A Phase I/II Study of First Line Gemcitabine, Cisplatin and MEK162 in Advanced Biliary Tract Carcinoma
Phase: PHASE1
Conditions: Advanced Biliary Tract Carcinoma
Sponsor: Memorial Sloan Kettering Cancer Center

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 1 of 46
 
 
 
 
 
 
A phase I/II study of first line gemcitabine, cisplatin and MEK162 in advanced 
biliary tract carcinoma. 
 
PROTOCOL FACE PAGE FOR 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
Principal Investigator/Department: 
Ghassan Abou-Alfa, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Leonard Saltz, MD 
Medicine 
Investigator(s)/Department: 
Andrea Cercek, MD 
Andrew Epstein, MD 
David Ilson, MD, PhD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O’Reilly, MD 
Diane Reidy-Lagunes, MD 
Neil Segal, MD 
Zsofia Stadler, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
Jedd Wolchok, MD, PhD 
Michael Berger, MD 
Jinru Shia, MD 
James Harding, MD 
Anna Varghese, MD 
Elizabeth Won, MD 
Scott Gerst, MD 
Murk Heinemann, MD 
Marinela Capanu, PhD 
Maria Pacis, NP 
Armin Shahrokni, MD 
Ellen Hollywood, NP 
Kinh Gian Do, MD 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Robin Brenner, RN 
Pamela Raasch, RN 
Nitya Raj, MD 
Jaclyn Rosenthal, NP 
Luis A. Diaz, MD 
Karuna Ganesh, MD, PhD 
Michal Segal, RN 
Medicine 
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Pathology 
Pathology 
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Radiology 
Surgery 
Epidemiology & Biostatistics 
Nursing 
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Nursing 
Consenting Professional(s)/Department: 
Ghassan Abou-Alfa, MD 
Andrea Cercek, MD 
Medicine 
Medicine 
Medicine 
Medicine 
Medicine 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 2 of 46
 
 
 
 
 
David Ilson, MD, PhD 
Andrew Epstein, MD 
Yelena Janjigian, MD 
David Kelsen, MD 
Nancy Kemeny, MD 
Geoffrey Ku, MD 
Eileen O’Reilly, MD 
Diane Reidy-Lagunes, MD 
Leonard Saltz, MD 
Neil Segal, MD 
Zsofia Stadler, MD 
Rona Yaeger, MD 
Kenneth Yu, MD 
James Harding, MD 
Anna Varghese, MD 
Elizabeth Won, MD 
Nitya Raj, MD 
Ellen Hollywood, NP 
Maria Pacis, NP 
Erica Kaufmann, NP 
Patricia Gabriel, NP 
Jaclyn Rosenthal, NP 
Luis A. Diaz, MD 
Karuna Ganesh, MD, PhD 
Medicine 
Medicine 
Medicine 
 
Medicine 
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Nursing 
Nursing 
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Medicine 
Medicine 
 
 
 
 
Ple ase Note: A Consenting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 3 of 46 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA............................................................................ 4 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ..................................................................................... 7 
 
3.0 
BACKGROUND AND RATIONALE ........................................................................................... 8 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ................................................................ 11 
 
4.1 
Design.................................................................................................................................... 11 
 
4.2 
Intervention ............................................................................................................................ 12 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS................................................................................. 15 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY................................................................................. 16 
 
6.1 
Subject Inclusion Criteria ....................................................................................................... 16 
 
6.2 
Subject Exclusion Criteria...................................................................................................... 17 
 
7.0 
RECRUITMENT PLAN ............................................................................................................. 18 
 
8.0 
PRETREATMENT EVALU ATION ............................................................................................ 19 
 
9.0 
TREATMENT/INTERVENTION  PLAN ..................................................................................... 20 
 
10.0 EVALU ATION DURING TREATMENT/INTERVENTION........................................................ 26 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT .......................... 33 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ............................................................................ 35 
 
14.0 BIOSTATISTICS ....................................................................................................................... 35 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 38 
 
15.1 Research Participant Registration ......................................................................................... 38 
 
15.2 Randomization....................................................................................................................... 38 
 
16.0 DAT A M AN AGEMENT ISSUES............................................................................................... 38 
 
16.2 Data and Safety Monitoring ................................................................................................... 39 
 
17.0 PROTECTION OF HUMAN SUBJECTS.................................................................................. 39 
 
17.1 Privacy ................................................................................................................................... 39 
 
17.2 Serious Adverse Event (SAE) Reporting .............................................................................. 39 
 
17.2.1 Reporting ............................................................................................................................ 41 
 
Ethics and Good Clinical Practice ........................................................................................................ 42 
 
18.0 INFORMED CONSENT PROCEDURES.................................................................................. 42 
 
19.0 REFERENCES .......................................................................................................................... 42 
 
20.0 APPENDICES ........................................................................................................................... 45 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 4 of 46 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title 
A phase I/II study of first line gemcitabine, cisplatin and 
MEK162 in advanced biliary tract carcinoma (BTC) 
Primary Objective 
To evaluate the safety and activity of MEK162 in 
combination with gemcitabine and cisplatin in patients 
with advanced BTCs naïve to systemic therapy 
Secondary Objective 
To assess tissue biomarkers and perform tumor whole 
genome sequencing to discern genotypic differences by 
anatomic location, histology and response to study 
therapy 
Rationale 
Median overall survival for patients with advanced biliary 
carcinomas is 8 months. Gemcitabine and cisplatin is 
considered the most active combination regimen and 
current standard of care for treatment of patients with 
advanced disease, however improvements in systemic 
therapy are urgently needed. The Ras/Raf/Mek/Erk 
cascade controls normal processes necessary for cell 
proliferation and survival and thus has the potential to 
cause malignant transformation if left unchecked. 
Mutations in KRAS and BRAF, both of which are 
upstream of MEK, indicate a role for this signaling 
pathway in the pathogenesis of BTCs. Direct inhibition of 
MEK1/2 by is considered a valid strategy to study for 
therapeutic targeting of the MEK pathway in BTC. 
Preliminary results of a phase II trial evaluating the MEK 
inhibitor AZD6244 in a mixed population of pretreated 
(39%) and treatment-naïve patients with BTC reported 
an objective response rate of 14% (including one 
complete response), stable disease in 60%, median 
progression-free and overall survival times of 5.4 and 8.2 
months, respectively. MEK162 is an oral, selective small 
molecule inhibitor of MEK1/2.  In vivo studies performed 
on human tumor explants have shown that MEK162 
activity is potentiated by various chemotherapy agents 
including gemcitabine and cisplatin, providing a rationale 
for the combination to be evaluated in this phase I/II trial. 
Study Design/Intervention 
Eligible patients must have evidence of recurrent 
disease, metastatic disease or locally advanced biliary 
tract carcinoma not amenable to surgical resection. 
Measurable disease (RECIST) is required in baseline 
imaging studies. Histologic or cytologic confirmation of 
diagnosis is mandatory. Patients will sign written 
informed consent. 
Phase I portion: 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 5 of 46 
 
 
 
 
 
 
In the phase I component of the study, a classic 3+3 
cohort dose escalation scheme will be used to identify 
the MTD of MEK162 when administered with 
gemcitabine at dose 800 mg/m2 and cisplatin given at 
dose 20 mg/m
2  week 2 & 3 of a 3 week cycle. The final 
cohort will receive gemcitabine 1000mg/m2  and cisplatin 
20mg/m2  week 2 and 3 of a 3 week cycle in combination 
with MEK162 at the MTD as determined above. MEK162 
will be self-administered orally BID from week 1 of each 
treatment cycle. MEK162 will be held for 2 days prior to 
chemotherapy administration and resumed the day 
following chemotherapy.  A minimum of 2 patients and a 
maximum of 18 patients will be enrolled in the phase I 
part of this study. 
 
 
Phase II portion: 
 
In the phase II part of the study, patients will receive 
MEK162 at 45mg BID plus gemcitabine (800 mg/m2) and 
cisplatin (20 mg/m
2) as determined by the  phase I 
portion. 29 patients will be enrolled on the phase II part; 
plus the 6 patients treated at the MTD level on the phase 
I portion will be evaluable for the primary and secondary 
endpoints of the phase II part. 
 
 
For both phase I/II portions: 
Imaging studies for restaging purpose will be obtained 
every 3 cycles. Medical and laboratory evaluation will be 
done on weeks 1, 2 and 3 of the first cycle and at week 2 
of every cycle thereafter. Vital signs, nursing 
assessment, CBC and creatinine will be obtained prior to 
every treatment. Treatment will continue until disease 
progression, development of unacceptable toxicity or 
consent withdrawal. 
Correlative studies: 
Tissue 
Targeted cancer gene sequencing of 230 genes using 
next generation techniques will be conducted in the 
pathology dept at MSKCC on available pre-treatment 
tissue samples to explore aberrations in the 
Ras/Raf/Mek/Erk signaling cascade and identify 
genotypic differences amongst tumors according to 
anatomic site, histology and response to study therapy. 
Tumor samples also will be examined for Ki67 staining, 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 6 of 46 
 
 
 
 
 
expression of pERK by immunohistochemistry and 
expression of markers of MEK activity (SPRY4 and 
DSUP6 mRNA by PCR). 
Blood: 
Pharmacodynamic studies exploring the biological 
efficacy  of the different doses of MEK162 will performed 
by measuring changes in peripheral blood pERK 
expression and cell cycle analysis using flow cytometry. 
Blood samples will be analysed pre and post treatment 
for circulating free DNA and results correlated with 
response to therapy. 
Statistical Design 
Phase I portion: 
The primary objective of the phase I portion is to 
determine the MTD of MEK162 in combination with 
gemcitabine/cisplatin chemotherapy.  A dose escalation 
scheme will be used whereby patients will be treated in 
sequential cohorts of 3. If no patients experience a DLT 
at dose level 1 in an initial group of 3 patients a new 
cohort of patients will be enrolled at dose level 2.  If 1 of 
3 patients experience a DLT, the cohort will be 
expanded to 6.  If no further DLT occurs, a new cohort 
will be enrolled at the next dose-level.  If 2 of 6 patients 
experience a DLT, MTD has been exceeded.  The MTD 
will be defined as the highest dose for which not more 
than 1 of 6 patients develop DLT. If three or fewer 
patients are treated at the dose considered to be the 
MTD, additional patients (to a total of six) will be treated 
at that level to confirm the MTD. No intrapatient dose 
escalation will occur. 
Phase II portion: 
The primary objective of the phase II part is to evaluate 
the efficacy of the combination of gemcitabine and 
cisplatin plus MEK162 in patients with advanced biliary 
cancers naïve to systemic chemotherapy. The primary 
efficacy endpoints are the 6 month progression-free 
survival (PFS) rate and response rate (RR) at one year. 
For the combination of gemcitabine and cisplatin, the 6 
month PFS rate is 59% and RR is 26%. An exact 
binomial single stage design will be used to discriminate 
between true 6-month PFS rates of 59% vs. 82%, and 
between true response rates of 26% and 50%. Thirty five 
patients will be enrolled. If at least 26 patients were 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 7 of 46 
 
 
 
