permitted). 
13. History or evidence of cardiovascular risk including any of the following: 
● 
LVEF< LLN 
● 
A QT interval corrected for heart rate using the Bazett’s formula (QTcB) 480 
msec; 
● 
History or evidence of current clinically significant uncontrolled arrhythmias. 


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● 
Clarification: Subjects with atrial fibrillation controlled (defined as not requiring 
change in cardiac drug dosing, emergency room visit, or hospital admission) for 
>30 days prior to dosing are eligible. 
● 
History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior to study 
enrollment. 
● 
History or evidence of current ≥ Class II congestive heart failure as defined by 
New York Heart Association (NYHA). 
● 
Treatment refractory hypertension defined as a blood pressure of systolic > 140 
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti- 
hypertensive therapy; 
● 
Patients with intra-cardiac defibrillators. 
3.4 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue for 24 
months or until: 
● 
Disease progression 
● 
Inter-current illness that prevents further administration of treatment 
● 
Unacceptable adverse event(s) 
● 
Patient decides to withdraw from the study 
● 
Significant patient non-compliance with protocol 
● 
General or specific changes in the patients’ condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
● 
The study is closed by the sponsor or investigator. 
 
Patients who are continuing to respond to the study drug after 24 months of therapy will be 
provided with continued access to the drug by Novartis. 
3.5 
Duration of Follow Up 
Patients will be followed for 30 days after completion of treatment or removal from study, or until 
death, whichever occurs first. Patients removed from study for unacceptable treatment related 
adverse event(s) will be followed until resolution or stabilization of all treatment related adverse 
events to Grade 2 or lower. 
3.6 
Study Timeline 
3.6.1 Primary Completion 
 
It is expected that the study will reach primary completion 36 months from the time the study 
opens to accrual. 
3.6.2 Study Completion 
 
It is expected that the study will reach full completion 48 months from the time the study opens 
to accrual. 


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4 
Study Drugs 
4.1 
Description, Supply and Storage of Investigational Drugs 
4.1.1 Investigational Drug 
 
Trametinib tablets are provided as immediate release tablets for oral administration containing 
trametinib dimethyl sulfoxide (GSK1120212B) equivalent to 0.5 mg or 2 mg of trametinib. All 
formulation excipients are compendial and are commonly used in oral formulations. Refer to the 
trametinib Investigator's Brochure for a list of excipients. 
 
The trametinib tablets are packaged in high-density polyethylene bottles with labels bearing the 
appropriate label text as required by governing regulatory agencies. All study drug will be 
dispensed in child-resistant packaging. 
 
Refer to the Pharmacy Manual/site investigational product manual for additional guidance on 
study drug storage, preparation and handling. 
Study drug labels will contain information to meet the applicable regulatory requirements. 
Classification 
Cytotoxic drug: molecular targeted cytotoxic drug 
 
Mechanism of Action 
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 
256 (MEK1) and MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are 257 
upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes 
258 cellular proliferation. 
 
Metabolism 
Trametinib is metabolized predominantly via deacetylation alone or with mono282 oxygenation 
or in combination with glucuronidation biotransformation pathways in vitro. 283 Deacetylation is 
likely mediated by hydrolytic enzymes, such as carboxyl-esterases or amidases. 284 Following 
a single dose of [14C]-trametinib, approximately 50% of circulating radioactivity is 285 
represented as the parent compound. However, based on metabolite profiling after repeat 
dosing 286 of trametinib, > 75% of drug-related material in plasma is the parent compound. 
 
Contraindications 
None. 
Availability 
Trametinib will be supplied by Novartis. 
 
Storage and handling 
Trametinib tablets should be stored refrigerated at 2° to 8°C (36° to 46°F). Do not freeze. 
Dispense in original bottle. Do not remove desiccant. Protect from moisture and light. Do not 
place medication in pill boxes. 


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Side Effects 
The following undesirable effects have been observed in subjects with metastatic melanoma 
receiving trametinib 2 mg once daily in the integrated safety population as of 25 June 2012 
cutoff date (n=329). Of these 329 subjects, 211 were from MEK114267 (Phase III randomized 
open label study), 97 were from MEK113583 (Phase II study), and 21 were from MEK111054 
(FTIH study). The most common adverse reactions (> 20%) for trametinib include rash, 
diarrhea, fatigue, edema peripheral, nausea, and dermatitis acneiform. In clinical trials with 
trametinib, adverse reactions of diarrhea and rash were managed with appropriate supportive 
care. 
 
Adverse reactions are listed below by MedDRA body system organ class. The following 
convention has been utilized for the classification of frequency: 
Very common >1 in 10 (> 10%) 
Common > 1 in 100 and < 1 in 10 (> 1% and <10%) 
Uncommon > 1 in 1,000 and < 1 in 100 (> 0.1% and <1%) 
Rare > 1/10,000 and <1/1,000 (> 0.01% and <0.1%) 
 
Categories have been assigned based on frequencies of AEs (considered related to trametinib) 
observed in the integrated safety summary (ISS) data (n=329). 
 
Infections and Infestations 
Very Common: 
Urinary tract infection 
Nasopharyngitis 
Common: 
Folliculitis 
Paronychia 
Cellulitis 
Rash pustular 
 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) 
Common: 
Cutaneous squamous cell carcinoma (SCC) including SCC of the skin, 
SCC in situ (Bowen’s disease), and keratoacanthoma 
Papilloma including skin papilloma 
Seborrhoeic keratosis 
Acrochordon (skin tags) 
Uncommon: 
New primary melanoma 
 
Blood and lymphatic system disorders 
Very Common: 
Neutropenia 
Common: 
Anemia 
Thrombocytopenia 
Leukopenia 
 
Immune system disorders 
Uncommon: 
Hypersensitivity 
May present with symptoms such as fever, rash, increased liver function 
tests, and visual disturbances 


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Metabolism and Nutrition Disorders 
Very Common: 
Decreased appetite 
Common: 
Dehydration 
Hyponatraemia 
Hypophosphataemia 
Hyperglycemia 
 
Nervous system disorders 
Very Common: 
Headache 
Dizziness 
 
Eye disorders 
Common: 
Vision blurred 
Periorbital edema 
Visual impairment 
Uncommon: 
Chorioretinopathy (also known as Retinal Pigment Epithelial Detachment 
(RPED)) 
Uveitis 
Retinal vein occlusion 
Papilledema 
Retinal detachment 
Peiorbital oedema 
 
Cardiac disorders 
Common: 
Left ventricular dysfunction 
Ejection fraction decreased 
Uncommon: 
Cardiac failure 
 
Vascular disorders 
Very common: 
Hypertension 
Hemorrhage. The majority of bleeding events were mild. Major events, 
defined as symptomatic bleeding in a critical area or organ, and fatal 
intracranial hemorrhages have been reported. 
Common: 
Lymphedema 
Hypotension 
 
Respiratory, thoracic and mediastinal disorders 
Very common: 
Cough 
Dyspnea 
Common: 
Epistaxis 
Pneumonitis 
Uncommon: 
Interstitial lung disease 
 
Gastrointestinal disorders 
Very common: 
Diarrhea 
Nausea 
Vomiting 
Constipation 
Abdominal pain 


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Dry mouth 
Common: 
Stomatitis 
Uncommon: 
Pancreatitis 
 
Hepatobiliary disorders 
Very Common: 
Aspartate aminotransferase increased 
Alanine aminotransferase increased 
Common: 
Blood alkaline phosphatase increased 
Gamma-glutamyltransferase increased 
 
Skin and subcutaneous tissue disorders 
Very common: 
Rash 
Dermatitis acneiform 
Dry skin 
Pruritus 
Alopecia 
Common: 
Skin chapped 
Erythema 
Palmar-plantar erythrodysaesthesia syndrome 
Skin fissures 
Actinic keratosis 
Night sweats 
Hyperkeratosis 
Hyperhidrosis 
Skin lesion 
Panniculitis 
 
Musculoskeletal and connective tissue disorder 
Very Common: 
Arthralgia 
Myalgia 
Pain in extremity 
Common: 
Blood creatine phosphokinase increased 
Muscle spasms 
 
Renal Disorders 
Uncommon: 
Renal Failure 
Nephritis 
 
General disorders 
Very Common: 
Fatigue 
Edema peripheral 
Pyrexia 
Chills 
Asthenia 
Common: 
Face edema 
Mucosal inflammation 
Influenza-like illness 
 
Complete and updated adverse event information is available in the Investigational Drug 
Brochure and product package insert. 


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4.2 
Drug Accountability 
The Investigational Pharmacist will manage drug accountability records. 
4.3 
Drug Ordering 
UCSF will obtain trametinib directly from pharmaceutical company as study supply. 
4.4 
Packaging and Labeling of Study Drugs 
Drugs will be packaged and labeled per UCSF institutional standards, adhering to applicable 
local and federal laws. 
5 
Treatment Plan 
5.1 
Dosage and Administration 
Treatment will be administered on an outpatient basis. 
 
Table 5.1 
Regimen Description 
Study Drug 
Premedication; 
precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Trametinib 
Take with a full glass 
of water, without food, 
at least 1 hour before 
or 2 hours after a 
meal. 
2 mg, once 
daily 
Oral 
Days 1-28 
4 weeks 
(28 days) 
 
If a dose of trametinib is missed, the dose can be taken if it is more than 12 hours until the next 
scheduled dose. 
 
The patient will be requested to maintain a medication diary of each dose of medication. The 
medication diary will be returned to clinic staff at the end of each 28 day cycle. 
5.1.1 Other Modalities or Procedures 
 
No other modalities will be used in this study. 
5.2 
Dose Modifications and Dosing Delays 
The management of adverse reactions may require treatment interruption, dose reduction, or 
treatment discontinuation. 
Table 5.2 
Dose Modifications and Dosing Delays 
Dose Level 
Dose of Study Drug 
 
-2 
1 mg daily 
-1 
1.5 mg daily 
1 
2 mg daily 
Dose adjustment for trametinib below 1 mg QD is not recommended. 


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A maximum of two trametinib dose level reductions are allowed. If a third dose level reduction is 
required, treatment will be permanently discontinued. 
 
If a dose reduction of trametinib is required, but the toxicity resolves and no additional toxicities 
are seen after two cycles of treatment, the dose of trametinib may be re-escalated but should 
not exceed 2 mg once daily. 
 
The following dose modification rules will be used with respect to potential toxicity. Toxicity will 
be assessed according to the NCI Common Terminology Criteria for Adverse Events Version  
4.03 (CTCAE v4.03. 
 
Table 5.3 Dose Delay and Modification for Events Considered Related to Trametinib 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1 
● 
Continue trametinib at current dose level 
● 
Monitor closely 
● 
Provide supportive care according to institutional standards 
Grade 2 
● 
Interrupt trametinib if clinically indicated 
● 
Monitor closely 
● 
Provide supportive care according to institutional standards 
● 
When toxicity resolves to Grade 1 or baseline, restart 
trametinib at current dose level 
Grade 3 
● 
Interrupt trametinib if clinically indicated 
● 
Monitor closely 
● 
Provide supportive care according to institutional standards 
● 
When toxicity resolves to Grade 1 or baseline, restart 
trametinib reduced by one dose level 
● 
If the Grade 3 toxicity recurs, interrupt trametinib 
● 
When toxicity resolves to Grade 1 or baseline, restart 
trametinib reduced by another dose level 
Grade 4 
● 
Interrupt trametinib 
● 
Monitor closely 
● 
Provide supportive care according to institutional standards 
● 
If event resolves to Grade 1 or baseline discuss potential 
continuation of trametinib with  investigator-sponsor; if 
continuation of treatment agreed then restart trametinib at 
dose reduced by one dose level 
● 
If event does not resolve permanently discontinue 
trametinib 
 
Note: Approval from the investigator-sponsor is required to restart study treatment 
after ≥ 28 days of interruption. 


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Trametinib dose modification guidelines are outlined in Table 5.2 and Table 5.3 for clinically 
significant toxicities that are deemed related to trametinib (i.e. peripheral and periorbital edema) 
with the exception of the following events of special interest: 
 
● 
rash (Section 5.2.1) 
● 
diarrhea (Section 5.2.2), 
● 
ejection fraction changes (Section 5.2.3), 
● 
hypertension (Section 5.2.4) 
● 
prolonged QTc (Section 5.2.5) 
● 
pneumonitis (Section 5.2.6), 
● 
visual changes (Section 5.2.7), 
● 
liver chemistry elevation (Section 5.2.8) 
 
For these, refer to the relevant sections for dose modification guidelines for adverse 
events of special interest. 
 
Treatment or visit delays for public holidays or weather conditions do not constitute a protocol 
violation. 
5.2.1 Guidelines for Rash 
 
 
Rash is a frequent AE observed in subjects receiving trametinib (see the Investigator Brochures 
for more information). Recommendations for supportive care and guidelines for dose 
modifications for rash are based on experience with other MEK inhibitors33 and EGFR 
inhibitors34 and are provided in Table 5.4 and Table 5.5. 
 
The institutional standards for the management of skin-related AEs can differ from these 
guidelines. In this case, best clinical judgment should be applied and a consultation with the 
investigator-sponsor may be required. 


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Table 5.4 
Guidelines for Supportive Care of Rash 
 
Type of Care 
Action 
Prevention/Prophylaxisa 
● 
Avoid unnecessary exposure to sunlight 
● 
Apply broad-spectrum sunscreen (containing titanium 
dioxide or zinc oxide) with a skin protection factor (SPF) 
≥15 at least twice daily. 
● 
Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least 
twice daily. 
● 
Topical steroids and antibiotics should be applied at least 
twice daily starting on Day 1 of study treatment, to body 
areas such as face, chest, and upper back. 
Use mild-strength topical steroid (hydrocortisone 1% 
cream) 
or 
topical antibiotic (e.g., clindamycin) or oral antibiotics 
(e.g.,doxycycline 100 mg BID, minocycline 100 mg BID) 
Symptomatic Careb 
● 
Pruritic lesions: cool compresses and oral antihistamine 
therapies 
● 
Fissuring lesions: Monsel’s solution, silver nitrate, or zinc 
oxide cream 
● 
Desquamation: thick emollients and mild soap 
● 
Paronychia: antiseptic bath, local potent corticosteroids in 
addition to oral antibiotics; if no improvement, consult 
dermatologist or surgeon 
● 
Infected lesions: appropriate bacterial/fungal culture-driven 
systemic or topical antibiotics 
Abbreviations: BID = twice daily; SPF = sun protection factor 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should 
receive evaluation for symptomatic/supportive care management 


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Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided in Table 5.5. 
 
Table 5.5 
Management and Dose Modification Guidelines for Rash 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
● 
Initiate prophylactic and 
symptomatic treatment 
measuresa 
● 
Use moderate strength 
topical steroidb 
● 
Reassess after 2 weeks 
● 
Continue trametinib 
● 
If rash does not recover to 
baseline within 2 weeks 
despite best supportive 
care, reduce trametinib by 
one dose levelc 
Grade 2 
● 
Initiate prophylactic and 
symptomatic treatment 
measures 
● 
Use moderate strength 
topical steroidb 
● 
Reassess after 2 weeks 
● 
Reduce trametinib by one 
dose level 
● If rash recovers to 
≤grade 1 within 2 weeks, 
increase dose to 
previous dose level 
● If no recovery to ≤grade 
1 within 2 weeks, 
interrupt trametinib until 
recovery to ≤grade 1 
● 
Restart trametinib at 
reduced dose levelc 
Grade ≥3 
● 
Use moderate strength 
topical steroidsb PLUS oral 
methyl-prednisolone dose 
pack 
● 
Consult dermatologist 
● 
Interrupt trametinib until 
rash recovers to grade ≤1, 
after discussion with study 
PI. 
● 
Restartc with trametinib 
reduced by one dose 
leveld 
● 
If no recovery to grade ≤2 
within 4 weeks, 
permanently discontinue 
trametinib 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events 
a. Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b. Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 
0.5% cream 
c. Approval of the investigator-sponsor is required to restart study treatment after >4 weeks of 
interruption. 
d. Escalation of study treatment to previous dose level may be considered if no rash is evident 4 
weeks after restarting study treatment 


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5.2.2 Guidelines for Diarrhea 
 
Episodes of diarrhea have occurred in subjects receiving trametinib (see the Investigator 
Brochures for more information). Other, frequent causes for diarrhea including concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or other 
pathogens, partial bowel obstruction, etc., should be clinically excluded. 
 
Guidelines regarding management and dose reduction for diarrhea considered to be related to 
trametinib by the investigator are provided in Table 5.6. 


