A Phase 1b Trial of a Combination of mFOLFIRI With MEK162 in Patients With Advanced RAS (HRAS, NRAS, or KRAS) Positive Metastatic Colorectal Cancers
Phase: PHASE1
Conditions: Advanced KRAS Positive Metastatic Colorectal Cancer
Sponsor: University of Utah

 
Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive 
metastatic colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
 
 
 
 
A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with 
advanced KRAS positive metastatic colorectal cancers 
 
Trial ID: HCI87144/IRB#87144 
 
 
 
Principal Investigator 
Ignacio Garrido-Laguna, MD, PhD 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
Sub-investigator(s) 
 
Glynn W. Gilcrease, MD 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
 
Theresa Werner, MD 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
Paula Hobson, APRN 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
Anne Marceau, APRN 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
Jonathan Whisenant, MD 
Huntsman Cancer Institute and University of Utah 
2000 Circle of Hope 
Salt Lake City, UT 84112 
 
 
Drug Sponsor  
Array BioPharma Inc. 
 
Investigational agent 
MEK162 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 2 of 67 
 
IND Number 
128679 
 
 
 
 
Historical Protocol Versions 
Version 1: 26JAN2016 
Version 2: 19MAY2016 
Version 3: 11NOV2016 
Version 4: 02NOV2017 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 3 of 67 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
Page 
PROTOCOL SIGNATURE PAGE……………………………………………………..9 
STUDY SUMMARY……………………………………………………………………10 
1 
OBJECTIVES ........................................................................................................... 11 
1.1 
Primary Objectives and Endpoints..................................................................... 11 
1.2 
Secondary Objectives and Endpoints................................................................. 11 
1.3 
Exploratory Objectives and Endpoints .............................................................. 11 
2 
BACKGROUND ...................................................................................................... 12 
2.1 
Importance of a pathway-based genomic approach ........................................... 15 
3 
MEK162 DRUG INFORMATION .......................................................................... 18 
3.1 
Non-Clinical Experience .................................................................................... 18 
3.2 
Clinical Experience ............................................................................................ 19 
3.3 
Pharmacokinetics ............................................................................................... 22 
3.4 
Rationale for dose and regimen selection of MEK162 ...................................... 23 
4 
STUDY DESIGN...................................................................................................... 24 
4.1 
Description ......................................................................................................... 24 
4.2 
Dose Limiting Toxicity ...................................................................................... 25 
4.3 
Number of Patients ............................................................................................ 27 
4.4 
Duration ............................................................................................................. 27 
5 
ELIGIBILITY CRITERIA........................................................................................ 29 
5.1 
Inclusion Criteria ............................................................................................... 29 
5.2 
Exclusion Criteria .............................................................................................. 31 
6 
STRATIFICATION FACTORS ............................................................................... 35 
7 
TREATMENT PLAN ............................................................................................... 35 
7.1 
Administration Schedule .................................................................................... 35 
7.2 
MEK162 Treatment ........................................................................................... 35 
7.3 
mFOLFIRI Treatment ........................................................................................ 36 
7.4 
Concomitant Medications .................................................................................. 37 
7.5 
Permitted Concomitant Medications to use with caution .................................. 37 
7.6 
Duration of Therapy ........................................................................................... 39 
8 
TOXICITIES AND DOSAGE MODIFICATION ................................................... 39 
8.1 
Dose Modifications for MEK162 ...................................................................... 39 
8.2 
Dose Modifications for mFOLFIRI ................................................................... 45 
8.3 
Supportive Care ................................................................................................. 46 
9 
STUDY CALENDAR .............................................................................................. 47 
9.1 
Study Procedures: Recommended Safety Assessments during MEK162 
treatment ....................................................................................................................... 49 
10 CITERIA FOR EVALUATION AND ENDPOINT ................................................ 50 
10.1 Safety ................................................................................................................. 50 
10.2 Efficacy .............................................................................................................. 50 
10.3 Stopping Rules ................................................................................................... 51 
11 STATISTICAL CONSIDERATIONS...................................................................... 52 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 4 of 67 
12 REGISTRATION GUIDELINES ............................................................................. 52 
13 DATA SUBMISSION SCHEDULE ........................................................................ 53 
14 SPECIAL INSTRUCTIONS .................................................................................... 53 
14.1 Pharmacokinetic Sample collection ................................................................... 53 
14.2 Correlative Studies ............................................................................................. 54 
15 ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 55 
15.1 Informed consent ............................................................................................... 55 
15.2 Institutional Review ........................................................................................... 55 
15.3 Data and Safety Monitoring Plan ....................................................................... 55 
15.4 Adverse Events / Serious Adverse Events ......................................................... 55 
15.5 SAE Reporting Requirements ............................................................................ 58 
15.6 Protocol Amendments ........................................................................................ 60 
15.7 Protocol Deviations ............................................................................................ 60 
15.8 FDA Annual Reporting ...................................................................................... 60 
15.9 Clinical Trials Data Bank................................................................................... 60 
15.10 Record Keeping ................................................................................................. 61 
16 BIBLIOGRAPHY ..................................................................................................... 62 
17 Appendices ................................................................................................................ 64 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 5 of 67 
LIST OF ABBREVIATIONS 
 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-hCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CK 
Creatine Kinase 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 6 of 67 
Abbreviation or Term1 
Definition/Explanation 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
eg 
Exempli gratia (for example) 
EGFR 
Epithelial Growth Factor Receptor 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 7 of 67 
Abbreviation or Term1 
Definition/Explanation 
LDH 
Lactate dehydrogenase 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
mCRC 
Metastatic colorectal cancer 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Frederichia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 8 of 67 
Abbreviation or Term1 
Definition/Explanation 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of non-childbearing potential 
 
1 All of these abbreviations may or may not be used in protocol.  
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 9 of 67 
PROTOCOL SIGNATURE 
 
 
I confirm that I have read this protocol, and I will conduct the study as outlined herein 
and according to the ethical principles stated in the latest version of the Declaration of 
Helsinki, the applicable ICH guidelines for good clinical practice, and the applicable 
laws and regulations of the federal government.  I will promptly submit the protocol to 
the IRB for review and approval.  Once the protocol has been approved by the IRB, I 
understand that any modifications made during the course of the study must first be 
approved by the IRB prior to implementation except when such modification is made 
to remove an immediate hazard to the subject. 
 
I will provide copies of the protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of this study.  I will discuss this material 
with them to ensure that they are fully informed regarding the study treatment, the 
conduct of the study, and the obligations of confidentiality. 
 
This document is signed electronically through submission and approval by the 
Principal Investigator at Huntsman Cancer Institute in the University of Utah IRB 
Electronic Research Integrity and Compliance Administration (ERICA) system.  For 
this reason, the Principal Investigator at Huntsman Cancer Institute will not have a hand-
written signature on this signature page.  
 
Instructions to multi-site Principal Investigators at locations other than Huntsman 
Cancer Institute: SIGN and DATE this signature page and PRINT your name.  
Return the original, completed and signed, to the HCI Research Compliance Office.  
Retain a copy in the regulatory binder.  
 
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator 
 
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
 
____________________________________ 
Name of Institution 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 10 of 67 
STUDY SUMMARY 
 
Title 
A phase 1b trial of a combination of mFOLFIRI 
with MEK162 in patients with advanced KRAS 
positive metastatic colorectal cancers 
Short Title 
MEK162 plus mFOLFIRI in KRAS positive 
mCRC 
Protocol Number 
IRB # 87144 
IND 
128679 
Phase 
Phase 1b 
Design 
Dose escalation, standard 3+3 design followed by 
dose expansion at the MTD  
Study Duration 
3 1/2 years 
Study Center(s) 
Huntsman Cancer Institute and the Huntsman-
Intermountain Cancer Care Program (HICCP) 
centers 
Objectives 
Primary:  
 To determine the maximum tolerated dose 
(MTD) of MEK162 when given in 
combination with mFOLFIRI 
Secondary: 
 To evaluate response rate  
 To evaluate clinical benefit rate  
 Additional Safety 
Exploratory: 
 To characterize the Pharmacokinetic 
profile of MEK162 in combination with 
mFOLFIRI.  
 To evaluate preliminary antitumor activity 
 To evaluate the tumor dynamics using 
plasma samples as surrogate tissue  
 To assess the sensitivity and specificity of 
the growth factor receptor network 
genomic profiles, including MEK, to 
predict response to mFOLFIRI plus 
MEK162 in mCRC 
 
Number of Subjects 
Dose escalation: up to 18 (3-6 patients per cohort) 
Dose expansion: 12 patients 
 
Diagnosis and Main Eligibility 
Criteria 
Dose escalation: KRAS positive mCRC in both 
irinotecan naïve and irinotecan refractory 
patients. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 11 of 67 
Dose expansion: KRAS positive irinotecan 
refractory patients  
Study Product, Dose, Route, 
Regimen 
MEK162: 30 mg and 45 mg BID PO  
mFOLFIRI: standard doses every 2 weeks (no 
bolus 5-FU or leucovorin) 
Duration of administration 
Until disease progression or unacceptable toxicity 
Statistical Methodology 
Dose escalation: A traditional 3+3 study design to 
investigate the safety of escalating doses of 
MEK162 in combination with mFOLFIRI. 
Dose expansion: 12 patients will be included for 
preliminary assessment of efficacy.  If the 
response rate is at least 20% (3 pts) then there is a 
84% probability of having 3 or more responses if 
the true response rate is 35%.  
1 
OBJECTIVES 
1.1 
Primary Objectives and Endpoints 
Primary Objectives: 
To determine the MTD of the combination of mFOLFIRI and MEK162.  
         Primary Endpoints:  
Incidence of dose-limiting toxicities (DLTs) 
 
1.2 
Secondary Objectives and Endpoints 
 
Secondary Objectives: 
 
To evaluate response rate 
 
To evaluate clinical benefit rate (PR/CR/SD at 4 months) 
 
Additional safety 
 
 Secondary Endpoints: 
 
Changes in size of target lesions according to RECIST 1.1 to assess 
PR/CR 
 
Changes in size of target lesions according to RECIST 1.1 to assess 
PR/CR/SD at 4months 
 
Incidence of adverse events (all grades) 
 
1.3 
Exploratory Objectives and Endpoints 
 
Exploratory Objectives: 
 
To evaluate the pharmacokinetic profile of MEK162 in combination with 
mFOLFIRI. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 12 of 67 
 
To evaluate preliminary anti-tumor activity  
 
To evaluate tumor dynamics using plasma samples as surrogate tissue 
 
To assess the sensitivity and specificity of the growth factor receptor 
network genomic profiles, including MEK, to predict response to 
mFOLFIRI plus MEK162 in mCRC 
 
Exploratory Endpoints: 
 
MEK162 serum time-concentration profile and estimated PK parameters: 
Cmax, Tmax, Tlast, AUC0-tlast, Cl, V and t1/2 
 
Changes in size of target lesions according to RECIST 1.1, 
Carcinoembryonic antigen (CEA) variation over the course of the treatment 
and PFS time from study entrance until patient has deceased or progressed.  
 
Quantification of KRAS from circulating cell free DNA (cfDNA) from 
plasma at baseline, C1D1, C2D1 and at every restaging visit thereafter  
 
Compare genomics-based measurements of pathway activity in responders 
(CR/PR) versus non-responders and patients who progress or do not 
progress using a non-parametric Mann–Whitney U test. 
2 
BACKGROUND 
 
Colorectal cancer (CRC) is the third most common cancer in US.  It is also the second 
leading cause of death by cancer in this country.1  Treatment for patients with unresectable 
metastatic CRC (mCRC) is mainly palliative chemotherapy.  5-fluorouracil or derivatives 
has been the standard treatment for unresectable mCRC for nearly 50 years.2 5-fluorouracil 
led to improvements in response rate without substantial benefit in survival.  In the last 
decade the addition of new cytotoxics (oxaliplatin, irinotecan) and more recently targeted 
therapies such as antiangiogenics (bevacizumab, aflibercept) or monoclonal antibodies 
against epithelial growth factor receptor (cetuximab or panitumumab) has led to a 
statistically significant improvement in survival for these patients.  We will summarize the 
evidence for the treatment of unresectable mCRC in the next lines.  
 
More than 10 years ago, a randomized phase 3 trial in the first line setting showed an 
improvement in progression free survival (PFS) when oxaliplatin was added to infusional 
5FU/LV (9 vs. 6 months, p=0.0003).3  However this benefit in PFS did not result in 
improved overall survival (OS). 
 
At the same time the results of a randomized phase 3 trial in chemo-naïve mCRC 
combining irinotecan with infusional 5-FU were reported.  The addition of irinotecan 
increased both response rate (49 vs. 31%, p < 0.001) as well as time to progression and 
overall survival (17.4 vs. 14 months, p=0.031).4  Similarly, EORTC 40896 also found that 
the addition of irinotecan to 5-FU increased response rate (RR) and PFS although in the 
EORTC trial there was no difference in survival with the addition of irinotecan.5 
 
The next step was to compare the efficacy of oxaliplatin versus irinotecan schedules.  Two 
randomized phase III trials (GOIM9901 and GERCOR) compared infusional 5-

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 13 of 67 
fluorouracil in combination with oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) in the 
first line setting.  There was no difference in RR, PFS or OS.6,7  Therefore either regimen 
was adopted worldwide as the backbone for the treatment of mCRC. 
 
In an effort to improve the survival of patients with mCRC novel targeted therapies have 
been tested in combination with either FOLFOX or FOLFIRI.  Overall, the addition of 
some of these targeted therapies has led to statistically significant improvement in survival 
although often of limited clinical relevance (a few weeks). 
 
Angiogenesis inhibitors have been extensively exploited in this context.  A randomized 
phase III trial showed that adding bevacizumab (a monoclonal antibody against vascular 
endothelial growth factor) to FOLFOX in the first-line setting increased PFS by 5 weeks 
(9.4 vs. 8 months, p=0.0023) although no difference was noted in median overall survival.8 
In the second line setting ECOG 3200 showed an 8-week improvement in survival when 
bevacizumab was added to FOLFOX (12.9 vs. 10.8 months, p=0.001).  More recently the 
TML study showed that maintenance of bevacizumab beyond progression led to 
statistically significant improvement in survival (11.2 vs. 9.8 months, p=0.0062).9  
Although the hazard ratio in this trial indicated a 20% reduction in the risk of death in the 
experimental arm, this only translated to an absolute gain in survival of around 5 weeks.  
 