 
 
observed to survive progression-free for at least 6 
months, or at least 14 responses were observed among 
the 35 patients, this agent would be considered worthy 
of further testing in this disease. 
This design yields 91% power to detect a true 6-month 
PFS rate of at least 82%, and a true RR of at least 50%. 
It yields a 0.05 probability of a positive PFS result if the 
true 6-month PFS rate is no more than 59%, and 
a 0.05 probability of a positive RR result if the true RR is 
no more than 26%. Therefore, assuming that PFS and 
RR are independent, the over-all type 1 error is .10.  The 
type 1 error decreases very slightly if PFS and RR are 
positively correlated, which is very likely. 
Progression free survival will be calculated from study 
entry to documented disease progression or death from 
any cause, whatever occurs first. Time to death 
(survival) will be calculated from study entry to death or 
last follow up. Patients who stop therapy for reasons 
other than progression of disease or death will be 
counted as events; however they will be encouraged to 
continue getting restaging radiologic evaluations until 
progression or death. In that case, their PFS will be 
recalculated. Progression free survival, time to 
progression and survival will be estimated using the 
Kaplan–Meier methodology. The documented response 
rate and exact 95% confidence intervals will be 
calculated 
Study Subject Number 
Phase I: 2-18 
Phase II: 29 (  6 patients treated at the MTD on phase I 
portion will be evaluable for the primary and secondary 
endpoints of the phase II portion. ) 
Estimated time to completion 
24 months 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary objective:  Phase I 
 
•  To evaluate the safety of MEK162 in combination with gemcitabine and cisplatin in patients 
with advanced BTCs naïve to systemic therapy 
  
Primary objective:  Phase II 
 
 
•  To evaluate the activity  of MEK162 in combination with gemcitabine and cisplatin in patients 
with advanced BTCs naïve to systemic therapy 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 8 of 46 
 
 
  
 
 
 
Secondary objectives: Phase I and II 
 
• Perform  genetic analysis on tissue samples to evaluate for mutations in the Ras/Raf/Mek/Erk 
signaling cascade and to look for genotypic differences between tumors that differ in 
response to therapy and anatomic/histologic classification 
• Evaluate potential predictive tissue biomarkers of response to MEK162  and markers of 
MEKactivity including  tumor expression of pERK, Ki67, SPRY4 and DSUP6 
• Measure peripheral T-lymphocyte pERK expression by flow cytometry. 
 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Biliar y tract carcinoma (BTC) 
 
Carcinomas of the biliary tract include gallbladder carcinoma, intrahepatic and extrahepatic 
cholangiocarcinomas (perihilar and distal cholangiocarcinomas).  In the United States, 
approximately 7500 cases of BTC are diagnosed annually, of which 5000 are gallbladder 
carcinomas and 2500 are cholangiocarcinomas.1   The global epidemiology of BTCs is influenced by 
gender and ethno-geographic variables.  Female sex, parity, advanced age and the metabolic 
syndrome are known risk factors.2-4   Gallbladder carcinoma is a leading cause of cancer mortality in 
northern India and Chile where infection with Salmonella typhi, a known risk factor, is endemic.
5,6
 
Cholangiocarcinomas are especially frequent in areas like northern Thailand where liver fluke 
infections are common.3 
 
The vast majority of patients diagnosed with BTCs present with advanced disease given the 
propensity for regional and distant spread.  Overall 5-year survival rates range from 5-12% with a 
median survival of approximately 6 months for those with metastatic disease 7-9   The poor prognosis 
of BTCs highlights a continued urgent need for effective systemic therapies. 
 
3.2 Syste mic therapy for advanced BTC 
 
Cytotoxic chemotherapy for BTC is typically composed of a fluoropyrimidine or gemcitabine 
backbone.  While some pooled analyses suggest that both agents have similar activity as 
monotherapies, others have reported better response rates with gemcitabine compared to 
fluoropyrimidines (20-30% vs. 10-20%).10,11    The combination of gemcitabine and cisplatin yields 
response rates of 30-50% based on phase II trials.10    A recent meta-analysis of randomized and 
non-randomized trials reported superior objective  response and tumor control rates with 
gemcitabine-platinum over fluoropyrimidine-platinum combinations.
11    There was also a trend 
towards improved time to tumor progression with gemcitabine-platinum, but this did not translate into 
an overall survival benefit.
11    The mechanism underlying the apparent synergism of gemcitabine- 
platinum combinations is thought to result from the inhibitory effect of gemcitabine on repair of 
cisplatin-induced DNA damage.12,13 
 
The activity of gemcitabine and cisplatin was confirmed in the ABC-02 trial, a randomized phase III 
trial comparing the combination with gemcitabine alone in patients with advanced (unresectable, 
recurrent or metastatic) BTC.  There were approximately 200 patients in each arm, and gemcitabine 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 9 of 46 
 
 
 
 
 
1000 mg/m2  and cisplatin 25 mg/m2  were given weekly for two weeks followed by a week of rest for a 
total of four cycles.  Compared to gemcitabine, combination therapy significantly improved overall 
survival (11.7 vs 8.1 months, p<0.001), progression-free survival (8.0 vs. 5.0 months, p<0.001) and 
disease control (81.4% vs. 71.8%, p = 0.049).  Differential activity was not seen among the various 
sites along the biliary tree. 14   The ABC-02 study established gemcitabine plus cisplatin as a new 
reference standard for the treatment of advanced BTC.  Although other chemotherapy doublets such 
as gemcitabine and oxaliplatin,15,16  gemcitabine and capecitabine, 17,18 and oral or IV 
fluoropyrimidines with cisplatin
19-21  have shown comparable activity, there have been no head-to- 
head comparisons with gemcitabine and cisplatin. 
 
3.3 Ge netic alterations and the Ras/Raf/Mek/Erk Pathway in  BTCs 
 
 
The rarity of BTCs poses a challenge for study recruitment, and many trials have been inadequately 
powered to detect differences in outcomes between gallbladder carcinomas, intrahepatic and 
extrahepatic cholangiocarcinomas.  In clinical practice, advanced BTCs are currently regarded as a 
single disease entity treated with the same agents regardless of anatomic site of origin.  There is 
however a growing awareness that BTCs are heterogeneous and efforts are underway to elucidate 
the common genetic alterations associated with different anatomic sites.22   For example, mutations 
in CTNNB1 have been documented in gallbladder carcinomas but not cholangiocarcinomas.22 
ERBB2/Her2 overexpression has been found in 15% of gallbladder carc inomas, 5% of extrahepatic 
cholangiocarcinomas and 0% of intrahepatic cholangiocarcinomas.23   Vascular endothelial growth 
factor (VEGF) overexpression has been reported in nearly 60% of cholangiocarcinomas and 91% of 
gallbladder carcinomas and is a poor prognosticator.24,25      KRAS mutations have been reported in all 
BTCs, although the frequency seems to be highest among intrahepatic cholangiocarcinomas at 48- 
54%.26-28    while BRAF mutations have been reported in 20-30% of BTCs in two European series, 
although none were identified in tumors taken from a North American and Chilean population.
26,29,30
 
It is unclear if this discordance reflects artifact or true geographic differences in mutation 
frequency.26   There is currently no available data on the expression levels or mutation frequency of 
MEK in different parts of the biliary duct. The Ras/Raf/Mek/Erk cascade controls normal processes 
necessary for cell proliferation and survival and thus has the potential to cause malignant 
transformation if left unchecked.  Mutations in KR AS and BRAF, both of which sit upstream of MEK, 
suggest a potential role of this signaling pathway in the pathogenesis of BTCs.22,26 
 
 
3.4 Targeting the MAP kinase (MEK) pathway in BTC 
 
 
Clinical evaluation of targeted therapies in advanced BTCs is a relatively new area of investigation 
and no such therapies have yet been approved for this setting.  The anti-tumor activity of MEK 
inhibition in BTCs has been assessed in several studies. 
 
Sorafenib is an oral multi-target tyrosine kinase inhibitor of the VEGF and platelet-derived growth 
factor receptors, c-kit, as well as the Raf/Mek/Erk pathway.  The results of two phase II trials 
evaluating single agent sorafenib 400 mg BID in both treatment-naïve and treatment-refractory 
advanced BTC have been reported.31-33    Despite the emerging data implicating aberrant KRAS, 
BRAF and VEGF expression in BTC, objective response rates on sorafenib have been disappointing 
at 2-6%, stable disease is achieved in 30-50%, and median survival ranges from 4-6 months .31,33 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
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Direct inhibition of MEK1/2 by AZD6244 appears to be a more promising strategy for targeting the 
MEK pathway in BTC.  Preliminary results of a phase II trial evaluating AZD6244 in a mixed 
population of pretreated (39%) and treatment-naïve patients reported an objective response rate of 
14% (including one complete response), stable disease in 60%, median progression-free and overall 
survival times of 5.4 and 8.2 months, respectively.  Furthermore, pERK positivity was present in 90% 
of patients who had disease control compared to 0% of patients who progressed on AZD6244.  In 
contrast, staining for pAKT did not correlate with response.34 
 
3.5  MEK162 (ARRY-438162) 
 
MEK162 is an oral, selective small molecule inhibitor of MEK1/2.  MEK162 exerts an anti- 
proliferative effect, induces apoptosis, and decreases phosphorylation of ERK, a downstream 
effector of MEK, in cancer cell lines and various solid tumor xenografts.35 
 
MEK162 has been evaluated in six clinical trials thus far.  Three of thes e were phase I studies 
conducted in healthy subjects.35   Two studies were conducted in patients with rheumatoid arthritis 
given the pro-inflammatory effects of Ras/Raf/Mek signaling, but primary efficacy endpoints were not 
met.36,37   A single oncologic phase I study is underway beginning with a dose escalation phase in 
advanced solid tumors followed by an expansion phase in patients with metastatic BTCs or 
colorectal carcinomas (www.clinicaltrials.gov, NCT00959127).  Preliminary pharmacodynamic 
analyses have shown that MEK162 suppresses pERK and significantly decreases markers of MEK 
activity and cell proliferation from pre-treatment levels, particularly at doses of 45 mg and 60 mg 
BID.  The most frequently reported grade 1-2 toxicities include asymptomatic elevations in creatine 
kinase, stomatitis/mucositis and diarrhea.  Retinal events including photopsia, darkened vision and 
altered color perception occurred in 14% of patients and reversed with cessation of MEK162. 
Efficacy data are currently pending.35 
 
The occurrence of retinal events, including more serious complications such as retinal vein 
occlusion, has been reported with multiple other MEK inhibitors being evaluated for their anti- 
neoplastic activity.38 -45  In a phase I study of the oral MEK1/2 inhibitor, PD-0352901, patients who 
developed retinal vein occlusion had predisposing risk factors including hypertension, diabetes, 
dyslipidemia and glaucoma.38   While the mechanism underlying ocular toxicity with MEK inhibition is 
poorly understood, pre-clinical studies on rat models have revealed increased retinal gene 
expression of markers of inflammation, oxidative stress, endothelial damage and procoagulability.
4 6
 
Furthermore, the severity and type of ocular toxicity may be dosing schedule dependent.  As an 
example, while retinal vein occlusions were observed on a continuous schedule of PD -0352901, 
none were seen with an intermittent schedule.38,41 
 
 
 
3.5 Combining MEK162 with chemotherapy 
 
Although incremental increases in survival have been observed with gemcitabine-based doublets in 
advanced BTC, the possibility of further improving outcomes with the addition of targeted agents is 
being actively explored.  In vivo studies performed on human tumor explants have shown that 
MEK162 activity is potentiated by various chemotherapy agents including taxanes, gemcitabine and 
cisplatin.35    In the Calu-6 mouse model, the combination of MEK162 plus gemcitabine and cisplatin 
has been shown to be tolerable and with improved delayed growth of tumors relative to single agent 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
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MEK 162 or the combination of gemcitabine and cisplatin. Clinical trials have shown that combining 
targeted agents with a gemcitabine-platinum doublet is feasible, safe, and effective. A phase II trial 
of bevacizumab, gemcitabine and oxaliplatin yielded an objective response rate of 40%, median 
progression-free and overall survival times of 7 and 12.7 months, respectively. 47 The addition of 
cetuximab to gemcitabine and oxaliplatin showed a promising improvem ent in 4-month progression- 
free survival over chemotherapy alone (61% vs. 44%).48  Furthermore, we recently completed a 
phase II trial at MSKCC of sorafenib, gemcitabine and cisplatin in advanced BTCs 
(www.clinicaltrials.gov, NCT00919061).  It should be noted that in this trial, gemcitabine and cisplatin 
were initially administered at the same doses as in the ABC-02 study (1000 mg/m2  and 25 mg/m2, 
respectively) concurrent with sorafenib at the standard dose of 400 mg BID.   However, these doses 
were poorly tolerated, resulting in a high frequency of hand-foot syndrome, diarrhea and elevated 
liver enzymes.  The study regimen was subsequently modified to gemcitabine 800 mg/m 2, cisplatin 
20 mg/m
2, and sorafenib 400 mg, providing the rationale for the dose of gemcitabine/cisplatin 
chosen for use in combination with MEK162. In addition, preclinical studies performed in biliary 
cancer models have demonstrated schedule dependence to the antitumor effect observed when 
sequencing the MEK inhibitor AZD6244 with gemcitabine. DNA synthesis was suppressed during 
treatment with AZD6244, and re-entry into S-phase was delayed by approximately 48hr post- 
treatment. Strong schedule dependence was seen in all four biliary cancer models tested, 
suggesting that combined treatment with AZD6244 plus gemcitabine would be more active in biliary 
cancer patients when gemcitabine is given following a 48hr interruption in AZD6244 dosing, rather 
than concurrently55. Based on this data we plan an interrupted dosing schedule of MEK162 in 
combination with gemcitabine and cisplatin. 
 