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Table 5.6 
Management and Dose Modification Guidelines for Diarrhea 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose 
Modification 
Uncomplicated 
Diarrheaa 
Grade 1 or 2 
● 
Diet: stop all lactose containing 
products; eat small meals, BRAT-diet 
(banana, rice, apples, toast) 
recommended 
● 
Hydration: 8-10 large glasses of clear 
liquids per day (e.g., Gatorade or broth) 
● 
Loperamidec: initially 4 mg, followed by 
2 mg every four hours or after every 
unformed stool; maximum 16 mg/day. 
Continue until diarrhea free for 12 hours 
● 
Diarrhea > 24h: loperamide 2 mg every 
two hours; maximum 16 mg/day. 
Consider adding oral antibiotics 
● 
Diarrhea > 48h: loperamide 2 mg every 
two hours; maximum 16 mg/day. Add 
budesonide or other second-line 
therapies (otreotide, or tincture of 
opium) and oral antibiotics 
● 
Continue trametinib 
● 
If diarrhea is grade 2 
for > 48h, interrupt 
trametinib until diarrhea 
resolves to grade ≤1 
● 
Restart trametinib at 
the same dose level 
Uncomplicated 
Diarrheaa 
Grade 3 or 4 
Any 
Complicated 
Diarrheab 
● 
Clinical evaluation mandatory 
● 
Loperamidec: initially 4 mg, followed by 
2 mg every four hours or after every 
unformed stool; maximum 16 mg/day. 
Continue until diarrhea free for 12 hours 
● 
Oral antibiotics and second-line 
therapies if clinically indicated 
● 
Hydration: intravenous fluids if clinically 
indicated 
● 
Antibiotics (oral or intravenous) if 
clinically indicated 
● 
Intervention should be continued until 
the subject is diarrhea free for ≥ 24 
hours 
● 
Intervention may require hospitalization 
for subjects at risk of life-threatening 
complications 
● 
Interrupt trametinib 
until diarrhea resolves 
to grade ≤1 
● 
Restart with trametinib 
reduced by one dose 
leveld 
● 
If 3 dose reductions of 
study treatment are 
clinically indicated, 
permanently 
discontinue 
trametinib 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events 
a.  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 


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b. 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 
c. Loperamide should be made available prior to start of study treatment so loperamide 
administration can begin at the first signs of diarrhea 
d. 
Escalation of trametinib to previous dose level is allowed after consultation with the medical 
monitor and in the absence of another episode of complicated or severe diarrhea in the 4 weeks 
subsequent to dose reduction. 
 
 
5.2.3 Guidelines for Ejection Fraction Changes 
 
Left Ventricular Ejection Fraction (LVEF) 
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib. Therefore, ECHO/MUGAs must be performed to assess cardiac ejection 
fraction in regular intervals as outlined in the Time and Events Table (Table X). 
 
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline and at follow-up visit(s).  Electronic copies of all ECHO/MUGA scans will 
be collected by Novartis for review.  Instructions for submission of ECHO/MUGA scans are 
provided in the Study Procedures Manual (SPM). 
 
Dose modification guidance and stopping criteria for LVEF decrease are provided in Table 5.7. 
 
Table 5.7 
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease 
Clinic 
LVEF-drop (%) or 
CTCAE grade 
Action and Dose Modification 
Asymptomatic Absolute decrease of 
>10% in LVEF compared 
to baseline and ejection 
fraction below the 
institution’s  LLN 
Interrupt trametinib and repeat 
ECHO/MUGA within 2 weeksa 
If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and absolute 
decrease ≤10% compared to baseline) 
● 
Consult with the Novartis medical 
monitor and request approval for 
restart 
● 
Restart treatment with trametinib 
reduced dose by one dose levelb 
● 
Repeat ECHO/MUGA 2 , 4 , 8 
and 12 weeks after re-start; 
continue in intervals of 12 weeks 
thereafter 
If  LVEF does not recover within 4 weeks 
● 
Consult with cardiologist 
● 
Permanently discontinue 
trametinib 
● 
Report as SAE 


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● 
Repeat ECHO/MUGA after 2, 4, 
8, 12, and 16 weeks or until 
resolution 
● 
Consult with Novartis medical 
monitorc 
Symptomaticc 
Grade 3: resting LVEF 39- 
20% or >20% absolute 
reduction from baseline 
Permanently discontinue trametinib 
Report as SAE 
Consult with cardiologist 
Repeat ECHO/MUGA after 2, 4, 8, 12, and 
16 weeks or until resolution 
Grade 4: resting LVEF 
<20% 
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN 
= lower limit of normal; LVEF = left ventricular ejection fraction; 
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 Novartis Medical Monitor is required. 
c. 
Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion 
and edema. 
 
 
5.2.4 Guidelines for 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 the following optimal conditions: 
 
● 
the subject has been seated with back support, ensuring that legs are uncrossed 
and flat on the floor 
● 
the subject is relaxed comfortably for at least 5 minutes 
● 
restrictive clothing has been removed from the cuff area and the right cuff size has 
been selected 
● 
the subjects arm is supported so that the middle of the cuff is at heart level 
● 
the subject remains quiet during the measurement. 
In subjects with an initial 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. The averaged value should be recorded in the eCRF. 
 
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 three consecutive visits with blood 
pressure assessments from two readings collected as described above. Visits to monitor 
increased blood pressure can be scheduled independently from the per-protocol visits outlined 
in the Schedule of Study Procedures and Assessments (Table 6.1). 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. 
 
 
 
 


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Management of Hypertension 
 
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 Table 5.8: 
 
Table 5.8 
Management and Dose Modification Guidelines for Hypertension 
 
Hypertension 
Action and Dose Modification 
(Scenario A) 
Asymptomatic and persistenta SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 
Clinically significant increase in DBP of 20 mmHg (but DBP 
still <100 mmHg). 
Continue trametinib at the current dose 
Adjust current or initiate new antihypertensive 
medication 
Titrate antihypertensive medication(s) during the next 
2 weeks as indicated to achieve well-controlledb 
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 
Interrupt trametinib if clinically indicated 
Adjust current or initiate new antihypertensive 
medication(s) 
Titrate antihypertensive medication(s) during the next 
2 weeks to achieve well-controlled BP 
Once BP is well controlledb, restart trametinib 
reduced by one dose levelc 
(Scenario C) 
Symptomaticd hypertension 
or 
Persistent SBP ≥160 mmHg, or DBP ≥100 mmHg, despite 
antihypertensive medication and dose reduction of 
trametinib 
Interrupt trametinib 
Adjust current or initiate new antihypertensive 
medication(s) 
Titrate antihypertensive medication during the next 2 
weeks to achieve well-controlled BP 
Referral to a specialist for further evaluation and 
follow-up is recommended 
Once BP is well controlled, restart trametinib reduced 
by one dose levelc 
(Scenario D) 
Refractory hypertension unresponsive to above 
interventions or having hypertensive crisis. 
Permanently discontinue trametinib 
Continue follow-up per protocol. 
Abbreviations: BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = systolic blood 
pressure; 
a. 
Hypertension detected in two separate readings during up to three consecutive visits 
b. 
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings during up to 
three consecutive visits. 
c. 
Escalation of trametinib to previous dose level can be considered if BPs remains well-controlled for 4 weeks after restarting 


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of trametinib. Approval from Novartis 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. 
 
 
 
5.2.5 Guidelines for Prolonged QTc 
 
Guidelines for dose modification and stopping criteria due to QTC-prolongation are provided in 
 
Table 5.9 
Withholding and Stopping Criteria for QTc-Prolongation 
 
QTc-Prolongationa 
Action and Dose Modification 
QTcB ≥501 msec or 
uncorrected QT>600 msec or 
QTcB>530 msec for subjects with 
bundle branch block 
Interrupt study treatment until QTcB prolongation 
resolves to Grade 1 or baseline 
● 
Test serum potassium, calcium, phosphorus and 
magnesium. If abnormal, correct per routine 
clinical practice to within normal limits. 
Review concomitant medication usage for a 
prolonged QTc. 
Restart at current dose levelb 
If event recurs, permanently discontinue study 
treatment 
Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the 
Bazett’s formula 
a. Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged 
QT interval, obtain two or more ECGs over a brief period, and then use the averaged QTc values of 
the three ECGs to determine if study treatments should be interrupted or discontinued. 
b.  If the QTc prolongation resolves to Grade 1 or baseline, the subject may resume study treatment if 
the investigator and Novartis medical monitor agree that the subject will benefit from further 
treatment. 
 
5.2.6 Guidelines for Pneumonitis 
 
Pneumonitis has been observed in subjects receiving trametinib. To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and 
functional tests. Dose modification and supportive care guidelines for pneumonitis are described 
in Table 5.10. 


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Table 5.10 
Management and Dose Modification Guidelines for Pneumonitis 
 
CTCAE Grade 
Adverse Event Management 
Action and Dose Modification 
Grade 1 
● CT scan (high-resolution with 
lung windows) recommended 
● Clinical evaluation and 
laboratory work-up for 
infection 
● Monitoring of oxygenation via 
pulse-oximetry 
recommended 
● Consultation of 
pulmonologist recommended 
● Continue trametinib at current dose 
Grade 2 
● CT scan (high-resolution with 
lung windows) 
● Clinical evaluation and 
laboratory work-up for 
infection 
● Consult pulmonologist 
● Pulmonary function tests –if 
< normal, repeat every 8 
weeks until ≥ normal 
● Bronchoscopy with biopsy 
and/or BAL recommended 
● Symptomatic therapy 
including corticosteroids if 
clinically indicated 
● Interrupt trametinib until recovery to 
grade ≤1 
● Restart with trametinib reduced by 
one dose level 
● Escalation to previous dose level 
after 4 weeks and consultation with 
medical monitor possible 
● If no recovery to grade ≤1 within 4 
weeks, permanently discontinue 
study treatment 
Grade 3 
● CT scan (high-resolution with 
lung windows) 
● Clinical evaluation and 
laboratory work-up for 
infection 
● Consult pulmonologist 
● Pulmonary function tests-if < 
normal, repeat every 8 
weeks until ≥ normal 
● Bronchoscopy with biopsy 
and/or BAL if possible 
● Symptomatic therapy 
including corticosteroids as 
clinically indicated 
● Interrupt trametinib until recovery to 
grade ≤1 
● After consultation with medical 
monitor, study treatment may be 
restarted reduced by one dose level 
● If no recovery to grade ≤1 within 4 
weeks, permanently discontinue 
study treatment 
Grade 4 
● Same as grade 3 
● Permanently discontinue trametinib 


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5.2.7 Guidelines for Visual Changes or Specified Ophthalmic Examination 
Findings 
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), then monitor closely as it may be reasonable 
to defer ophthalmic examination. Special attention should be given to retinal findings (e.g., 
retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or 
central retinal vein occlusions (RVO)). 
 
Guidelines regarding management and dose reduction for visual changes and/or ophthalmic 
examination findings considered to be related to study treatment are provided in Table 5.11. 
 
Table 5.11 
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 diagnosed: 
see RPED dose modification 
table Y 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, 
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 


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Grade 4 
● 
Consult ophthalmologist 
immediately 
● 
Interrupt trametinib 
● 
Report as SAE 
● 
If RPED and RVO excluded, may 
consider restarting trametinib at 
same or reduced dose after 
discussion with study medical 
monitor 
● 
If RVO or RPED diagnosed, 
permanently discontinue 
trametinib 
Abbreviations: RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology 
Criteria for Adverse Events; RVO= retinal vein occlusion; SAE = serious adverse event 
a.  Refers to CTCAE Version 4.03 ‘Eye disorders – Other, specify’ 
c. 
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), 
monitor closely but ophthalmic examination is not required. 
 
 
Table 5.12 
Recommended dose modifications for trametinib for retinal pigment epithelial 
detachments (RPED)a 
 
CTCAE Grade 
Action and Dose Modification 
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only) 
● 
Continue treatment with retinal evaluation 
monthly until resolution. If RPED worsens 
follow instructions below 
Grade 2-3 RPED (Symptomatic with 
mild to moderate decrease in visual 
acuity; limiting instrumental ADL) 
● 
Interrupt trametinib 
● 
Retinal evaluation monthly 
● 
If improved to ≤ Grade 1, restart trametinib 
at lower dose (reduced by 0.5 mg) or 
discontinue in patients taking trametinib 1 
mg daily 
a.  Refers to CTCAE Version 4.03 ‘Retinopathy’ 
 
 
5.2.8 Guidelines for Liver Chemistry Elevation 
 
Table 5.13 
Grade of 
Event 
Management/Next Dose for Trametinb 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1 
Resume at same dose level 
Grade 3 
Hold* until ≤ Grade 1 
Resume at one dose level lower, if indicated** 
Grade 4 
Off protocol therapy 


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5.2.9 Guidelines for other toxicity 
 
Table 5.14 
Worst toxicity (CTCAE 4.03 
Grade)* 
Dose Modifications for trametinib 
GENERAL DISORDERS 
Fatigue (asthenia) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
If grade 3 fatigue resolves to Grade 2 in ≤ 7 days, 
maintain dose level 
If grade 3 fatigue lasts > 7 days, omit dose until resolved to 
≤ Grade 2 and then ↓dose level 
PULMONARY 
Notes: 
● 
Withhold trametinib for acute onset of new or progressive unexplained pulmonary 
symptoms, such as dyspnea, cough and fever and during diagnostic workup for 
pneumonitis/ILD. 
● 
During evaluation of potential grade 2, 3, and 4 pneumonitis, if an infectious etiology is 
confirmed (i.e., pneumonia) and pneumonitis is excluded, then consider resuming at 
current dose level after the pneumonia resolves. 
PNEUMONITIS 
Worst toxicity (CTCAE 4.03 
Grade)* 
Dose Modifications for trametinib 
Any Grade treatment-related 
ILD/pneumonitis 
Permanently discontinue patient from study. 
CARDIAC  INVESTIGATIONS 
Electrocardiogram QT corrected (QTc) interval prolonged 
Grade 1 (QTc 450-480 ms) 
Grade 2 (QTc 481-500 ms) 
Maintain dose level 
Grade 3 (QTc ≥ 501 ms 
on at least two separate 
ECGs) 
Omit dose until QTC is less than 481 ms, then ↓dose level 
Perform an analysis of serum potassium, and if below lower 
limit of normal, correct with supplements to within normal limits. 
-Repeat ECG in 24 hours, or less, as clinically indicated; 
continue monitoring as clinically indicated until QTc < 481 ms 
-Repeat ECGs 7 days after dose resumption for all patients who 
had therapy interrupted due to QTc ≥ 501 ms. 
Grade 4 (QTc ≥ 501 or > 
60ms change from 
baseline and Torsades de 
pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious 
arrhythmia) 
Permanently discontinue patient from trametinib. 


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Table 5.15 
 
Worst toxicity (CTCAE 4.03 Grade)* 
Dose Modifications for trametinib 
BRADYCARDIA 
Grade 1 or Grade 2 
Omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
Evaluate concomitant medications known to cause 
bradycardia and adjust the dose of trametinib 
Grade 3 
Grade 4 (in patients taking a concomitant 
medication also known to cause 
bradycardia or a medication known to 
cause hypotension) 
Omit dose until recovery to asymptomatic 
bradycardia or to a heart rate ≥ 60 bpm 
If the concomitant medication can be adjusted 
or discontinued, resume trametinib at ↓1 dose 
level with frequent monitoring 
Grade 4 (in patients who are not taking a 
concomitant medication also known to 
cause bradycardia or known to cause 
hypotension) 
Permanently discontinue trametinib 
PANCREATIC 
Amylase and/or lipase elevations (in the absence of clinical symptoms) 
Grade 1 (> ULN and ≤1.5 x ULN) 
Maintain dose level 
Grade 2 (>1.5 - 2.0 x ULN) 
Maintain dose level 
Grade ≥3 (> 2.0 x ULN) 
Omit dose until resolved to ≤ Grade 1, then ↓ 1 
dose level 
Note: Withhold trametinib for acute onset of new or progressive unexplained abdominal 
symptoms, such as severe pain or vomiting; perform diagnostic procedures (e.g., abdominal 
CT scan or ultrasound) to exclude pancreatic pathology. 