The addition of bevacizumab to irinotecan based schedules has also lead to improvements 
in survival.  Indeed that largest benefit in survival with bevacizumab was evidenced in a 
randomized phase III trial which tested a suboptimal chemotherapy schedule, bolus 5FU 
plus irinotecan (IFL), in combination with bevacizumab.10  Survival in the experimental 
arm was improved by 5 months.  Overall, a recent retrospective SEER review evidenced 
an improvement in OS when bevacizumab was added to irinotecan regimens.  A benefit in 
OS was not found with oxaliplatin-based regimens.11  Similar findings have been evidenced 
with novel monoclonal antibodies against VEGF such as aflibercept.  A randomized phase 
3 trial in the second line setting in patients with mCRC also evidenced a 6-week 
improvement in median survival when aflibercept was added to FOLFIRI (13.5 vs. 12.1, 
HR 0.81, p=0.0032).12   
 
A different strategy consisting of blocking the epithelial growth factor receptor (EGFR) 
using different monoclonal antibodies (mAb) have also been evaluated in several clinical 
trials.  The CRYSTAL trial was a randomized phase 3 trial that tested cetuximab in 
combination with FOLFIRI in patients with mCRC in the first line setting.  A posthoc 
subgroup analysis in KRAS wild-type patients showed a 3 months increase in median 
survival in the experimental arm (23.5 vs. 20 months, HR 0.696, p=0.0012).  However this 
survival advantage could not be extrapolated to schedules with FOLFOX.  In this regard, 
two randomized trials failed to show any survival benefit with the addition of cetuximab 
to FOLFOX in the first line even for KRAS wild-type patients.  Median survival for KRAS-
wt patients in the experimental versus control arm in MRC COIN was 17.9 vs. 17 months 
(HR 1.04, p=0.67).13  Similarly, a posthoc analysis of KRAS-wt patients included in the 
OPUS trial found no improvement in survival after adding cetuximab to FOLFOX (22.8 
vs. 18.5, HR 0.85, p=0.39).14  It remains unknown why the efficacy of cetuximab is in part 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 14 of 67 
related to the chemotherapy backbone used.  This is further complicated by the fact that a 
different EGFR mAb (panitumumab) seems to be synergistic with both FOLFOX and 
FOLFIRI.  A randomized phase 3 trial in the first line tested the benefit of adding 
panitumumab to FOLFOX (PRIME study).  The trial included a prospective analysis by 
KRAS status.  The experimental arm showed a statistically significant improvement in PFS 
and a trend to increased survival (23.9 vs. 19.7 months, HR 0.83, p=0.07).  Similarly, a 
randomized phase 3 study in the second line setting found that in the KRAS-wt subset, the 
addition of panitumumab to FOLFIRI resulted in a 2 months increase in PFS (5.9 vs. 3.9 
months, HR 0.73, p=0.004) with a non-significant trend to increased OS (14.5 vs. 12.5, HR 
0.85, p=0.12).  In this trial, the response rate in patients with KRAS-mutant treated with 
FOLFIRI in the second line setting was 15%.15 
 
The next step was to combine chemotherapy with simultaneous inhibition of VEGF and 
EGFR.  Several randomized trials, including PACCE and CAIRO trial, tested this strategy.  
Surprisingly dual inhibition not only failed to improve outcome but was indeed 
detrimental.16, 17 
 
According to the evidence presented above, first line therapy for unresectable mCRC most 
often include infusional 5-fluorouracil in combination with oxaliplatin (FOLFOX) or 
irinotecan (FOLFIRI) plus a monoclonal antibody against vascular endothelial growth 
factor (VEGF) or epithelial growth factor receptor (EGFR).  In the US FOLFOX is often 
the preferred first line treatment option due to a better toxicity profile including absence of 
alopecia.  FOLFIRI is therefore most commonly used in the second line setting in US.  
 
The RAS/RAF/MEK/ERK pathway plays a major role in cell growth and survival.  The RAS 
oncogenes are the most frequently mutated class of oncogenes in human cancers.18  This 
family of oncogenes includes: KRAS, NRAS and HRAS.  KRAS is mutated in 40% of 
patients with colorectal cancer.  KRAS is considered undruggable therefore efforts at 
silencing the pathway have focused at actionable mutations downstream KRAS such as 
BRAF, MEK or ERK.  MEK mutations have been found in 2% of CRC (Sanger, COSMIC). 
 
MEK inhibitors have shown activity in RAS activated preclinical models.  Abrogation of 
MEK led to tumor growth inhibition in cell line derived colorectal cancer xenografts (HT-
29, COLO205, LoVo and CRC13B02).19,20  MEK162 also showed dose and time-
dependent inhibition of phosphorylation of ERK in HT-29 colorectal xenografts.  
(Unpublished data from MEK162 IB).  Preclinical evidence suggests that the combination 
of cytotoxics (irinotecan) and MEK inhibition (AZD6244) is indeed synergistic in 
colorectal cancer cell lines (HCT-116).  Indeed recent clinical evidence suggests that this 
combination may be also synergistic in patients (Hochster et al ASCO 2013 abst. 3587).  
This early dose finding study tested irinotecan in combination with AZD6244 in the second 
line setting in patients with KRAS or BRAF positive mCRC.  The RR was 10% and median 
PFS was 3.4 months.  These figures compare favorably with historical controls when 
FOLFIRI was used in the second line after progression to FOLFOX and suggest that this 
strategy should be further explored.7  
  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 15 of 67 
A recent phase 1 trial tested the safety of FOLFIRI in combination with a different MEK 
inhibitor (pimasertib) as second line treatment in KRAS mutant mCRC.  Unfortunately 
effective doses of pimasertib could not be reached due to toxicity.21 
 
The schedule of administration of MEK inhibitors is critical for the efficacy of the 
treatment when they are given in combination with cytotoxics.  The MAPK pathway plays 
a key role in cell-cycle progression.  Pathway inhibitors could decrease cell population in 
S-phase and potentially antagonize the activity of cytotoxics that are S-phase specific such 
as irinotecan or 5-fluorouracil.  Indeed in vivo data from patient derived xenografts from 
biliary cancers have shown that gemcitabine activity is increased with a sequential schedule 
of AZD6244 (MEK inhibitor).  In this work AZD6244 was given after gemcitabine 
administration and held 48h prior to next dose of gemcitabine.  MEK inhibition led to cell-
cycle arrest and this could decrease tumor repopulation following chemotherapy 
administration.  On the other hand, holding pathway inhibitor for 48 hours prior to the 
administration of gemcitabine allowed reentry into S-phase which likely explains higher 
tumor growth inhibition seen with this schedule.22  Accordingly, patients in this protocol 
will hold MEK162 for 48h prior to the administration of mFOLFIRI.  
 
Here we propose a dose finding study with the combination of mFOLFIRI + MEK162 in 
patients with KRAS positive mCRC.  mFOLFIRI (irinotecan and 5-fluorouracil continuous 
infusion without 5-fluorouracil bolus and leucovorin) was chosen over FOLFIRI per our 
standard local practice of dropping the 5-FU bolus when using FOLFOX or FOLFIRI in 
the palliative care setting. This is based on the observation that removal of the 5-FU bolus 
does not decrease the efficacy of the treatment but reduces the risk of hematologic toxicities 
(as shown in the OPTIMOX1 study27 where FOLFOX-7 without 5-FU bolus was found to 
be equivalent to FOLFOX-4).  The study will include a lead in period of MEK162 single 
agent for 6 days to evaluate early changes in tumor dynamics by cfDNA.  During the dose 
escalation phase we will evaluate toxicity and MTD of the combination in irinotecan naïve 
and irinotecan-refractory mCRC patients.  During the dose expansion phase, we will plan 
to enroll approximately 12 patients with irinotecan-refractory mCRC.  
 
We hypothesize that MEK162 + mFOLFIRI can be given safely in patients with KRAS 
positive advanced colorectal cancer, and that adding a MEK inhibitor improves the activity 
of mFOLFIRI. 
 
The correlative studies in the dose expansion cohort will include assessment of KRAS 
mutations in circulating free DNA (cfDNA) at baseline, C1D1, C2D1 and at each restaging 
visit thereafter.  We will evaluate tumor dynamics by changes in plasma cfDNA and 
correlate with changes in CEA as well as target lesions by RECIST 1.1 
2.1 
Importance of a pathway-based genomic approach 
 
Understanding the aberrant signaling events that occur in a patient’s tumor is an important 
challenge facing researchers attempting to predict drug sensitivity.  While linking single 
mutations to drug sensitivity has been successful in some settings, in practice drug response 
and genetic aberrations do not necessarily follow a linear pattern due to complex pathway 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 16 of 67 
interactions.  As an example, subsets of lung cancer patients without EGFR mutations still 
respond to drugs that target this pathway, perhaps due to alternative mechanisms of 
pathway activation.  Additionally, KRAS mutations confer resistance to EGFR targeted 
therapy in colon cancer, and approximately one-third of breast cancer patients with 
amplified HER2 do not respond to trastuzumab in part due to deregulation of downstream 
or parallel pathway components such as PTEN or PI3K.  These findings highlight the 
importance of simultaneous and comprehensive mapping of pathway activity and crosstalk 
of GFRN to predict tumor responses to targeted therapies.  
 
Our previous work has used oncogenic signature profiles to predict pathway activity and 
drug sensitivity.  Briefly, we generate these genomic pathway signatures by expressing an 
active protein in a quiescent normal human epithelial cell, thereby specifically isolating the 
subsequent events as defined by the activation/deregulation of that single pathway.  We are 
currently extending this approach to profile more than one pathway at a time so that we 
can study pathway crosstalk and interaction.  We capture the acute downstream 
consequences of gene deregulation by isolating RNA directly after pathway activation and 
performing gene expression analysis.  We are using RNA to measure the acute 
transcriptional activation of genes following a pathway’s activation, as the alteration of 
transcription integrates signaling pathway activation and generation of new molecular 
species (mRNA and miRNA) that is dynamic and transient in nature but readily evaluated.  
To build a signature, we isolate the specific genes deregulated by the induction of a 
particular pathway component and together use these genes to model pathway status in 
human tumors.  As an example, if a human tumor has a pathway specific gene expression 
pattern that correlates more with the quiescent control gene pattern, this tumor is predicted 
to have low pathway activity, and vice-versa.  By identifying genes whose transcriptional 
deregulation best reflects a pathway’s activation, we can more accurately model that 
pathway’s status in a human tumor.  
 
Our approach can accurately measure a pathway’s activation status in individual tumors.  
Strikingly, we have previously published the ability of our PI3K genomic signature to 
predict smokers at high-risk for lung cancer, and those who have dysplastic lesions that 
respond to a PI3K inhibitor, myoinositol [Ref 2 in comments].23  Additionally, other studies 
highlight the ability of our RAS and SRC signatures to predict RAS mutation or SRC 
pathway deregulation status, respectively, in tumors as well as response to drugs that target 
these pathways.24  Further, this approach has been able to identify subsets of more 
aggressive tumors that have unique patterns of pathway deregulation, highlighting the 
clinical relevance of our pathway profiles.23-26  Thus, these studies show a significant 
relationship between pathway predictions in human tumors and drug sensitivity, and are 
the basis for our correlative genomic studies in this trial. 
 
Our genomic biomarkers focus on the core GFR pathway components currently targeted 
in many cancers, including the GFR receptors EGFR, HER2, IGFR and their downstream 
partners PI3K, AKT, MEK, RAS, and PLC-.  We will use our multi-pathway genomic 
biomarkers to map GFR-MEK signaling in colon cancer, and characterize tumors that are 
MEK-pathway “active” and “inactive”.  To model pathway activity in tumors, we will use 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 17 of 67 
a Bayesian factor analysis approach to pathway modeling, which uses the pathway 
signatures and correlation structure as prior information to inform the factor analysis as to 
the underlying pathway structure in the patient samples.  This approach also enables us to 
effectively predict multi-pathway status using discrete ‘omic’ data types, such as gene 
expression and mutation data.  These models will be correlated to drug responsiveness to 
test whether “active” tumors are more likely to respond to the MEK inhibitor/mFOLFIRI 
treatment than “inactive” tumors, using the methods described below. 
 
Briefly, in order to model GFR/MEK network activity for gene expression profiles, we 
generate pathway signatures by expressing an active protein in quiescent normal human 
primary epithelial cells, thereby isolating the specific events as defined by the 
activation/deregulation of that single pathway.  We capture the acute downstream 
consequences of gene deregulation by isolating RNA after pathway activation and 
performing gene expression analysis.  These pathway signatures often contain a subset of 
genes known to be relevant for a particular pathway’s activation—but importantly also 
involve many genes not previously discovered.  As tumor tissue amounts are often limiting, 
this approach enables us to examine pathway activity or many signaling networks 
concurrently, and more comprehensively than measurement of a single protein or gene.  In 
this study we will use established gene expression signatures of key signaling pathways in 
the growth factor receptor network, such as EGFR and MEK, to study how these signaling 
network’s activity correlates to drug treatment in patients.  
 
Following isolation of RNA from patient biopsies in this trial, we will perform RNA-
sequencing to generate expression data.  High-throughput sequencing will be performed 
using an Illumina HiSEQ instrument as previously described.  We will multiplex 4 samples 
per lane to generate approximately 30-50 million ~100bp single-end reads per sample.  
Image analysis and base quality scoring will be performed using the Genomic Analyzer 
Pipeline.  We will map reads to the reference human genome assembly using the Burrows-
Wheeler Aligner69, and process data using TPM. 
 
Following data processing, gene-level data is filtered to exclude probesets with signals 
present at background noise levels, and for probesets that do not vary significantly across 
samples.  A binary probit regression model is then estimated using Bayesian methods to 
select genes that best distinguish the quiescent and pathway-activated states.  When this 
model is then applied to an individual patient tumor sample, the expression of the selected 
geneset for each tumor sample is summarized as a single value, called the metagene score, 
which corresponds to the value from the first principal component as determined by a 
singular-value decomposition.  The metagene score is scaled to range from 0: “no pathway 
activity”; to 1 “full pathway activity”.  This metagene score, which is the output of the 
pathway signature, gives a measure of the activation of that pathway in that individual 
sample. 
 
In order to assess the relationship between pathway prediction and response to drug in 
patients, we will compare the metagene scores from each patient to their response as 
determined by RECIST 1.1 criteria.  Specifically, we will obtain the correlation between 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 18 of 67 
predicted and actual response rate.  As our previous signatures for drugs have exceeded 
0.5, we are expecting a correlation of 0.5 or higher in this study. 
3 
MEK162 DRUG INFORMATION 
 
MEK162, previously named ARRY 438162, is a potent and selective allosteric, ATP non-
competitive inhibitor of MEK1/2 that is active in inhibiting pERK and growth of BRAF 
mutant cancer cells in the low nanomolar range.  MEK162 is currently being investigated 
as a single agent and in combination with paclitaxel, PI3K or RAF or IGF-1R inhibitors in 
patients with selected advanced or metastatic solid tumors, including melanoma, biliary, 
colorectal, and ovarian cancers.  MEK162 is also being investigated in Noonan syndrome 
in patients with hypertrophic cardiomyopathy, based on the role of the 
RAS/RAF/MEK/ERK pathway in cardiomyocyte growth and presence of mutations in the 
MAPK pathway in this disease. 
 
Four phase I/Ib studies exploring MEK162 in combination with RAF and PI3K inhibitors 
in patients with advanced RAS/RAF and PIK3CA mutated tumors are ongoing.  
 
The dose of 45 mg BID is considered safe and efficacious and is the dose used in an 
ongoing Phase 2 study in cancer patients.  The maximum tolerated dose (MTD) of 
MEK162 is 60 mg BID. 
3.1 
Non-Clinical Experience 
 
The biological activity of MEK162 has been evaluated in vitro (both enzymatic and cell 
culture assays) and in vivo in mouse xenograft studies.  MEK162 potently inhibits MEK1/2 
in both biochemical assays using purified protein, and in cells.  MEK162 has demonstrated 
robust, but selective, growth inhibitory activity in a wide variety of cancer cell lines.  In a 
collection of ~500 genetically annotated cell lines, MEK162 showed anti-proliferative 
activity preferentially in cells harboring activating mutations of the MAP kinase pathway 
(e.g. BRAF, NRAS and KRAS), and in particular, activating mutations in BRAF and 
NRAS.  In vivo, MEK162 has demonstrated dose dependent tumor growth inhibition in 
various subcutaneous tumor transplants harboring BRAF V600E mutations (HT29, 
COLO205, A-375) as well as activating mutations in both NRAS (Hs. 944T) and KRAS 
(MiaPaCa2, A549, LoVo, Calu6).  These data suggest that MEK162 may provide a 
potential therapeutic benefit in cancer indications harboring these mutations, including 
melanoma. 
Nonclinical in vitro and in vivo data indicate that MEK162 is metabolized mainly by 
glucuronidation pathways (mainly via UDP-glucuronosyl transferase [UGT]1A1, 1A3 and 
1A9) and to a lesser extent by oxidation pathways (mainly via cytochrome P450 [CYP] 
1A2 and 2C19).  UGT1A1 was shown to be the major contributor (90%) to the formation 
of the direct glucuronide in human liver microsomes.  UGT1A3 and UGT1A9 contributed 
3% and 7%, respectively, to the glucuronidation activity.  MEK162 is a reversible inhibitor 
of CYP2B6 (inhibition constant [Ki] ~ 1.67 μM) and a weak inhibitor of CYP1A2 and 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 19 of 67 
CYP2C9 in vitro.  MEK162 is not considered an in vitro time-dependent inhibitor of 
CYP1A2, CYP2C9, CYP2D6 or CYP3A4/5. 
 