3.6 Summar y 
 
MEK1/2 is a therapeutic target in BTC due to the frequent occurrence of activating KRAS and BRAF 
tumor mutations resulting in oncogenic signaling through the Ras/Raf/Mek/Erk  pathway. Clinical 
activity of single agent MEK1/2 inhibition has been observed in patients with advanced BTC, and 
pre-clinical evidence indicates enhanced activity of MEK162 when given with chemotherapy. 
Gemcitabine-cisplatin is the current reference regimen for advanced BTC; the combination of a 
direct MEK inhibitor with chemotherapy has not previously been clinically evaluated in BTCs. W e 
propose a phase I/II study evaluating the safety and activity of gemcitabine, cisplatin and MEK162 
as first-line therapy for advanced BTCs. 
 
 
 
 
 
 
 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
This is a non-randomised, open label, single institution phase I/II study of gemcitabine, 
cisplatin and MEK162 in patients with advanced BTC naïve to systemic therapy. 
 
In the phase I portion, up to 18 patients will be enrolled in classic 3+3 cohort dose escalation 
design to identify the MTD of MEK162 when administered with gemcitabine and cisplatin 

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IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 12 of 46
 
 
 
 
 
given weeks 2 and 3 of a 3 week cycle . MEK162 will be self-administered orally from week 
one of each cycle and held 2 days prior to chemotherapy administration. Treatment with 
MEK162 will resume the day following each chemotherapy administration. Patients will be 
observed for 6 weeks ( 2 cycles) prior to determination of the MTD.  Patients treated at the 
MTD in the phase I portion will be evaluable for primary and secondary endpoints of the 
phase II portion. 
 
In the phase II portion, up to 29 patients will be treated with gemcitabine 800mg/m2 , cisplatin 
20mg/m2  week 2 and 3 of a 3 week cycle and MEK162 at 45mg BID. The dose of 
gemcitabine used in the phase II portion will be dependent on results of the phase I portion. 
 
Phase I: 
 
• Primary endpoint is to determine the MTD of MEK162 in combination with 
gemcitabine/cisplatin chemotherapy. 
 
Phase II: 
 
• Primary endpoints are six-month progression free survival and objective response 
rate at one year 
• Secondary endpoints are:  median PFS, median overall survival, safety/toxicity profile 
• Joint primary endpoints of PFS6 and response rate were chosen for the phase II 
portion as responses to treatment with single agent MEK inhibitor were observed in a 
previous phase I trial in biliary cancer. The use of a dual primary endpoint therefore 
ensures that if a significant  increase in response rate is observed but PFS6 does not 
reach significance, the combination will still be considered worthy of further 
investigation. 
 
 
 
Correlative studies: 
 
 
• Perform  genetic analysis on tissue samples to evaluate for mutations in the 
Ras/Raf/Mek/Erk signaling cascade and to look for genotypic differences between 
tumors that differ in response to therapy and anatomic/histologic classification
54
 
• Evaluate potential predictive tissue biomarkers of response to MEK162  and markers 
of MEK activity including  tumor expression of pERK, Ki67, SPRY4 and DSUP6 
• Measure changes in peripheral T-lymphocyte pERK expression and cell cycle by flow 
cytometry.49-53 
•
 
 
4.2 
Intervention 
 
Phase I: 
 
Patients will receive treatment on the following schedule: 
 
• 
Gemcitabine over 30 mins IV week 2 & 3 of a 3 week cycle. 

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o NOTE: Infusions within 10 minutes of the specified time will be allowed at the 
discretion of the treating nurse (e.g. to allow patients to use the restroom) and 
will not be considered a protocol violation. 
• 
Cisplatin over 30 mins IV week 2 & 3 of a 3 week cycle 
o NOTE: Infusions within 10 minutes of the specified time will be allowed at the 
discretion of the treating nurse (e.g. to allow patients to use the restroom) and 
will not be considered a protocol violation. 
• 
MEK162 orally BID starting week one of each cycle, with treatment held 2 days prior to 
each chemotherapy administration and resumed one day following chemotherapy. 
• 
Dose escalation schedule for gemcitabine, cisplatin and MEK162 as below: 
  
 
Table 1: Dose levels for MEK162, gemcitabine and cisplatin 
 
Dose level 
MEK162* 
Ge mcitabine 
Cisplatin 
1 
30 mg PO BID 
800 mg/m2 
20 mg/m2 
2 
45 mg PO BID 
800 mg/m2 
20 mg/m2 
3 
MTD 
1000mg/m2 
20mg/m2 
 
A dose escalation scheme will be used whereby patients will be treated in sequential cohorts of 3-6. 
If no patients experience a DLT at dose level 1 in an initial group of 3 patients a new cohort of 
patients will be enrolled at dose level 2.  If 1 of 3 patients experience a DLT, the cohort will be 
expanded to 6.  If no further DLT occurs, a new cohort will be enrolled at the next dose-level.  If 2 of 
6 patients experience a DLT, MTD has been exceeded.  The MTD will be defined as the highest 
dose for which not more than 1 of 6 patients develop DLT. If three or fewer patients are treated at 
the dose considered to be the MTD, additional patients (to a total of six) will be treated at that level 
to confirm the MTD. No intrapatient dose escalation will occur. Dose-limiting toxicities (DLT) are 
defined as: 
 
1) Ocular disorders defined by: 
 
•   Central serous retinopathy (CSR): 
 
- 
CTCAE v4.0 grade 2 lasting > 14 days confirmed by ophthalmologic 
examination 
 
- 
CTCAE v4.0 grade > 3 confirmed by ophthalmologic examination 
 
- 
CTCAE v4.0 grade > 2 recurrence with same severity following suspension of 
study therapy followed by resolution and resumption of therapy at the same or 
lower dose 
 
•  CTCAE v4.0 grade > 1 non-CSR retinopathy confirmed by ophthalmologic examination 
 
•  CTCAE v4.0 grade > 3 visual disturbances (blurring, floaters, flashing lights) without retinal 
changes 

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•  CTCAE v4.0 grade > 2 uveitis 
 
•  Any other CTCAE v4.0 grade > 3 eye disorders 
 
2) Cardiac dysfunction defined by: 
 
•  CTCAE v4.0 grade > 2 cardiac dysfunction; relative decrease in ejection fraction > 20% from 
baseline value 
 
3) Liver dysfunction defined by: 
 
•  Elevation of AST/ALT > 4 times baseline level or CTCAE v4.0 grade   3, whichever is 
greatest. 
4) Skin toxicity defined by: 
 
•   Rash/ photosensitivity > CTCAE v4.0 grade 3 lasting > 48 hours despite skin toxicity treatment 
 
5) Delay of more than 4 weeks in receiving MEK162 due to toxicity. 
 
6) CTCAE v4.0 grade > 3 non-hematologic toxicity, considered potentially irreversible or life 
threatening despite best supportive efforts. 
 
7) CTCAE v4.0 grade > 4 hematologic toxicity 
 
Phase II: 
 
Patients will receive treatment on the following schedule: 
 
• 
Gemcitabine 30 mins IV week 2 & 3 of a 3 week cycle, at dose of 800mg/m2  as 
determined by phase I portion. 
o NOTE: Infusions within 10 minutes of the specified time will be allowed at the 
discretion of the treating nurse (e.g. to allow patients to use the restroom) and 
will not be considered a protocol violation. 
• 
Cisplatin 20mg/m
2  over 30 mins IV week 2 & 3 of a 3 week cycle 
o NOTE: Infusions within 10 minutes of the specified time will be allowed at the 
discretion of the treating nurse (e.g. to allow patients to use the restroom) and 
will not be considered a protocol violation. 
• 
MEK162 orally BID starting week one of each cycle, with treatment held 2 days prior to 
each chemotherapy and resuming one day post chemotherapy at a dose of 45mg BID as 
determined by the phase I portion. 
 
For both phase I/II portions: 
 
Imaging studies for restaging purpose will be obtained every 3 cycles. Medical (vital signs and 
physical exam) and laboratory evaluation (CBC, comprehensive metabolic panel, direct bilirubin, 
magnesium, amylase, lipase, and ldh) will be done on week 1,2 and 3 of the first cycle and at week 
2 of every cycle thereafter. Vital signs, nursing assessment, CBC and creatinine will be obtained 
prior to every treatment. Cardiac function will be evaluated by transthoracic echocardiogram at 
baseline and every 3 cycles. Patients will complete a pill diary, which will be collected and reviewed 
at each clinic visit. All patients will complete the Amsler grid test (test of central visual field) at 
baseline and week 2 of each cycle thereafter. If a patient has an abnormal Amsler grid test, he/she 
will undergo ophthalmologic assessment. 

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Treatment will continue until disease progression, development of unacceptable toxicity or consent 
withdrawal. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Ge mcitabine 
  
5.1.1 Definition: Gemcitabine is a pyrimidine analogue of deoxycytidine in which the deoxyribose 
moiety contains 2 fluorine atoms at the 2’-position. The drug acts as an inhibitor to 
ribonucleotide reductase and inhibition of DNA synthesis may result in perturbations of 
deoxynucleotide pools and interference with DNA chain elongation. The drug is cell-cycle 
specific and blocks cells in the G1/S interface. Cytotoxicity is schedule-dependent and 
increases with increasing duration of exposure. The drug is rapidly eliminated from plasma, 
owing mainly to deamination. Renal clearance of drug is less than 10% of parent drug. 
 
5.1.2 Supply: The drug is supplied as either a 200 mg or 1 gram lyophilized powder in a 50-mL 
sterile single vial for reconstitution. 
 
 
5.1.3 Administration: The drug is administered via a freely running intravenous catheter per 
institutional guidelines. 
  
5.1.4 Toxicity: Nausea, vomiting, alopecia, stomatitis, anorexia, fatigue, elevations of hepatic 
transaminases, reversible myelosuppression, rash, flu-like symptoms, edema, constipation, 
paresthesias, hypersensitivity reactions, phlebitis, proteinuria, hematuria, and rarely 
interstitial pneumonitis, ARDS and hemolytic uremic syndrome.. 
 