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5.3 
Monitoring and Toxicity Management 
Each patient receiving trametinib will be evaluable for safety. The safety parameters include all 
laboratory tests and hematological abnormalities, physical findings, and spontaneous reports of 
adverse events reported to the investigator by patients. 
Each patient will be assessed periodically for the development of any toxicity as outlined 
in Section 6 Study Procedures and Observations. Toxicity will be assessed according to the 
NCI CTCAE v4.03. Dose adjustments will be made according to the system showing the 
greatest degree of toxicity. 
We will monitor for potential adverse effects including but not limited to fatigue, dehydration, 
cytopenias, leukocytosis, nausea, vomiting, signs and symptoms of infection. In addition, we will 
monitor specifically for the following adverse events of special interest (please see 
corresponding subsections in Section 5.2 for acute toxicity management and dose 
modifications): 
 
● 
Diarrhea (Section 5.2.2), 
● 
Ejection fraction changes (Section 5.2.3), 
● 
Hypertension (Section 5.2.4) 
● 
Prolonged QTc (Section 5.2.5) 
● 
Pneumonitis (Section 5.2.6), 
● 
Visual changes (Section 5.2.7), 
● 
Liver chemistry elevation (Section 5.2.8) 
 
Acute toxicity will be managed by supportive care and/or delay of dose. Further management 
will depend upon the judgment of the treating clinician and may include dose reduction. Patients 
will also be monitored for visual changes and change in cardiac function and QTc as described 
below. 
Ophthalmic Examination 
 
Subjects are required to have a standard ophthalmic examination conducted by an 
ophthalmologist at baseline, week 4/Month 1 (prior to commencement of cycle 2), Month 6 and 
then annually thereafter unless clinically indicated sooner. 
 
The exam will include visual acuity (best corrected), tonometry (intraocular pressure 
measurement), visual field examination, slit lamp biomicroscopy of the anterior segment (with 
special attention to inflammation) and the posterior segment, and indirect fundoscopic 
examination with special attention to possible retinal abnormalities. Optical coherence 
tomography is strongly recommended at scheduled visits, and if retinal abnormalities are 
suspected or noted. Other types of ancillary testing including color fundus photography and 
fluorescein angiography are also recommended if clinically indicated. 
 
Cardiac monitoring 
 
LVEF will be assessed by echocardiogram or multigated acquisition (MUGA) scan within 28 
days prior to initiation of trametinib. The same cardiac monitoring procedure (either 
echocardiogram or MUGA scan) will be repeated at one month after initiation of trametinib, and 
then at every 3 month intervals while on treatment. 


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An electrocardiogram will be performed within 28 days prior to initiation of trametinib to assess 
QTc. An electrocardiogram will be repeated on Cycle 1 Day 1, at one month after initiation of 
trametinib, and then at every 3 month intervals while on treatment. 
 
 
6 
Study Procedures and Observations 
6.1 
Schedule of Procedures and Observations 
The study-specific assessments are detailed in this section and outlined in Section 6 Schedule  
of Study Procedures and Assessments.  Screening assessments must be performed within 28 
days prior to the first dose of investigational product.  Any results falling outside of the reference 
ranges may be repeated at the discretion of the investigator. All on-study visit procedures are 
allowed a window of ± 3 days unless otherwise noted. Treatment or visit delays for public 
holidays or weather conditions do not constitute a protocol violation. 
 
A written, signed, informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated.  A copy of the signed ICF will be given to the subject and a copy will 
be filed in the medical record. The original will be kept on file with the study records. 
 
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller Family 
Comprehensive Cancer Center Clinical Trial Management System (CTMS). The system is 
password protected and meets HIPAA requirements. 
6.1.1 Pretreatment Period 
 
6.1.1.1 Screening Assessments 
Visit Windows: The Screening procedures and assessments must be completed within 28 days of 
the Day 1 Visit. 
● 
Physical examination 
● 
Vital signs 
● 
Complete medical history including history of prior treatments and any residual toxicity 
relating to prior treatment 
● 
Baseline conditions assessment 
● 
Performance status 
● 
Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis and brain 
for tumor/lesion assessment  
● 
Baseline medications  
● 
Research tumor biopsy for biomarker analysis (to be paid for by study), unless deemed 
medically unsafe  
● 
Complete blood count (CBC) with differential and platelet count 
● 
Blood chemistry assessments, including: 
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase (ALT/AST), 
total bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), creatinine, albumin, 
fasting glucose, potassium, sodium, chloride, bicarbonate. 


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● 
Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR) 
● 
Urinalysis 
● 
Serum or urine pregnancy test within 3 days prior to the start of study drug for patients of 
child-bearing potential. 
● 
Electrocardiogram (ECG) in triplicate 
● 
Cardiac assessment (MUGA or TTE) 
● 
Ophthalmic exam 
● 
Specimen collection for biomarkers and banking 
6.1.2 Treatment Period 
 
6.1.2.1 Study Procedures, Cycle 1, Day 1 
Visit Windows: Screening laboratory tests completed within 3 days of Cycle 1 Day 1 do not 
need to be repeated 
 
● 
Physical examination 
● 
Vital signs 
● 
Performance status 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Complete blood count (CBC) with differential and platelet count 
● 
Blood chemistry assessment, including: 
Alkaline phosphatase, ALT/AST, total bilirubin, BUN, creatinine, fasting glucose, 
potassium, sodium, chloride, bicarbonate 
● 
Coagulation assessment, including PT/PTT/INR 
● 
Urinalysis 
● 
Serum or urine pregnancy test 
● 
Electrocardiogram (ECG) in triplicate 
● 
Administration of Trametinib in clinic 
● 
Blood collection for ctDNA and cfDNA biomarkers 
6.1.2.2 Study Procedures Cycle 1 Day 8 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Administration of Trametinib in clinic 
● 
Blood collection for ctDNA and cfDNA biomarkers 


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6.1.2.3 Study Procedures Cycle 1 Day 15 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Administration of Trametinib in clinic 
● 
Blood collection for ctDNA and cfDNA biomarkers 
● 
Ophthalmic exam prior to cycle 2 day 1 
6.1.2.4 Study Procedures Cycle 2 and beyond 
 
Visit Windows: Lab tests must be completed within 3 days of Day 1 and imaging studies must 
be completed within 7 days of Day 1. 
 
● 
Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis for 
tumor/lesion assessment – Cycles 3, 5, 7, and every other cycle thereafter 
● 
If known lesions, brain imaging (CT or MRI) – Cycles 3, 5, 6, and every other cycle 
thereafter 
● 
Physical examination 
● 
Vital signs 
● 
Performance status 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Complete blood count (CBC) with differential and platelet count 
● 
Blood chemistry assessments, including: 
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, 
total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate 
● 
Coagulation assessment, including PT/PTT/INR 
● 
Urinalysis 
● 
Serum or urine pregnancy test 
● 
Brain imaging, if known metastases for tumor/lesion assessment (every other cycle, 
starting with cycle #3) 
● 
Electrocardiogram (ECG) in triplicate 
● 
Cardiac Assessments (TTE or MUGA) Cycle 2 day 1, and then every 3 cycles 
● 
Blood collection for ctDNA and cfDNA biomarkers 
● 
Optional Biopsy (at best response to therapy) for biomarkers and banking 
● 
Ophthalmic exam prior to cycle 2 day 1, again at 6 months, and then annually thereafter 
unless clinically indicated sooner. 


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6.1.3 End-of-Treatment Study Procedures 
 
 
To be completed within 30 days of the last dose of study drug. 
● 
Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis, and brain 
(if lesions found in screening), for tumor/lesion assessment 
● 
Physical examination 
● 
Vital signs 
● 
Performance Status 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Hematology labs (other than CBC with diff) 
● 
Complete blood count (CBC) with differential and platelet count 
● 
Blood chemistry assessment, including: 
● 
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, 
total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, 
● 
Coagulation assessment, including PT/PTT/INR 
● 
Urinalysis 
● 
Electrocardiogram (ECG) 
● 
Blood collection for ctDNA and cfDNA biomarkers 
● 
Optional tumor biopsy for biomarker analysis and exploratory studies. 
6.1.4 Post-treatment/Follow Up Visits 
 
Patients will be followed every 3 months +/- 14 days for up to 18 months after enrollment or until 
disease progression. 
The following procedures will be performed at the Follow Up Visit(s): 
● 
Disease assessment including imaging (CT or MRI) of chest/abdomen/pelvis, and brain 
(if lesions found in screening) for tumor/lesion assessment. Scans would only be 
completed in follow-up for patients whose disease has not yet progressed since entering 
the study. 
● 
Physical examination 
● 
Vital signs 
● 
Performance Status 
● 
Evaluation of adverse events 
● 
Concomitant medications 
● 
Hematology labs (other than CBC w/ Diff) 
● 
CBC with differential and platelet count 
● 
Blood chemistry assessment, including: 
Alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, BUN, creatinine, 
total protein, albumin, fasting glucose, potassium, sodium, chloride, bicarbonate, 
● 
Coagulation assessment, including PT/PTT/INR 


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● 
Urinalysis 
6.1.5 
6.1.6 
Long Term/Survival Follow-up Procedures 
Discontinuation of Therapy 
 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests. Reasons for withdrawing a patient include, but are not limited to, 
disease progression, the occurrence of an adverse event or a concurrent illness, a patient’s 
request to end participation, a patient’s non-compliance or simply significant uncertainty on the 
part of the Investigator that continued participation is prudent. There may also be administrative 
reasons to terminate participation, such as concern about a patient’s compliance with the 
prescribed treatment regimen. 


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Table 6.1 Schedule of Study Procedures and Assessments 
 
Period/ Procedure 
Screeninga 
Cycle 1 
Cycle 2 and future Cycles 
End of 
Treatment 
visit 
Follow- 
up visits 
Study Day/Visit Day 
-28 to 0 
(+/- 3) 
1 
(+/- 3) 
8 
(+/- 3) 
15 
(+/- 3) 
22 
(+/- 3) 
29 
(+/- 3) 
1 
(+/- 3) 
8 
(+/- 3) 
15 
(+/- 3) 
22 
(+/- 3) 
29 
(+/- 3) 
30d after 
last dose 
of study 
drug 
FU every 
3 
months 
(+/- 14d) 
Informed consent 
X 
Baseline conditionsb 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
Blood collection for 
biomarkers 
X 
X 
X 
X 
X 
X 
Required Research 
Biopsy)c 
X 
Optional Research 
Biopsy 
X +/- 7d 
(C 2only) 
X 
Treatment/Drug  Administration 
Trametinibd 
X 
X 
X 
X 
Clinical procedures 
Physical exam 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
Medical historye 
X 
X 
X 
X 
Disease assessmentf 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
Laboratory  procedures
g 
CBC w/ Diff 
X 
X 
X 
X 
X 
Blood chemistry 
X 
X 
X 
X 
X 
 
 
 
 


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Period/ Procedure 
Screeninga 
Cycle 1 
Cycle 2 and future Cycles 
End of 
Treatment 
visit 
Follow- 
up visits 
Study Day/Visit Day 
-28 to 0 
(+/- 3) 
1 
(+/- 3) 
8 
(+/- 3) 
15 
(+/- 3) 
22 
(+/- 3) 
29 
(+/- 3) 
1 
(+/- 3) 
8 
(+/- 3) 
15 
(+/- 3) 
22 
(+/- 3) 
29 
(+/- 3) 
30d after 
last dose 
of study 
drug 
FU every 
3 
months 
(+/- 14d) 
Coagulation 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
Pregnancy test (HCG) 
X 
X 
X 
Imaging procedureh 
Imaging (CT or MRI) h 
X 
X 
X 
X 
Cardiac Assessment 
(ECHO, MUGA) 
X 
X 
ECG/EKG (in triplicate) 
X 
X 
X 
X 
Ophthalmology Exam 
X 
X 
a. 
Screening procedures and assessments must be completed -28d of Day 1 visit. Screening labs completed within 3 days of C1D1 need not be 
repeated. 
b. 
Baseline conditions include all ongoing medical conditions at time of consent. 
c. 
Archival tissue collection and research biopsy during screening and for exploratory biomarker assessments. Biopsy will be CT guided (or via 
bronchoscopy if unable to obtain) unless deemed medically unsafe. 
Optional tumor biopsy: for exploratory analyses, best response and resistance (C2D1 +/- 7d and at end of treatment visit). 
d. 
Trametinib will be taken with a full glass of water, without food, at least 1 hour before or 2 hours after a meal, 2mg, once a day. See section 5.0 Table 5.1 
for treatment regimen details. Safety assessments (AE assessments and concomitant medication check) to be completed during clinic visits. 
e. 
Medical history documentation of past conditions or procedures that have been resolved. 
f. 
Disease assessment documentation at screening (presence of measurable disease) and on trial includes restaging (per RECIST), which will occur q2 
cycles beginning cycle #3. During Follow-up visits, scans would only be completed in follow-up for patients whose disease has not yet progressed since 
entering the study 
g. 
Blood chemistry labs: alkaline phosphatase, ALT/AST, total bilirubin, calcium, phosphorus, (BUN), creatinine, total protein, albumin, fasting glucose, 
potassium, sodium, chloride, bicarbonate 


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Coagulation labs: PT/PTT/INR 
Serum or urine pregnancy test must be negative within 3 days prior to start of C1D1. 
h. 
Imaging exams: if known lesions, brain imaging every other cycle starting with cycle #3. 
Cardiac assessments to be completed every 3 months after cycle #2. 
Ophthalmology exams to be completed prior to cycle 2 day 1, again at 6 months, and then annually thereafter unless clinically indicated sooner. 


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6.2 
Usage of Concurrent/Concomitant Medications 
No formal drug interaction studies have been conducted with trametinib. There is a low 
likelihood of drug-drug interactions with trametinib. 
 
Trametinib has a high passive permeability and is eliminated primary via deacetylation, which is 
mediated by hydrolytic enzymes that are generally not associated with drug interaction risks. It 
is also not an in vitro substrate for human Pgp, BCRP, MRP2 and MATE1. In addition, due to 
trametinib’s low efficacious dose and low systemic maximal concentration (22 ng/mL or 0.04 
μM) relative to its in vitro CYP inhibition/induction potency. Therefore, the risk of a drug-drug 
interaction by trametinib as both perpetrator or as a victim is low. See also Section 4.3.6 for 
detailed discussion. 
 
6.3 
Dietary Restrictions 
Trametinib should be taken with a full glass of water, without food, at least 1 hour before or 2 
hours after a meal. If a dose of trametinib is missed, the dose can be taken if it is more than 12 
hours until the next scheduled dose. 
 
Administration of a single dose of trametinib with a high-fat, high-calorie meal resulted in a 70%, 
24%, and 10% decrease in Cmax, AUC(0-t), and AUC(0-∞), respectively compared to fasted 
conditions. 
6.4 
Prohibited Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. Palliative and supportive care is permitted during the course of the trial for 
underlying medical conditions and management of symptoms. Surgery or radiotherapy for tumor 
controls not permitted during the study; however, radiotherapy or procedures for symptom 
management is allowed. 
 
Subjects are prohibited from receiving antineoplastic systemic chemotherapy or biological 
therapy not specified in this protocol. 
 
Bisphosphonates or denosumab are allowed for patients with bone metastases. 
 
Growth factor support may be considered for patients with neutropenia after discussion with the 
study PI. 
 
Avoid concurrent use of strong CYP3A inhibitors during treatment. 
 
Medications known to produce QT prolongation should be avoided during treatment of patients 
with and trametinib. See http://crediblemeds.org/ for the most up-to-date reference lists of 
QT-prolonging medications. Please note that the lists contain common supportive medications, 
such as anti-emetics (ondansetron [and other 5HT3 antagonists], metoclopramide, 
hydroxyzine), antibiotics (azithromycin, ciprofloxacin, metronidazole) and anti-depressants 
(escitalopram). 


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Medications to consider for nausea that are not associated with QT prolongation include: 
● 
Steroids (dexamethasone, methylprednisolone) 
● 
Benzodiazepines 
● 
Aprepitant 
● 
Select anticholinergic agents (scopolamine) 
● 
Trimethobenzamide 
● 
Cannabinoids 
7 
Reporting and Documentation of Results 
7.1 
Evaluation of Efficacy (or Activity) 
7.1.1 Antitumor Effect – Solid Tumors 
 
Response and progression in this study will be evaluated using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [JNCI 
92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST v1.1 criteria. 
Definitions  
Evaluable for toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with the study drug. 
Evaluable for objective response 
Only those patients who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These patients will have their response classified according to the definitions stated 
below.  (Note:  Patients who exhibit objective disease progression prior to the end of Cycle 1 will 
also be considered evaluable.) 
7.1.1.1 Disease Parameters 
Measurable disease 
Measurable disease is defined as lesions (or tumors) that can be accurately measured in at 
least one dimension (longest diameter to be recorded) with a minimum size of 10mm by CT 
scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a 
minimum of 10mm), 10mm caliper measurement by clinical exam (when superficial), and/or 
20mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
 
All tumor measurements will be recorded in millimeters or decimal fractions of centimeters. 
Previously irradiated lesions are considered non-measurable except in cases of documented 
progression of the lesion since the completion of radiation therapy. 
Target lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions per 
organ) representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline. Target lesions will be selected on the basis of their size (lesions with 
the longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically).  A sum of the longest diameter (LD) for all target lesions will be 


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calculated and reported as the baseline sum LD. The baseline sum LD will be used as 
reference by which to characterize the objective tumor response. 
 