Acute, subchronic, chronic and reproductive toxicity, genotoxicity and phototoxicity 
studies were completed to support the chronic administration of MEK162 to adult cancer 
patients.  The toxic effects of MEK inhibitors in humans are similar to the toxic effects 
observed in monkeys.  The toxic effects include gastro-intestinal intolerance and diarrhea, 
rash, central serous retinopathy (only seen in humans) and retinal vein occlusion (rarely 
seen in humans).  In vitro and in vivo phototoxicity studies conducted in mice indicate that 
MEK162 has a very low risk of weak phototoxic potential at therapeutic doses.  
Furthermore, there has been no evidence of phototoxicity or photosensitivity in humans 
being treated with MEK162 for cancer or for rheumatoid arthritis.  This includes 686 
patients and healthy volunteers who have received at least one dose of MEK162 and is 
based on data as of January 7, 2013.  Given the embryo-lethal effects seen in rats and 
rabbits and the teratogenic effects seen in rabbits, MEK162 should not be used in pregnant 
women.  Women of child-bearing potential must be advised to use highly effective 
contraception methods. 
3.2 
Clinical Experience 
 
As of 07-January-2015, a total of 2430 healthy subjects and patients have been enrolled in 
MEK162 studies and 1945 of whom received at least one dose of MEK162, and have been 
evaluated for safety, including 204 healthy subjects, 6 liver dysfunction patients, 164 
patients with rheumatoid arthritis and 1571 patients with advanced cancer.  The study 
[CMEK162Y2201-NCT01556568] is an open label, phase II, single-agent study to assess 
safety, tolerability, pharmacokinetics and pharmacodynamics of MEK162 in Noonan 
syndrome patients with hypertrophic cardiomyopathy opened in February-2012.  This 
study has been voluntarily delayed pending more comprehensive evaluation of AEs 
observed in other studies with MEK162, as detailed in this IB.  As of 07-January-2015, 
two patients have been screened, but no patient has been treated with MEK162. 
 
The experience of MEK162 in healthy subjects includes 204 subjects in 10 phase I clinical 
studies.  Nine of these 10 studies are completed and 1 study [CMEK162A2104-
NCT02050815] (hepatic impairment) is ongoing.  
 
The experience of MEK162 in patients with advanced cancer either as a single agent or in 
combination with targeted or standard chemotherapy agents includes 20 clinical studies. 
 
As of the data-cutoff MEK162 experience as a single agent in 705 cancer patients includes 
6 studies.  [ARRAY-162-111-NCT00959127]: phase I, dose-escalation study in patients 
with advanced solid tumors followed by expansion cohorts in patients with advanced or 
metastatic biliary cancer or KRAS- or BRAF-mutant metastatic colorectal cancer (CCR). 
[CMEK162X2201-NCT01556568]: phase II study in patients with locally advanced and 
unresectable or 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 20 of 67 
metastatic malignant cutaneous melanoma, harboring BRAFV600 or NRAS mutations.  
[CMEK162X1101-NCT01469130]: phase I, dose escalation study in Japanese patients 
with advanced 
solid tumors with the expansion part in patients whose tumors harbor RAS or BRAF 
mutations.  [CMEK162A2301-NCT01763167]: phase III, two-arm, randomized study in 
patients with advanced unresectable or metastatic NRAS Q61 mutation-positive 
melanoma.[ARRAY-162-311-NCT01849874]: phase III, two-arm, randomized study in 
patients with recurrent or 
persistent low-grade serous carcinomas of the ovary, fallopian tube or primary peritoneum.  
[CMEK162AUS11-NCT01885195]: phase II study in patients with RAS/RAF/MEK 
activated tumors.  MEK162 as a single agent at 45 mg BID has been explored in two phase 
I studies [ARRAY-162-111-NCT00959127], [CMEK162X1101], conducted in patients 
with advanced solid tumors, advanced or metastatic biliary cancer and KRAS- or BRAF-
mutant metastatic colorectal cancer (CRC) and in Japanese patients with advanced solid 
tumors, respectively; in two phase II studies [CMEK162X2201-NCT01320085], 
[CMEK162AUS11-NCT01885195], conducted in BRAFV600 or NRAS-mutant 
melanoma patients and advanced solid tumors, respectively; and two phase III studies 
[CMEK162A2301-NCT01763164], [ARRAY-162-311-NCT01849874] in patients with 
NRAS-mutant melanoma and low-grade serous carcinomas of the ovary, fallopian tube or 
primary peritoneum, respectively.  The two phase I studies ([ARRAY-162-111-
NCT00959127], [CMEK162X1101-NCT01469130]) are completed.  The study [ARRAY-
162-111-NCT00959127] was a phase I, open-label, dose-escalation of oral MEK162 in 
patients with advanced solid tumors followed by expansion cohorts in patients with 
advanced or metastatic biliary cancer or KRAS- or BRAF-mutant metastatic CRC.  A total 
of 93 patients received at least 1 dose of MEK162.  Four dose levels were evaluated: 30 
mg BID, 45 mg BID, 60 mg BID and 80 mg BID.  Two of 4 patients receiving 80 mg BID 
experienced dose limiting toxicities (DLTs), thus the 80 mg BID dose was declared non-
tolerable.  Seven patients were enrolled at 60 mg BID and no DLTs were observed, 
therefore, 60 mg BID was declared the MTD.  Following completion of the Dose-escalation 
Phase, a total of 74 patients were enrolled in the Expansion Phase.  The dose of 45 mg BID 
was determined as the recommended phase II dose (RP2D) mainly due to the frequency of 
ocular AEs in patients at the 60 mg dose level.  The study [CMEK162X1101-
NCT01469130] is an ongoing, phase I, open label, dose escalation study of MEK162 in 
Japanese patients with advanced solid tumors with an expansion part in patients whose 
tumors harbor RAS or BRAF mutations.  A total of 21 patients received at least 1 dose of 
MEK162: 6 patients received 30 mg BID and 15 patients received 45 mg BID.  Eighteen 
patients (as of 10-February-2014) were discontinued from the study and 3 patients were 
still ongoing.  Two patients in the 45 mg BID dose level cohort (dose escalation part) 
reported 2 DLTs, both were recurrent Grade 2 detachment of retinal pigment epithelium.  
Therefore, 45 mg BID was declared the MTD in Japanese patients.  No DLT was reported 
in patients enrolled in the expansion part.  The most frequently reported AEs suspected to 
be related to MEK162, regardless of grade and MEK162 dose were dermatological events 
(rash, dermatitis acneiform), gastrointestinal (GI) events (nausea, vomiting, diarrhea), 
edema peripheral, fatigue and CPK increased.  The majority of these AEs were Grade 1 or 
2 with less than 5% of cases Grade 3 or 4, with the exception of elevation of blood CPK, 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 21 of 67 
reported as 24% (44/183 patients) Grade 3 or 4 in [CMEK162X2201-NCT01320085] and 
17.2% (10/58 patients) in dose escalation and 16.6% (11/66 patients) in dose expansion 
[CMEK162X1101-NCT01469130] studies.   
 
MEK162 in combinations: 
MEK162 experience in combination with others agents include 866 patients in 13 studies: 
Five studies with RAF inhibitors encorafenib or RAF265: 
[CMEK162X2102-NCT01352273]: phase II study of sequential, single-agent encorafenib 
followed by a rational combination with targeted agents (including MEK162) after 
progression, to 
overcome resistance in adult patients with locally advanced or metastatic BRAFV600 
melanoma.  [CMEK162X2110-NCT01543698]: phase Ib dose finding, dose escalation 
study of MEK162 in combination with encorafenib, in selected advanced solid tumors.  
[CLGX818X2102-NCT01820364]: phase II study of MEK162 in combination with 
encorafenib in patients with locally advanced or metastatic BRAFV600 mutant melanoma.  
[CMEK162B2301-NCT01909453]: phase III, randomized, 2-part study in patients with 
BRAFV600- mutant locally advanced unresectable or metastatic melanoma.  
[CLGX818X2109-NCT02159066]: phase II, open-label study of encorafenib and 
MEK162, followed by a rational combination with targeted agents after progression on 
encorafenib and MEK162, to overcome resistance in adult patients with locally advanced 
or metastatic BRAF V600 melanoma. 
Three studies with PI3KC/AKT pathway inhibitors BEZ235 (pan-PI3K/mTOR) buparlisib 
(pan-PI3K) or BYL719 (PI3Kα) [CMEK162X2103-NCT01337765], [CMEK162X2101-
NCT01363232] and [CMEK162X2109-NCT01449058]: all three are phase Ib, dose 
escalation and expansion studies in selected advanced solid tumors.  One study with PKC-
selective inhibitor sotrastaurin [CMEK162X2203-NCT01801358]: phase Ib/II study in 
patients with metastatic uveal melanoma. 
One study with CDK4/6 inhibitor LEE011.  [CMEK162X2114-NCT01781572]: phase 
Ib/II study, in patients with NRAS mutant melanoma.  One study with IGF-1R monoclonal 
inhibitor ganitumab.  [CMEK162X2111-NCT01562899]: phase Ib/II dose-escalation and 
expansion study in patients with selected advanced solid tumors.  One study with EGFR 
inhibitor panitumumab [CMEK162X2116-NCT01927341]: phase Ib/II, dose-escalation 
study in patients with mutant RAS or wild-type RAS metastatic CRC.  One study with 
standard chemotherapy agent paclitaxel [ARRAY-162-112-NCT01649336] phase Ib, 
dose-escalation and expansion study in women with platinum-resistant or refractory 
epithelial ovarian, fallopian tube or primary peritoneal cancer.  The target RP2D of 
MEK162 for combination studies with targeted agents is 45 mg BID.  In combination with 
paclitaxel, two dosing schedules of MEK162 plus weekly paclitaxel 80 mg/m2 were 
evaluated in the ongoing [ARRAY-162-112-NCT01649336] study: a continuous dose 
schedule, in which MEK162 was administered at 30 or 45 mg BID continuously and an 
intermittent dose schedule, in which MEK162 was administered at 45 mg BID on Days 1-
5 of each week for 3 weeks out of 4.  On the continuous dose schedule, the RP2D was 
declared as MEK162 30 mg BID with weekly paclitaxel and on the intermittent dose 
schedule, the RP2D was confirmed as MEK162 45 mg BID with weekly paclitaxel.  
Currently one phase III study of MEK162 at 45 mg BID is being conducted in patients with 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 22 of 67 
unresectable or metastatic BRAFV600-mutant melanoma in combination with encorafenib 
[CMEK162B2301-NCT01909453].  The exposure of MEK162 when combined with 
encorafenib described by Cmax and AUC has the same ranges of values founded in the 
single agent studies.  In the phase Ib study [CMEK162X2102-NCT01352273], Sponsor 
concluded that the safety available data of the combination of MEK162 with RAF265 no 
longer supported the enrollment of additional patients into the study.  The enrollment was 
closed on 17-September-2012 and the study was terminated (study information provided 
in Section 5.2). 
Overall, the frequently reported AEs suspected to be related to MEK162 in combination 
studies were found to be similar to those found in single-agent studies, which include GI 
events (diarrhea, nausea, vomiting), dermatological events (dermatitis acneiform, rash) 
CPK elevation and retinal events, described in (Section 5.2.3). 
The percentage of patients that discontinued study drug due to AEs regardless of 
relationship to MEK162 ranged from 2.6% [CMEK162X2203-NCT01801358] to 36% 
[CMEK162X2101-NCT01363232].  A total of 52 DLTs were observed in the dose-
escalation part of combination studies, as following: 10 DLTs in [CMEK162X2102-
NCT01352273], 
6 
DLTs 
in 
[CMEK162X2110-NCT01543698], 
7 
DLTs 
in 
[CMEK162X2111-NCT01562899], 6 DLTs in [CMEK162X2103-NCT01337765], 
13DLTs in [CMEK162X2101-NCT01363232] and 10 DLTs in [CMEK162X2201-
NCT01320085] study.  Of these 52 DLTs, 13 were reported in the [CMEK162X2101-
NCT01363232] study combining MEK162 with the PI3K inhibitor buparlisib.  The most 
frequents DLTs reported were gastrointestinal events, followed by ocular and 
dermatological events.  A total of 128 deaths were reported during the study or within 30 
days of last dose of study drug in cancer patients, either in single-agent or combination 
studies (45 and 46 respectively).  The most frequent cause of treatment discontinuation was 
disease progression and other events not related to study drug.  Based on the experience 
from the 13 completed phase I studies (9 in healthy subjects , 3 in cancer patients, 1 in 
rheumatoid arthritis patients) and 1 completed phase II study (in rheumatoid arthritis 
patients), MEK162 has demonstrated an acceptable and manageable safety profile with the 
majority of AEs Grades 1 or 2 of intensity and reversible.  In order to appropriately describe 
the incidence of clinically notable AEs (CNAEs)/AEs of special interest observed in 
patients receiving MEK162, when applicable, terms were pooled into combined categories 
(regardless of the assessment on relationship with study drug) such as gastrointestinal 
events, ocular events, cardiac events, dermatological events, liver events, muscular events, 
edema events, hemorrhage events, thrombotic and embolic events, hypertension events, 
pneumonitis events, and fatigue/asthenia events.  These categories will be described for 
each study and the pooled data in Section 5.2.3.  See Appendix 1 for CNAE/AEs of special 
interest groupings and the constituent preferred terms.  For further information regarding 
clinical experience with MEK162, refer to the Investigator’s Brochure. 
3.3 
Pharmacokinetics 
Pre-clinical studies in mice support that >50% inhibition in pERK in HT-29 tumors for 24 
hours is optimal for significant tumor growth inhibition.  This degree of sustained pERK 
inhibition was best achieved with BID dosing at lower doses (< 10 mg/kg/dose) or QD 
dosing at higher doses (> 30 mg/kg/dose).  Given that little to no drug was apparent in 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 23 of 67 
plasma at 24 hours post-dose (at low doses) in the pre-clinical xenograft studies, a BID 
dosing regimen was considered to be the most reliable murine schedule to maintain plasma 
concentrations for optimal efficacy.  Therefore, a BID dosing regimen of (i.e., 45 mg) 
should provide sufficient exposure with acceptable safety and adequate continuous 
pharmacological inhibition of the primary target. 
The PK of MEK162 is characterized by moderate to high variability, approximate dose 
proportionality and 1.5-fold accumulation at steady state (~15 days).  The median t1/2 
ranged from ~ 4 – 13 hours across human studies (patient and healthy volunteer). 
A human ADME study showed the primary metabolic pathways include glucuronidation 
(up to 61.2% via UGT1A1), N-dealkylation, amide hydrolysis (up to 17.8% via CYP1A1 
and CYP2C19).  In urine, 6.5% of the radioactive dose was excreted as unchanged 
MEK162.  
 
Food-effect clinical studies have shown the influence of food on PK of MEK162 is mild 
and not clinically relevant; therefore, MEK162 can be taken without regard to food.  A 
drug interaction study with MEK162 and midazolam was conducted; the results suggest 
that continuous intake of MEK162 produces no relevant CYP3A4 induction.  In vitro 
studies also demonstrated that MEK162 is a P-gp and BCRP substrate, but the effects of 
inhibitors of these substrates on the PK of MEK162 in vivo is unknown.  The impact of 
UGT1A1 inhibitors or inducers has not been clinically assessed.  In the cases where the 
extent of a drug interaction is unknown, it is recommended to co-administer drugs with 
caution. 
For further information refer to the current MEK162 Investigator’s Brochure. 
3.4 
Rationale for dose and regimen selection of MEK162 
 
The 45 mg BID dose of MEK162 was selected as the recommended phase II dose based 
on safety, antitumor activity and pharmacodynamics considerations.  
 