5.2 Cisplatin 
 
5.2.1 Definition: Cisplatin is a planar inorganic metal salt that function as an alkylating agent. In 
aqueous solution, the drug is equated to a diaquo species as the two chloride groups leave 
the molecule. The reactive diaquo species binds to N7 residues of guanine bases on DNA 
resulting in strand scission, and intra-inter strand cross-linking. 
 
5.2.2 Supply: Cisplatin is commercially supplied as a lyophilized powder in 10 mg and 50 mg vials, 
and stored at room temperature. The drug should be reconstituted using 10 ml and 50 ml 
respectively of sterile water for injection, USP, to yield a concentration of 1 mg/ml. Pre- 
reconstituted multi-dose vials of 100 mg are also available. Once the multidose vial has been 
entered, the remaining cisplatin is stable for 28 days when protected from light. 
 
5.2.2 Administration: Cisplatin should be given IV drip per institutional guidelines. Needles and IV 
sets using aluminum should not be used in the administration of cisplatin. 
 
5.2.3 Toxicity: Fatigue, asthenia, nausea, vomiting, nephrotoxicity, ototoxicity, myelosuppression, 
anaphylaxis, peripheral neuropathy, diarrhea, alopecia, hypersensitivity reactions, and rarely 
myocardial infarction, stroke, seizure, and blindness. 

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5.3 MEK162 
 
5.3.1  Definition: MEK162 (also known as ARRY-438162) is a potent, selective, allosteric small 
molecule inhibitor of mitogen-activated protein (MAP) kinase kinase (MEK) that is 
uncompetitive with adenosine triphosphate (ATP). 
 
5.3.2  Supply: MEK162 is supplied as film coated tablets. The film coated tablets consist of 
MEK162,lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide, 
croscarmellose sodium, magnesium stearate and a commercial film coating. The capsule- 
shaped film coated tablets are yellow to dark yellow, and are supplied as a dosage 
strength of 15mg. MEK162 film coated tablets are packed in a high-density polyethylene 
bottle with an induction seal and a child resistant closure. MEK162 film coated tablets 
should be stored below 25°C,protected from light. 
 
5.3.3  Administration: MEK162 will be orally administered by the patient themselves, as directed 
by the physician. Patients must take 90% of MEK162 doses per cycle. If a patient lives out of 
state and forgets to pick up their MEK162 refill, pharmacy may ship the MEK162 drug to the 
patient’s home address at the discretion of the PI or co-PI. 
 
 
5.3.4  Toxicity:  rash-like events (acne, rash, dermatitis acneiform, etc.), elevations of CK, 
diarrhea, nausea, vomiting, stomatitis/mucositis, edema and visual changes related to retinal 
events. See investigator brochure (ADDENDUM 1) for full description of human and animal 
toxicity and pharmacokinetic studies. 
 
 
5.3.5 Management of MEK162 related toxicity: 
 
 
Rash: treatment with topical or oral antibiotics, topical or oral anti-inflammatories, topical or 
oral corticosteroids. The use of emollients and sunscreens has not been evaluated with 
MEK162 but may be used prophylactically or as treatment for rash. 
Elevated CK levels: patients may remain on MEK162 per investigator discretion if 
asymptomatic. 
Nausea, vomiting and diarrhea: treat with standard anti-emetic and anti-diarrhoeal 
medications. Prophylactic treatment for MEK162-related nausea and diarrhea is not required. 
Edema: treatment with diuretic medications if clinically indicated. 
Stomatitis/mucositis-like events: institutional standard of care treatment 
Visual changes or new ocular findings: study drug should be immediately held and an 
ophthalmologic evaluation initiated. If visual changes or new ocular findings are assessed as 
not related to study drug after ophthalmologic evaluation, then study drug can be resumed at 
the previous dose. See section 4.2 for definition of ophthalmologic DLTs 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
6.1.1 Histologically / cytologically verified, non-resectable, recurrent, or metastatic biliary 
tract carcinoma including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma 

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and gallbladder carcinoma. Combined cholangiocarcinoma and hepatocellular carcinoma is 
allowed. 
 
6.1.2 Patients must have measurable disease by RECIST 1.1 
 
6.1.3 KPS ≥ 80% 
 
6.1.4 Age ≥ 18 years 
 
6.1.5 Adequate bone marrow function defined as: Hb ≥ 8 g/dl, ANC ≥ 1.5 K/mcL, Platelets ≥ 
100 K/mcL 
 
6.1.6 Adequate renal function defined as serum creatinine < 1.6 mg/dl and/or measured 
creatinine clearance from 24-hour urine collection of ≥ 60 ml/min 
 
6.1.7 Adequate hepatic function defined as total bilirubin ≤ 2 mg/dl, ALT/AST ≤ 5 x ULN. 
Patients with biliary obstruction can join if bilirubin corrects to required limit after adequate 
biliary drainage. 
 
6.1.9 Adequate cardiac function defined as ejection fraction  ≥ 45% as determined by 
transthoracic echocardiogram or MUGA 
 
6.1.8 Patients who have received prior local therapy, including but not limited to 
embolization, chemoembolization, radiofrequency ablation, radiation therapy, are eligible 
provided that measurable disease falls outside the treatment field or within the field but has 
shown an increase of ≥ 20% in the size. Prior local therapy must be completed at least 4 
weeks prior to the baseline scan 
 
6.1.9 Women of childbearing potential must have a negative pregnancy test within 7 days 
prior to study treatment 
 
6.1.10 Men and women of childbearing potential must be willing to consent to using effective 
contraception while on treatment and for at least 3 months thereafter. 
 
6.1.11 Ability to understand and the willingness to sign a written informed consent document 
 
6.2 
Subject Exclusion Criteria 
 
6.2.1  Any previous chemotherapy, biologic therapy, or investigational agent, except for 
adjuvant therapy or as radio-sensitizing agents limited to 5-fluorouracil/capecitabine  and 
gemcitabine. Patient must have completed adjuvant therapy no less than six months prior to 
accrual. 
 
6.2.2 Evidence of another active cancer that may influence patient outcome as determined 
by the Principal Investigator (PI) or co-Principal Investigator (co-PI), except for non- 
melanoma skin carcinoma, melanoma in-situ, in-situ carcinoma of the cervix curatively 
treated, treated superficial bladder cancer, and adenocarcinoma of the prostate that has 
been surgically treated with a post-treatment PSA that is non-detectable. 
 
6.2.3 Known brain metastases or primary central nervous system tumors with seizures that 
are not well controlled with standard medical therapy. 

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6.2.5 Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social 
situations that would limit compliance with study requirements. 
 
6.2.6 Known HIV positive patient 
 
6.2.7 Significant cardiovascular disease including congestive heart failure (New York Heart 
Association Class II or higher) or active angina pectoris. 
 
6.2.8 History of a myocardial infarction within 6 months. 
 
6.2.9 History of a stroke or transient ischemic attack within 6 months. 
 
6.2.10 Clinically significant peripheral vascular disease. 
 
6.2.11 Major surgical procedure within 4 weeks. 
 
6.2.12 Uncontrolled infection. 
 
6.2.13 Known or suspected allergy to gemcitabine or cisplatin 
 
6.2.14 Pregnant (positive pregnancy test) 
 
6.2.15 Breast-feeding should be discontinued if a nursing mother is to be treated on clinical 
trial. 
 
6.2.16 Any condition that impairs patient’s ability to swallow whole pills 
 
6.2.17 Malabsorption problem that may limit or inhibit the absorption of MEK 162 
 
6.2.18 Patients with a history or current known evidence of central serous retinopathy (CSR), 
retinal vein occlusion (RVO) or ophthalmopathy at baseline that would be considered a risk 
factor for CSR or RVO. 
 
6.2.19 History of any organ or bone marrow transplant. 
 
7.0 
RECRUITMENT PLAN 
 
This study will be conducted at Memorial Sloan-Kettering Cancer Center. Between 2 and 47 
patients will be needed to meet the study endpoints, projected accrual rate is two patients / 
month. 
 
All patients with biliary tract carcinomas referred for considerations of systemic therapy will be 
screened regardless of gender or ethnicity. Participation is voluntary. Before any protocol 
intervention and after discussion of the experimental nature of the therapy, alternatives, 
potential benefits, side effects, risks and discomforts, patients may sign informed consent. 
Patients who agree to join, will sign an institution's IRB approved written consent form. Three 
copies of the informed consent will be signed and dated by the patient or the patients legally 
authorized representative. One copy will be given to the patient, one copy will be filed in the 
patient’s medical record, and one copy will be stored in the research file. Written consent will 
be obtained by either the principal investigator or participating investigators. Patients who 
prefer to be consented using another language than English will be consented in their 

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preferred language as per the standard operating procedures established by the IRB at 
MSKCC. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the 
recruitment and enrollment process. The investigator/research staff may also review portions 
of their medical records at MSKCC in order to further assess eligibility. They will use the 
information provided by the patient and/or medical record to confirm that the patient is 
eligible and to contact the patient regarding study enrollment. If the patient turns out to be 
ineligible for the research study, the research staff will destroy all information collected on the 
patient during the initial conversation and medical records review, except for any information 
that must be maintained for screening log purposes. 
 
The protocol will be advertised on the MSKCC website and also will be registered and posted 
on clinicaltrials.gov. The protocol however does not contemplate the use of any other form of 
advertisements or payment to participants.  In view of the high incidence of certain BTC 
among woman, and the large referral circle based on previous experience accruing to 
studies of BTC, there is no envisioned limitation in accruing women and minorities in the 
research study. 
 
8.0 
PRETREATMENT EVALUATION 
 
Te st 
≤ 28 days prior 
to re gistration 
≤ 7 days prior
to tre atment 
Complete medical history and physical examination 
X 
KPS / ECOG 
X 
Height / Weight / Body surface area 
X 
Complete blood count with differential 
X 
Comprehensive biochemistry profile* 
X 
Amylase/Lipase 
X 
LDH 
X 
Magnesium 
X 
Direct bilirubin 
X 
CEA / CA 19.9/AFP 
X 
PT/INR and PTT 
X 
Urinalysis 
X 
Pregnancy test (females of child-bearing potential) 
X 
CT Chest, Abdomen, Pelvis** 
X 
24-hour urine collection for creatinine clearance**** 
X 
EKG 
X 
Transthoracic echocardiogram / MUGA 
X 
Audiogram**** 
X 
Amsler grid test (eye test) 
X 

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Confirmation of pathologic diagnosis at MSKCC 
X*** 
Informed consent 
X 
Research blood draw 
X 
* Including plasma electrolytes, BUN, creatinine, glucose, calcium, total protein, albumin, alkaline 
phosphatase, AST, AST, total bilirubin. 
** MRI of the abdomen and pelvis with non-contrast CT of the chest may be obtained instead of CT 
chest/abdomen/pelvis with contrast (or with liver tri-phasic) if patients liver disease is not visible on 
triphasic liver CT, or if the patient is allergic to CT scan contrast despite pre-treatment 
*** Prior pathologic confirmation at MSKCC before 4 weeks is acceptable 
**** Audiography / 24 hour creatinine clearance only if clinically indicated, i.e. if patient has a 
baseline complaint of hearing loss / serum creatinine > 1.6 and documentation of 24 hour CCL > 
60ml/min is needed to confirm eligibility. 
  