Non-target lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 5 
target lesions should be identified as non-target lesions and should also be recorded at 
baseline.  It is possible to record multiple non-target lesions involving the same organ as a 
single item on the case record form (e.g. “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”).  Bone lesions may be measureable if ≥ 1 cm on MRI. 
Measurements of 
these lesions are not required, but the presence or absence of each will be noted throughout 
follow-up. 
Non-measurable disease (Tumor Markers) 
Non-measurable disease is all other lesions (or sites of disease), including small lesions 
(longest diameter < 20 mm with conventional techniques or < 10 mm using spiral CT scan). 
Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified 
by physical exam that is not measurable by reproducible imaging techniques are all non- 
measurable. (e.g., PSA, CA-125, CA19-9, CEA) 
7.1.1.2 Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations will be performed as closely as possible to the beginning of treatment and 
never more than 28 days before the beginning of the treatment. 
 
The same method of assessment and the same technique will be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the antitumor effect of a treatment. 
Conventional CT and MRI 
Spiral CT scans should be performed using a 5 mm contiguous reconstruction algorithm. 
7.1.1.3 Response Criteria 
Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions, determined by two separate observations conducted not 
less than 4 weeks apart. Any pathological lymph nodes (whether target or non-target) must 
have reduction in short axis to <10 mm (the sum may not be “0” if there are target nodes). 
There can be no appearance of new lesions. 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD. There can be no appearance of new lesions. 
Progressive Disease (PD) 
At least a 20% increase in the sum of the SLD of target lesions, taking as reference the smallest 
sum SLD recorded since the treatment started and minimum 5 mm increase over the nadir, or 
the appearance of one or more new lesions. 


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Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum LD since the treatment started. 
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). 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target 
lesions. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
Table 7.1 
Response Criteria 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
 
CR 
CR 
No 
CR 
> 4 weeks confirmation 
CR 
PR 
Non-CR/ 
Non-PD 
Non-PD 
No 
No 
PR 
PR 
> 4 weeks confirmation 
SD 
Non-PD 
No 
SD 
documented at least once > 4 weeks 
from baseline 
PD 
Any 
Any 
Any 
PD* 
Any 
Yes or No 
Yes or No 
Yes 
PD 
PD 
PD 
no prior SD, PR or CR 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression 
 
Duration of Response 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for 
CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 


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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. 
 
 
Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression. 
7.2 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE v4.03 for reporting of non-hematologic adverse events and modified 
criteria for hematologic adverse events, 
 
 
For multicenter studies, the Principal Investigator at the UCSF Coordinating Center will hold the 
role of Study Chair. The Study Chair is responsible for the overall conduct of the study and for 
monitoring its safety and progress at all participating sites. 
7.3 
Definitions of Adverse Events 
7.3.1 Adverse Event 
 
An adverse event (also known as an adverse experience) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug 
related.  More specifically, an adverse event (can be any unfavorable and unintended sign (e.g., 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
drug, without any judgment about causality.  An adverse event can arise from any use of the 
drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. 
7.3.2 Adverse reaction 
 
An adverse reaction is defined as any adverse event caused by the use of a drug. Adverse 
reactions are a subset of all suspected adverse reactions for which there is reason to conclude 
that the drug caused the event. 
7.3.2.1 Suspected 
A suspected adverse reaction is defined as any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. For the purposes of IND safety reporting, 
“reasonable possibility” indicates that there is evidence to suggest a causal relationship between 
the drug and the adverse event.  A suspected adverse reaction implies a lesser degree             
of certainty about causality than an adverse reaction. 
7.3.2.2 Unexpected 
An adverse event or suspected adverse reaction is considered unexpected if it is not listed in 
the investigator brochure or package insert(s), or is not listed at the specificity or severity that 
has been observed, or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 


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“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation. 
 
Adverse events that would be anticipated to occur as part of the disease process are 
considered unexpected for the purposes of reporting because they would not be listed in the 
investigator brochure. For example, a certain number of non-acute deaths in a cancer trial 
would be anticipated as an outcome of the underlying disease, but such deaths would generally 
not be listed as a suspected adverse reaction in the investigator brochure. 
Some adverse events are listed in the Investigator Brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not been observed with the drug under investigation.  Such events would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class 
effect, the first case of angioedema observed with the drug under investigation should be 
considered unexpected for reporting purposes. 
7.3.2.3 Serious 
An adverse event or suspected adverse reaction is considered serious if, in the view of either 
the investigator- sponsor, it results in any of the following outcomes: 
● 
Death 
● 
Life-threatening adverse event 
● 
Inpatient hospitalization or prolongation of existing hospitalization 
● 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
● 
Congenital anomaly/birth defect 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  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. 
7.3.2.4 Life-threatening 
An adverse event or suspected adverse reaction is considered life-threatening if, in the view of 
either the investigator- sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred 
in a more severe form, might have caused death. 
7.4 
Recording of an Adverse Event 
All grade 3 and above adverse events will be entered into OnCore®, whether or not the event is 
believed to be associated with use of the study drug.  Data about these events and their severity 
will be recorded using the NCI CTCAE v4.03. 


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The Investigator will assign attribution of the possible association of the event with use of the 
investigational drug, and this information will be entered into OnCore® using the classification 
system listed below: 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
Unrelated 
The AE is clearly NOT related to the 
intervention 
drug/intervention 
 
 
Related to investigational 
drug/intervention 
 
The AE is doubtfully related to the 
intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
Unlikely 


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Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE. When specific adverse events are not listed in the CTCAE they will be 
graded by the Investigator as none, mild, moderate or severe according to the following grades 
and definitions: 
 
Grade 0 
No AE (or within normal limits) 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self- 
care ADL 
Grade 4: 
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
 
7.5 
Follow-up of Adverse Events 
All adverse events will be followed with appropriate medical management until resolved. 
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  For selected adverse events for which administration of the 
investigational drug was stopped, a re-challenge of the subject with the investigational drug may 
be conducted if considered both safe and ethical by the Investigator. 
7.6 
Adverse Events Monitoring 
All adverse events, whether or not unexpected, and whether or not considered to be associated 
with the use of the study drug, will be entered into OnCore®, as noted above. 
The Investigator will assess all adverse events and determine reportability requirements to the 
UCSF Data and Safety Monitoring Committee (DSMC) and UCSF’s Institutional Review Board 
(IRB); and, when the study is conducted under an Investigational New Drug Application (IND), 
to the Food and Drug Administration (FDA) if it meets the FDA reporting criteria. 
All adverse events entered into OnCore® will be reviewed by the Helen Diller Family 
 
 
 
Comprehensive Cancer Center Site Committee on a weekly basis. The Site Committee will 
 
review and discuss at each weekly meeting the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s). 
All grade(s) 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at 
the Site Committee meetings. The Site Committee will review and discuss the selected toxicity, 
the toxicity grade, and the attribution of relationship of the adverse event to the administration of 
the study drug(s). 
 
In addition, all suspected adverse reactions considered “serious” entered into OnCore®, will be 
reviewed and monitored by the Data and Safety Monitoring Committee on an ongoing basis and 


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discussed at DSMC meetings, which take place every six weeks. 
 
For a detailed description of the Data and Safety Monitoring Plan for a Multicenter Phase 2 or 3 
Institutional Study at the Helen Diller Comprehensive Cancer Center please refer Appendix 4 
Multicenter Institutional Studies. 
7.7 
Expedited Reporting 
Reporting to the Data and Safety Monitoring Committee 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) 
or to a study procedure, the Investigator or his/her designee must notify the DSMC Chair (or 
qualified alternate) within 1 business day of knowledge of the event. The contact may be by 
phone or e-mail. 
Reporting to UCSF Committee on Human Research (Institutional Review Board) 
The Principal Investigator must report events meeting the UCSF IRB definition of “Unanticipated 
Problem” (UP) within 10 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration 
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected. The Sponsor-Investigator needs to ensure that the event meets all 
three definitions: 
● 
Suspected adverse reaction (as defined in 6.1.30) 
● 
Unexpected (as defined in 0) 
● 
Serious (as defined in 6.1.5) 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 
 
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days after 
the Investigator determines that the suspected adverse reaction qualifies for reporting (21 CFR 
312.32(c)(1)). 
 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA no 
later than 7 calendar days after the Investigator’s initial receipt of the information (21 CFR 
312.32(c)(2)). 


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Any relevant additional information that pertains to a previously submitted IND safety report will 
be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
Reporting to Pharmaceutical Companies providing Study Drug 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided the main informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department - Fax: (877-778-9739). The original 
copy of the SAE Report Form and the fax confirmation sheet must be kept with the case report 
form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow-up to the previously reported 
SAE and giving the date of the original report. Each re-occurrence, complication, or progression 
of the original event should be reported as a follow-up to that event regardless of when it  
occurs. The follow-up information should describe whether the event has resolved or continues, 
if and how it was treated, whether the blind was broken or not, and whether the patient 
continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same drug 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) 
will be collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in participating 
countries. 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 


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of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
Warnings and precautions 
Additional safety information collected between IB updates will be communicated in the form of 
Investigator Notifications. This information will be included in the patient informed consent and 
should be discussed with the patient during the study as needed 
8 
Statistical Considerations and Evaluation of Results 
8.1 
Study Endpoints 
See Section 2.4 for study endpoints. 
 
This is a Phase II, open-label, multicenter clinical trial evaluating the efficacy and safety of 
trametinib monotherapy in patients with advanced non-squamous NSCLC whose tumors harbor 
a non-synonymous NF1 mutation and are wildtype for KRAS.  Patients will receive trametinib 
monotherapy in 28 day cycles. 
8.1.1 Randomization 
 
This is a single-arm, open-label phase II study without any randomization. 
8.1.2 Unblinding Subjects 
 
Study is open-label so unblinding subjects is not applicable. 
 
8.1.3 
None 
Stratification Factors 
 
 
8.2 
Determination of Sample Size and Accrual Rate 
8.2.1 Sample Size and Power Estimate 
 
The primary endpoint is objective response rate (ORR). To provide 80% power to detect a 30% 
ORR compared to the null hypothesis of a 10% ORR in each cohort, 27 patients will be enrolled, 
with the goal of obtaining 24 evaluable patients. Using a Simon 2-stage design, if we do not 
observe at least 2 responses within the first 15 patients, enrollment will be stopped due to lack  
of efficacy. 
 
The primary efficacy analysis will be based on one-sided exact binomial test comparison of the 
observed ORR in patients receiving at least one dose of study treatment to the null- 
hypothesized value of 10%, using the 5% significance level. Secondary time-to-event endpoints 
(DR, PFS and OS) will be summarized using Kaplan-Meier estimates with associated 95% 
confidence limits. The secondary DCR endpoint will be summarized as a proportion with an 
exact binomial 95% confidence interval. Safety analyses will be descriptive summaries of AEs 
by patient and type. 


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8.2.2 
Replacement Policy 
All patients who receive a dose of trametinib will be analyzed for safety and efficacy. Subjects 
who discontinue from study participation prior to receiving any dose of study therapy may be 
replaced after discussion with the Principal Investigator. Patients removed from study for 
unacceptable treatment related adverse event(s) will be followed until resolution or stabilization 
of all treatment related AEs to grade 2 or lower; however, they will not be replaced. 
8.2.3 
Accrual estimates 
At UCSF, UC Davis, and UC San Diego we see > 200 patients per month with advanced 
NSCLC, 80% of whom have non-squamous histology. Based on The Cancer Genome Atlas 
(TCGA) Research Network studies described in Section 1.1, we predict that about,11% of lung 
adenocarcinomas will harbor NF1 mutations.17 Conservatively, we expect that 10 patients per 
month will harbor one of these mutations and that 1-2 patients per month will be eligible and will 
consent to participate in the study. 
 
Interim Analyses and Stopping Rules 
Using a Simon 2-stage design, if we do not observe at least 2 responses within the first 15 
patients in a given cohort, enrollment to that arm would be stopped due to lack of efficacy. 
 
8.3 
Analyses Plans 
8.3.1 Analysis Population 
 
All patients who receive a dose of trametinib will be analyzed for safety and efficacy. Subjects 
who discontinue from study participation prior to receiving any dose of study therapy may be 
replaced after discussion with the investigator sponsor. Subjects who have received any dose of 
study therapy will not be replaced. 
 
Demographic and baseline characteristics will be summarized by each cohort and overall. In 
general, frequency distribution and percentage will be used to summarize categorical 
measurements, while mean with standard deviation and median with interquartile range will be 
used to describe symmetric and skewed continuous measurements, respectively. Univariate 
analysis among variables will be assessed using the two-sample t-test, Wilcoxon-rank-sum test, 
Chi-square test, as appropriate. 
8.3.2 Primary Analysis (or Analysis of Primary Endpoints) 
 
The ORR is defined as the best overall response recorded from the start of the treatment until 
disease progression or recurrence as assessed over a 1-year period from the start of treatment. 
The frequency and percentages of patients with a best overall response rate of complete 
response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be 
determined. We will test the hypothesis that the ORR is greater than the null hypothesis of 10% 
using the Fisher’s exact test. 


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8.3.3 
Secondary Analysis (or Analysis of Secondary Endpoints) 
Definition and analytical plan for secondary efficacy endpoints: 
 
(a) Duration of response (DR): The DR for CR and PR will be measured from the date that 
the best response if first recorded until the date that PD is documented over the period of 1 
year.  For patients who continue treatment post progression, the date of PD documentation 
will be used for analysis. The DR will be summarized using descriptive statistics (N, mean, 
standard deviation, minimum, and maximum). 
 
(b) Disease control rate (DCR): DCR will be defined as the percentage of patients who 
have achieved CR, PR, or SD for at least 12 weeks. The DCR will be summarized using 
descriptive statistics (N, mean, standard deviation, minimum, and maximum). 
 
(c) Progression-free Survival (PFS):  PFS will be calculated as 1+ the number of days from 
the first dose of study drugs to documented radiographic progression or death due to any 
cause over a period of 1 year. For patients who continue treatment post-progression, the date 
of radiographic progression will be used for PFS analysis. The Kaplan-Meier analysis 
will be used to calculate the median PFS with 95% confidence interval. 
 
(d) Overall Survival (OS): OS will be calculated as 1+ the number of days from the first 
dose of study drugs to death due to any cause over a period of 1 year. The Kaplan-Meier 
analysis will be used to calculate the median OS with 95% confidence interval. 
 
(3) Definition and analytical plan for safety and tolerability endpoints: The safety 
population will consist of all subjects who receive any amount of study treatment. Safety will be 
assessed by evaluation of AEs. All safety analyses will be performed using the safety 
population. Adverse event terms recorded on the CRFs will be mapped to preferred terms using 
the Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and 
relationship to study treatment will be assessed by the investigator. Severity grade will be 
defined by the National Cancer Institute (NCI) CTCAE v4.03. Listings of AEs will be provided. 
 
Separate tables will present the following by dose group and study phase: 
 
• All treatment-emergent AEs 
• Treatment-emergent AEs by CTCAE grade 
• Grade 3 or greater treatment-emergent AEs 
• Treatment-related, treatment-emergent AEs 
• Dose-limiting toxicity AEs 
• Serious treatment-emergent AEs 
• Treatment-emergent AEs with an outcome of death 
• Treatment-emergent AEs leading to discontinuation of trametinib. 
• Treatment-emergent AEs resulting in interruption or reduction or delay of trametinib. 
 
8.3.4  Other Analyses/Assessments 
 
Exploratory Analysis: Understanding the mechanisms of response and resistance to 
trametinib therapy will be critical to identifying patients who may preferentially benefit the most 
from this therapy. We propose to investigate this by: 


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(a) Assess pre-treatment, at time of first scan to assess response, trametinib resistant tumors 
V(ienrsoiopntidoantae:l 0b2i-o1p5s-2y01s8pecimens) for evidence MAPK pathway activation.  IHC wiPll rboteocpoel rCfCor#m
: 1e6d6521 
to assess ERK1/2 phosphorylation.  Phosphorylation will be  scored in a continuous manner, 
and difference in phosphorylation between pre-treatment, best response, and post-resistant 
specimens will be determined by a two-tailed T-test. 
 