A Phase I study of MEK162 in patients with advanced or metastatic solid tumors is ongoing 
(ARRAY-162-111).  Enrollment of the dose-escalation phase is completed and the 
maximum tolerated dose (MTD) of MEK162 has been identified as 60 mg twice daily 
(BID).  Enrollment of an expansion cohort in patients with advanced or metastatic biliary 
cancer has also been completed and an additional expansion cohort in patients with KRAS- 
and BRAF-mutated metastatic colorectal cancer is currently ongoing.  After enrollment of 
6 patients at 60 mg BID the starting dose of MEK in the colorectal cancer cohort was 
reduced to 45 mg BID due to the frequency of reversible visual/retinal events observed at 
the 60 mg BID dose level.  The 45 mg dose was generally well tolerated.  Additionally, in 
CMEK162X2201 single agent study, the 60 mg dose was also explored in a cohort of 25 
patients.  Two patients presented unexpected suspected SAEs (one case of acute liver 
failure with a fatal outcome and another case of decreased ejection fraction, heart failure, 
myocarditis, and tachycardia) that led to Investigator Notification letters and provided 
further support for the selection of 45 mg as the recommended phase II dose.  
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 24 of 67 
It is assumed a BID dosing regimen should provide sufficient exposure and adequate 
continuous pharmacological inhibition of the primary target. 
 
The 45 mg dose was generally well tolerated.  The most frequently reported AEs in patients 
treated at 45 mg BID were dermatitis acneiform (44%) peripheral edema (36%), diarrhea 
(33%) and CPK increase (27%).  The incidence of visual events at the recommended dose 
was 20%, most of them grade 1-2. 
 
Importantly, MEK162 showed consistent antitumor activity in patients with NRAS or 
BRAF mutations.  The CMEK162X2201 study reported a response rate of 23% in both 
cohorts and a PFS of 3.65 months and 3.58 months, in NRAS and BRAF mutant patients, 
respectively. 
 
Healthy volunteers have previously received a single dose of MEK162 up to 80 mg.  
Treatment-related adverse events were reported in 20% of subjects who received MEK162, 
compared with 80% who received placebo.  All events were classified as mild symptoms 
in intensity.  In the multiple dose study, healthy volunteers received up to 60 mg QD or 20 
mg BID MEK162 for 14 days.  Adverse events were reported in 97% of subjects who 
received MEK162, compared to 75% who received placebo.  All events were mild or 
moderate in intensity.  
4 
STUDY DESIGN 
4.1 Description 
 
This is a Phase 1b, open label, dose-finding study to determine the Maximum Tolerated 
Dose (MTD) of MEK162 in combination with mFOLFIRI, and to evaluate the response 
rate, clinical benefit rate and additional safety parameters of the treatment combination:   
 
Dose Escalation Phase:   
 
Prior to starting the combination MEK162 and mFOLFIRI treatment, all patients will 
undergo a 6-day lead in period with single agent MEK162.  Patients will then have 2-days 
off MEK162 prior to beginning the combination therapy.   
 
MEK162 will be given on days 1-12 of a 14 day cycle PO in combination with mFOLFIRI 
given every 2 weeks to evaluate the incidence of toxicities and determine the MTD in 
patients with KRAS positive mCRC.   
 
The standard 3+3 design will be used for the dose escalation phase.  Patients will be accrued 
to each dose level as shown in Table 4.1 in cohorts of up to 3-6 patients.  Escalation will 
continue to a second dose level, or until a dose limiting toxicity (DLT) is observed.  This 
study will test 30 mg BID or 45 mg BID dose levels of MEK162 in combination with 
mFOLFIRI.  
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 25 of 67 
Initially 3 patients will be enrolled at dose level 1.  If 2/3 patients at dose level 1 experience 
a dose limiting toxicity (DLT) during the first two cycles of combined treatment, then the 
next 3 patients will be enrolled at dose level -1.  If 1/3 patients at dose level 1 experiences 
a DLT, three more patients will be added.  If 2/6 patients at dose level 1 experience a DLT, 
then dose level -1 will be used for the next 3 patients.  If 0/3 or 1/6 patients at dose level 1 
complete two cycles of the study combination experience a DLT, the study will proceed to 
enroll 3 patients at dose level 2.  If ≤ 1/6 patients at the highest dose level experience a  
DLT, then the dose expansion portion will be open for enrollment.  If ≥ 2/6 patients 
experience a DLT at the highest dose level, then the dose expansion portion will be open 
and patients will be treated at the next lower dose level.  At least 6 patients must be treated 
at the MTD before proceeding to the dose expansion phase.   
 
 
Table 4.1 
 
Dose Level 
Treatment 
MEK Dose 
 -1 
mFOLFIRI at 80% + MEK162 
30 mg BID 1 week on 1 week off * 
 1  
mFOLFIRI + MEK162 
30 mg BID  
 2 
mFOLFIRI + MEK162 
45 mg BID  
 
* 30 mg BID dosing for one week starting after FOLFIRI administration on day 1 
of a cycle followed by one week of dose hold.  
 
Dose expansion phase: 
 
After determination of the MTD, an additional 12 patients will be enrolled in the study at 
that dose to accumulate additional information about response rate, clinical benefit rate and 
drug safety.   
 
Patients will be treated with the dose of MEK162 as determined in the dose escalation 
phase.  The schedule will be identical to the dose escalation phase schedule, including the 
MEK162 lead-in which will allow evaluation of early changes in tumor dynamics by 
cfDNA as well correlation with tumor response by imaging or CEA at 8 weeks.  Patients 
with KRAS positive mCRC will be evaluated for response.  Patients must complete the first 
set of scans at cycle 4 to be considered evaluable for response. After the response 
evaluation period, patients are allowed to continue on MEK162 in combination with 
mFOLFIRI for as long as the patient receives clinical benefit.  Patients will be removed 
from treatment for disease progression, unacceptable toxicities, patient withdrawal, death 
or if deemed appropriate by the investigator. 
4.2 Dose Limiting Toxicity  
Toxicity will be assessed using the NCI CTCAE, version 4.03 unless otherwise specified.  
A DLT is defined as an AE or abnormal laboratory value (assessed as possibly, probably 
or definitely related to the study medication)  which occurs ≤ 28 days following the first 
dose of mFOLFIRI + MEK162 (or 2 cycles of therapy, each cycle = 14 days), and meets 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 26 of 67 
any of the criteria listed in Table 4.2.1.  The DLT assessment will begin at Cycle 1 Day 1 
at the beginning of the combination treatment and after the 6 day lead in period with 
MEK162.  Patients who experience unacceptable toxicities during the 6 day lead-in period 
will be taken off study, considered non-evaluable for DLT and will be replaced.  If a patient 
experiences toxicity that fulfills the criteria for a DLT during the DLT observation window 
(cycle 1 day 1 through cycle 3 day 1, treatment with the study drug will be interrupted and 
the toxicity will be followed up.  Patients will be allowed to remain on study if the DLT is 
resolved within 4 weeks at the discretion of the investigator.  Patients will continue on 
study at the next lowest dose level.  If treatment is reduced during the DLT period, or is 
held for > 2 weeks for any reason, this will be considered a DLT. 
 
Table 4.2.1 
 
TOXICITY  
DLT CRITERIA 
Hematology 
CTCAE grade 4 neutropenia lasting more than 7 consecutive  
days  
CTCAE grade 4 thrombocytopenia  
CTCAE Grade 3 or 4 neutropenia with fever (temperature ≥ 
38.5°C)  
Skin and subcutaneous 
tissue disorders 
 
Rash, hand-foot skin reaction or photosensitivity CTCAE 
Grade 3 lasting more than 14 consecutive days despite 
maximal skin toxicity treatment (as per local practice) 
Rash, hand-foot skin reaction or photosensitivity CTCAE 
Grade 4 
Eye disorders 
Retinal events CTCAE Grade 2 lasting more than14 
consecutive days confirmed by ophthalmologic examination 
Retinal events CTCAE Grade ≥ 3, confirmed by 
ophthalmologic examination 
Gastro-intestinal 
CTCAE grade ≥ 3 nausea or vomiting lasting more than or 
equal to 48 hrs despite optimal anti-emetic therapy 
CTCAE grade ≥ 3 diarrhea lasting more than or equal to 48 
hrs despite optimal anti-diarrhea treatment 
Hepato-biliary 
CTCAE grade ≥ 3 total bilirubin  
CTCAE grade ≥ 3 ALT (isolated increases in AST without 
concomitant increases in ALT will not be considered dose-
limiting, because of the non-specific nature of AST) 
Serum alkaline phosphatase CTCAE Grade 4 lasting more 
than 7 consecutive days 
Respiratory 
CTCAE grade ≥ 2 interstitial lung disease and pneumonitis 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 27 of 67 
ECG QTc Interval 
QTc interval ≥ 501 ms on at least two separate consecutive 
ECGs taken 5 min apart 
Renal 
Serum creatinine > 2x ULN 
Cardiac disorders 
Absolute decrease of LVEF >10% compared to Baseline and 
the LVEF is below the LLN 
Symptomatic left ventricular systolic dysfunction grade ≥ 3 
Other cardiac disorders Grade ≥ 3 
Non-hematologic 
events 
Any non-hematological CTCAE grade ≥ 3, except for the 
exclusions noted below 
Exceptions to DLT 
criteria 
CTCAE grade 3 fatigue lasting fewer than 5 days 
CTCAE grade 3 edema lasting fewer than 5 days 
Grade 3 laboratory abnormalities that are responsive to oral 
supplementation or deemed by the investigator to be  not 
clinically significant 
CTCAE version 4.03 will be used for all grading.  
Optimal therapy for vomiting or diarrhea will be based on institutional guidelines, with 
consideration of the prohibited medications listed in this protocol. 
 
4.3 Number of Patients 
 
During the dose escalation phase, a minimum of 9 patients and up to 18 patients total are 
anticipated to be treated.  At least 6 patients must be treated at the MTD level before 
proceeding to the dose expansion phase.  
 
During dose expansion phase, up to 12 additional irinotecan-refractory patients will be 
treated at the MTD.   
4.3.1 Number of Study Centers 
 
 
The study will be conducted primarily at the Huntsman Cancer Institute at the University 
of Utah but may also enroll patients through the Huntsman-Intermountain Cancer Care 
Program (HICCP) for the dose expansion portion of the study. 
 
4.4 Duration  
 
Study patients may remain on treatment with mFOLFIRI in combination with MEK162 
until confirmed RECIST 1.1 disease progression, or as long as they are receiving clinical 
benefit and have not experienced intolerable toxicities at the discretion of the 
investigator.  After a response but with intolerable toxicity from mFOLFIRI patients will 
be allowed to continue on MEK162 alone if deemed appropriate by the investigator.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 28 of 67 
The estimated duration for accrual in the dose escalation phase is anticipated to be 12 
months.  Accrual for the dose expansion phase is anticipated to take 12 months.  
Estimated duration of total accrual and patient participation is approximately three and a 
half years.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 29 of 67 
5 
ELIGIBILITY CRITERIA 
 
This eligibility checklist is used to determine patient eligibility and filed with 
signature in the patient research chart.  
  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 _____ Age > 18 years old 
5.1.2 _____ Patients with histologically confirmed KRAS positive metastatic 
colorectal cancer.  
5.1.3 _____Patients must have progressed during or after first-line treatment 
for metastatic disease with oxaliplatin and fluoropyrimidines based 
chemotherapy (with failure within six months) or not be a candidate for 
oxaliplatin (i.e. neuropathy). 
5.1.4 _____ ECOG Performance Status 0-1 
5.1.5 _____ Able to provide informed consent and willing to sign an 
approved consent form that conforms to federal and institutional 
guidelines. 
5.1.6 _____ Women of childbearing potential must have a negative blood 
pregnancy test at the screening visit 
5.1.7 _____ Adequate bone marrow, organ function and laboratory 
parameters as defined by the following: 
 
 
Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 
 
Hemoglobin (Hgb) ≥ 9 g/dL without transfusions, 
 
Platelets (PLT) ≥ 75 x 109/L without transfusions, 
 
AST or ALT ≤ 2.5 × upper limit of normal (ULN); patient with 
liver metastases ≤ 5 ×ULN, 
 
Total bilirubin ≤ 1.5 × ULN and <2mg/dl, 
Note: Patients who have a total bilirubin level >1.5 × ULN will 
be allowed if their indirect bilirubin level is ≤1.5 × ULN 
 
Creatinine ≤ 1.5 mg/dL × ULN, or calculated creatinine 
clearance (determined as per Cockcroft-Gault)  
5.1.8 _____ Adequate cardiac function as defined by the following: 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 30 of 67 
 
Left  ventricular ejection fraction (LVEF) ≥ 50% as determined 
by a multigated acquisition (MUGA) scan or echocardiogram, 
 
QTc interval ≤ 480 ms (preferably the mean from triplicate 
ECG’s) 
 
5.1.9 _____ Must have recovered from adverse effects of any prior surgery, 
radiotherapy or other antineoplastic therapy.  CTCAE adverse events 
less than or equal to grade 1 are acceptable.  CTCAE adverse events 
grade 2 or greater may be acceptable as determined by the Principal 
Investigator 
5.1.10 _____ Willingness and ability to comply with all study procedures and 
able to take oral medications 
 
 
Dose Expansion Phase Additional Inclusion Criteria 
5.1.11 _____Patients must be willing and able to undergo biopsy 
according to the institute’s own guidelines and requirements 
for such procedures 
5.1.12 _____ Patients must have measurable disease as defined by RECIST 
v1.1 (at least one lesion ≥ 10mm in at least one dimension when 
assessed by CT or MRI, or a cutaneous lesion with clearly defined 
margins that measures ≥ 10 mm in at least one dimension) 
5.1.13 _____Patients must be irinotecan refractory.  Patients must have 
progressed on prior irinotecan therapy but must be able to tolerate 
standard irinotecan doses.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 31 of 67 
5.2 Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 _____  
UGT1A1 *28 homozygous patients  
5.2.2 _____ Previous treatment with any MEK inhibitor 
5.2.3 _____ Treatment with systemic antineoplastic therapy (including 
unconjugated therapeutic antibodies and toxin immunoconjugates) or 
any investigational therapy within 4 weeks (< 6 weeks for nitrosurea or 
mitomycin-C, antibodies except for trastuzumab) or within 5 half-lives 
of the investigational therapy prior to starting study treatment,  
whichever is longer 
5.2.4 _____ Patient received radiotherapy within 2 weeks prior to the first 
dose of study treatment except localized radiation therapy for 
symptomatic bone metastasis. 
5.2.5 ______ Have had a diagnosis of another malignancy, unless the patient   
has been disease-free for at least 3 years following the completion of 
curative intent therapy, with the following exceptions: 
     Patients with treated non-melanoma skin cancer, in situ 
carcinoma, or cervical intraepithelial neoplasia, 
regardless of the disease-free duration, are eligible for 
this study if definitive treatment for the condition has 
been completed. 
     Patients with organ-confined prostate cancer with no 
evidence of recurrent or progressive disease based on 
prostate-specific antigen (PSA) values are also eligible 
for this study if hormonal therapy has been initiated or 
a radical prostatectomy has been performed. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 32 of 67 
5.2.6 _____ History or current evidence of retinal vein occlusion (RVO) or 
current risk factors for RVO (e.g. uncontrolled glaucoma or ocular 
hypertension, history of hyperviscosity or hypercoagulability 
syndromes. 
5.2.7 _____ Personal history of Gilbert’s syndrome. 
5.2.8 _____ Uncontrolled arterial hypertension defined by blood pressure > 
140 (systolic) or100 (diastolic) mm Hg at rest (average 3 consecutive 
readings at least 5 minutes apart) despite appropriate medical therapy. 
5.2.9 _____ Impaired cardiovascular function or clinically significant 
cardiovascular diseases, including any of the following: 
     History of acute coronary syndromes (including myocardial 
infarction, unstable angina, coronary artery bypass grafting, 
coronary angioplasty, or stenting) < 6 months prior to 
screening, 
     Symptomatic chronic heart failure; evidence of clinically 
significant 
cardiac 
arrhythmias 
and/or 
conduction 
abnormalities < 6 months prior to screening except atrial 
fibrillation and paroxysmal supraventricular tachycardia. 
5.2.10 _____ Known positive serology for HIV, active Hepatitis B, and/or 
active Hepatitis C infection (Note: if not suspected, testing is not 
required at baseline). 
5.2.11 _____ Patients who have neuromuscular disorders that are associated 
with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, 
amyotrophic lateral sclerosis, spinal muscular atrophy). 
5.2.12 _____ Patients who are planning on embarking on a new strenuous 
exercise regimen after first dose of study treatment.  Muscular 
activities, such as strenuous exercise, that can result in significant 
increases in plasma CK levels should be avoided while on MEK162 
treatment. 
5.2.13 _____ Impairment of gastrointestinal function or gastrointestinal 
disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, or small bowel resection that under 
the judgment of the PI may impair absorption of study drugs). 
5.2.14 _____ Any other condition that would, in the Investigator’s judgment, 
contraindicate the patient’s participation in the clinical study due to 
safety concerns or compliance with clinical study procedures, e.g., 
infection/inflammation, intestinal obstruction, unable to swallow 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 33 of 67 
medication.(patients may not receive drug through a feeding tube), 
social/ psychological issues, etc. 
5.2.15 _____ Patients who have undergone major surgery ≤ 3 weeks prior to 
starting study drug or who have not recovered from side effects of such 
procedure. 
5.2.16 _____ Pregnant or nursing (lactating) women, where pregnancy 
is defined as the state of a female after conception and until the 
termination of gestation, confirmed by a positive β-hCG 
laboratory test. 
5.2.17 _____ Women of child-bearing potential, defined as all women 
physiologically capable of becoming pregnant, unless they are using 
highly effective methods of contraception throughout the study and for 
15 days after study drug discontinuation.  Highly effective 
contraception methods include:  
 Total abstinence 
 Female sterilization-bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least 6 weeks before starting 
study treatment.  In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by 
follow up hormone level assessment is she considered not of 
child bearing potential. 
 Male sterilization of subject partner- vasectomy at least 6 
months prior to screening. 
 Combination of any two of the following (a+b or a+c or b+c): 
a. Use of oral, injected, or implanted hormonal methods of 
contraception. 
b. Placement of an intrauterine device (IUD) or intrauterine 
system (IUS). 
c. Barrier methods of contraception: condom or occlusive cap 
(diaphragm or cervical/vault caps) with spermicidal 
.foam/gel/film/cream/vaginal suppository 
 