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Ge mcitabine and cisplatin administration 
 
9.1.1 Patients will receive treatment under the following schedule: 
 
• Gemcitabine: over 30 minutes IV,  week 2 & 3 of a 3 week cycle at dose of 800 
mg/m2 
• 
Cisplatin: 20 mg /m2 over 30 minutes IV, week 2 & 3 of a 3 week cycle 
 
9.1.2  One cycle corresponds to three weeks of treatment (21 days) 
 
9.1.3  Before week 2 of each cycle of therapy a CBC, complete metabolic panel including 
LDH, magnesium, amylase and lipase will be obtained. The total granulocyte counts must be 
≥ 1,500 and the platelet count ≥ 100,000 to proceed with therapy at week 2 of treatment.The 
serum creatinine must be ≤ 1.6 mg/dl or the CrCl has been measured at ≥ 60 ml/min at 
screening) to proceed with treatment. Otherwise, hold therapy and re-evaluate weekly. 
 
9.1.4  Before week 3 of each cycle of therapy a CBC and creatinine will be obtained. The 
total granulocyte counts must be ≥ 1,000 and the platelet count ≥ 75,000 to proceed with 
therapy. The serum creatinine must be ≤ 1.6 mg/dl to proceed with treatment. Otherwise, 
hold therapy and re-evaluate weekly. Patients with a baseline serum creatinine of > 1.6 
mg/dL but with a creatinine clearance of ≥ 60 ml/min at screening, will be treated as long as 
creatinine does not increased by more than 30% from their baseline obtained at the start of 
the study. 
 
9.1.5  A maximum of four weeks delay of treatment is allowed. If gemcitabine and cisplatin 
treatment is held for toxicity week 2 of any cycle, that cycle and week of treatment is given 
when toxicity has resolved (i.e missed treatments are made up).  If gemcitabine and cisplatin 
treatment is held for toxicity week 3 of any cycle, that treatment is not made up and treatment 
continues per previous schedule once toxicity has resolved. If MEK162 treatment is held for 
toxicity, patients continue on gemcitabine and cisplatin treatment per previous schedule and 
resume MEK162 when toxicity has resolved. 

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9.1.6 Patients who require to come off one of the two chemotherapeutic agents, can continue 
with the other one along with MEK162. At the discretion of the PI and/or Co-PI, patients may 
be permitted to continue MEK162 alone without gemcitabine or cisplatin after completion of 6 
months of combined treatment with MEK162, gemcitabine, and cisplatin. In this situation, 
MEK162 dosing will continue at the previous dose level. 
 
9.1.7  Ancillary medications: 
 
9.1.7.1 Primary prophylactic G-CSF support is not indicated. Secondary 
prophylaxis as indicated in section 11.2. 
 
9.1.7.2 Anti-emetic therapy will be given according to institutional guidelines. 
 
9.1.7.3 Erythropoietin may be used according to institutional guidelines or 
investigator preference. 
 
9.1.8  Treatment will continue until disease progression (clinical or radiological), development 
of unacceptable toxicity or consent withdrawal. 
 
9.1.9  Dose modifications: see section 11.2 
 
9.2 MEK162 Administration 
 
9.2.1 Starting  cycle # 1 day #1 the patient will initiate MEK162 at the appropriate dose 
level as per table 1 (see section 4.2.) . Treatment with MEK162 will be held 2 days prior to 
chemotherapy administration and resumed the following chemotherapy. 
 
9.2.2 MEK162 in 15 mg tablets will be dispensed through the outpatient pharmacy. Detailed 
instructions regarding taking the medication will be provided. Adherence will be determined 
by evaluating patient medication diaries. All non-used tablets will be collected and returned to 
the pharmacy at the end of each cycle. 
 
9.2.3 MEK162 will be continued, as long as tolerated, until the time of disease progression, 
or consent withdrawal. Patient whose gemcitabine and cisplatin have been 
discontinued for toxicity may continue taking MEK162 until recovery. 
 
9.2.4 MEK162 will be supplied by Array BioPharmaand provided at no cost to the patient. 
 
9.2.5 See section 11.2 for dose modifications of MEK162 on the phase II portion. 
 
9.3 Correlative studies: 
 
Tissue correlatives: Archival tissue will be obtained on all patients where available; paraffin 
block or 8-10 unstained slides. 
 
9.3.1    Genotyping: 
 
Archival FFPE tumor tissue and stored buffycoat samples will be used for genotyping studies. 
Sections will be reviewed by the reference pathologist (Dr. Jinru Shia) DNA will be extracted 
from reviewed FFPE tumor sections in the genomics core laboratory using Agilent alternative 
DNA extraction kit . Matched germline DNA will be extracted from stored buffycoat 

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samples using Gentra Puregene Blood Kit (Qiagen).  Tumor samples and matched germline 
DNA will be sequenced for mutations in over 230 target genes (see Appendix A). These 
genes include oncogenes and tumor suppressor genes commonly mutated in biliary 
cancer as well as a wider selection of candidate genes.  This targeted gene sequencing 
platform will be evaluated and interpreted by Dr Michael Berger from the  Department of 
Pathology. Custom oligonucleotides will be used to capture all exons of the target genes, 
with exon capture performed by hybridization (Agilent SureSelect Target Enrichment System) 
followed by next generation sequencing (Illumina HiSeq).  The accuracy and reproducibility 
of this platform has been demonstrated internally at MSKCC. This method of genotyping will 
allow the identification of sequence variants, small insertions and deletions and copy number 
alterations in the target genes. See appendix A for full list of genes to be studied. 
 
9.3.2  Analysis of SPRY4 and DSUP6 gene expression 
 
RNA will be extracted from archival FFPE tumor tissue using High Pure R NA extraction kit in 
the Geoffrey Beene Translational Core Facility at MSKCC. Reverse transcriptase PCR will 
be performed using Taqman gene expression assay to assess mRNA expression of markers 
of MEK activation SPRY4 and DSUP6. Gene expression data will be analysed in conjunction 
with the bio-informatics core facility. 
 
9.3.2    pERK/Ki67 pre-treatment immunostaining: 
 
Sections (5–6 μm thick) cut from paraffin-embedded pre-treatment tumor biopsies will be 
analyzed with immunohistochemistry using a rabbit polyclonal antibody for pERK (phospho- 
p44/42 MAPK [Thr202/Tyr204]; Cell Signaling Technology Inc., MA, USA). Positive and 
negative controls will ensure that the integrity of all tumor samples and reagents is 
maintained. Positive controls, selected to encompass a range of pERK staining, include 
human xenograft MD A-MB-231 (breast) and MiaPaCa (pancreas) cells, and a renal cell 
carcinoma biopsy. Slides from each biopsy will be stained with a species, isotype (IgG), and 
concentration-matched negative control antibody. A hematoxylin-eosin slide will also be 
stained for each sample. Stained slides will be evaluated independently by two pathologists. 
Localization of pERK staining to cell nuclei or cytoplasm will be ev aluated qualitatively. 
Nuclear pERK staining intensity will be graded semi-quantitatively using a five-point scale 
that will be based on the percentage of tumor showing positive staining in relation to the total 
amount of tumor present in the section.: 0, no staining; 1+, weak; 2+, moderate; 3+, strong 
and 4+, intense. Ki67 will be performed on all samples as per established clinical laboratory 
protocol. The experiments will be performed in the Pathology Immunohistochemistry Core 
Laboratory at MSKCC, under the guidance of Dr Jinru Shia. Samples will be preserved in the 
pathology department at MSKCC. 
 
 
 
9.3.3    pERK flow cytometry and cell cycle analysis: 
 
Pharmacodynamic studies exploring the biological efficacy  of the different doses of MEK162 
will be performed by measuring changes in peripheral blood pERK expression using flow 
cytometry. The use of pERK for optimal biologic effective dose is meant to be an exploratory 
investigation to complement but not replace MTD. In addition, PBMCs will be analyzed for 

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changes in cell cycle by flow cytometry using PI staining These studies will be performed by 
the Immune Monitoring Core Facility in collaboration with the Wolchok laboratory  under the 
supervision of Dr Margaret Callaghan and Dr Jedd Wolchok. 
 
Blood samples will be analysed for presence of circulating free D NA. The detection of tumor 
derived DNA circulating within a blood sample provides the opportunity for relatively non- 
invasive assessment of the genetic alterations harbored in the tumor.  Optimally the analysis 
of cfDNA can be used to determine tumor mutation status for patients in whom a biopsy is 
not feasible and potentially serial assessment for new genetic alterations that occur during 
tumor progression and therapeutic resistance.  Genotype concordance will be assessed 
between tumor and cfDNA, the primary 
endpoint.  We will also assess genotype 
concordance between multiple separate collections of cfDNA as this has not been explored 
previously.  We will further assess clinical correlates that may associate with variance 
including cfDNA characteristics (fragment size/quantity),  
tumor burden, and sites of 
metastatic disease. Supernatent from prepared buffycote samples will be used for this 
analysis,to be performed in the Jasin laboratory, RRL and the genomics core facility. DNA 
will be extracted using Qiagen QIAmp CAN columns. Somatic mutations detected in the 
primary tumor will be assessedin cfDNA through digital PCR 
 
 
 
Blood correlatives: Collection and processing of samples: 
 
9.3.5    Buffycoat preparation from blood samples: performed in ETC 
 
Colle ction of blood: 
 
• Blood should be drawn into a 10-mL Lavendar top EDTA tube 
 
• Mix immediately by gentle inversion 8 to 10 times. 
 
• After collection, store tube upright at room temperature until centrifugation. Blood samples 
should be centrifuged within one hour of blood collection for best results. 
 
 
 
Ce ntrifugation steps: 
 
• For best results, blood samples should be centrifuged within one hours of blood collection 
at room temperature (18-25°C). Store tube upright until centrifugation. 
 
• Remix the blood samples immediately prior to centrifugation by gently inverting the tube 8 to 
10 times. 
 
• Centrifuge tube/blood samples at room temperature (18-25ºC) in a horizontal rotor (swing-out 
head) for a minimum of 20 minutes at 1500 to 1800 RCF (Relative Centrifugal Force). 
Some specimens may require 30 minutes. Centrifugation beyond 30 minutes has little 
additional effect. The tube may be re-centrifuged if the mononuclear “band” or layer is not 
disturbed. Always check to see that the tube is in the proper centrifuge carrier/adapter and 
balanced properly. 

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Pipe tting steps: 
 
• Label a conical centrifuge tube. 
 
• After centrifugation, mononuclear cells and platelets will be in a whitish layer just under the 
plasma layer 
 
• Using a pipette, aspirate approximately half of the plasma from each Lavendar EDTA 
tube without disturbing the whitish cell layer and aliquot into 2ml Eppendorf tubes. The 
plasma aspirates should be clear so as not to contain any white cells. 
 
• Spin the 2 ml Eppendorf tubes containing plasma at 16,000xg x 10 minutes at 4 degrees. 
 
• Aliquot supernatant into labeled Eppendorf tube and freeze at -80 degrees. 
 
• Using a fresh pipette, collect the whitish cell layer from the Lavendar EDTA tube and 
transfer into a separate properly labeled 15 mL size conical centrifuge tube. This layer will 
contain the remaining plasma layer plus the PBMC layer (this is the entire remaining layer 
above the gel). Collection of cells immediately following centrifugation will yield best re sults. 
The Lavendar EDTA tube will now only contain the unusable layers under the gel, and can 
be disposed of according to MSKCC SOP on the disposal of biohazardous waste. 
 
You should now have a conical tube containing the whitish cell layers (PBMC layers) 
Step 1: Pre paration of phosphate buffered saline (PBS) Ple ase allow 15-20 minutes 
for this step. 
• PBS is used for cell washing in step 2. NOTE: This will yield enough washing solution for use 
on both conical tubes containing PBMCs. The phosphate buffer should be prepared fresh for 
each subject and kept at room temperature. Any unused buffer should be discarded 
according to disposal SOPs at your facility. 
 