(b) We will use whole exome and transcriptome deep sequencing (WES; RNAseq) in the pre- 
treatment, at time of first scan to assess response (optional), and post- progression (optional) 
tumor biopsy samples to uncover somatic genetic alterations (mutations 


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and copy number alterations) and transcriptional events associated with clinical resistance 
(either de novo or acquired), with a minimum depth of WES coverage of 100X to capture events 
occurring down to ~10% frequency. We will use tumor microdissection to maximize tumor purity 
and peripheral leukocytes as normal/germline controls, with appropriate standard correction of 
the genetic findings for cancer cell fraction. This unbiased analysis is warranted to ensure we 
capture resistance events that are anticipated (e.g. secondary BRAF or MEK pathway mutations 
or ERK1/2 upregulation, or HIPPO-YAP pathway upregulation32,35 and unexpected and 
coordinated changes (e.g. genomic amplification + concordant RNA overexpression of a 
resistance gene). This approach will enable identification and/or validation of RNA signatures of 
potential resistance events (such as ERK1/2 transcriptional output). The analysis of samples 
from patients with de novo resistance and of matched paired tumor samples acquired from 
individual patients before treatment and at acquired resistance will be prioritized for study to 
facilitate the clinical correlation of the genetic findings with bona fide clinical resistance. For 
instance, we may find that genetic mutation/amplification or transcriptional upregulation of 
ERK1/2 is present in tumors from patients with de novo or acquired trametinib resistance.  All 
statistical and genomic analyses will be done with custom scripts and extensively developed 
pipelines in the R statistical computing framework 
). Descriptive 
statistics and graphical methods will be used to analyze the data. Orthogonal validation of 
specific findings will be done using individualized assays in the clinical specimens (e.g. direct 
sequencing, SNP arrays, fluorescence in situ hybridization for DNA alterations; q-RT-PCR, IHC 
for RNA and protein abundance changes) and associated circulating free DNA, where feasible. 
 
(c) When possible, we will generate patient-derived organoids and/or patient-derived 
xenografts from biopsy specimens from patients that participate in the trial in order to fully 
interrogate pathways of response and resistance in a highly clinically relevant system. We will 
use these  models to perform pre-clinical trials aimed at overcoming mechanisms of resistance 
with rationally designed polytherapy. 
 
(d) Circulating cell free DNA (cfDNA) will be assessed for biomarkers of resistance that are 
identified above. Descriptive statistics and graphical methods will be used to analyze the data. 
8.4 
Evaluation of Safety 
Analyses will be performed for all patients having received at least one dose of study drug. The 
frequencies of individual toxicities thought to be probably, possible, or definitely related to study 
drug will be reported as well as the incidence of any grade 3, 4, and 5 toxicities regardless of 
attribution.  Analyses will be performed for all patients having received at least one dose of 
study drug. The study will use the NCI CTCAE v4.03. 
 
9 
Study Management 
9.1 
Pre-study Documentation 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject recruitment 
materials, and any other written information to be provided to subjects before any protocol 
related procedures are performed on any subjects. 


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The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable regulatory 
requirements. The IRB must comply with the regulations in 21 CFR §56 and applicable 
regulatory requirements. 
9.2 
Institutional Review Board Approval 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB (UCSF Institutional Review Board).  Prior to obtaining IRBIRB 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC). The initial protocol and 
all protocol amendments must be approved by the IRB prior to implementation. 
9.3 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for each participant to make an informed decision regarding their participation.  Participants 
must sign the IRB-approved informed consent form prior to participation in any study specific 
procedure. The participant must receive 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. 
9.4 
Changes in the Protocol 
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment. The amendment must be signed by the Investigator 
and approved by PRC and the IRB prior to implementation. 
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after implementation. 
The Study Chair and the UCSF study team will be responsible for updating any participating 
sites. 
9.5 
Handling and Documentation of Clinical Supplies 
The UCSF Principal Investigator and each participating site will maintain complete records 
showing the receipt, dispensation, return, or other disposition of all investigational drugs. The 
date, quantity and batch or code number of the drug, and the identification of patients to whom 
study drug has been dispensed by patient number and initials will be included. The sponsor- 
investigator will maintain written records of any disposition of the study drug. 
 
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow the 
investigational drug to be used in any manner other than that specified in this protocol. 


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9.6 
Case Report Forms (CRFs) 
The Principal Investigator, and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account. The Clinical Research Coordinator (CRC) will complete the CRFs as soon as 
possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
 
All source documentation and CTMS data will be available for review/monitoring by the UCSF 
DSMC and regulatory agencies. 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked. Any changes to the data entered into the CRFs after that time can only 
be made by joint written agreement among the Study Chair, the Trial Statistician, and the 
Protocol Project Manager. 
9.7 
Oversight and Monitoring Plan 
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI- 
approved Data and Safety Monitoring Plan (DSMP). The DSMC will routinely review all adverse 
events and suspected adverse reactions considered “serious”. The DSMC will audit study- 
related activities to ensure that the study is conducted in accordance with the protocol, local 
standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  Significant 
results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable.  See 
Appendix 2 Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study, for additional 
information. 
9.8 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center for Phase II studies will also coordinate, at minimum, monthly conference 
calls with the participating sites at the completion of each cohort or more frequently as needed 
to discuss risk assessment. 
The following issues will be discussed as appropriate: Enrollment information 
● 
Adverse events (i.e., new adverse events and updates on unresolved adverse events and 
new safety information) 
● 
Protocol violations 


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● 
Other issues affecting the conduct of the study 
Record Keeping and Record Retention 
The Principal Investigator is required to maintain adequate records of the disposition of the 
drug, including dates, quantity, and use by subjects, as well as written records of the disposition 
of the drug when the study ends. 
The Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each 
individual administered the investigational drug or employed as a control in the investigation. 
Case histories include the case report forms and supporting data including, for example, signed 
and dated consent forms and medical records including, for example, progress notes of the 
physician, the individual's hospital chart(s), and the nurses' notes. The case history for each 
individual shall document that informed consent was obtained prior to participation in the study. 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
In accordance with FDA regulations, the investigator shall retain records for a period of 2 years 
following the date a marketing application is approved for the drug for the indication for which it 
is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until 2 years after the investigation is discontinued and FDA is notified. 
9.9 
Coordinating Center Documentation of Distribution 
It is the responsibility of the Study Chair to maintain adequate files documenting the distribution 
of study documents as well as their receipt (when possible). The HDFCCC recommends that 
the Study Chair maintain a correspondence file and log for each segment of distribution (e.g., 
FDA, drug manufacturer, participating sites, etc.). 
Correspondence file: should contain copies (paper or electronic) of all protocol versions, cover 
letters, amendment outlines (summary of changes), etc., along with distribution documentation 
and (when available) documentation of receipt. 
 
Correspondence log: should be a brief list of all documents distributed including the date sent, 
recipient(s), and (if available) a tracking number and date received. 
 
At a minimum, the Study Chair must keep documentation of when and to whom the protocol, its 
updates and safety information are distributed. 
9.10 Regulatory Documentation 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Institutional Review Board (IRB). Prior to implementing this protocol at the 
participating sites, approval for the UCSF IRB approved protocol must be obtained from the 
participating site’s IRB. 


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The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 
 
● 
Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization 
● 
Participating Site IRB approved consent form 
● 
Participating Site IRB membership list 
● 
Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number 
● 
Curriculum vitae and medical license for each investigator and consenting professional 
● 
Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site 
● 
Participating site laboratory certifications and normals 
Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment. 
10 
Protection of Human Subjects 
10.1 Protection from Unnecessary Harm 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the process of informed consent. The 
IRB reviews all proposed studies involving human experimentation and ensures that the 
subject’s rights and welfare are protected and that the potential benefits and/or the importance 
of the knowledge to be gained outweigh the risks to the individual. The IRB also reviews the 
informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
10.2 Protection of Privacy 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient’s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 


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References 
 
1. 
Cancer Genome Atlas Research Network: Comprehensive molecular profiling of 
lung adenocarcinoma. Nature 511:543-50, 2014 
2. 
Davies H, Bignell GR, Cox C, et al: Mutations of the BRAF gene in human 
cancer. Nature 417:949-54, 2002 
3. 
Comprehensive molecular profiling of lung adenocarcinoma. Nature 511:543-50, 
2014  
4. 
Chapman PB, Hauschild A, Robert C, et al: Improved survival with vemurafenib 
in melanoma with BRAF V600E mutation. N Engl J Med 364:2507-16, 2011 
5. 
Pratilas CA, Hanrahan AJ, Halilovic E, et al: Genetic predictors of MEK 
dependence in non-small cell lung cancer. Cancer Res 68:9375-83, 2008 
6. 
Trejo CL, Juan J, Vicent S, et al: MEK1/2 inhibition elicits regression of 
autochthonous lung tumors induced by KRASG12D or BRAFV600E. Cancer Res 72:3048-59, 
2012 
7. 
Xu GF, O'Connell P, Viskochil D, et al: The neurofibromatosis type 1 gene 
encodes a protein related to GAP. Cell 62:599-608, 1990 
8. 
Xu GF, Lin B, Tanaka K, et al: The catalytic domain of the neurofibromatosis type 
1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. Cell 
63:835-41, 1990 
9. 
Martin GA, Viskochil D, Bollag G, et al: The GAP-related domain of the 
neurofibromatosis type 1 gene product interacts with ras p21. Cell 63:843-9, 1990 
10. 
Patil S, Chamberlain RS: Neoplasms associated with germline and somatic NF1 
gene mutations. Oncologist 17:101-16, 2012 
11. 
Imielinski M, Berger AH, Hammerman PS, et al: Mapping the hallmarks of lung 
adenocarcinoma with massively parallel sequencing. Cell 150:1107-20, 2012 
12. 
Nissan MH, Pratilas CA, Jones AM, et al: Loss of NF1 in cutaneous melanoma is 
associated with RAS activation and MEK dependence. Cancer Res 74:2340-50, 2014 
13. 
Verhaak RG, Hoadley KA, Purdom E, et al: Integrated Genomic Analysis 
Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in 
PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98-110, 2010 
14. 
Side LE, Emanuel PD, Taylor B, et al: Mutations of the NF1 gene in children with 
juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 
92:267-72, 1998 
15. 
Chang T, Krisman K, Theobald EH, et al: Sustained MEK inhibition abrogates 
myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123:335-9, 2013 
16. 
Falchook GS, Lewis KD, Infante JR, et al: Activity of the oral MEK inhibitor 
trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol 
13:782-9, 2012 
17. 
Cancer Genome Atlas Research N: Comprehensive molecular profiling of lung 
adenocarcinoma. Nature 511:543-50, 2014 
18. 
Redig AJ, Capelletti M, Dahlberg SE, et al: Clinical and Molecular Characteristics 
of NF1-Mutant Lung Cancer. Clin Cancer Res 22:3148-56, 2016 
19. 
Shannon KM, O'Connell P, Martin GA, et al: Loss of the normal NF1 allele from 
the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N 
Engl J Med 330:597-601, 1994 
20. 
Bollag G, Clapp DW, Shih S, et al: Loss of NF1 results in activation of the Ras 
signaling pathway and leads to aberrant growth in haematopoietic cells. Nat Genet 12:144-8, 
1996 


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21. 
Ingram DA, Yang FC, Travers JB, et al: Genetic and biochemical evidence that 
haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates 
in vivo. J Exp Med 191:181-8, 2000 
22. 
McGillicuddy LT, Fromm JA, Hollstein PE, et al: Proteasomal and genetic 
inactivation of the NF1 tumor suppressor in gliomagenesis. Cancer Cell 16:44-54, 2009 
23. 
Malone CF, Fromm JA, Maertens O, et al: Defining key signaling nodes and 
therapeutic biomarkers in NF1-mutant cancers. Cancer Discov 4:1062-73, 2014 
24. 
Kris MG, Johnson BE, Berry LD, et al: Using multiplexed assays of oncogenic 
drivers in lung cancers to select targeted drugs. JAMA 311:1998-2006, 2014 
25. 
Comprehensive genomic characterization of squamous cell lung cancers. Nature 
489:519-25, 2012 
26. 
Stieger B: Role of the bile salt export pump, BSEP, in acquired forms of 
cholestasis. Drug Metab Rev 42:437-45, 2010 
27. 
Hillgren KM, Keppler D, Zur AA, et al: Emerging transporters of clinical 
importance: an update from the International Transporter Consortium. Clin Pharmacol Ther 
94:52-63, 2013 
28. 
Hotta K, Fujiwara Y, Kiura K, et al: Relationship between response and survival 
in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic 
chemotherapy in 143 phase III trials. J Thorac Oncol 2:402-7, 2007 
29. 
Wan PT, Garnett MJ, Roe SM, et al: Mechanism of activation of the RAF-ERK 
signaling pathway by oncogenic mutations of B-RAF. Cell 116:855-67, 2004 
30. 
Andreadi C, Cheung LK, Giblett S, et al: The intermediate-activity (L597V)BRAF 
mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the 
RAF/MEK/ERK pathway. Genes Dev 26:1945-58, 2012 
31. 
Chang T, Krisman K, Theobald EH, et al: Sustained MEK inhibition abrogates 
myeloproliferative disease in Nf1 mutant mice. J Clin Invest 126:404, 2016 
32. 
Lin L, Sabnis AJ, Chan E, et al: The Hippo effector YAP promotes resistance to 
RAF- and MEK-targeted cancer therapies. Nat Genet, 2015 
33. 
Balagula Y, Barth Huston K, Busam KJ, et al: Dermatologic side effects 
associated with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs 
29:1114-21, 2011 
34. 
Lacouture ME, Anadkat MJ, Bensadoun RJ, et al: Clinical practice guidelines for 
the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care 
Cancer 19:1079-95, 2011 
35. 
Lin L, Asthana S, Chan E, et al: Mapping the molecular determinants of BRAF 
oncogene dependence in human lung cancer. Proc Natl Acad Sci U S A 111:E748-57, 2014 


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Appendices 
Appendix 1  QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB)  
 
 
Bazett's formula used to correct QT interval for heart rate is: 
 
QTcB 
 QT 
 
RR 
 
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. 


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


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Appendix 3  UCSF Policy/Procedure for Required Regulatory Documents for a 
UCSF Investigator-Initiated Oncology Clinical Trials with an Investigator held 
Investigational New Drug (IND)  
 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) for both IND and IND-exempt trials. 
 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) Guidelines 
define Essential Regulatory Documents as those documents which individually and collectively 
permit evaluation of the conduct of a trial and the quality of data produced. These documents 
serve to demonstrate compliance with standards of GCP and with all applicable regulatory 
requirements. Filing essential documents in a timely manner can greatly assist in the successful 
management of a clinical trial. 
 
The Regulatory Documents will consist of electronic files in both iRIS and OnCore®, as well as 
paper files in the Regulatory Binders for both the Coordinating Site and the Participating Site(s) 
in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
 
Procedures 
 
1. Single Site (HDFCCC) Therapeutic Essential Regulatory Documents: 
Documents Filed in iRIS: 
● 
Current and prior versions of the Informed Consent Form(s) (ICFs). 
● 
IRB approvals for initial submission of application, all modifications, and continuing 
annual renewals. 
● 
Current and prior approved protocol versions. 
● 
Current IRB roster 
● 
Current and prior versions of the Investigator Brochure (IB). 
● 
Serious Adverse Event (SAE) Reports. 
● 
Subject diary and handouts (if applicable). 
● 
Single Patient Exception (SPE) Report(s) to the IRB with Approval Letter(s) from IRB. 
● 
Protocol Violation (PV) Reports with acknowledgement from the IRB. 
 
Documents Filed in OnCore®: 
● 
Package Insert (if the study drug is commercial). 
● 
Protocol signature page(s) with Pl signature(s) for all protocol versions. 
● 
Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) document. 
● 
Screening/enrollment log. 
● 
Data and Safety Monitoring Committee (DSMC) monitoring reports. 
● 
DSMC dose escalation approvals with study status summary forms. 
● 
Case Report Form (CRF) completion manual. 
● 
Drug Destruction Standard Operating Procedure (SOP). 


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● 
Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator's signature. 
● 
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, and Staff Training Documents (i.e., 
Collaborative Institute Training Initiative (CITI), etc.). 
● 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center. 
● 
Serious Adverse Event (SAE) reports to IRB and sponsor. 
● 
MedWatch reporting to FDA and sponsor. 
● 
Drug Destruction Standard Operating Procedure (SOP). 
● 
For all laboratories listed on the FDA 1572, will need CUA certifications, CAP 
certifications, lab licenses, CV(s) and Medical License(s) of Lab Director(s), and 
laboratory reference ranges. 
 