Women are considered post-menopausal and not of child 
bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or 6 
months of spontaneous amenorrhea with serum FSH levels > 
40 mIU/mL [for US only: and estradiol < 20 pg/mL]. 
5.2.18 _____ Sexually active males unless they use a condom during 
intercourse while taking the drug and for 15 days after stopping 
treatment and should not father a child in this period.  A condom is 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 34 of 67 
required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. 
5.2.19 _____ Medical, psychiatric, cognitive or other conditions that may 
compromise the patient's ability to understand the patient information, 
give informed consent, comply with the study protocol or complete the 
study. 
 
I certify that this patient meets all inclusion and exclusion criteria for enrollment 
onto this study.  
 
______________________________ 
_________ 
_______ 
Investigator Signature  
 
 
Date 
 
Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 35 of 67 
6 
STRATIFICATION FACTORS 
 
Does not apply. 
7 
TREATMENT PLAN 
7.1 Administration Schedule 
 
mFOLFIRI Treatment 
 
mFOLFIRI treatment will be carried out in accordance with standard of care guidelines 
with omission of the 5-fluorouracil bolus (400 mg/m2 slow IV push over 5 minutes on day 
1) and leucovorin (400 mg/m2 IV over 2 hours on day 1).  Doses are based on screening or 
cycle 1 day 1 Body Surface Area (BSA) determined from actual body weight.  Doses will 
be recalculated for > 10% weight loss.  Dose may be recalculated for > 10% weight gain 
at the investigator’s discretion.   
 
Irinotecan 180 mg/m2 IV over 90 minutes on day 1. 
 
5-fluorouracil 1200 mg/m2 continuous infusion for 48 hours (2400 mg/m2 in 48 hours). 
 
MEK162 Treatment 
 
MEK162 doses will be 30 mg or 45 mg BID PO daily starting on day 1.  When in 
combination with mFOLFIRI (on day 1 of each cycle), MEK162 will be taken AFTER 
irinotecan infusion.  MEK162 will be taken BID PO daily on days 1 through 12.  MEK162 
should be held for 48 hours prior to the next dose of mFOLFIRI on days 13 and 14 .  If a 
cycle lengthened or shortened in accordance with the protocol-specified windows, 
MEK162 should be held for 48 hours prior to the next dose of mFOLFIRI 
Prior to beginning the combination, all patients will receive MEK162 single agent 6 day 
lead in.  The subject will discontinue MEK162 for 2 days prior to receiving the MEK162 
mFOLFIRI combination on C1D1. 
7.2 
MEK162 Treatment  
7.2.1 How Supplied, Stored, Packaged and Labeled 
 
MEK162 will be provided by Array as film-coated tablets for oral use of 
dosage strength 15 mg.  The study drug will be administered as a flat-
fixed dose, and not by body weight or body surface area. 
 
Upon receipt, MEK162 will be stored at the Huntsman Cancer Institute 
Investigational Pharmacy.  MEK162 will be stored according to the 
instructions specified on the drug labels.  Study medication will be 
provided by Array by an authorized person at the investigator’s site.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 36 of 67 
7.2.2 Preparation and Administration 
Patients will be provided with adequate supply of MEK162 for self-
administration at home until at least their next scheduled study visit.   
 
MEK162 will be administered with water, irrespective of food.  Prescribed 
BID doses should be taken 12 ± 2 hours apart.  
Complete dosing instructions will be provided to study patients and will 
include the minimum times between doses and instructions for missed 
doses.  Patients will also be instructed not to crush MEK162 tablets.  
Patients should not take extra doses of MEK162 to compensate for doses 
missed for AEs or any other reason.  If a patient vomits at any time after 
dosing, the dose of MEK162 should not be re-administered 
7.2.3 Accountability and Compliance  
Clinical drug supply must be accounted for and patients will be asked to 
return all unused study drug and packaging on a regular basis, at the end 
of the study or at the time of study drug discontinuation. 
Patients will be asked to complete and return a pill calendar each cycle 
to verify drug compliance. 
At the conclusion of the study, and, as appropriate during the course of 
the study, the Investigator will return all used and unused study drug, 
packaging, drug labels, and a copy of the completed drug accountability 
ledger to Array.  
 
 
7.3 
mFOLFIRI Treatment 
7.3.1 How Supplied, Stored, Packaged and Labeled 
 
Agents contained in the mFOLFIRI regimen are commercially 
available and approved by the United States FDA and other regulatory 
agencies for use in treating patients with multiple types of cancer. 
 
5-Fluorouracil and irinotecan will be supplied by the study site and 
billed to patients and/or their third-party payer (insurance, a healthcare 
provider, or applicable government program).  5-Fluorouracil and 
irinotecan should be stored, handled, and labeled per institutional 
guidelines. 
7.3.2 Preparation and Administration 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 37 of 67 
5-Fluorouracil and irinotecan should be prepared and administered per 
institutional guidelines. 
7.3.3 Accountability and Compliance 
Accountability and compliance should be handled per institutional 
policies for commercially available medications.   
7.4 
Concomitant Medications 
 
In general, the use of any concomitant medication/therapies deemed necessary 
for the care of the patient is permitted.  Refer to section 7.5 for permitted 
concomitant medications to be used with caution.  Medications required to treat 
AEs, manage cancer symptoms, concurrent stable diseases and supportive care 
agents, such as PRBCs, pain medications, anti-emetics, short courses of 
steroids, and anti-diarrheals are allowed.  Oral contraceptive pills are 
permitted.  
 
Patients taking concomitant medication chronically should be maintained on 
the same dose and dose schedule throughout the study period, as medically 
feasible.  
 
The investigator should instruct the patient to notify the study site about any 
new medications including vitamins, supplements and herbal supplements 
he/she takes after the start of the study drug and significant non-drug therapies 
(including physical therapy and blood transfusions) administered after the 
patient starts treatment with study drug must be noted. 
 
Palliative radiation therapy for a single site of bone or brain metastasis is 
allowed on the study as long as these are the only site of disease progression.  
The radiation field must not affect any of the target lesions designated for 
disease assessment.  Protocol treatment (MEK and mFOLFIRI) will be held 
during radiation therapy and will be re-started 2 weeks following the 
conclusion of therapy.  
7.5 
Permitted Concomitant Medications to use with caution 
 MEK162 has been identified to be primarily metabolized by UGT1A1.  It is 
advised that inhibitors and inducers of UGT1A1 should be taken with caution 
when co-administered with MEK162.  Patients should be closely monitored for 
the occurrence of AEs.  Please refer to Table below for a list of these known 
drugs; however, this list may not be exhaustive. 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 38 of 67 
List of inhibitors/inducers of UGT1A1 to be used with caution 
Inhibitors of UGT1A1  
atazanavir, erlotinib, flunitrazepam, gemfibrozil, 
indinavir, ketoconazole, nilotinib, pazopanib, 
propofol, regorafenib, sorafenib  
Inducers of UGT1A1  
carbamazepine, nicotine, rifampicin, testosterone 
propionate  
Abbreviations: UGT1A1 = UDP-glucuronosyl transferase 1A1  
 
 In vitro data showed that MEK162 is a substrate of P-gP and BCRP and thus 
the use of drugs that are known to inhibit these transporters should be used 
with caution.  Please refer to Table below for a list of these drugs. 
 
List of inhibitors of human transporters to be used with caution 
Transporters  
Category 
Substrate 
P-gP 
Calcium Channel Blockers 
felopidine, verapamil, diltiazem, mibefradil, nifedipine, 
nitrendipine 
 
Protease inhibitors 
indinavir, ritonavir, lopinavir, telaprevir, saquinavir, 
nelfinavir 
Antibiotics 
Fexofenadine, clarithromycin, azithromycin, 
erythromycin, rifampin 
Antiarrhythmics 
quinidne, dronedarone, amiodarone 
Adrenergic Antagonist 
carvedilol, talinolol 
Herbal Medications 
Schisandra chinensis, St. John’s wort, milk thistle 
(silybum marianum), ginkgo biloba 
Others 
valspodar (PSC 833), elacridar (GF120918), ranolazine, 
fluvoxamine, itraconazole, querceptin, captopril, 
conivaptan, paroxetine, ticagrelor, telmisartan, tolvaptan 
BCRP 
Others 
elacridar (GF120918) 
* This table was compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” and from the 
University of Washington’s Drug Interaction Database. 
For further information, please see the FDA’s website: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm08
1177.htm#PgpTransport 
 MEK162 potently inhibits CYP2B6 (IC50 ~ 6 µM).  Based on these in vitro findings, 
MEK162 may inhibit the metabolic clearance of co-medications metabolized by 
CYP2B6, if sufficiently high concentrations are achieved in vivo.  Caution should 
be used in patients receiving concomitant treatment with other drugs that are 
substrates of this enzyme. 
 CYP3A4 induction by MEK162 has been clinically evaluated and co-administration 
should not impact the exposure of MEK162 with CYP3A4 substrates.  
CYP3A5 and 7 and CYP2B6 substrates to be used with caution 
 
The following therapies should be used with caution unless otherwise specified: 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 39 of 67 
 Strong inducers or inhibitors of CYP3A4 (Refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/)  
 Substrates of CYP3A4 with narrow therapeutic windows (Refer to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/) 
 Medications that carry a strong risk for QT prolongation  
 Grapefruit, grapefruit juice, and Seville orange juice 
 Concurrent anti-neoplastic therapy other than those antineoplastic treatments 
specified as a part of this protocol are prohibited 
 Drugs with a known, a conditional or a possible risk to induce Torsade de Pointes (TdP) 
should be used with caution.  Patients receiving such medications must be carefully 
monitored for potentiating of toxicity due to any individual concomitant medication, 
and may require dose titration of the drug substance.  For further information, please 
visit the website of the QTdrugs.org Advisory Board of the Arizona CERT. 
7.6 
Duration of Therapy 
 
Patients will continue treatment until there is any of the following: 
1. Evidence of disease progression, unless receiving clinical benefit as 
determined by the investigator 
2. Unacceptable toxicities and/or SAEs that under the investigator judgment 
warrants treatment discontinuation 
3. Patient withdraws from participation on the study 
8 
TOXICITIES AND DOSAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse 
Events) Version 4.03 for adverse event and serious adverse event reporting.  A copy of 
the 
CTCAE 
Version 
4.03 
can 
be 
downloaded: 
(http://safetyprofiler-
ctep.nci.nih.gov/CTC/CTC.aspx). 
8.1 
Dose Modifications for MEK162 
For patients who do not tolerate MEK162, dose adjustments are permitted as 
described in the table below in order to allow the patient to continue on study 
drug in both the escalation and expansion phases of the trial.  Two dose 
reductions are permitted from dose level 2 according to the table below.  If 
patients at dose level 1 need a dose reduction an intermittent schedule of 
MEK162 will be used.  Patients requiring additional reductions below dose 
level -1 must be discontinued from study treatment.  Dose interruptions of 
more than 21 days are not allowed unless approved by the study Medical 
Monitor. 
Missed/skipped doses will not be made up (i.e. the patient should not double 
their dose if the previous dose was missed).  
No dose re-escalation is allowed. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 40 of 67 
If MEK162 dosing is interrupted for toxicity reasons, patients will be allowed 
to continue treatment with mFOLFIRI at the discretion of the treating 
physician and principal investigator.   
Dose reduction/interruption/discontinuation decisions should be based on the 
CTCAE grade of the toxicity and the guidelines provided below.  In general, 
doses should not be reduced or interrupted for Grade 1 toxicities, but treatment 
to control symptoms should be provided as appropriate.  All adverse events 
(AE) should be followed weekly or as clinically appropriate until stabilization 
or resolution. 
Skin toxicity (such as macular popular rash, acne, rash, dermatitis acneiform, 
etc.), visual changes (related to Retinal Pigment Epithelial Dystrophy 
(RPED)), nausea, diarrhea and asymptomatic reversible elevation of CK have 
been associated with MEK162 administration.  Please refer to the tables below 
for the study drug dose adjustment recommendations for MEK162 induced 
toxicities.  
 