• Fill the 250 mL graduated disposable beaker (provided in kit) up to the 200 mL mark with 
deionized/purified lab water. Place one phosphate buffered saline (PBS) tablet into the 
beaker. Make sure the tablet has dissolved completely and is completely mixed and in 
solution before proceeding with step 2. 
 
 
 
 
 
 
Step 2: Ce ll Washing Ste ps 
 
• Using a fresh pipette, add PBS to bring the total volume to 15 mL in each of the graduated 
conical tubes containing the whitish cell layer (PBMCs). Cap the tubes. Mix cells by inverting 
the tubes 5 times. 
 
• Centrifuge both conical tubes for 15 minutes at 300 RCF. Aspirate as much supernatant as 
possible from both tubes without disturbing cell pellets. 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 25 of 46
 
 
 
 
 
• Resuspend cell pellet in both conical tubes by gently vortexing or tapping tube with index 
finger. 
 
• To each conical tube containing PBMC pellets, add PBS to bring volume to 10 mL in each 
tube. Cap tubes. Mix cells by inverting tubes 5 times. 
 
• Centrifuge both conical tubes for 10 minutes at 300 RCF. Aspirate as much supernatant from 
both conical tubes as possible without disturbing cell pellet. 
 
• Cap the conical tubes containing PBMC pellets, make sure tubes are tightly capped to 
prevent desiccation. Do not freeze tubes in a styrofoam tray because tubes may crack. 
 
• Freeze the dry pellet (do not re-suspend the pellet in additional PBS) in an open tube rack at 
-80°C.  Samples will be stored at MSKCC for planned genetic studies, in -80ºC freezer at 3
rd 
floor, room 312 (3rd floor) of the Rockefeller Outpatient Pavilion at 160 E 53r d street. All 
samples will be labeled with the protocol number (IRB# 13-004), the patient initials, date and 
time of collection.. 
 
9.3.6: Serum sample processing and storage 
 
Serum samples will be obtained for pharmacokinetic studies and for future studies to be 
specified at that time. 
 
1. Draw 10 ml of blood in red top vacuum tube (no anticoagulant).  Allow the tubes to remain 
at room temperature for 30 to 60 minutes to clot. 
 
2. Centrifuge tubes at 1500 RPM for 15 minutes. 
 
3. Divide the serum samples into 3 equal aliquots. 
 
4. Label cryovials with the protocol number (IRB# 13-004), the patient name, MRN,study 
number and date of collection. 
 
5. Freeze and store the serum samples at -20º to -80º C as soon as possible once they are 
aliquoted and labeled. 
 
6. Specimen will be stored in the -80º C freezer located at 160 E 53rd street, 3rd floor, Room 
312 
 
 
 
 
9.4.7: Blood samples for pERK studies 
 
1.  Draw blood into 4 x CPT tubes 
2.  Invert all tubes several times immediately after collection 
 
 
3.  Write patient initials, date, and time of collection on each tube 
 
 
4.  Fill in date and time of collection in requisition form 
 
 
5.  Place all collected tubes in biohazard ziplock bag 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 26 of 46
 
 
  
 
 
 
6.  Please send all specimens via Stat Messengers to Immune Monitoring Core located at 
Zuckerman Research Building Room 1513. (There is a blood bin on the table.) 
  
Contact details: Immune Monitoring Core ext 125-2114 (Lab), Attention: Teresa Rasalan ext. 
125-2114; Rosemarie Ramsalwak 125-3106 (Pager 2877) 
 
 
 
9.4.9: Blood samples for cfDNA studies 
 
 
1.  Within one hour of sample collection, centrifuge 10 ml lavender EDTA vacutainer tube at 
low speed (~3000 RPM) for 10 minutes at 4 degrees. 
 
2.  Carefully aliquot plasma into 2ml Eppendorf tubes, avoiding buffy coat. Each Eppendorf 
tube will be labeled with the protocol number (IRB# 13-004), the patient initials, date and 
time of collection. 
 
3.  Spin 16,000xg x 10 minutes at 4 degrees. 
 
4.  Aliquot supernatant into labeled Eppendorf tube and freeze at -80 degrees in the -80°C 
freezer located in room 312 (3rd floor) of the Rockefeller Outpatient Pavilion at 160 E 53r d 
street 
 
 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
Evaluation during treatment to document disease status and treatment toxicity will occur at 
prespecified intervals according to the following calendar: 
 
Te st Type 
We ek 1 of 
tre atment* 
We ek 2 of 
tre atment 
We ek 3 of 
tre atment 
Eve ry 
cycle 
Eve ry 3
rd
 
cycle 
Clinical 
History & physical 
x
a
 
x 
x
a
 
x 
KPS/ECOG 
x 
x 
Weight 
x 
x 
Vital signs 
x 
x 
x 
x 
Vital signs 
x 
x 
x 
x 
Adverse event 
monitoring 
x
b
 
x 
x
b
 
x 
Laboratory 
CBC 
Comp 
Direct bilirubin 
LDH 
Magnesium 
Amylase, lipase 
x
a
 
x 
x
a
 
x 
CBC, Comp 
xc 
x 
ECHO or MUGA 
x
g 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 27 of 46
 
 
 
 
 
24 hour urine 
collection for 
creatinine clearance 
As clinically indicated 
CA 19.9/CEA/AFP 
x 
 
x 
Radiology 
CT d 
Chest/abdomen/pelvis 
x 
 
x
g
 
Othe r 
Audiogram 
As clinically indicated 
Amsler grid test 
x (once per cycle) 
Pre-treatment tissue 
x
e
 
 
Research bloodsh 
See timetable below for research blood collection 
*Week 1 MD visit and labs required  for cycle 1 only 
 
a On week 3 of therapy will only take place during the first cycle 
 
b On week 3 of therapy will only take place during the first cycle, then as nurse assessment. 
This is not a formal RN visit, but rather an assessment done by the chemo nurse. 
 
c Bloods of week 3 for cycle 2 and thereafter 
 
d MR I of the abdomen and pelvis with non-contrast CT of the chest may be obtained instead 
of CT chest/abdomen/pelvis with contrast (or with liver tri-phasic) if patients liver disease is 
not visible on triphasic liver CT, or if the patient is allergic to CT scan contrast despite pre- 
treatment. 
 
e Can be obtained anytime after consenting 
 
f  Windows for testing/ treatment are as follows: 
Radiology, cardiology investigations:  +/- 7 days 
Lab and research blood draws, MD visit, clinical evaluation and treatment administration:  +/- 
3 days 
However, MEK162 should always be held for at least 2 days prior to intravenous 
chemotherapy administration, MEK162 maybe held for an extra 72 hours to facilitate 
rescheduling of gemcitabine/cisplatin. 
g If treatment is held for toxicity, radiographic imaging and cardiac assessments should 
continue per original treatment schedule i.e every 9 weeks +/- 1 week from initiation of study 
treatment. 
hPatients who travel from far may be exempt from Cycle 1 day 3 and Cycle 2 day 3 research 
blood draws at the discretion of the PI or co-PI. 
 
Investigators will keep track of patient's medical condition for at least three years by calling 
the patient once a year. This will help checking on patients condition and look at the long- 
term effects of the study. 
 
Re search blood draws: 
 
Time: 
Research bloods to be drawn: 
Cycle 1 day 1 or ≤ 7 days prior to first study 
treatment (pre 1st  dose of MEK162) 
1,2, 3,4 
Cycle 1 day 3 (at least 90 mins post AM dose of 
2 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 28 of 46
 
 
 
 
 
MEK162 ) 
Cycle 1 week 2 (same day as chemotherapy admin) 
2 
Cycle 2 day 3 
2,3 ,4 
Cycle 3 week 2 
4 
 
1.  1 x 10ml BD vacutainer with EDTA (lavendar top) for buffycoat processing 
2.  2. 4 x 8ml CPT tubes with sodium heparin (green & red) for pERK studies 
3.  1 x 10ml BD  vacutainer serum tube (red-top) for Serum PK samples 
4.  1 x 10ml BD vacutainer with EDTA (lavendar top) for cfDNA processing 
  
:11.0  TOXICITIES/SIDE EFFECTS 
 
All toxicities will be rated as per the NC I Common Toxicity Criteria, version 4. 
 
 
 
 
11.1 
Anticipated adverse e ffects are as follows: 
 
 
11.1.1 Gemcitabine: Nausea, vomiting, alopecia, stomatitis, anorexia, fatigue, elevations of 
hepatic transaminases, reversible myelosuppression, rash, flu-like symptoms, 
edema, constipation, paresthesias, hypersensitivity reactions, phlebitis, proteinuria, 
hematuria, diarrhea or constipation, and rarely interstitial pneumonitis, ARDS and 
hemolytic uremic syndrome, or sepsis. 
 
11.1.2 Cisplatin: Fatigue, asthenia, nausea, vomiting, loss of appetite, nephrotoxicity, 
ototoxicity, myelosuppression, anaphylaxis, peripheral neuropathy, diarrhea, 
alopecia, hypersensitivity reactions, transient elevation of liver enzymes, electrolyte 
disturbances and rarely myocardial infarction, stroke, seizure, sepsis and blindness. 
 
11.1.3 MEK162: Nausea, vomiting, diarhoea, abdominal pain, rash, oedema 
peripheral/generalized/peri-orbital,  fatigue,  anaemia, dry skin/pruritus, stomatitis, 
dry mouth, dyspepsia, increased creatine phosphokinase (CK) mucosal 
inflammation, anorexia and eye events including retinal events, blurred vision, and 
myodesopsia. 
 
Reproductive risks: Patients should not become pregnant or father a baby while on this study 
because the drug in this study can affect an unborn baby. Women should not breastfeed a baby 
while on this study. Patients need to use birth control while on this study. These precautions should 
be in place for the whole duration of the study therapy and for at least 3 months after the last dose of 
gemcitabine, cisplatin, or MEK162. 
 
 
11.2.1 Dose reductions for gemcitabine and cisplatin: 
Specific doses for Gemcitabine dose modification: each gemcitabine dose level is 
decreased by 20% from previous one: 
 
 
 
Dose Level 
Ge mcitabine 
Starting dose 
800 mg/m2 

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IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
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Dose level -1 
640 mg/m2 
Dose level -2 
512 mg/m2 
a
 
 
Dose Level 
Ge mcitabine 
Starting dose 
1000 mg/m2 
Dose level -1 
800 mg/m2 
Dose level -2 
640 mg/m2 
 
a Patients who begin at the cohort 3 gemcitbine dose level (1000 mg/m2  gemcitabine) and continue 
on to the phase II portion may be dose reduced to the lowest gemcitabine dose level (512 mg/m 
2) 
per discretion of the PI or co-PI. 
 
 
 
Specific doses for Cisplatin dose modification: each cisplatin dose level is decreased by 20% from 
previous one: 
 
Dose Level 
Cisplatin 
Starting dose 
20 mg/m2 
Dose level -1 
16 mg/m2 
Dose level -2 
13 mg/m2 
 
Neutropenia: 
• 
Week 2 of therapy of any given cycle, including MEK162 treatment will not be administered 
unless the ANC is ≥ 1500. Treatment may be held a maximum of 4 weeks. 
• 
Week 3 of therapy of any given cycle, including MEK162 treatment will not be administered 
unless the ANC is ≥ 1000. Treatment may be held a maximum of 4 weeks. 
• 
If patients experience recurrent grade II hematologic toxicity (platelets or neutrophils) that 
delays therapy on ≥ 2 occasions, the investigator may choose to decrease the dose of 
gemcitabine or cisplatin for subsequent cycles of therapy.  Gemcitabine should be decreased 
by 1 dose level first and subsequently cisplatin as needed 
• 
Colony stimulating factors:  Patients should not routinely receive prophylactic colony 
stimulating factors (e.g., G-CSF, GM-CSF) during cycle 1. Subsequent use will be at the 
discretion of the treating physician. 
  