Documents Filed in Regulatory Binder: 
● 
Delegation of Authority Log with signatures (to be scanned in OnCore once the trial is 
complete). 
 
2. Additional Essential Documents for Therapeutic Multicenter Trials for the 
Coordinating Center (filed in OnCore or Zip Drive): 
 
• 
Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act {HIPAA) Consent Form for 
the Participating Site(s). 
• 
For all Principal Investigators and Sub-Investigators listed on the 1572 at the 
Participating Site(s), will need Financial Disclosure Forms, CVs, MD Licenses, and Staff 
Training documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) (for 
investigational New Drug Application). 
• 
Site Initiation Visit (SIV) minutes and correspondence with the Participating Site(s). 
• 
As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s). 
• 
Protocol Violations (PV) Reports to IRB with acknowledgement from IRB for Participating 
Site(s). 
• 
Single Patient Exception (SPE) Reports to IRB with IRB Approval Letters for 
Participating Site(s). 
• 
Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s). 
• 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s). 
• 
For all laboratories listed on FDA 1572, will need CUA certifications, CAP certifications, 
lab licenses, CVs and Medical License(s) of Lab Director(s), and laboratory reference 
ranges for the Participating Site(s). 
• 
Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan 
(if an outside CRO is used for the study). 
• 
Serious Adverse Event (SAE) forms submitted to the IRB for the Participating Site(s). 


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3. Required Multicenter Essential Regulatory Document Checklist for Therapeutic 
and Non-Therapeutic Trials (For Start-Up Only): 
 
• 
See attached checklist(s). 
 
4. Required Essential Regulatory Documents for Single Site and Multicenter 
Therapeutic IND-Exempt Studies (filed in OnCore): 
 
• 
For IND Exempt studies, the Essential Regulatory Documents for UCSF would include 
all documents in Section #1 of this policy. The Essential Regulatory Documents from the 
participating site(s) for Multicenter Trials when UCSF is the Coordinating Center would 
only include the signed protocol signature page, CV of the Pl, and the IRB approval 
letters. All other documents in Section #2 of this policy would be the responsibility of the 
Participating Site(s). 
 
5. Required Essential Regulatory Documents for Single Site Non-Therapeutic 
Studies (filed in OnCore): 
 
• 
For Single Site non-therapeutic trials, all Regulatory Documents in Section #1 of this 
policy are required except for: current and prior versions of the Investigator Brochure 
(IB), package insert (if the study drug is commercial), DSMC dose escalation approvals 
with study status summary forms, approvals for Biosafety Committee, Radiation 
Committee, and Infusion Center, and drug destruction SOPs. 
 
6. Required Essential Regulatory Documents for Multicenter Non-Therapeutic 
Studies (filed in OnCore): 
 
• 
For Multicenter non-therapeutic trials with UCSF as the Coordinating Site, all required 
Regulatory Documents listed above in Section #5 for Single Site non-therapeutic trials 
are required for the Coordinating Site. The only required Regulatory Documents from the 
Participating Site(s) will be: IRB approval letters, IRB roster, and ICF and HIPAA consent 
forms, the Delegation of Authority Log (with NIH or CITI human subject protection  
training certificates or GCP training certification), Protocol Violations and Single Patient 
Exception (SPE) reports to the IRB with supporting fax documentation (if applicable), 
Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor, and the 
Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s). If applicable, a copy of the Data and Safety Monitoring Plan (DSMP) Monitoring 
Plan for all participating site(s) in Multicenter studies or Contract Research Organization 
(CRO) Monitoring Plan (if an outside CRO is used for the study) will be required. 
 
Alternate Procedures 
 
There are no alternate procedures to the HDFCCC policy for requirements for Essential 
Regulatory Documents for Multicenter Investigator-Initiated Oncology Clinical Trials. 
 
References 
 
• 
ICH Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance (current 
version). 


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• 
International Conference on Harmonization: Good Clinical Practice: Consolidated 
Guideline (current version). 
• 
International Conference on Harmonization: Essential Documents for the Conduct of a 
Clinical Trial (current version). 
• 
21CFR50 
• 
21 CFR56.11 
• 
45CFR46 
• 
21 CFR312 
 
Required Regulatory Documents for Sub-sites Participating in Therapeutic UCSF Investigator 
Initiated Multicenter trial 
 
Directions: Scan the documents in a zip drive and upload to OnCore. 
 
1572 
PI and Sub investigators: 
● 
CV and Medical license 
● 
Financial disclosure form 
● 
NIH or CITI human subject protection training certification 
 
Laboratories: 
● 
CLIA &CAP and Lab Licenses 
● 
CV and Medical License of Lab Director 
● 
Laboratory reference ranges 
Local Institutional Review Board 
IRB Approval letter 
Reviewed/Approved documents 
● 
Protocol version date: 
  
 
● 
Informed consent version date:    
 
● 
Investigator Brochure version date:    
 
● 
HIPAA 
Current IRB Roster 
 
Other 
 
Delegation of Authority Log 
● 
Include NIH or CITI human subject protection training certificates or GCP training 
certification 
Pharmacy 
● Drug destruction SOP and Policy 
Protocol signature page 
Executed sub contract 


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Appendix 4  Data Safety Monitoring Plan for a Multicenter Study (Phase II or III study) 
 
1. Oversight and Monitoring Plan 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and patient safety for all 
HDF CCC institutional clinical studies. A summary of DSMC activities for this study includes: 
 
• 
Review of patient data. 
• 
Review of serious adverse events. 
• 
Monitoring every six months (depending on patient accrual). 
• 
Minimum of a yearly regulatory audit. 
 
2. Monitoring and Reporting Guidelines 
 
All institutional Phase II or III therapeutic studies are designated with a moderate risk assessment 
(see Appendix H).  The data is monitored by a DSMC Monitor twice per year with twenty percent of 
the patients monitored (or at least three patients if the calculated value is less than three). 
 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. The 
Study Chair is responsible for the overall conduct of the study and for monitoring its safety and 
progress at all participating sites. The Study Chair will conduct continuous review of data and  
patient safety and discuss each patient’s treatment at monthly UCSF Site Committee meetings. The 
discussions are documented in the UCSF Site Committee meeting minutes. 
 
Multicenter communication 
 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate monthly conference calls with the participating sites. The 
following issues will be discussed as appropriate: 
 
• 
Enrollment information. 
• 
Adverse Events (i.e., new adverse events and updates on unresolved adverse events and new 
safety 
information). 
• 
Protocol Violations. 
• 
Other issues affecting the conduct of the study. 
 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating Center, 
as well as the participating sites. The DSMC will be responsible for monitoring all data entered in 
OnCore® at the UCSF Coordinating Center and the participating sites as per the study-specific 
guidelines listed in Appendix H. The data (i.e., copies of source documents) from the participating 
sites will be downloaded into the PC console of OnCore prior to the monitoring visits in order for the 
DSMC to monitor the participating site’s compliance with the protocol and FDA regulations. 
 
 
 


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3. Review and Oversight Requirements 
 
3.1 
Adverse Event Monitoring 
 
All Grade 3-5 Adverse Events (AEs), regardless of being unexpected or considered to be 
associated with the use of the study drug will be entered into OnCore®, UCSF’s Clinical Trial 
Management System. 
 
Adverse Events are graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) as developed and revised by the Common Therapy Evaluation Program (CTEP) of the 
National Cancer Institute. Adverse Events are further given an assignment of attribution or 
relationship to treatment or medical procedure. Attribution categories are: 
 
• 
Definite – The adverse event is clearly related to the investigational agent(s) or 
medical procedure. 
• 
Probable – The adverse event is likely related to the investigational agent(s) or 
medical procedure. 
• 
Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure. 
• 
Unlikely – The adverse event is doubtfully related to the investigational agent(s) 
or medical procedure. 
• 
Unrelated – the adverse event is clearly not related to the investigational agent(s) 
or medical procedure. 
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All adverse events entered into OnCore® will be reviewed on a 
monthly basis at the UCSF Coordinating Center Site Committee meetings. 
All clinically 
significant adverse events must be reported to the UCSF Coordinating Center by the  
participating sites within 10 business days of becoming aware of the event or during the next 
scheduled 
monthly conference call, whichever is sooner. The UCSF Site Committee will 
review and discuss the selected toxicity, the toxicity grade, and the attribution of relationship of 
the adverse event to the administration of the study drug(s) from the UCSF Coordinating Center 
and the participating sites. 
 
3.2 
Serious Adverse Event Reporting 
 
By definition, an Adverse Event is defined as a Serious Adverse Event (SAE) according to the 
following criteria: 
 
• 
Death. 
• 
Life-threatening (i.e. results in an immediate risk of death). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Permanent or significant disability/incapacity. 
• 
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience that 
suggests a significant hazard, contraindication, side effect, or precaution that may 
require medical or surgical intervention to prevent one of the outcomes listed 
above. 
• 
Event occurring in a gene therapy study. 
• 
Event that changes the risk/benefit ratio of a study. 
• 
Any other event the Principal Investigator judges to be serious or which would 


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suggest a significant hazard, contraindication, side effect, or precaution. 
 
 
Serious Adverse Event reporting will be in accordance with the UCSF IRB Regulations and Code 
of Federal Regulation Title 21 Part 312.32. The SAE will be reported on a Med Watch form. 
 
UCSF IRB website for guidance in reporting serious adverse events:  
https://irb.ucsf.edu/adverse-event 
FDA website for guidance in reporting serious adverse events:  
www.fda.gov/Safety/MedWatch/HowToReport/default.htm 
Med Watch forms and information:  
www.fda.gov/medwatch/getforms.htm 
All Serious Adverse Events are entered into OnCore®, as well as submitted to the IRB (per IRB 
guidelines) via iRIS®. All SAEs, whether expected or unexpected, must be reported to the 
UCSF Coordinating Center within 1 business days of becoming aware of the event. The SAEs 
are reviewed and monitored by the UCSF Data and Safety Monitoring Committee on an ongoing 
basis and discussed at DSMC meetings, which take place every six weeks. The date the SAE 
was sent to all required reporting agencies will be documented in OnCore®. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be possibly, probably, or 
definitely related either to the investigational drug or any research related procedure, the Study 
Chair at the UCSF Coordinating Center or the assigned designee must be notified within 1 
business day from the participating site(s) and the Study Chair must then notify the DSMC Chair 
or qualified alternate within 1 business day of this notification. The reporting procedure is by 
communication via phone or in person with written documentation of the one-on-one 
communication via e-mail, with a copy of the e- 
mail to the DSMC Manager. 
 
3.3 
Review of Adverse Event Rates 
 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in  the 
Investigator Brochure or package insert) is noted in the study, the Study Chair at the UCSF 
Coordinating Center is responsible for notifying the DSMC at the time the increased rate is 
identified. The report will indicate if the incidence of adverse events observed in the study is 
above the range stated in the Investigator Brochure or package insert. 
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the 
DSMC Chair and DSMC Manager must be notified within 1 business day and the IRB must be 
notified within 10 business days via an iRIS Reporting Form. 


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Data and Safety Monitoring Committee Contacts: 
 
 
 
 
 
 
 
 
 
 
DSMC Monitors 
Box 0128 
UCSF HDFCCC 
San Francisco, CA 94143 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 5  Prohibited Medications  
 


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The following is a list of medications to avoid while you are participating in this study. If you go 
to any medical visit, please take this list with you for the doctor’s reference. 
 
Before you begin treatment, Dr. Blakely or one of his associates will review all medications you 
are taking. Make sure you talk with Dr. Blakely before you start or stop taking any medications. 
This list contains only the most common drugs that are known to interact with the drugs used in 
this study. It is very important to discuss all medications that you are taking with your study 
doctor. This information will be reviewed at each study visit. 
 
 
 
Strong inducers of CYP3A or CYP2C8 
Strong inhibitors of CYP3A 
Generic Name 
Brand Names ® 
Generic Name 
Brand Names ® 
Rifampin 
Rifadin 
Clarithromycin 
Biaxin 
Rifabutin 
Mycobutin 
Telithromycin 
Ketek 
Rifapentine 
Priftin 
Troleandomycin 
Carbamazepine 
Tegretol, Carbatrol, 
Equetro 
Nefazodone 
Serzone 
Oxcarbazepine 
Trileptal 
Itraconazole 
Sporanox, Onmel 
Phenobarbital 
Ketoconazole 
Nizoral, Xolegel, Extina 
Phenytoin 
Dilantin, Phenytek, 
Dilantin-125, Cerebyx 
Posaconazole 
Noxafil 
s-mephenytoin 
Voriconazole 
Vfend 
Bosentan 
Ritonavir 
Norvir 
St. John’s Wort 
Saguinavir 
Atazanavir 
Reyataz 
Gemfibrozil 
Lopid 
Conivaptan 
Vaprisol 
Medications to Avoid 
CC# pending:  A Phase II Trial to Evaluate Trametinib in Molecular subpopulations 
of patients with advanced non-small cell lung cancer 


Phase II – Trametinib 
Page 84 of 86 
Version date: 02-15-2018 
Protocol CC#: 166521 
 
 
 
 
 
Appendix 6  Specimen Collection  
 
Sampling and shipping information 
 
For the purposes of this study, a whole blood sample is collected by standard 
phlebotomy procedures. Blood should be drawn in the morning prior to drug 
administration. Aliquots of 5-10 ml of venous blood will be drawn from each patient 
using PPT and SST vacutainers and or PAXGene tubes. 
 
1) Two Plasma Preparation (EDTA) Tubes (PPT, 6-10ml) 
2) One Serum Separator Tube (SST, 8.5ml) 
3) In cases in which sequencing to be performed immediately by the Bivona lab, 
one PAXGene tube will be collected for transport 
 
These samples will be used by the clinical coordinator to generate: 
1) 6 x 300 µl of plasma aliquots, frozen at -80o Celsius 
2) 6 x 300 µl of sera aliquots, frozen at -80o Celsius 
3) 4 x 1.5ml whole blood aliquots, frozen at -80o Celsius 
4) Two “Crude Buffy Coat” aliquots 
 
 
Processing of the samples will be carried out using following protocols: 
 
Plasma and Crude Buffy Coat Preparation SOP 
 
● 
Gently inverts the Plasma Preparation Tube 8 -10 times following 
venipuncture 
● 
The sample will be hold at room temperature (RT) until processing. 
Processing should occur within 2 hours of the blood draw. 
● 
The sample will be centrifuged at 1,100 x g for 10 minutes at RT in a 
swing out rotor. 
● 
Plasma aliquots will be transferred from the vacutainer to cryo vials 
● 
Plasma samples will be frozen and archived at -80Co Celsius. 
● 
The “Crude” Buffy Coat is removed with a transfer pipette and two equal 
aliquots are generated in 1.8 ml cryovial. 
● The cryo vials are immediately placed in a –800 Celsius freezer (no 
transfer in slow freezing chamber). 
● The clinical coordinator transfers samples into a Tissue Core–800 Celsius 
freezer for temporary storage, the time when the samples have been 
frozen will be noted. 
 
 
 
 
 


Phase II – Trametinib 
Page 85 of 86 
Version date: 02-15-2018 
Protocol CC#: 166521 
 
 
 
 
 
 
Serum Preparation SOP 
 
● 
Inverts the Serum Preparation Tube 5 times following venipuncture and 
records the blood draw time 
● 
Hold sample at room temperature. Wait for blood to clot 30 - 45 minutes 
after blood collection in order to ensure that proper blood clotting 
occurred. Blood processing should occur within 2 hours of blood draw. 
● 
Centrifuge at 1,100 x g for 10 minutes at room temperature in a swing out 
rotor. 
● 
Serum aliquots will be transferred from the vacutainer to the cryo vials 
using a 200 µl transfer pipette. 
● 
Serum samples will be frozen and archived at -80o Celsius. 
 
Whole Blood Preparation SOP 
● 
The EDTA tube is inverted 5 – 10 times before 4 x 1500 µl aliquots are 
transferred into 1.8 ml cryo vials. 
● 
The vials are immediately placed in a –800 Celsius freezer (no transfer in 
slow freezing chamber). 
 
PaxGene tube Blood Preparation SOP 
● 
The PaxGene tube is inverted 5 – 10 times. 
● 
The tube is stored at room temperature for up to 2 hours. 
 
If not picked up or delivered to the Bivona lab within 2 hours, the tube is temporarily stored at – 
20 Celsius freezer for up to 72 hours 
Sample shipment instructions 
 
For each shipment, an inventory of the samples should accompany the shipment. This inventory 
should include the study ID, subject ID, sample number, visit number scheduled time of collection. 
 