Table 8.1.1: Guidelines for Skin Rash Management 
 
Step Grade 
Severity 
Management 
MEK162 Dose 
Adjustment 
1 
Mild 
(Grade 1) 
 Localized  
 Minimally 
symptomatic 
 No impact on 
activities of 
daily living 
(ADL) 
 No sign of 
superinfection 
 Initiate regimen if not 
already started.  
Consider using 
moderate strength 
topical steroids (e.g. 
hydrocortisone 2.5% 
cream or fluticasone 
propionate 0.5% 
cream) 
 Reassess after 2 
weeks 
; if rash worsens or 
does not improve, 
proceed to step 2. 
 Continue 
current dose. 
 Reassess 
after 2 
weeks; if 
rash worsens 
or does not 
improve, 
proceed to 
step 2. 
2 
Moderate 
(Grade 2) 
 Generalized 
 Mild 
symptoms 
 Initiate regimen if not 
already started, but 
using moderate 
strength topical 
 Consider 
holding 
treatment 
Dose reduction* 
MEK162 
 45 mg BID  
 30 mg BID   
 
30 mg BID** 
* Dose reduction should be based on the highest AE grade 
** Dose reduction below 30 mg is not allowed.  Dose reduction from the standard 30 mg BID 
includes an intermittent schedule 1 week on 1 week off: 30 mg BID dosing for one week 
starting after FOLFIRI administration on day 1 of a cycle followed by one week of dose hold. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 41 of 67 
(e.g., pruritus, 
tenderness) 
 Minimal 
impact on 
ADL 
 No sign of 
superinfection 
steroids (e.g. 
hydrocortisone 2.5% 
cream or fluticasone 
propionate 0.5% 
cream) 
 Reassess after 2 
weeks; if rash 
worsens or does not 
improve, proceed to 
step 3 
until rash 
improves 
 Maintain at 
current dose 
 Reassess 
after 2 
weeks; if 
rash worsens 
or does not 
improve, 
proceed to 
step 3 
3 
Severe 
(> Grade 3) 
 Generalized 
 Severe 
symptoms 
(e.g. pruritus, 
tenderness) 
 Significant 
impact on 
ADL 
 Sign of or 
potential for 
superinfection 
 Initiate regimen if not 
already started, but 
using moderate 
strength topical 
steroids PLUS 
methylprednisolone 
dose pack 
 Consider obtaining 
dermatology 
consultation 
 Manage rash per 
dermatologist’s 
recommendations 
 Hold 
treatment 
until rash 
improves 
(moderate or 
mild) or 
resolves 
 Reduce dose 
by 1 level 
 Reassess 
after 3 
weeks; if 
rash worsens 
or does not 
improve, 
discontinue 
treatment 
with 
MEK162 
 
Table 8.1.2: MEK162– Recommended Dose Modifications Associated with 
Treatment-Related Adverse Events  
Worst toxicity 
CTCAE v4.03 Grade (unless 
otherwise specified*) 
Dose Adjustment for Study Drug MEK162 
Eye disorder - Central Serous Retinopathy (CSR) like events 
Grade 1 
Maintain dose level of MEK162 and increase frequency of 
ophthalmic monitoring to at least every 14 days. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 42 of 67 
Worst toxicity 
CTCAE v4.03 Grade (unless 
otherwise specified*) 
Dose Adjustment for Study Drug MEK162 
Grade 2  
Maintain dose level of MEK162 and refer the patient to 
ophthalmologist within one week:  
- If resolved to Grade ≤ 1 in ≤ 21 days, maintain dose of MEK162.  
- If not resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose level** 
of MEK162 or maintain dose of MEK162 based upon the 
Investigator’s discretion after consultation with the ophthalmologist 
Grade 3 
Interrupt MEK162 and refer the patient to ophthalmologist within 
one week: 
- If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose level*** of 
MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, discontinue patient 
from study drug treatment. 
Grade 4 
Permanently discontinue MEK162 and close follow up of 
ophthalmic monitoring. 
Eye disorders – Retinal Vein Occlusion (RVO) 
Any grade 
Permanently discontinue MEK162 
Other eye disorders 
Grade 1 – 2 
Maintain dose level of MEK162 and increase frequency of 
ophthalmic monitoring to at least every 14 days. 
Grade 3 
Interrupt MEK162 and refer patient to ophthalmologist within one 
week: 
-If resolved to Grade ≤ 1 in ≤ 21 days, reduce 1 dose level*** of 
MEK162 
- If not resolved to Grade ≤ 1 in ≤ 21 days, discontinue patient 
from study drug treatment. 
Grade 4 
Permanently discontinue MEK162 
Liver related Adverse Events 
Grade 1   
AST or ALT 
(> ULN - 3 x ULN) 
Maintain dose level of MEK162  
Grade 2  
AST or ALT (> 3.0 – 5.0 x ULN 
or 3 X baseline value*****) AND 
bilirubin elevationa < 2.0 x ULN 
 
 
AST or ALT > 3.0 - 5.0 x ULN 
and blood bilirubina > 2.0 x 
ULN  
Interrupt dose of MEK162 until resolved to Grade ≤ 1 (or Grade ≤ 
2 in case of liver metastasis), then: 
- If resolved in ≤ 14 days, maintain dose level of MEK162.  
- If resolved in > 14 days, reduce dose level** of MEK162. 
 
 
Interrupt dose of MEK162 until resolved to Grade ≤ 1 or baseline, 
then: 
- If resolved in ≤ 7 days, reduce dose level** of MEK162. 
- If resolved in > 7 days, discontinue patient from study drug 
treatment. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 43 of 67 
Worst toxicity 
CTCAE v4.03 Grade (unless 
otherwise specified*) 
Dose Adjustment for Study Drug MEK162 
Grade 3 
AST or ALT (> 5.0 - 8.0 x ULN)  
AND blood bilirubina < 2.0 x 
ULN 
 
AST or ALT (> 8.0 x ULN)  
 
AST or ALT > 5.0 x ULN  
AND blood bilirubina > 2.0 x 
ULN 
Interrupt dose of MEK162 until resolved to Grade ≤ 1 (or Grade ≤ 
2 in case of liver metastasis), then:  
- If resolved in ≤ 14 days, maintain dose level of MEK162. 
- If resolved in > 14 days, reduce dose level** of MEK162. 
 
Permanently discontinue MEK162 
 
 
Permanently discontinue MEK162  
AST or ALT Grade 4 (> 20.0 x 
ULN) 
Permanently discontinue MEK162 
 
Cardiac* 
 
Asymptomatic, absolute 
decrease in LVEF of greater 
than 10% from baseline that is 
below the LLN 
Withhold MEK162 and evaluate LVEF every 2 weeks. If the LVEF 
recovers (define as LVEF> 50% or >LLN and absolute decrease 
<10% compared to baseline) within 21 days, resume treatment 
with a dose reduction. Monitor LVEF 2 weeks after resuming 
MEK162, every 4 weeks for 12 weeks and subsequently as per 
protocol.  
 
If the LVEF does not recover within ≤ days permanently 
discontinue MEK162.  
Symptomatic congestive heart  
Permanently discontinue MEK162 
 
 
QTCF > 480 ms (confirmed with 
repeat ECG) during treatment 
and change from pre-
pretreatment value remains ≤ 60 
ms  
1st occurrence: 
 
Temporarily interrupt dosing of MEK162 until QTcF < 
480 ms. then resume treatment at reduced dose.  
 
2nd occurrence: 
 
Permanently discontinue MEK162  
QTcF increase (confirmed with 
repeat ECG) during treatment is 
both > 480 ms and > 60 ms 
change from pre-treatment 
values 
Permanently discontinue MEK162 
 
 
Creatine Kinase (CK) elevation  
Grade 1-2 
Continue treatment on same dose level 
(If total CK > 3 ULN, measure isoenzymes and myoglobin in blood 
or urine) 
Grade 3  
(> 5.0 ULN- 10.0 ULN) 
If asymptomatic: Maintain dose of MEK162 and monitor closely  
If symptomatic (muscle pain/spasms): Interrupt dose of MEK162 
until resolved to CTCAE Grade ≤ 1 and monitor closely (then:  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 44 of 67 
Worst toxicity 
CTCAE v4.03 Grade (unless 
otherwise specified*) 
Dose Adjustment for Study Drug MEK162 
- If resolved to grade 1 or baseline in ≤ 21 days, reduce 1 dose 
level** of MEK162 
- If resolved to grade 1 or baseline in > 21 days, then discontinue 
patient from study drug treatment 
Grade 4 
If asymptomatic: interrupt and monitor closely  
- If resolved in ≤ 21 days, reduce 1 dose level** of MEK162 
- If resolved in > 21 days, then discontinue patient from study drug 
treatment 
If symptomatic : permanently discontinue treatment 
Diarrhea 
Uncomplicated Grade 1-2 
Consider temporary interruption of MEK162 until resolved to 
Grade ≤ 1.  Treatment may then be resumed at current dose level 
Complicated 
Grade 1-2 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 
1.  Restart MEK162 at a reduced dose level 
Grade 3 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 
1.  Restart MEK162 at a reduced dose level 
Grade 4 
Temporarily interrupt MEK162 treatment until resolved to Grade ≤ 
1.  Restart MEK162 at a reduced dose level 
Interstitial lung disease / pneumonitis 
Grade 1 
Maintain dose level of MEK162 
Grade 2 
Withhold MEK162 for up to 3 weeks 
If improved to Grade 0 or 1, resume treatment at 1 reduced dose 
level of MEK162 
If not resolved within 3 weeks, permanently discontinue MEK162 
Grade 3-4 
Permanently discontinue MEK162 
All other adverse events (suspected to be related) 
Grade 1-2 
In the event is a persistent Grade 2 AE, not responsive to a 
specific therapy, consider study drug interruption or reduction. 
Grade 3 
Interrupt study drug until resolution to Grade ≤1 or to pre-
treatment/ baseline level.  If the event resolves within 21 days 
then study drug may be restarted at a lower dose (one level below 
that previously received) based upon the Investigator’s discretion. 
Grade 4 
Permanently discontinue MEK162**** 
* Not according to CTCAE 
** Dose reduction below 30 mg BID is not allowed (intermittent dosing at Dose level -1 should be used 
when applicable)  
*** Ophthalmic monitoring recommended: further evaluation with specialized retinal imaging (e.g. 
ocular coherence tomography, angiography) 
**** A patient with a Grade 4 AE may resume treatment at the lower dose level if the AE recovers to 
Grade ≤1 within 21 days of discontinuing drug and, if in the opinion of the Investigator and DSMC 
Medical Monitor , the event is not life-threatening, and the patient can be managed and monitored for 
recurrence of AE.  Any patients requiring a treatment interruption of longer than 21 days must 
discontinue study drug permanently. 
***** For patients enrolled with liver metastases and baseline LFT elevations 
a Refers to total bilirubin 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 45 of 67 
8.2 Dose Modifications for mFOLFIRI 
 
For patients who do not tolerate mFOLFIRI, dose adjustments are permitted 
as described in the table below.  There will be no more than 2 dose level 
reductions in mFOLFIRI.  No dose re-escalation is allowed. 
 
If mFOLFIRI dosing is interrupted for toxicity reasons, patients will be 
allowed to continue treatment with MEK162 at the discretion of the treating 
physician and principal investigator and if they meet the requirements listed 
in the protocol.  A 48-hours dose hold for MEK162 will be observed prior to 
restarting treatment with mFOLFIRI 
 
TOXICITY AT THE 
START OF 
SUBSEQUENT CYCLES 
OF THERAPY  
Grade or Value 
Irinotecan 
5-FU Continuous Infusion 
ANC* 
< 1.2 k/µL 
HOLD until resolution 
Platelets  
< 75 k/µL 
Diarrhea  
≥ 1 
Mucositis  
≥ 2 
Bilirubin (total) 
 ≥ 1.5 x ULN 
Hand/foot syndrome  
3-4 
100% 
STOP 
PREVIOUS TOXICITY 
(After resolution) 
First occurrence 
Neutropenia > 5 days  
3-4 
100% 
 
100% 
Febrile Neutropenia  
3-4 
Thrombocytopenia  
3-4 
Diarrhea  
3 
80% 
80% 
Diarrhea  
4 
60% 
60% 
Stomatitis  
3 
100% 
80% 
Stomatitis  
4 
100% 
60% 
Myocardial Ischemia  
— 
100% 
STOP 
PREVIOUS TOXICITY 
(After resolution) 
Second occurrence 
Neutropenia > 5 days  
3-4 
80% 
80% 
Febrile Neutropenia  
3-4 
Thrombocytopenia  
3-4 
Diarrhea  
3 
60% 
60% 
Diarrhea  
4 
STOP 
STOP 
Stomatitis  
3 
80% 
60% 
Stomatitis  
4 
80% 
STOP 
 
*For ANC between 1.0 and 1.2 k/µL the patient can be treated if felt safe by 
the treating physician.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 46 of 67 
8.3 Supportive Care 
 
8.3.1 All supportive measures consistent with optimal patient care will be 
given throughout the study. 
8.3.2 Refer to Appendix 1 and Appendix 2 for additional supportive care 
guidelines for the management of MEK162 induced skin toxicity 
and diarrhea respectively.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 47 of 67 
9 
STUDY CALENDAR 
 
CYCLE Calendar: 1 cycle = 14 days, cycles begin the day of a mFOLFIRI infusion  
For all visits, there is a ± 3 day window if not explicitly specified otherwise.  
Examination 
Screening1 
Single 
Agent 
Lead in 
(6 days)2 
C120 
 
C1 
C2 
C2 
C3 
C4 
C5 
C6 
Subsequent 
Cycles Until 
Progression 
EOT 3, 18 
30 day 
Follow
-up3 
Day of Cycle: 
-28 to -1 
 
1 
8 
1 
8 
1 
1 
1 
1 
1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs, 
weight16 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical 
examination 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
ECOG 
performance status 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
Ophthalmologic 
examination4 
X 
 
 
 
 
 
X 
 
X 
 
X4 
X 
 
Hematology5 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry6 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LDH, Magnesium, 
Phosphorus, and 
uric acid7 
X 
As clinically indicated 
UGT1A1 
Genotyping 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CK and Troponin8  
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
 
Thyroid Function 
Tests9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Pregnancy test10 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
ECG15  
X 
 
 
 
X 
 
 
X 
 
X 
X 
 
 
ECHO/ Cardiac 
MUGA11 
X 
 
 
 
X 
 
X 
 
 
 
X 
X 
 
CT12 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Adverse Event 
Collection 
 
X 
Concomitant 
Medication 
Collection 
X 
MEK16213 
 
X 
X (BID PO daily, held 48h prior to each dose of mFOLFIRI) 
 
 
mFOLFIRI 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
PK (see 14.1)14 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
Carcinoembryonic 
Antigen (CEA) 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
Dose expansion 
only 
 
 
 
 
 
cfDNA19  (see 
14.2) 
X 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Biopsy (see 14.2) 
X 
 
 
 
 
 
 
X17 
 
 
 
X 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 48 of 67 
1. ALL Pre-study/Screening procedures should be completed within 4 weeks of study enrollment.  Day -1 is the day before the 6 
day MEK162 lead in. 
2.   Physical exam and laboratory assessments do not need to be repeated if performed within 7 days of single agent lead-in.  
Pregnancy test must be performed within 72hours of single agent lead-in. 
3.   Evaluation of adverse events, concomitant medication and antineoplastic therapies since discontinuation of study drug only. 
4.   Ophthalmologic exam to be conducted at baseline and every 4 weeks thereafter; include slit lamp examination, visual acuity 
testing, visual field testing, intraocular pressure (IOP) and indirect fundoscopy with attention to retinal abnormalities.  If there 
is a clinical suspicion of Retinal detachment or RVO, additional assessments including Ocular Coherence Tomography  
(OCT)  and Fluorescence angiography (FA) , respectively will be done.  
5.   Hematology includes CBC with differential and platelets.  Will be done weekly during the first two cycles. 
6.   Chemistry includes Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine Aminotransferase, Total Bilirubin 
(if total bilirubin is abnormal, direct and indirect bilirubin will be assessed as clinically indicated), Calcium, Carbon Dioxide, 
Creatinine, Chloride, Glucose, Potassium, Protein, Sodium, Urea Nitrogen.  Will be done weekly during the first two cycles. 
7.   To be performed at baseline/screening and as clinically indicated while on study.  
8.   Cardiac/Muscle Enzymes: CK and troponin will be performed on Day 1, every 4 weeks (i.e. Screening/Baseline, C3D1, 
C5D1, etc.).  Follow up for total creatine kinase (CK) ≥ 3 X ULN will include weekly assessment of isoenzymes and 
myoglobin in blood/or urine, and troponin as applicable. 
9.   TSH only at screening.  If TSH is abnormal, T3 and free T4 to be performed. 
10. Pregnancy test must be done at screening, within 72 hours of single agent lead-in, and the EOT for all women of childbearing 
potential and repeated as clinically indicated. 
11. MUGA/ultrasound or ECHO will be performed to determine cardiac ejection fraction at screening, 3 and 6 weeks after 
beginning single agent treatment and every 9 weeks thereafter.   
12. CT scans must be repeated every 8 weeks (± 5 days), until progression. 
13. Single dose lead of MEK162 will be given for 6 days followed by 2 days off prior to starting the combination.  When in 
combination with mFOLFIRI, MEK162 will be taken AFTER the mFOLFIRI infusion on Day 1.  MEK162 will be taken BID 
PO daily on days 1 - 12.  MEK162 should be held on Days 13 and 14 in order for MEK162 to be held for 48 hours prior to the 
next dose of mFOLFIRI.  For cycles lasting more or less than 14 days, MEK162 will be held for 48 hours prior to the next 
dose of mFOLFIRI. 
14. PK samples must be drawn before MEK162 dosing and 2, 6 and 24 hr post MEK162 dosing on Day 1 of the MEK162 lead in 
period and before irinotecan, before MEK162 and 2, 6 and 24 hr post MEK162 on C1D1/2 and C2D1/2.  24 hr PK draws 
must take place before the 3rd dose of MEK 162 is taken. An additional PK should be taken at the time of biopsy.  See section 
14.1 for more details.  
15. If QTc interval is ≥ 501 ms, a second ECG should be obtained within 5 minutes to confirm the QTc interval.  
16. At screening, blood pressure measurement to be taken once to determine eligibility. If uncontrolled arterial hypertension (see 
exclusion criteria 5.2.8).   
17. Biopsy at C4D14 (± 3 days) is optional. 
18. Within 30 days of last dose. 
19. cfDNA should be collected at baseline, C1D1, C2D1 of the combination therapy and at every restaging visit thereafter during 
the combination therapy.   
20. C1D1 is on Day 9 after the start of the MEK162 lead in (6 days MEK162 dosing 2 days off).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 49 of 67 
9.1 
Study Procedures: Recommended Safety Assessments during MEK162 
treatment 
At every visit, the following assessments should be performed (until drug 
discontinuation) for safety purposes: physical examination, weight, vital signs, 
laboratory assessments (hematology, chemistry).  
 Hematology: hemoglobin, hematocrit, red blood cell count, white blood cell 
count with differential (total neutrophil count including lymphocyte, monocyte, 
eosinophil and basophil counts) and platelet count will be measured.  Will be 
done weekly during the first two cycles.  
 Clinical Chemistry: BUN/urea (uric acid), serum creatinine, sodium, potassium, 
magnesium, calcium, glucose (fasting or non-fasting), total protein, albumin, 
phosphate and LDH will be measured.  Additionally liver function test including 
AST, ALT, alkaline phosphatase, total bilirubin (direct and indirect bilirubin will 
be measured as clinically indicated).  Will be done weekly during the first two 
cycles.   
At every four week visit, the following assessments should be performed 
cardiac/muscle enzymes), urinalysis, and ophthalmic examination.  
Full ophthalmic examination including slit lamp examination, visual acuity testing, 
visual field testing, intraocular pressure (IOP) and indirect fundoscopy with attention 
to retinal abnormalities, especially RPED like events and RVO.  
 For patients with clinical suspicion of retinal abnormalities (i.e. photopsia, 
metamorphopsia, impairment of visual acuity, etc.) or RVO, additional 
assessments of optical coherence tomography (for RPED) and fluorescein 
angiography (for RVO) are mandatory.  
 Cardiac/Muscle Enzymes: CK and troponin will be performed on day 1 of every 
other cycle.  Follow up for total creatine kinase (CK) ≥ 3 X ULN will include 
weekly assessment of isoenzymes and myoglobin in blood/or urine, and troponin 
as applicable. 
 Pregnancy and assessments of fertility: All females of childbearing potential 
(pre-menopausal or less than 1 year after the onset of menopause) will have a 
serum pregnancy test (β-hCG) at the following time points: Baseline/Screening, 
C1D1 (not required if Baseline/Screening assessment was done within 72 hours 
of C1D1), and the End of Treatment visit.  Additional serum or urine pregnancy 
tests are recommended approximately every other cycle for women of child 
bearing potential.  For confirmation of post-menopausal status, serum FSH and 
estradiol will be determined if amenorrhea is less than 12 months.  
 MUGA/ultrasound will be performed to determine cardiac ejection fraction at 3 
and 6 weeks after beginning treatment and every 9 weeks thereafter.   
 Blood pressure will be measured in the clinic every 14 days.  More frequent 
assessments during the study drug treatment period may also be performed at the 
discretion of the investigator and if medically indicated.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 50 of 67 
10 CITERIA FOR EVALUATION AND ENDPOINT 
10.1 Safety 
 