Dose reductions for neutropenia 
Absolute ANC Nadir 
MEK162 
Gemcitabine 
Cisplatin 
Grade 3 (no fever) 
No change 
No change 
No change 
Grade 4 (no fever) 
No change 
Dose level -1 
Dose level -1 
Grade 3-4 (with fever) 
Dose level -1 
Dose level -1 
Dose level -1 
Grade 4 (no fever) 
2nd episode 
No change 
Dose level -2 
Dose level -2 
Grade 4 (no fever) 
3rd episode 
Dose level -2 
Dose level -2 
Dose level -2 
Grade 3-4 (with fever) 
Dose level -2 
Dose level -2 
Dose level -2 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 30 of 46
 
 
  
 
 
 
• 
If the patient requires gemcitabine and cisplatin to be held despite prophylactic use of G- 
CSF, cisplatin will be reduced one dose level for further cycles. 
• 
If the patient required gemcitabine and cisplatin to be held despite prophylactic use of G-CSF 
and prior dose reduction of cisplatin for neutropenia, both gemcitabine and cisplatin will be 
reduced one dose level for further cycles. 
• 
If patients end up receiving either gemcitabine or cisplatin, same guidelines that are pertinent 
to the drug they remain on apply. 
 
 
 
Thrombocytopenia: 
• 
No gemcitabine and cisplatin or MEK162 will be administered unless platelets ≥100,000 
week 2 of treatment, and ≥ 75,000 week 3 of treatment.. 
• 
If patients experience recurrent grade II hematologic toxicity (platelets or neutrophils) that 
delays therapy on ≥ 2 occasions, the investigator may choose to decrease the dose of 
gemcitabine or cisplatin for subsequent cycles of therapy.  Gemcitabine should be decreased 
by 1 dose level first and subsequently cisplatin as needed. 
• 
If patients end up receiving either gemcitabine or cisplatin, same guidelines that are pertinent 
to the drug they remain on apply. 
 
Dose reductions for thrombocytopenia 
Nadir Platelet Count 
MEK162 
Gemcitabine 
Cisplatin 
Grade 3-4 1st episode 
No change 
Dose level -1 
Dose level -1 
Grade 3-4 2nd episode 
No change 
Dose level -2 
Dose level -2 
 
 
 
Neutropenic Fever: 
• 
Defined as: ANC <1000/mm3  with a single temperature of >38.3 degrees C (101 degrees F) 
or a sustained temperature of >=38 degrees C (100.4 degrees F) for more than one hour. 
• 
Patients will receive prophylactic pegfilgrastim or filgrastim with each subsequent cycle of 
gemcitabine and/or cisplatin 
• 
If patients end up receiving either gemcitabine or cisplatin, same guidelines that are pertinent 
to the drug they remain on apply. 
  
Nephrotoxicity: 
• 
If on week 2 or week 3 of any given cycle of gemcitabine and cisplatin, the creatinine is > 1.6 
mg/dl or more than 30% from baseline for patients with baseline creatinine of >1.6mg/dL b ut 
with CrCl ≥ 60mL/min, therapy should be held until the serum creatinine ≤ 1.3 mg/dl or < 30% 
from baseline for patients with baseline creatinine of >1.6mg/dL but with CrCl ≥ 60mL/min. 
• 
Cisplatin should be dose reduced one dose level for further cycles, with no change in the 
gemcitabine dose. 
• 
If no recovery occurs within 4 weeks of holding therapy, gemcitabine should be continued as 
a single-agent and dose reduced one level. 
• 
If patients end up receiving either gemcitabine or cisplatin, same guidelines that are pertinent 
to the drug they remain on apply. 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 31 of 46
 
 
  
 
 
 
Neurologic Toxicity: 
• If neurologic toxicity ≥ grade 2 occurs, at any point of the cycle, then gemcitabine and 
cisplatin should be held until resolution to grade < 1, with the cisplatin dose reduced one 
dose level with no change in the gemcitabine dose. 
 
Cardiovascular Toxicity: 
• If during any cycle of therapy a patient develops ≥ grade 3 cardiovascular toxicity, then 
treatment should be permanently discontinued and the PI or co-PI contacted. 
 
 
Pulmonary Toxicity: 
• If during any cycle of gemcitabine and cisplatin therapy a patient develops ≥ grade 3 
pulmonary toxicity, then study treatment should be permanently discontinued and the PI or 
co-PI contacted. 
 
Hepatic Dysfunction: 
• If bilirubin > 2 (in the absence of Gilbert’s disease) or transaminases > 4 X baseline or = 
CTCAE v4.0 grade 3, whichever is greater, evaluate for biliary obstruction or progressive 
disease. If drug toxicity suspected, hold until toxicity ≤ grade 2 and resume gemcitabine and 
cisplatin at reduction of one dose level each. 
 
 
 
 
 
 
 
Othe r Toxicities: 
• For any grade 3 or 4 toxicity attributable to gemcitabine and/or cisplatin not mentioned 
above, despite appropriate and adequate supportive therapy (e.g. antiemetics or anti- 
diarrheals) the treatment should be withheld until patient’s recovery and the possibility of 
resumption of therapy should be discussed with the Study PI or co-PI, and gemcitabine 
and/or cisplatin will be reduced one dose level. 
• Patients who develop a gastrointestinal perforation, grade 4 hemorrhage, or symptomatic 
grade 4 venous thromboembolic event will not be eligible for re-treatment. 
• Any grade alopecia does not call for any change in therapy. 
• Patients who have an abnormal Amsler grid test during treatment will hold MEK162 pending 
ophthalmologic review, then dose reduction will be as per instructions for ophthalmologic 
toxicity detailed below (11.2.2). If patients have abnormal Amsler grid tests and are cleared 
by ophthalmology to resume treatment, they may forego additional ophthalmology 
evaluations and continue taking MEK162 per the discretion of the PI or co-PI. This will not 
compromise the assessment of potential MEK162 mediated impact upon vision. Patients will 
be monitored for changes in vision at clinic visits and referred for ophthalmology assessment 
of any new ocular symptoms. 
 
Maximum Duration of Tre atment De lays/Maximum Dose Re ductions: 
• Treatment with gemcitabine and cisplatin may be held up to a maximum of 4 weeks from the 
scheduled cycle initiation date to await resolution of toxicity according to the guidelines 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 32 of 46
 
 
 
 
 
above. If more than 4 weeks are needed for recovery, the study PI or co-PI should be 
contacted. 
 
11.2.2: Dose re ductions for MEK162 
For grade 3 and 4 toxicities attributable to treatment with MEK162, treatment should be 
withheld until   patient’s recovery to grade ≤ 2 and the possibility of resumption of therapy 
should be discussed with the Study PI or co-PI. 
 
 
• Treatment with MEK162 will be held in patients enrolled on the phase II portion with 
MEK162 related toxicity meeting criteria as below until toxicity resolves to ≤ grade 2. 
• If the dose of MEK162 used in the phase II portion is 45mg BID, treatment may be re- 
introduced at a dose reduction to 30mg BID, following resolution of toxicity as above 
and at the discretion of the study PI or co-PI. 
• If the dose of MEK162 used in the phase II portion is 30mg BID, treatment may be re- 
introduced at a dose reduction to 15mg BID, following resolution of toxicity as above 
and at the discretion of the study PI or co-PI. 
• If toxicity meeting criteria in section 4.2 recurs at MEK162 dose of 15mg BID, study 
treatment will be discontinued. 
• Patients may continue to receive MEK162 if treatment with gemcitabine or cisplatin 
has been discontinued for nephrotoxicity, neurotoxicity or  pulmonary toxicity as per 
section 11.1.1. 
• See section 11.2.1 for specific instructions regarding MEK162 treatment and 
hematologic toxicity. 
 
 
 
1) Ocular disorders defined by: 
 
•   Central serous retinopathy (CSR): 
 
o CTCAE v4.0 grade 2 lasting > 14 days confirmed by ophthalmologic examination 
 
o CTCAE v4.0 grade > 3 confirmed by ophthalmologic examination 
 
o CTCAE v4.0 grade > 2 recurrence with same severity following suspension of study 
therapy followed by resolution and resumption of therapy at the same or lower dose 
 
•  CTCAE v4.0 grade > 1 non-CSR retinopathy confirmed by ophthalmologic examination 
 
•  CTCAE v4.0 grade > 3 visual disturbances (blurring, floaters, flashing lights) without retinal 
changes 
 
•  CTCAE v4.0 grade > 2 uveitis 
 
•  Any other CTCAE v4.0 grade > 3 eye disorders 
 
2) Cardiac dysfunction defined by: 
 
•  CTCAE v4.0 grade > 2 cardiac dysfunction; relative decrease in ejection fraction > 20% from 
baseline value 
 
3) Liver dysfunction defined by: 

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IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 33 of 46
 
 
 
 
 
•  Elevation of AST/ALT  ≥  x 4 times baseline level or CTCAE v4.0 grade   3, whichever 
is greater. 
 
4) Skin toxicity defined by: 
 
•   Rash/ photosensitivity > CTCAE v4.0 grade 3 lasting > 48 hours despite skin toxicity treatment 
 
5) Delay of more than 4 weeks in receiving MEK162 due to toxicity. 
 
 
6) CTCAE v4.0 grade > 3 non-hematologic toxicity, considered potentially irreversible or life 
threatening despite best supportive efforts. 
 
 
7) CTCAE v4.0 grade > 4 hematologic toxicity 
 
Maximum Duration of Tre atment De lays/Maximum Dose Re ductions: 
Treatment with MEK162 may be held up to a maximum of 4 weeks to await resolution of 
toxicity. If more than 4 weeks are needed for recovery, the study PI or co-PI should be 
contacted. 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Tumor assessments will be based on Response Evaluation Criteria in Solid Tumors (RECIS T 
1.1) guidelines. 
 
12.1 
Measurability of Tumor Le sions at Baseline 
12.1.1 Measurable – Tumor lesions: Must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
10mm by CT scan (irrespective of scanner type) and MR I (no less than double the slice 
thickness and a minimum of 10mm) or 10mm caliper measurement by clinical exam (when 
superficial) 
 
12.1.2 Nonmeasurable – leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
12.1.3 Target lesions: All lesions up to a maximum of five lesions total (and a maximum of 
two lesions per organ) representative of all involved organs should be identified as target 
lesions.  It may be the case that, on occasion, the largest lesion does not lend itself to 
reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected 
 
12.1.4 Non-target lesions: all other lesions (or sites of disease) should be identified as non- 
target lesions and should also be recorded at baseline. It is possible to record multiple 
nontarget lesions involving the same organ as a single item on the case record form (e.g. 
“multiple enlarged pelvic lymph nodes” or “multiple liver metastases”). Measurements of 
these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 

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IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
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If there is a defined objective that includes the assessment/measurement of therapeutic 
response to the defined treatment intervention, then detailed description of the measure, 
methods to be used (e.g., scales and/or definitions to assess response) and the criteria to 
determine each level of therapeutic response should be included. 
 
If appropriate, indicate what are the limiting factors required to 1) assess response and 2) 
determine if subject is evaluable and to be included in the study results. This may include 
total number of treatment interventions required, duration of on-study period, total number of 
measures utilized to assess therapeutic response, etc. 
 