Clearly indicate any missing specimens. The original inventory will be retained at the site in the 
Investigator’s file. 
 
All samples will be kept at the temperature specified up to and during the shipment. Unless 
instructed otherwise, the samples will be packed carefully with suitable packing material and dry 
ice to keep them frozen. 
 
All shipments should be sent (Monday through Wednesday only) by a carrier guaranteeing 
overnight delivery. The following items should be considered: 
 
● 
Advise the carrier of the type of service desired, need for personalized door-to-door 
pickup, and delivery guaranteed within 24 hours. 


Phase II – Trametinib 
Page 86 of 86 
Version date: 02-15-2018 
Protocol CC#: 166521 
 
 
 
● 
Advise the carrier of the nature of the shipment's contents (human biological specimens) 
and label the package accordingly. 
● 
Indicate Novartis drug code and Study No. on the face of the parcel to be shipped. The 
parcel also must carry a "dangerous goods" label because of the dry ice (labels supplied 
by the courier). 
● 
The carrier must be asked to store the parcel(s) in a freezer if shipment is delayed and 
to replace exhausted dry ice before transportation continues. 
 
Instructions for shipment of biological samples 
 
Samples have to be packed according to the ICAO/IATA-Packing-Instructions in an insulated 
box. To guarantee that the samples remain deep frozen during transport, use about 10 kg of 
dry ice per box which will keep the samples frozen during the whole duration of the transport 
(air freight). Send the parcel to the following. 
A shipping log must be included with the shipment. 
Ship to: 
Helen Diller Family Comprehensive Cancer Center 
Tissue Core 
C/O Collin Blakely 
 
 
 
 
Please notify the addressee in advance of the shipment and indicate: 
● 
Number of the airbill 
● 
The time and date of shipping and approximate time of arrival 
● 
To whom the shipment is addressed, the study number, carrier and the shipping form 
number (or equivalent airbill number) 
● 
The sender’s name, telephone number and alternative contact personnel 
● 
The total number of cartons and unit weight of each carton 
Also notify the Clinical Trial Leader 
 when a shipment has been scheduled. 
 
The samples should be sent at the beginning of a week in order to arrive no later than 
Thursday. 

ICF_000.pdf: 
ICF 06-20-2018
CC# 166521
PAGE 1 OF 18
COLLIN BLAKELY, MD, PHD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: Phase II trial to evaluate trametinib in patients with advanced NF1 
mutant non-small cell lung cancer.
This is a clinical trial, a type of research study.  Your study doctor, Collin Blakely, MD, PhD, or 
one of his associates from the University of California, San Francisco (UCSF) Helen Diller 
Family Comprehensive Cancer Center, will explain this study to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your study doctor.
You are being asked to take part in this study because you have been diagnosed with either late 
locally advanced or metastatic (cancer that has spread beyond its original site) non-small cell 
lung cancer (NSCLC) with a mutation in the neurofibromatosis type 1 (NF1) gene, which has 
been confirmed in prior testing. 
Why is this study being done?
The purpose of this study is to test the safety of the study drug trametinib (Mekinist) in patients 
like you, with advanced NF1 mutant NSCLC, and to find out what effects, good and/or bad, 
trametinib has on you and your cancer. The study drug, trametinib, is an investigational drug. 
Investigational means that trametinib has not been approved by the U.S. Food and Drug 
Administration (FDA) for use in lung cancer, including NSCLC. Trametinib is approved by the 
FDA for the treatment of certain patients with advanced melanoma.
Trametinib acts by targeting the MEK protein and disrupting the tumor growth signaling 
pathway called the RAS-MAPK pathway. Previous studies with NF1-mutant NSCLC laboratory 
models suggested that MEK inhibition with Trametinib may cause tumors to shrink. 
The American Cancer Society is providing funding to UCSF for this study.  Novartis, the makers 
of trametinib, is also providing funding to UCSF for this study, and is supplying the study drug 
free of charge.
How many people will take part in this study?
Up to 27 patients will take part in this study across multiple sites, including 15 at UCSF.
What will happen if I take part in this research study?
Everyone who participates in this study will receive the study drug trametinib.
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020
NCT# 03232892


ICF 06-20-2018
CC# 166521
PAGE 2 OF 18
COLLIN BLAKELY, MD, PHD
Before you begin the main part of the study...
If you sign the consent form and agree to participate in the study, you will need to have the 
following exams, tests or procedures to find out if you can be in the main part of the study. Some 
of these exams, tests or procedures are part of routine cancer care and may be done even if you 
do not join the study. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor. 
All procedures must be done within 28 days prior to starting the study drug.
Screening
This visit will take approximately 5-6 hours to complete.
 
Medical history review – You will be asked about your health, any current and past 
illnesses.

Performance status (you will be asked about your general health, how you have been 
feeling, and about how well you can do your regular daily activities).

A full review of all of the medications you are taking, including any prescription or non-
prescription medications such vitamins, herbals, and recreational drugs. This will also 
include a review of all of your prior treatments for cancer.

Full physical examination including vital signs (blood pressure, heart rate, respiratory 
rate, and body temperature) height, and weight. 

Blood (about 1-3 tablespoons) will be drawn for routine tests including: 
o
Routine safety tests
o
Clotting tests
o
Tumor markers
o
Biomarkers - Biomarkers are substances in your tissues that may provide 
information on any changes to your genes or DNA, how your cancer cells are 
responding to study treatment and whether your cells are becoming resistant (no 
longer responding) to the study treatment.

Pregnancy testing – if you are a woman of child bearing potential (either a blood test or a 
urine test, and must be done within 3 days before starting the study drug)

Urinalysis (routine urine test)

ECG (electrocardiogram) in triplicate – an ECG records the electrical activity of your 
heart. 12 wires or “leads” will be attached to your chest with an adhesive and you will be 
asked to lie still while the machine prints out an electrical “record” of your heart activity.  
The ECG will be performed three times in series.  This takes about 45 minutes. 

Echocardiogram (ECHO) or MUGA scan to assess your heart function
o
An ECHO examination uses sound waves to make pictures of your heart, which 
helps determine how well your heart squeezes blood.  You will be asked to lie on 
your left side while a technician places a probe with gel on your chest to create 
images of your heart to determine the function and size.  The procedure is done in 
the cardiology department and will take approximately 45-60 minutes.
o
A MUGA scan is a test that makes a motion picture that shows how well your 
heart pumps blood.  The scan is performed by taking a small sample of your own 
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


ICF 06-20-2018
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COLLIN BLAKELY, MD, PHD
blood that is then “labeled” with a radioactive substance.  The labeled blood 
sample is then re-injected into a vein in your arm and allowed to circulate in your 
body.  Once the labeled blood has circulated around your body, a series of images 
(similar to a movie) are taken of your heart.  You will be asked to lie flat on a 
table and remain still for about 10-20 minutes while the pictures of your heart are 
being taken.  This test is done in the Nuclear Medicine department and takes 
about 90 minutes.

Tumor assessment by CT scan of the thorax, abdomen, pelvis and brain; or MRI 
(Magnetic Resonance Imaging)
o
A CT scan uses special x-ray equipment to make detailed pictures of body tissues 
and organs.  For the CT scan, you may be given a "contrast material" (a special 
dye that makes it easier for doctors to see different tissues in your body).  The 
contrast material may be given orally, intravenously, or rectally (less likely).  Oral 
contrast material is given to you to drink and is used to help outline the stomach 
and intestines.  Intravenous (IV) contrast material is given to you by injecting the 
contrast material into a line which is attached to a needle in your arm, and is used 
to get clearer pictures of your body cavity.  A rectal contrast fills up the loops of 
your lower bowel so the doctors can see your tumor better.  After you have been 
given the contrast material (either by mouth, by vein, or rectum), you will lie flat 
on a table that will move you into the CT scan machine.  You will be asked to lie 
still and may be asked to hold your breath for a few seconds.  The CT scan is 
done in the radiology department and takes about half an hour.
o
An MRI scan takes an image of your head or body to observe the location and 
size of your tumor.  For the MRI scan, you may be given a "contrast material" (a 
special dye that makes it easier for doctors to see different tissues in your body).  
Gadolinium is contrast material that causes some tumors to appear much brighter 
than normal tissue on MRI scans (these tumors may not be visible without 
gadolinium).  The contrast material may be given to you in your arm through an 
intravenous catheter (a tiny tube inserted into a vein).  You will then lie down on 
a narrow bed which will be placed in a tunnel that is 6 feet long by 22 inches wide 
and open at each end.  You will lie there quietly for about one hour, during which 
time you will hear a loud machine-like noise.  The MRI scan is done in the 
radiology department and takes approximately an hour and a half to complete.  

Eye exam - a complete eye exam performed by an ophthalmologist or an experienced 
optometrist (eye doctor).  The eye exam will include checking your eyesight, eyelids, 
eyelashes and surfaces of your eyes.  To make this exam easier, your eye doctor will also 
put drops in your eyes.  Your eye doctor may also measure the amount of tears your eyes 
produce by placing little strips of paper in the corners of your eyes for 3 minutes.  The 
eye exam will take about 45 minutes.

Tissue collection for research will be required at screening, with another two optional 
tissue collections in Cycle 2 and at the end of treatment. Tissue will be sequenced (testing 
the genes) in order to look for changes and differences.  Tissue will also be used for 
biomarker research.  The researchers will grow cancer cells outside of the body for 
further research on response and resistance to treatment.  Please see the section About 
Using Blood and Tissue for Research at the end of this consent form for more 
information.
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


ICF 06-20-2018
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COLLIN BLAKELY, MD, PHD
o
Archival tissue – if there is leftover tissue from a prior biopsy or surgery you have 
had and if you agree, the study team will request this sample for this study.
o
Fresh biopsy – if leftover tissue from a prior biopsy or surgery is not available, the 
study doctor will obtain a small piece of tumor tissue using a special needle. The 
biopsy will only be performed if the study doctor determines it is medically safe. 
 
This procedure will be done at the site where we can most easily get a 
piece of the tumor and the biopsy can involve the lungs, liver, bone, lymph 
node, skin or other. The biopsy needle will be inserted into tumor tissue, 
using a CT to guide the procedure, and a small piece of the tumor will be 
removed. 1-3 passes with this needle will be made. This procedure takes 
about 30 minutes.

If the above procedure cannot be done, another way the biopsy may be 
obtained is via a bronchoscopy. This involves passing a flexible tube 
(bronchoscope) through your mouth or nose and into your airway to 
remove a lung tissue sample. You may be sedated for this procedure. This 
procedure takes about 1 hour.
During the main part of the study...
If the exams, tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will have the procedures listed below.
Study Treatment:
Each cycle of treatment is 28 days.  
You will receive a month’s supply of the study drug at the beginning of each cycle at your clinic 
visit. Trametinib is given by mouth and will be taken once a day.  Trametinib should be taken 
one hour before or two hours after a meal. If you miss a dose of trametinib, you can make it up 
as long as your next dose is at least 12 hours later.  If your next dose is sooner than that, skip the 
missed dose. For your clinic visits on Day 1 of each cycle, you will be asked to take your dose of 
trametinib at clinic.
You will receive a diary with detailed information on how and when you should take trametinib.  
You will record the date, time and the number of pills of each study drug you take each day.  
You must bring your diary to the clinic at each visit for review by the study team. 
If the exams, tests, and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will need the following tests and procedures.
Clinic visits will take about 2 hours but may take up to 5-6 hours if tumor imaging or biopsy is 
done.
Cycle 1, Day 1
This visit will take approximately 5 hours to complete.

Review of side effects you may be experiencing 
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


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COLLIN BLAKELY, MD, PHD

Review of medications that you are taking 

Physical exam including vital signs

Ask how well you can perform the regular activities of daily life

Blood samples (approximately 4 tablespoons) for the following tests:
o
Routine safety testing
o
Clotting tests 
o
Biomarkers 

Blood or urine pregnancy test (if not done in last 3 days)

Urine sample
o
Urinalysis

Your daily dose of trametinib (your study doctor will advise when to take this)

Triplicate ECG
Cycle 1, Days 8 
This visit will take approximately 1 hour to complete.

Review of side effects you may be experiencing 

Review of medications that you are taking 

Ask how well you can perform the regular activities of daily life

Blood sample (approximately 4 tablespoons) for biomarkers
Cycle 1, Days 15
This visit will take approximately 1-3 hours to complete.

Review of side effects you may be experiencing 

Review of medications that you are taking 

Ask how well you can perform the regular activities of daily life

Blood sample (approximately 4 tablespoons) for biomarkers

Eye exam (does not need to be on this day, but must be done before Cycle 2 Day 1).
Cycle 2 and beyond, Day 1
For cycle 2 and beyond, you will only need to attend clinic on the first day of each 28 day cycle. 
These visits will take approximately 5-6 hours to complete.

Review of side effects you may be experiencing 

Review of medications that you are taking 

Physical exam including vital signs

Ask how well you can perform the regular activities of daily life 

Blood samples (approximately 4 tablespoons) for the following tests:
o
Routine safety testing
o
Clotting tests 
o
Biomarkers 

Pregnancy testing – if you are a woman of child bearing potential

Urine sample for:
o
Urinalysis 
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


ICF 06-20-2018
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COLLIN BLAKELY, MD, PHD

Your daily dose of trametinib (your study doctor will advise when to take this)

Triplicate ECG

Cardiac assessment (ECHO or MUGA) – Cycles 2, 5, 8, and then every 3 cycles 
thereafter

CT or MRI scan of your chest, abdomen and pelvis – Cycles 3, 5, 7, and every other 
cycle thereafter

CT or MRI scan of your brain (if there were brain metastases found in screening) – 
Cycles 3, 5, 7, and every other cycle thereafter

Eye exam – to be done prior to Cycle 2, again at 6 months, and then every year thereafter

OPTIONAL tumor biopsy (Cycle 2 only) – to assess response to study drug.
When you are finished receiving study treatment….
End of Treatment Visit
This visit will take approximately 1-3 hours to complete.
Approximately 30 days after the last dose of the study drug, you will return to the study clinic for 
the following assessments:

Review of side effects you may be experiencing 

Review of medications that you are taking 

Physical exam including vital signs

Ask how well you can perform the regular activities of daily life 

Blood samples (approximately 4 tablespoons) for the following tests:
o
Routine safety testing
o
Clotting tests 
o
Biomarkers 

Triplicate ECG

Urine sample for:
o
Urinalysis

CT or MRI scan of your chest, abdomen and pelvis

CT or MRI scan of your brain (if there were brain metastases found in screening)

OPTIONAL tumor biopsy 
Follow Up Visits
These visits will take approximately 2-4 hours to complete.
After your End of Treatment Visit, you will be asked to come into the clinic every 3 months for 
up to 1 year to evaluate your health, any remaining illnesses, and any side effects you may have 
experienced since the administration of the last dose.  The following assessments will be 
performed:

Review of side effects you may be experiencing 

Review of medications that you are taking 

Physical exam including vital signs

Ask how well you can perform the regular activities of daily life 

Blood sample (approximately 4 tablespoons) for the following tests: 
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


ICF 06-20-2018
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COLLIN BLAKELY, MD, PHD
o
Routine safety testing
o
Clotting tests 

Urinalysis 

CT or MRI scan of your chest, abdomen and pelvis (if your disease has not worsened 
since entering the study)

CT or MRI scan of your brain (if there were brain metastases found in screening)
Study location: All study procedures will be done at UCSF Helen Diller Family Comprehensive 
Cancer Center.
How long will I be in the study?
The length of time you are on the study will depend upon how you are feeling, how well you 
tolerate trametinib and whether your disease responds to the study drugs.  You can continue 
receiving the study drug for up to 24 months from study entry, as long as you have no severe side 
effects and your cancer has not gotten worse.  Once you have stopped taking the study drug, you 
will be followed for every 3 months for up to 1 year.  It is estimated that this study will reach 
completion 4 years from the time it opens.
Can I stop being in the study?
Yes. You can decide to stop at any time. If you decide not to participate in the study or to 
withdraw from the study, the quality of your medical care or any benefits to which you are 
otherwise entitled will not be affected.  Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely.  
It is important to tell the study doctor if you are thinking about stopping so any risks from the 
study drug can be evaluated by your doctor. Another reason to tell your doctor that you are 
thinking about stopping is to discuss what follow-up care and testing could be most helpful for 
you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules. 
What side effects or risks can I expect from being in the study?
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. 
Your health care team may give you medicines to help lessen side effects.  Many side effects go 
away soon after you stop taking the study drug.  In some cases, side effects can be serious, long 
lasting, or may never go away. 
There also is a risk of death.
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