The primary endpoint for the dose escalation portion of this study is safety as 
determined by the incidence of DLT.  Routine safety and tolerability will be 
evaluated from the results of reported signs and symptoms, scheduled physical 
examinations, vital sign measurements, and clinical laboratory test results.  More 
frequent safety evaluations may be performed if clinically indicated or at the 
discretion of the investigator.  
 
Physical Examination 
 
Complete and symptom-directed physical examinations will be performed by a 
licensed physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be 
obtained in the clinic setting.  Patients should be sitting for 3-5 minutes prior to 
obtaining vital signs.  Height is required at screening only.  Weight is required on 
day 1 of each cycle.  
 
Safety Laboratory Determinations 
 
Laboratory evaluations will be performed as noted in the study calendar.  
10.2 Efficacy 
 
The primary endpoint of the dose expansion portion is to evaluate response rate 
and clinical benefit rate (PR/CR/SD at 4 months).  Tumor response will be 
measured according to RECIST 1.1 criteria. Patients receiving at least 80% of 
MEK162 are considered evaluable.   
 
The following definitions and criteria (RECIST version 1.1) should be used for 
the baseline evaluations of existing disease, and for the ongoing evaluation of 
tumor responses.  
 
Measurable lesions - lesions that can be accurately measured in at least one 
dimension with longest diameter (LD) ≥ 10 mm using CT, MRI, or caliper 
measurements or ≥ 20 mm with x-ray. 
 
Non-measurable lesions - all other lesions including small lesions (LD < 10 mm 
with CT, MRI, or caliper measurements or < 20 mm with x-ray). 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 51 of 67 
Documentation of “Target” and “Non-Target” Lesions 
 All measurable lesions up to a maximum of two lesions per organ and five 
lesions in total, representative of all involved organs should be identified as 
target lesions and recorded and measured at baseline. 
 Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinical assessments). 
 A sum of the LD for all target lesions will be calculated and reported as the 
baseline sum LD.  The baseline sum LD will be used as the reference by 
which to characterize the objective tumor response. 
 All other lesions (or sites of disease) should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these 
lesions are not required, but the presence or absence of each should be noted 
throughout restaging and follow-up. 
10.2.1 Response Criteria 
 
 
Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions  
(Must persist for a minimum of four weeks) 
Partial Response (PR) 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD  
(Must persist for a minimum of four weeks) 
Progressive Disease 
(PD) 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
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 
Stable Disease (SD) 
Persistence of one or more non-target lesion(s) 
Progressive Disease 
(PD) 
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions 
10.3 Stopping Rules 
 
Refer to section 4.2 for definition and evaluation of Dose Limiting Toxicities.  Refer 
to Section 7.6 for reasons to discontinue study medication.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 52 of 67 
11 STATISTICAL CONSIDERATIONS 
 
Dose Escalation Phase 
 
For the Dose escalation phase of the study a 3+3 design will be used, dose levels will be 
assigned as outlined earlier in Table 4.1.  The primary endpoint is safety as summarized by 
dose limiting toxicity (DLT). All patients who receive any study treatment will be included 
in the final summaries and listings of safety data.  Detailed information collected for each 
AE will include a description of the event, duration, severity, relatedness to study drugs, 
action taken, and clinical outcome.  Severity of the AEs will be graded according to the 
CTCAE version 4.03.  The statistical analysis of the safety data will be descriptive and 
tabular in nature.  
 
For the PK analysis we will use WinNonlin  
 
Changes in plasma levels of KRAS (at baseline, C1D1, C2D1 and at the time of restaging 
thereafter) will be correlated with changes in CEA levels measured at similar time points. 
 
Dose Expansion Phase   
 
An expansion cohort of up to 12 patients with KRAS positive irinotecan refractory disease 
will be enrolled at the MTD determined in the dose escalation phase.  An exact binomial 
confidence interval will be used to summarize objective response (OR) and Kaplan-Meier 
methodology will be used to estimate progression-free survival (PFS) in the expansion 
cohort.  Three or more responses in an expansion cohort of up to 12 patients will be 
considered preliminary evidence of efficacy.  There is an 84% probability of 3 or more 
responses in 12 patients if the true response rate is 35%.  There is an 11% probability of 3 
or more responses in 12 patients if the true response rate is 10%.   
 
Genomic Biomarkers will be tested for accuracy by a Mann Whitney U test. 
12 REGISTRATION GUIDELINES 
 
Patients must meet all of the eligibility requirements listed in Section 5 prior to 
registration.   
 
Study related screening procedures can only begin once the patient has signed a 
consent form.  Patients must not begin protocol treatment prior to registration. 
 
Treatment should start within five working days after registration. 
 
To register eligible patients on study, complete a Clinical Trials Office Patient Registration 
Form and submit to: CTORegistrations@hci.utah.edu.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 53 of 67 
13 DATA SUBMISSION SCHEDULE 
 
The Case Report Forms (CRFs) are a set of electronic forms for each patient that provides 
a record of the data generated according to the protocol.  CRF’s should be created prior to 
the study being initiated and updated (if applicable) when amendments to the protocol are 
IRB approved.  Data capture should be restricted to endpoints and relevant patient 
information required for planned manuscripts.  These forms will be completed on an 
on-going basis during the study.  The medical records will be the source of verification of 
the data.  During the study, the CRFs will be monitored for completeness, accuracy, 
legibility and attention to detail by a member of the Research Compliance Office. The 
CRFs will be completed by the Investigator or a member of the study team as listed on the 
Delegation of Duties Log.  The data will be reviewed no less than annually by the Data and 
Safety Monitoring Committee.  The Investigator will allow the Data and Safety Monitoring 
Committee or Research Compliance Office personnel access to the patient source 
documents, clinical supplies dispensing and storage area, and study documentation for the 
above-mentioned purpose.  The Investigator further agrees to assist the site monitors in 
their activities. 
14 SPECIAL INSTRUCTIONS  
14.1 Pharmacokinetic Sample collection 
Blood samples will be collected to determine the PK of MEK162 and its primary 
active metabolite AR00426032 in combination with mFOLFIRI (CPT-11 and 
SN-38).  Blood samples will be collected on all patients (both dose escalation and 
dose expansion). 
Required time points for PK collection 
 
Blood for full PK profiling of MEK162 and CPT-11 (Irinotecan) will be 
collected at different time points on C1D1 and C2D1 of mFOLFIRI + 
MEK162. 
 
Schedule of PK sample collections:  PK samples will be taken on Day 1 of 
the MEK162 lead and Cycles 1 and 2 of the MEK mFOLFIRI 
combination therapy, and at the time of any biopsy.  
The 24 hr post MEK162 PK draws must be completed before the patient 
takes their dose of study medication.  
 
Cycle 
Day 
Sample 
window 
MEK162 lead in 
1 
Pre dose MEK162 
Within 15 prior 
to dosing 
MEK162 
 
1 
2hr post MEK162 
dosing 
+/- 15 min 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 54 of 67 
 
1 
6hr post MEK162 
dosing 
+/- 15 min 
 
 
2 
24hr post MEK162 
dosing 
+/- 30 min 
 
Cycle 1 and 2 
1 
Pre dose Irinotecan 
Within 15 prior 
to dosing 
Irinotecan 
 
1 
Pre dose MEK162 
Within 15 prior 
to dosing 
MEK162 
 
1 
2hr post MEK162 
dosing 
+/- 15 min 
 
 
1 
6hr post MEK162 
dosing 
+/- 15 min 
 
 
2 
24hr post MEK162 
dosing 
+/- 30 min 
 
PK sample collection details will be covered in the lab manual. 
14.2 Correlative Studies 
14.2.1 Tumor specimens 
 
Tumor biopsies will be collected before and, if the patient allows, during 
treatment with MEK162 and mFOLFIRI. 
 
Fresh pre- and post-treatment tumor biopsies will be obtained, if accessible, 
from all patients included in the dose expansion cohort only.  The pre-
treatment tumor biopsy sample is required.  However, the post-treatment 
samples are optional and will be obtained after four cycles of therapy 
(C4D14 +/- 3 days).  If feasible it is recommended that a third biopsy will 
also be collected at the time of progression. 
 
Pharmacodynamic assessments will be performed in tumor tissues to 
provide evidence of specific target inhibition by the study drug combination 
(this will include but is not limited to evaluation of p-MEK, p-ERK, p-AKT) 
 
Collection of Fresh tumor sample details will be covered in the lab manual 
Inquiry Contact Email Address Office Cell 
 
14.2.4 Collection of cell-free DNA (cfDNA)  
5-30mL of blood will be collected from the patient to quantify KRAS 
mutations in circulating cell-free DNA at baseline, C1D1, C2D1 and at 
every restaging visit thereafter for all patients included in the dose 
expansion cohort only.  Levels of KRAS mutations from circulating cell-
free DNA isolated from plasma will be measured and correlated with 
biochemical response by CEA as well as radiological response by CT scan. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 55 of 67 
 
Collection of cfDNA sample details will be covered in the lab manual 
15 ETHICAL AND REGULATORY CONSIDERATIONS 
15.1 Informed consent  
Informed consent will be obtained from all research participants prior to 
performing any study procedures using the most recent IRB approved version.  
15.2 Institutional Review 
Study will be approved by the Institutional Review Board of University of Utah. 
15.3  Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman 
Cancer Institute (HCI) and approved by the NCI to assure the well-being of 
patients enrolled on Investigator Initiated Trials that do not have an outside 
monitoring review.  Roles and responsibilities of the DSMC are set forth in the 
NCI approved plan.  The activities of this committee include a quarterly review 
of adverse events including SAEs, important medical events, significant revisions 
or amendments to the protocol, and approval of cohort/dose escalations.  If the 
DSMC and/or the PI have concerns about unexpected safety issues, the study will 
be stopped and will not be resumed until the issues are resolved.  The DSMC also 
reviews and approves audit reports generated by the Research Compliance Office.  
 
 
This is a Phase I study.  For each phase I study using an agent of potential risk a 
member of the DSMC will be assigned as the primary medical monitor.  The 
primary medical monitor will be notified immediately of all SAEs.  A formal 
report should be submitted to the primary medical monitor within 10 days.  All 
serious adverse events (SAEs) occurring in patients treated at HCI or its affiliates 
will also be reviewed by the full DSMC quarterly.  Approval from the primary 
medical monitor is required for all dose escalations.  The full committee will also 
review all grade 3 or greater toxicities for patients on treatment and within 30 day 
follow-up window (only if possibly, probably or definitely related).  
 
 
15.4 Adverse Events / Serious Adverse Events 
This study will utilize the CTCAE (NCI Common Terminology Criteria for 
Adverse Events) Version 4.0.3 for AE and SAE reporting.  An electronic copy of 
the CTCAE Version 4.0.3 can be downloaded from:  
http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx 
15.4.1 Adverse Events (AE) 
An adverse event is the appearance or worsening of any undesirable sign, 
symptom, or medical condition occurring after starting the study drug even 
if the event is not considered to be related to study drug.  For the purposes 
of this study, the terms toxicity and adverse event are used interchangeably.  
Medical conditions/diseases present before starting study drug are only 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 56 of 67 
considered adverse events if they worsen after starting study drug.  
Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
 
Adverse event collection will begin after the first dose of study treatment 
and end 30 days after the last dose of study treatment.   
 
Information about all adverse events, whether volunteered by the subject, 
discovered by investigator questioning, or detected through physical 
examination, laboratory test or other means, will be collected and recorded 
and followed as appropriate. 
The occurrence of adverse events should be sought by non-directive 
questioning of the patient at each visit or phone contact during the study.  
Adverse events also may be detected when they are volunteered by the 
patient during or between visits or through physical examination, laboratory 
test, or other assessments.  As far as possible, each adverse event should be 
evaluated to determine: 
1. 
the severity grade based on CTCAE v.4 (grade 1-5) 
2. its relationship to the all study drugs (definite, probable, possible, 
unlikely, not related)  
3. 
its duration (start and end dates or if continuing at final exam) 
4. action taken (no action taken; study drug dosage adjusted/temporarily 
interrupted; study drug permanently discontinued due to this adverse 
event; concomitant medication taken; non-drug therapy given; 
hospitalization/prolonged hospitalization) 
5. 
whether it constitutes an SAE 
 
All adverse events will be treated appropriately.  Such treatment may 
include changes in study drug treatment as listed in the dose modification 
section of this protocol (see section 8 for guidance).  Once an adverse event 
is detected, it should be followed until its resolution, and assessment should 
be made at each visit (or more frequently, if necessary) of any changes in 
severity, the suspected relationship to the study drug, the interventions 
required to treat it, and the outcome. 
 
Information about common side effects already known about the 
investigational drug is described in the Drug Information (section 3) and the 
most recent Investigator Brochure.  This information will be included in the 
patient informed consent and will be discussed with the patient during the 
study as needed. 
 
All adverse events will be immediately recorded in the patient research 
chart.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 57 of 67 
15.4.2 Adverse Events of Special Interest 
As a result of signals observed from previous studies, several AEs requiring 
a close follow-up were identified.  For each category, selected AEs similar 
in nature, will be identified and grouped: 
• 
Ocular/Visual Events 
• 
Retinal Vein Occlusion 
• 
Rash and related events 
• 
Peripheral/generalized edema/anasarca 
• 
Serum CK elevation 
• 
Cardiac failure related events 
• 
Hepatic events 
15.4.3 Serious Adverse Event (SAE) 
Information about all serious adverse events will be collected and recorded.  
A serious adverse event is an undesirable sign, symptom or medical 
condition which: 
 is fatal or life-threatening 
 results in persistent or significant disability/incapacity 
 is medically significant, i.e., defined as an event that jeopardizes the 
patient or may require medical or surgical intervention to prevent 
one of the outcomes listed above 
 causes congenital anomaly or birth defect 
 requires inpatient hospitalization or prolongation of existing 
hospitalization, unless hospitalization is for: 
o routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition (procedures such 
as central line placements, paracentesis, pain control) 
o elective or pre-planned treatment for a pre-existing condition 
that is unrelated to the indication under study and has not 
worsened since the start of study drug 
o treatment on an emergency outpatient basis for an event not 
fulfilling any of the definitions of a SAE given above and not 
resulting in hospital admission 
o social reasons and respite care in the absence of any 
deterioration in the patient’s general condition 
 
Any death from any cause while a patient is receiving treatment on this 
protocol or up to 30 days after the last dose of protocol treatment, or any 
death which occurs more than 30 days after protocol treatment has 
ended but which is felt to be treatment related, must be reported. 
 
Toxicities which fall within the definitions listed above must be reported 
as an SAE regardless if they are felt to be treatment related or not.  

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 58 of 67 
Toxicities unrelated to treatment that do NOT fall within the definitions 
above, must simply be documented as AEs in the patient research chart.   
15.5 SAE Reporting Requirements 
 
SAEs must be reported to the DSMC, the FDA, the IRB, and Array, according to 
the requirements described below: 
 
A MedWatch 3500A form must be completed and submitted to 
compliance@hci.utah.edu as soon as possible, but no later than 10 days of first 
knowledge or notification of event (5 days for fatal or life threatening event). 
 
DSMC Notifications: 
 An HCI Research Compliance Officer (RCO) will process and submit the 
MedWatch form to the proper DSMC member as necessary for each 
individual study.  
 The RCO will summarize and present all reported SAEs according to the Data 
and Safety Monitoring Plan at the quarterly DSMC meeting. 
 For multisite studies the HCI DSMC will notify all participating sites of all 
unexpected and related SAEs via the Research Compliance Office.  The RCO 
will also notify all investigators at remote clinical sites participating in a 
multisite trial of any other safety update, including external safety reports, 
manufacturer’s reports and updates to the investigator’s brochure. 
 
FDA Notifications: 
 Adverse events occurring during the course of a clinical study that meet the 
following criteria will be promptly reported to the FDA: 
 Serious 
 Unexpected 
 Definitely, 
Probably 
or 
Possibly 
Related 
to 
the 
investigational drug 
 Fatal or life-threatening events that meet the criteria above will be reported 
within 7 calendar days after first knowledge of the event by the investigator; 
followed by as complete a report as possible within 8 additional calendar 
days. 
 All other events that meet the criteria above will be reported within 15 
calendar days after first knowledge of the event by the investigator. 
 The RCO will review the MedWatch report for completeness, accuracy and 
applicability to the regulatory reporting requirements. 
 The RCO will ensure the complete, accurate and timely reporting of the event 
to the FDA. 
 The Regulatory Coordinator will submit the report as an amendment to the 
IND application. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 59 of 67 
 All other adverse events and safety information not requiring expedited 
reporting that occur or are collected during the course of the study will be 
summarized and reported to the FDA through the IND Annual Report. 
 
IRB Notification: 
 Events meeting the University of Utah IRB reporting requirements 
(http://www.research.utah.edu/irb/) will be submitted through the IRB’s 
electronic reporting system within 10 working days. 
 
Array Notifications: 
 The investigator must complete the FDA MedWatch 3500a form and Array 
SAE coversheet in English, assess the relationship to study treatment and send 
the initial completed MedWatch form and Array SAE coversheet by fax 
1.303.386.1516 within 24 hours to Array Drug Safety.  The investigator must 
then ensure that the form and coversheet are accurately and fully completed 
with follow-up information and fax those to Array Drug Safety within 2 to 3 
calendar days for deaths or life-threatening events and 5 calendar days for 
other serious adverse events.  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 discontinued 
study participation.  The MedWatch form, Array fax coversheet, and fax 
confirmation sheet must be retained.  Pregnancy follow-up should describe 
the outcome of the pregnancy, including any voluntary or spontaneous 
termination, details of the birth, and the presence or absence of any congenital 
abnormalities or birth defects. 
 
 Pregnancies: To ensure patient safety, each pregnancy occurring while the 
patient is on study treatment  and for up to 3 months after last dose, must be 
reported to Array 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 Study Pregnancy Form and 
reported by the investigator to Array Drug Safety.  Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the 
possible relationship to the Array study drug of any pregnancy outcome.  Any 
SAE experienced during pregnancy must be reported on the SAE Report 
Form. 
 
*Medwatch 3500A form can be found at 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadFor
ms/ucm082728.pdf 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 60 of 67 
15.6 Protocol Amendments 
 
Any amendments or administrative changes in the research protocol during the 
period, for which the IRB approval has already been given, will not be initiated 
without submission of an amendment for IRB review and approval.    
 
These requirements for approval will in no way prevent any immediate 
action from being taken by the investigator in the interests of preserving the 
safety of all patients included in the trial.  
 
Any amendments to the protocol that significantly affect the safety of 
subjects, scope of the investigation, or the scientific quality of the study are 
required to be submitted amendment for FDA review. 
15.7 Protocol Deviations 
 
A protocol deviation (or violation) is any departure from the defined procedures 
and treatment plans as outlined in the protocol version submitted and previously 
approved by the IRB.  Protocol deviations have the potential to place participants 
at risk and can also undermine the scientific integrity of the study thus 
jeopardizing the justification for the research.  Protocol deviations are unplanned 
and unintentional events.  
 
Because some protocol deviations pose no conceivable threat to participant safety 
or scientific integrity, reporting is left to the discretion of the PI within the context 
of the guidelines below.  The IRB requires the prompt reporting of protocol 
deviations which are: 
 
Exceptions to eligibility criteria. 
 
Intended to eliminate apparent immediate hazard to a research 
participant or  
 
Harmful (caused harm to participants or others, or place them at 
increased risk of harm - including physical, psychological, economic, or 
social harm), or  
 
Possible serious or continued noncompliance  
15.8 FDA Annual Reporting  
 
An annual progress report will be submitted to the FDA within 60 days of the 
anniversary of the date that the IND went into effect (21 CFR 312.33).   
15.9 Clinical Trials Data Bank 
 
The study will be registered on http://clinicaltrials.gov and the NCI CTRP 
(Clinical Trials Reporting Program) by the Clinical Trials Office. 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
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15.10 Record Keeping  
 
Per 21 CFR 312.57, Investigator records shall be maintained for a period of 2 
years following the date a marketing application is approved; or, if no 
application is filed or the application is not approved, until 2 years after the 
investigation is discontinued and the FDA is notified. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 62 of 67 
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Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
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Macarulla T, et al. Phase I/II Study of FOLFIRI Plus The MEK1/2 Inhibitor 
Pimasertib (MSC1936369B) As Second-Line Treatment For KRAS Mutated 
Metastatic Colorectal Cancer. Annals of Oncology 2012;23. 
22. 
Xu J, Knox JJ, Ibrahimov E, et al. Sequence dependence of MEK inhibitor 
AZD6244 combined with gemcitabine for the treatment of biliary cancer. Clin 
Cancer Res 2013;19:118-27. 
23. 
Gustafson AM, Soldi R, Anderlind C, et al. Airway PI3K pathway activation is an 
early and reversible event in lung cancer development. Sci Transl Med 
2010;2:26ra25. 
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Bild AH, Yao G, Chang JT, et al. Oncogenic pathway signatures in human 
cancers as a guide to targeted therapies. Nature 2006;439:353-7. 
25. 
Cohen AL, Soldi R, Zhang H, et al. A pharmacogenomic method for 
individualized prediction of drug sensitivity. Mol Syst Biol 2011;7:513. 
26. 
Chin K, DeVries S, Fridlyand J, et al. Genomic and transcriptional aberrations 
linked to breast cancer pathophysiologies. Cancer Cell 2006;10:529-41. 
27. 
Tournigand C, Cervantes A, de Gramont A, et al. OPTIMOX1: a randomized 
study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in 
advanced colorectal cancer--a GERCOR study. J Clin Oncol 2006; 24(3): 394-
400. 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 64 of 67 
17 Appendices  
 
Appendix 1: Recommended Guidelines for the management of MEK162 induced skin 
toxicity  
Clinical judgment and experience of the treating physician should guide the management 
plan of each patient.  In general, the following interventions are in addition to the MEK162 
induced rash dosing guidelines in Table 8.1.1 of the protocol 
Prophylactic treatment for skin toxicity is recommended.  Prophylaxis of skin toxicity to 
be initiated   24 hours prior to the first treatment with MEK162 or later as needed.  Apply 
topical agents to the mostly common affected areas such as face, scalp, neck, upper chest, 
and upper back. 
 Non oily sunscreen (PABA free, SPF ≥ 15, UVA/UVB protection) Topical steroid, 
preferably mometasone cream (i.e. Elocon®) 
 Topical erythromycin evening (i.e.Eryaknen®) 
 Possibly oral  doxycycline (100 mg daily) for the first 2-3 weeks of study drug 
administration. 
Topical agents should be applied on a daily basis starting on Day 1 of study treatment or 
24 hours prior to first treatment, and more often as needed. 
Effective medications also include antihistamines, other topical corticosteroids, other 
topical antibiotics and low-dose systemic corticosteroids  
The treatment algorithm based on CTCAE grade is as follows: 
 
Mild Rash (CTCAE Grade 1) 
 Consider prophylactic rash treatment as described above if not already started 
 Topical mometasone cream or other topical corticosteroid and/or topical antibiotic 
(erythromycin (2%)) are recommended. 
 The patient should be reassessed after 2 weeks or sooner if rash worsens or as per 
investigator opinion. 
Moderate Rash (CTCAE Grade 2) 
 Although there has been no evidence of phototoxicity or photosensitivity in patients 
being treated with MEK162, doxycycline (or minocycline as second-line) should 
be used with careful UV protection (i.e., avoid direct exposure to sunlight, use 
sunglasses, use sunscreen, etc.).  
 Use of topical erythromycin or clindamycin (1%) plus mometasone or 
pimecrolimus (1% cream) plus oral antibiotics such as:  oral lymecycline (408 mg 
once daily),  doxycycline (100 mg BID) or minocycline (50 to 100 mg QD). 
Use of acitretin is not recommended 
 
Severe Rash (CTCAE Grade 3-4) 
CTCAE Grade 3 
  In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg.  Upon improvement, taper the dose in a stepwise 
manner (25 mg for 7 days, subsequently decreasing the dose by 5 mg/day every day). 
  Alternatively, in addition to the interventions recommended for moderate rash, 
consider oral isotretinoin (low doses, i.e. 0.3 to 0.5 mg/kg) (Lacouture et al 2011) 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 65 of 67 
 Use of acitretin is not recommended 
CTCAE Grade 4 
 Immediately discontinue the patient from study drug and treat the patient with oral and 
topical medications (see recommendation CTCAE Grade 3). 
Symptomatic treatment: 
It is strongly recommended that patients who develop rash/skin toxicities receive 
symptomatic treatment: 
 For pruritic lesions,  use of cool compresses and oral antihistamine agents 
 For fissuring, use of Monsel’s solution, silver nitrate, or zinc oxide cream.  If not 
sufficient use mild steroid ointments or combination of steroids and antibiotics such as 
Fucicort. 
 For desquamation, use emollients with mild pH 5 (best containing urea 10%) 
 For paronychia, antiseptic bath and local potent corticosteroids, use  oral antibiotics  
and, if no improvement is seen,  refer to a dermatologist or surgeon  
 For infected lesions, obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics based on sensitivity of culture 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 66 of 67 
Appendix 2: Guidelines for the management of MEK162 induced diarrhea 
Proactively investigate for occurrence of diarrhea 
 
Educate patient 
1. Remind patients at each visit to contact the site immediately upon the first sign of loose 
stool or symptoms of abdominal pain.  Additionally, at each study visit, each patient 
should be specifically asked regarding occurrence of diarrhea or diarrhea-related 
symptoms.  If the patient had symptoms, the patient should be asked regarding the 
actions taken for these symptoms and re-instruct if indicated. 
2. In addition to dietary modification, the patients should be instructed on early warning 
signs of diarrhea and potentially life-threatening illnesses (e.g. severe cramping → 
severe diarrhea, fever with diarrhea → infection and dizziness on standing might be a 
sign for shock). 
3. Patients should be instructed on what to report to the investigator if possible (i.e. 
number of stools, stool composition, stool volume)  
 
Anti-diarrhea therapy 
In order to effectively manage diarrhea and mitigate the escalation in severity or duration 
of diarrhea, patient education as well as proper management of diarrhea is mandatory.  
Management of diarrhea should be instituted at the first sign of abdominal cramping, loose 
stools or overt diarrhea.  All concomitant therapies used for treatment of diarrhea must be 
recorded on the Concomitant Medications eCRF.  It is recommended that patients be 
provided loperamide tablets and are instructed on the use of loperamide on the first day of 
MEK162 treatment  In addition to the MEK162 induced diarrhea dosing guidelines in 
Table 8.1.2 of the protocol, these instructions should be provided at each visit and the site 
should ensure that the patient understands the instructions.  
Explain the frequency of diarrhea and its relationship to NCI CTCAE grading (Table  8.1.2 
of the protocol) 
Determine if diarrhea is complicated versus uncomplicated (Table 8.1.2 of the protocol) 
 
Rule out other or concomitant causes. 
These may include: 
 Infection by Candida spp, Salmonella spp., Clostridium difficile, Campylobacter 
spp. Giardia, Entamoeba, Cryptosporidium which can lead to opportunistic 
infections in immunosuppressed patients, 
 Medication-induced diarrhea  
 Malabsorption/lactose intolerance 
 Fecal impaction, partial bowel obstruction 
 
For uncomplicated Grade 1 to Grade 2 diarrhea 
 Stop all lactose-containing products and alcohol and eat frequent small meals that 
include bananas, rice, applesauce or toast) 
 Stop laxatives, bulk fiber (i.e. Metamucil®) and stool softeners (e.g. docusate 
sodium; Colace®) 

Protocol name: A phase 1b trial of a combination of mFOLFIRI with MEK162 in patients with advanced KRAS positive metastatic 
colorectal cancers 
Version Date: 02NOV2017 
Principal Investigator: Ignacio Garrido-Laguna, MD 
 
Page 67 of 67 
 Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus (with 
fiber) 
 Drink 8 to 10 large glasses of clear liquids per day (e.g. water, Pedialyte®, 
Gatorade® or broth) 
 Consider administration of standard dose of loperamide: initial administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed stool. 
 Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval. 
 If uncomplicated Grade 1 to Grade 2 diarrhea persists for more than 24 hours, 
escalate to high dose loperamide: 2 mg every 2 hours (max. of 16 mg/day) or after 
each unformed stool. 
 
Note: Oral antibiotics may be started as prophylaxis for infections under the discretion of 
the physician. 
 
For complicated Grade 1 to Grade 2 diarrhea or Grade 3 to 4 diarrhea 
 The patient must call the investigator immediately 
 If loperamide has not been initiated, initiate loperamide immediately.  Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after 
each unformed stool. 
 Administer IV fluids and electrolytes as needed.  In case of severe dehydration, 
replace loperamide by octreotide. 
 Monitor/Continue IV fluids and antibiotics as needed.  Intervention should be 
continued until the patient is diarrhea free for at least 24 hours. 
 
Hospitalization may need to be considered