ICF 06-20-2018
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COLLIN BLAKELY, MD, PHD
You should talk to your study doctor about any side effects that you experience while taking part 
in the study.
Possible Risks of Trametinib
Common (seen in 10% or more of people)

Diarrhea, nausea

Constipation, heartburn, vomiting

Swelling of the arms and legs 

Tiredness

High blood pressure

Bleeding

Cough

Shortness of breath

Dry mouth

Rash

Dry and/or itchy skin

Hair loss

Chills, fever
Occasional (seen in between 1% and 10% of people)

Skin infection, skin reddening, skin breaks

Anemia (a lack of red blood cells) which may require blood transfusion

Abnormal heartbeat

Blurred vision or other visual disturbances

Dry eyes, swelling and redness of the eyelids

Swelling of one or more limbs (lymphedema)

Pain

Sores in the mouth which may cause difficulty swallowing

Facial swelling

Infection

Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of 
breath, swelling of the face or throat

Change in heart function 

Loss of appetite, dehydration

Dizziness, headache 

Nose bleed

Redness, pain or peeling of palms and soles

Pneumonitis (inflammation of the lung)

Increased levels of the enzyme creatinine phosphokinase in your blood, potentially 
indicating damage to muscle or the heart

Increased levels of certain enzymes in the blood that may indicate liver damage
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020


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COLLIN BLAKELY, MD, PHD
Rare but Serious (seen in less than 1% of people)

Heart failure which may cause shortness of breath, swelling of ankles, and tiredness

Changes in the eyes (blood clot or retinal detachment) which can cause blindness

Scarring of the lungs (interstitial lung disease)

Sudden loss or decrease of kidney function (“acute renal failure”)

Swelling with fluid in abdomen (ascites)

Loss of consciousness (syncope)

Blood clot in lungs (pulmonary embolism)

Intestinal obstruction or perforation, inflammation of the colon
Risks and side effects related to the study procedures
Safe handling risks: Handling the study drug and having contact with urine, feces or vomit from 
patients receiving the study drug may pose some risk to you and your caregivers. To avoid 
exposure to the study drug and any associated risks, you and your family members/caregivers 
will be educated by a member of the study team on how to safely handle the study drug, properly 
dispose of the study drug, and how to clean products that may be contaminated with the study 
drug.
Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort from 
the needle stick, bruising, infection, and fainting.
Electrocardiogram (ECG) risks: The ECG involves placing electrodes on the skin.  You may 
experience an allergic reaction to the adhesive used to attach the electrodes to the skin.  These 
symptoms are generally mild and clear up on their own.  Please let your doctor know if you are 
aware of any allergies.
Eye Exam:  During the eye examination, your pupils will be dilated with eye drops to allow a 
good view of the back of the eye.  This will result in some blurred vision lasting for a few hours.  
You will not be able to drive during this time. Before the test, tell your eye or study doctor if you 
are allergic to dilating or anaesthetic (numbing) eye drops.  In some people, the dilating or 
anaesthetic eye drops can cause brief episodes of nausea, vomiting, dryness of the mouth, 
flushing, and dizziness. In rare cases, severe reactions can occur. If you experience any side 
effects after the examination, tell your study doctor or your eye doctor immediately.
Echocardiogram (ECHO) risks:  The cardiac echogram might cause you to be uncomfortable 
from the pressure of the probe on your chest or lying still for the examination.
MUGA scan risks: The MUGA scan involves exposure to radiation (see above). Like all 
injections it may feel like a small sting and there may be possible bruising at the injection site. 
You may be uncomfortable lying flat.  
Radiation risks: This research study involves exposure to radiation.  Not all this radiation 
exposure is necessary for your medical care and is for research purposes only.  This amount of 
radiation may involve a low risk of cancer.  However, we believe that this risk, given your 
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overall medical condition is not clinically relevant.  If you have any questions regarding the use 
of radiation or the risks involved, please consult your study doctor.
CT scan risks:  CT scans involve the risks of radiation.  In addition, if contrast material (iodine 
dye) is used, there is a slight risk of developing an allergic reaction, from mild (itching, rash) to 
severe (difficulty breathing, shock, or rarely, death).  The contrast material may also cause 
kidney problems, especially if you are dehydrated or have poor kidney function.  The study 
doctors will ask you about any allergies or related conditions before the procedure.  If you have 
any of these problems, you may not be allowed to have a CT scan with contrast.  If you are 
taking metformin (or similar drugs by mouth to treat high blood sugar), such treatment will be 
stopped for 2-3 days around the time a scan is planned in order to avoid kidney side effects.
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time.  If contrast material is used, you may feel discomfort when it is injected by vein.  
You may feel warm and flushed and get a metallic taste in your mouth. Rarely, the contrast 
material may cause nausea, vomiting or a headache.
MRI risks:  Because the MRI machine acts like a large magnet, it could move iron-containing 
objects in the MRI room during your examination, which in the process could possibly harm 
you.  Precautions have been taken to prevent such an event from happening; loose metal objects, 
like pocket knives or key chains, are not allowed in the MRI room.  If you have a piece of metal 
in your body, such as a fragment in your eye, aneurysm clips, ear implants, spinal nerve 
stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have an 
MRI.
Having an MRI may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia and by the loud banging noise during the study.  Temporary 
hearing loss has been reported from this loud noise.  This is why you will be asked to wear ear 
plugs.  At times during the test, you may be asked to not swallow for a while, which can be 
uncomfortable.
Because the risks to a fetus from MRI are unknown, pregnant women must not participate in this 
study. 
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection such as mild 
headache, nausea, and local pain may occur. Rarely (less than 1% of the time) low blood 
pressure and lightheadedness occurs. This can be treated immediately with intravenous fluids. 
Very rarely (less than on in one thousand), patients are allergic to gadolinium. These effects are 
most commonly hives and itchy eyes, but more severe reactions have been seen which result in 
shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. The 
condition is called nephrogenic systemic fibrosis (NSF). It can cause skin to tighten or scar and 
can damage internal organs. Sometimes it can be life-threatening. There are no reports of NSF in 
patients with normal kidney function. Before you have a MRI scan requiring an injection of 
gadolinium contrast, you will have a blood test in order to check the function of your kidneys. 
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Based on your medical history and the results of the test, a doctor will decide whether it is safe 
for you to undergo the MRI scans.
Tumor biopsy risks: The biopsy has small but serious risks.  While we make every effort to 
minimize the pain related to the procedure, the procedure is usually uncomfortable and 
sometimes painful.  Wherever the biopsy is done in your body, it can lead to bleeding in that 
area, damage of organs near where the biopsy is done, or infection.  While it is uncommon, 
sometimes bleeding or pain from the biopsy will require you to stay overnight in the hospital or 
require you to go to the operating room to control any bleeding.  We check your laboratory 
values before the biopsy to make sure that the procedure is as safe as possible and to minimize 
your chance of having a complication. We try to take as little tissue as possible when we do the 
biopsy, and this means that sometimes the biopsy procedure can be unsuccessful and require a 
repeat biopsy to get enough tissue. If sedation is required for the biopsy, this may cause 
hypoventilation (slow or shallow breathing) or hypoxia (decrease of oxygen reaching body 
tissues). Other potential risks will be described to you and discussed with you by doctors who 
conduct these biopsies.
Additional tumor biopsy risks: You may agree to have two additional optional tumor biopsies. 
Having additional tumor biopsies done for research purposes might cause pain, discomfort, 
infection, bleeding and injury to nearby organs.
Lung biopsy risks: A pneumothorax (when air leaks into the space between the lung and chest 
wall, potentially making the lung collapse) may occur. Symptoms include sudden chest pain and 
shortness of breath. Treatment may involve inserting a flexible tube or needle between the ribs to 
remove the excess air. If you have a bronchoscopy, you may also experience a pneumothorax, 
bleeding at the biopsy site, allergic reaction to medicine and hoarseness.
Reproductive risks:  You should not become pregnant or father a baby while on this study 
because the drugs in this study can affect an unborn baby.  If you are a woman and become 
pregnant after receiving the study drug, or are male and your partner becomes pregnant during 
the study, you must notify the study doctor right away. Women should not breastfeed a baby 
while on this study.  It is important to understand that both men and women need to use birth 
control while on this study and for at least 4 months after your last dose of the study drugs.  
Check with your study doctor about what kind of birth control methods to use and how long to 
use them.  Some methods might not be approved for use in this study.
  
Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet.  The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study.
For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope the study 
drug will be more useful against cancer compared to the usual treatment, there is no proof of this.  
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COLLIN BLAKELY, MD, PHD
We do know that the information from this study will help doctors learn more about trametnib as 
a treatment for cancer.  This information could help future cancer patients.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting no treatment

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Please talk to your doctor about your choices before deciding if you will take part in this study.
How will information about me be kept confidential?
Participation in research involves some loss of privacy.  We will do our best to make sure that 
information about you is kept confidential, but we cannot guarantee total privacy.  Some 
information from your medical records will be collected and used for this study.  If you do not 
have a UCSF medical record, one will be created for you.  
Your signed consent form and some of your research tests will be added to your UCSF medical 
record.  Therefore, people involved with your future care and insurance may become aware of 
your participation and of any information added to your medical record as a result of your 
participation.  
Study tests that are performed by research labs, and information gathered directly from you by 
the researchers will be part of your research records but will not be added to your medical record.  
Your personal information may be given out if required by law.  If information from this study is 
published or presented at scientific meetings, your name and other personal information will not 
be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis or analyze your blood or tumor samples include:
 
Novartis and its authorized agents

The University of California

The National Cancer Institute (NCI) and other government agencies, e.g., the Food and 
Drug Administration (FDA), involved in keeping research safe for people.
What are the costs of taking part in this study?
Novartis is supplying trametinib at no cost to you.
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Two types of procedures will be done during this study. Some are part of your standard 
medical care and others are only for research. You or your insurer will be billed for the 
standard medical care. You will be responsible for your co-pays, deductibles, and any other 
charges that your insurer will not pay. There is a possibility that your insurer may not cover all 
standard medical care costs if you are receiving medical services out of network. Any 
procedures done only for research will not be charged to you or your insurer.
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, Collin Blakely, MD, PhD, if you feel that you have 
been injured because of taking part in this study. You can tell the doctor in person or call him  
.
Treatment and Compensation for Injury:  If you are injured as a result of being in this 
study, the University of California will provide necessary medical treatment.  The costs 
of the treatment may be billed to you or your insurer just like any other medical costs, or 
covered by the University of California depending on a number of factors.  The 
University does not normally provide any other form of compensation for injury.  For 
further information about this, you may call the UCSF Institutional Review Board (IRB) 
at 415- 476-1814.  
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor Collin Blakely, MD, PhD, 
.
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the UCSF Institutional Review Board (IRB) at 415-476-1814.  
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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
******************************************************************************
OPTIONAL RESEARCH
Please note: This section of the informed consent form is about additional research studies 
that are being done using left-over or “extra” blood and tumor samples after the main 
research has been completed. You can still be a part of the main study even if you say "no" 
to taking part in any of these additional studies.
You can say "yes" or "no" to each of the following studies. Please mark your choice for 
each study.
About Using Tissue, Blood and Urine for Future Research
To better understand what effect trametinib is having on your cancer, biomarker studies will also 
be conducted as companion research to the main study. Biomarkers are important biological 
‘indicators’ which can be measured from the samples that are collected from you such as blood, 
urine, and tumor tissue.  Biomarker studies are done to look at changes in genes and proteins and 
are important because they help us learn about your cancer in addition to the effect of the drug on 
your body and your cancer. Biomarker studies will be performed on blood and urine samples 
collected. If you agree, any leftover blood, urine and tumor specimens collected during this study 
would also be saved (“banked”) for future research to learn more about cancer and other 
diseases.
You will also be undergoing a tumor biopsy (at screening). The study doctor would like you to 
consider participating in another two optional tumor biopsies at the following time points for the 
biomarker studies:

Cycle 2, Day 1

30 days after your last dose of study drug (at the end of treatment visit).
The research that may be done with tissue is not designed specifically to help you.  It might help 
people who have cancer and other diseases in the future.
Reports about research done with your tissue will not be given to you or your doctor.  These 
reports will not be put in your health record.  The research will not have an effect on your care. 
Results from the future research may be published but your data will not be reported 
individually. 
Things to Think About
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COLLIN BLAKELY, MD, PHD
The choice to let us keep specimens for future research is optional and is up to you. No matter 
what you decide to do, it will not affect your care.
Your specimens will be stored in a repository at UCSF. If you decide now that your specimens 
can be kept for future research, you can change your mind at any time. Just contact the study 
doctor, Collin Blakely, MD, PhD, in writing at the address below, and let us know that you do 
not want us to keep your specimens. 
Collin Blakely, MD, PhD
San Francisco, CA 94143-1705
Any identifiable specimen that remains will no longer be used for research and destroyed. 
However, if any research has already been done using portions of your specimens, the data will 
be kept and analyzed as part of those research studies.
In the future, people who do research may need to know more about your health. While the study 
doctor may give them reports about your health, he will not give them your name, address, phone 
number, or any other information that will let the researchers know who you are.
Your specimen will be used only for research and will not be sold. The research done with your 
tissue may help to develop new products in the future. You will not be paid for allowing your 
tumor samples to be used in research even though the research done with your samples may help 
to develop new products in the future. You will not receive any payment or financial benefit 
from any products, tests, or discoveries derived from these samples.
Benefits
The benefits of research using tissue and blood include learning more about what causes cancer 
and other diseases, how to prevent them, and how to treat them.
Risks
The greatest risk to you is the release of information from your health records.  We will do our 
best to make sure that your personal information will be kept private.  The chance that this 
information will be given to someone else is very small.
Confidentiality: Donating specimens may involve a loss of privacy, but information about you 
will be handled as confidentially as possible. The manager of the tissue bank and select tissue 
bank staff members will have access to information about you but they will not release any 
identifying information about you to researchers using your specimen. The UCSF IRB and other 
University of California personnel also may see information about you to check on the tissue 
bank such as for auditing purposes. 
All records will be coded and permanently kept in password protected electronic files or locked 
files with access limited to the study investigators. All collected specimens will be assigned a 
corresponding code number by the study investigators and will then be processed without 
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knowledge of your identity.  Only the UCSF investigator has access to the records that link this 
coded ID number to you.  In addition, specimens shared with other researchers, and the coded ID 
number will be used to identify your specimens. 
Genetic information about your blood, urine or tumor samples that results from this study does 
not have medical or treatment importance at this time, so you will not receive the results of this 
testing.  However, there is a risk that information about taking part in a genetic study may 
influence insurance companies and/or employers regarding your health. Since some genetic 
variations can help to predict the future health problems of you and your relatives, this 
information might be of interest to employers, health providers, insurance companies, and others. 
Patterns of genetic variation also can be used by law enforcement agencies to identify a person or 
his/her relatives. Therefore, your genetic information potentially could be used in ways that 
could cause you or your family distress, such as by revealing that you (or a relative) carry a 
genetic disease or by leading to the denial of employment or insurance for you (or a relative). To 
further safeguard your privacy, genetic information obtained in this study will not be placed in 
your medical record.
It is also possible that your or your family’s privacy could be invaded in ways that are currently 
not possible but made possible in the future by advances in technology. For instance, some 
scientists performing research with tissue bank materials may try to determine the code of part or 
all of your chromosomes. This coding could be a way to accurately identify the sample as 
coming from you. If a scientist publishes your coding, the source of that coding could be 
identified as you if someone else has your code through other means to compare to the published 
coding. The likelihood of this happening is very small, but future technology developments may 
increase the possibility of this occurring.
Additionally, due to the rarity of the cancer and the likelihood that the research done with the 
tissue samples will be published in the future, it may be possible to identify you from 
publications even though your name will not be used in any published reports.  
Making Your Choice
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Please read each sentence below and think about your choice. After reading each sentence put 
your initials in the "Yes", or "No" box. If you have any questions, please talk to your doctor or 
nurse, or call our research review board at 415-476-1814.
No matter what you decide to do, it will not affect your care.  
1. I agree to the optional tumor biopsy at Cycle 2, Day 1.
YES
NO
2. I agree to the optional tumor biopsy at the end of treatment visit (30 days after the last 
dose of the study drug).
YES
NO
3. Any leftover blood, urine and tissue samples collected for this clinical trial may be kept 
for future research.
YES
NO
******************************************************************************
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CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY.  You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Person Obtaining Consent
Date
Witness – Only required if the participant is a non-English speaker
IRB NUMBER: 17-22236
IRB APPROVAL DATE: 04/09/2019
IRB EXPIRATION DATE: 04/08/2020