12.1.5 Guidelines for evaluation of measurable disease: all measurements should be taken 
and recorded in metric notation. The same method of assessment and the same technique 
should be used to characterize each identified and reported lesion at baseline and during 
follow-up. 
 
12.2 Response criteria 
 
 
12.2.1 Complete Response (CR) - Target Lesions: Disappearance of all target lesions. Any 
pathological lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm (the sum may not be “0” if there are target nodes) Non-target Lesions: 
disappearance of all non - target lesions and normalization of tumor marker level. All lymph 
nodes must be non-pathological in size (< 10 mm short axis) . Non-CR: Persistence of 1 or 
more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits 
 
12.2.2 Partial Response (PR) - a 30-99% decrease in the sum of the longest diameter of 
target lesions, taking as reference the baseline sum longest diameter. 
 
12.2.3 Stable Disease (SD) - neither sufficient shrinkage to qualify for partial response nor 
sufficient increase to qualify for progressive disease, taking as reference the smallest sum 
longest diameter since the treatment started, or the persistence of one or more nontarget 
lesions. 
 
12.2.4 Progressive Disease (PD) – at least a 20% increase in the sum of the longest 
diameter of target lesions, taking as reference the smallest sum longest diameter recorded 
since the treatment started and minimum 5mm increase over the nadir, or the appearance of 
one or more new lesions and/or unequivocal progression of existing nontarget lesions. 
 
12.3 Best Overall Response – the best response recorded from the start of treatment until 
disease progression/recurrence. The table below should be used to determine best overall 
response. Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
Overall Re sponses for All Combinations of Tumor 
Re sponses in Target and Non-target Lesions with or without 
the Appe arance of Ne w Lesions 
Targe t 
Nontarget 
Ne w 
Overall 

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Le sions 
Le sions 
Le sions 
Re sponse 
CR 
CR 
No 
CR 
CR 
Non CR/non 
PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one 
of the following criteria applies: 
 
• Disease progression 
• Duration of therapy delay of therapy more than 4 weeks. In the rare instance where the 
investigator considers the therapy still be beneficial and more than 4 weeks are needed for 
recovery, the study PI or co-PI should be contacted 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse event(s) 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
• If at any time the patient is found to be ineligible for the protocol as designated in the s ection 
on Criteria for Patient/Subject Eligibility (i.e., a change in diagnosis), the patient will be 
removed from the study. 
 
Patients who are removed from study for any of these reasons will continued to be monitored 
for survival, unless consent for continued follow-up is withdrawn. Patients will be encouraged 
to continue to undergo repeat staging radiologic studies scans until progression or death. 
 
14.0 
BIOSTATISTICS 
 
This trial contains a dose escalation phase I portion to determine the MTD of MEK162 in 
combination with gemcitabine and cisplatin. This will be followed by a non-randomized phase 
II portion to assess the PFS at six months in patients with advanced biliary cancer treated 
with gemcitabine, cisplatin and MEK162 at the MTD determined in the phase I trial. Six 
patients treated at the MTD of MEK162 in the phase I trial will be considered evaluable for 
the primary and secondary endpoints of the phase II trial. Anticipated accrual is 2 patients 
per month. 
 
Phase I 
 
In the phase I component of the study, a classic 3+3 cohort dose escalation scheme will be 
used to identify the MTD of MEK162 when administered with gemcitabine at dose 800 mg/m 2 

Memorial Sloan Kettering Cancer Center
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and cisplatin given at dose 20 mg/m2  day 1 and 8 of a 21 day cycle. MEK162 will be self- 
administered orally BID continuously. Three dose levels are planned. A minimum of 2 
patients and a maximum of 18 patients will be enrolled in the phase I part of this study. 
 
Table 1: Dose levels for MEK162, gemcitabine and cisplatin 
 
 
Dose level 
MEK162* 
Ge mcitabine 
Cisplatin 
1 
30 mg PO BID 
800 mg/m2 
20 mg/m2 
2 
45 mg PO BID 
800 mg/m2 
20 mg/m2 
3 
MTD (30mg or 
45mg PO BID) 
1000 mg/m2 
20 mg/m2 
 
 
 
A dose escalation scheme will be used whereby patients will be treated in sequential cohorts 
of 3. If no patients experience a DLT at dose level 1 in an initial group of 3 patients a new 
cohort of patients will be enrolled at dose level 2.  If 1 of 3 patients experiences a DLT, the 
cohort will be expanded to 6.  If no further DLT occurs, a new cohort will be enrolled at the next 
dose-level.  If 2 of 6 patients experience a DLT, MTD has been exceeded.  The MTD will be defined 
as the highest dose for which not more than 1 of 6 patients develop a DLT. If three or fewer patients 
are treated at the dose considered to be the MTD, additional patients (to a total of six) will be treated 
at that level to confirm the MTD. No intrapatient dose escalation will 
occur. This escalation 
scheme is summarized in Table 2. 
 
Table 2: Dose e scalation scheme using 3 + 3 de sign. 
 
Numbe r of patients with DLT 
Action 
0/3 
Increase to next dose level 
1/3 
Accrue 3 more patients to same dose level 
> 2/3 
Stop, recommend previous dose level 
1/6 
Accrue 3 more patients to next dose level 
> 2/6 
Stop, recommend previous dose level 

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The dose escalation scheme provides the following probabilities of escalation based on the true 
chances of DLT at a specific dose level. One can see that the probability of escalation is high if the 
toxicity risks are low: 
 
Table 3: Probabilities of dose escalation and toxicity: 
 
True probability 
of toxicity 
.10 
.20 
.30 
.40 
.50 
.60 
Probability of 
escalation 
.91 
.71 
.49 
.31 
.17 
.08 
 
Phase II 
 
A randomized phase II trial conducted in 80 patients with locally advanced or metastatic 
BTCs reported a 6-month progression-free survival rate (PFS6) of 59% and response rate 
(RR) of 26% for the combination of gemcitabine and cisplatin.55      An exact binomial single 
stage design will be used to discriminate between true 6-month PFS rates of 59% vs. 82%, 
and between true response rates of 26% and 50%. Thirty five patients will be enrolled. If at 
least 26 patients were observed to survive progression-free for at least 6  months, or at least 
14 responses were observed among the 35 patients over one year, this agent would be 
considered worthy of further testing in this disease. 
 
This design yields 91% power to detect a true 6-month PFS rate of at least 82%, and a true 
RR of at least 50%.  It yields a 0.05 probability of a positive PFS result if the true 6- month 
PFS rate is no more than 59%, and a 0.05 probability of a positive RR result if the true RR is 
no more than 26%. Therefore, assuming that PFS and RR are independent, the overall type 1 
error is .10.  The type 1 error decreases very slightly if PFS and RR are positively correlated, 
which is very likely. 
 
Patients who drop out of the study before 6 months due to toxicity or other reason without 
documented disease progression will be counted as events (disease progression) for the 
primary endpoints. However these patients will be encouraged to continue to undergo repeat 
staging radiologic studies until progression or death. 
 
The PI and co-PI will be monitoring the outcome of the study on frequent basis. If it is found 
at any time that there are 10 patients that die or progress within the first 6 months, the trial 
will be stopped as at that point it is mathematically impossible to achieve the desired 
endpoint of having 26 out of 35 patients alive and progression free at 6 months. 
 
Time to progression will be calculated from study entry to documented disease progression, 
while progression free survival will be calculated from study entry to documented disease 
progression or death from any cause, whatever occurs first. 
 
Patients who progress at the 26-week (+/- 2 weeks) planned scan, regardless of the actual 
calendar date of that scan, will be declared as have progressed at six-months. 
 
Time to death (survival) will be calculated from study entry to death or censored at last follow 
up. 

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Time to progression, overall and progression free survival will be estimated using the 
Kaplan–Meier methodology. The documented response rate and exact 95% confidence 
intervals will be calculated. 
 
For the correlative study endpoints described in Section 9.3, progression-free- 
survival, tim e-to-progression, and overall survival will be correlated w ith categorical 
markers using the log-rank test, w hile C ox regression will be used for c ontinuous 
markers. Tumor respons e will be correlated using Fishers exact test for categoric al 
biom arkers and using Wilcoxon rank sum test for continuous m arkers. The frequency 
of the CTC in the pre and post treatm ent biopsies w ill be summ arized   descriptively. If 
CTC are detected, the change in CTC from pre to post treatment biopsies w ill be 
associated with response using the Wilc oxon rank sum test. These studies are 
exploratory. Not all patients may have tissue available so the analyses may involve 
fewer than 35 patients. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Re search Participant Re gistration 
 
 
 
Confirm in the electronic medical record that the patient has received the Notice of Privacy 
Practice. This must be obtained before the eligibility confirmation and obtaining of the 
research informed consent. Confirm eligibility as defined in the section entitled Criteria for 
Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) Office 
at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday from 
8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR Electronic 
Registration System (http://ppr/).  The completed signature page of the written consent/RA or 
verbal script/RA, a completed Eligibility Checklist and other relevant documents must be 
uploaded via the PPR Electronic Registration System. 
 
15.2 
Randomization 
 
No randomization required in this study 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. The data collected for this study will be entered into a secure 
database, the Clinical Research Database (CRDB).  Source documentation will be available 

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to support the computerized patient record. 
 
 
16.1 
Quality Assurance 
Weekly registration reports will be generated to monitor patient accruals and completeness 
of registration data. Routine data quality reports will be generated to assess missing data 
and inconsistencies. Accrual rates and extent and accuracy of evaluations and follow -up will 
be monitored periodically throughout the study period and potential problems will be brought 
to the attention of the study team for discussion and action. Random-sample data quality and 
protocol compliance audits will be conducted by the study team, at a minimum of two times 
per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research. The MSKCC Data and 
Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://mskweb5.mskcc.org/intranet/_assets/_tables/content/359709/DSMPlans07.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional pr ocesses in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) for 
Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III 
clinical trials, report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, 
in-house sponsored, industrial sponsored, NC I cooperative group, etc.) will be addressed 
and the monitoring procedures will be established at the time of protocol activation 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
  
 
 
17.1 
Priv acy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Se rious Adverse Event (SAE) Re porting 

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Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar 
days. The IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office at sae@mskcc.org.  The report should contain the following 
information: 
 
Fields populated from CRDB: 
 
• 
Subject’s name (generate the report with only initials if it will be sent outside of 
MSKCC) 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
➢   A explanation of how the AE was handled 
➢   A description of the subject’s condition 
➢   Indication if the subject remains on the study 
➢   If an amendment will need to be made to the protoc ol and/or consent form. 
 
The PI’s signature and the date it was signed are required on the completed report. 
 
For IND/IDE protocols: 
The CRDB AE report should be completed as above and the FD A assigned IND/IDE number 
written at the top of the report. If appropriate, the report will be forwarded to the FD A by the 
SAE staff through the IND Office. 
 
Serious adverse event (SAE) is defined as one of the following: 
 
• 
Is fatal or life-threatening 
 
• Results in persistent or significant disability/incapacity 
 
• Constitutes a congenital anomaly/birth defect 
 
• 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 
 
• Requires inpatient   hospitalization   or   prolongation   of   existing   hospitalization,   unless 
hospitalization is for: 
 
➢
  
Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition (specify what this includes) 

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IRB Number: 13-004 A(11) 
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➢
  
Elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication  under  study  and  has  not  worsened  since  signing  the informed 
consent 
 
➢
  
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 
 
➢
 
Social reasons  and respite care in the absence of any deterioration  in the 
patient’s general condition 
 
➢
  
Any SAEs that are expected due to the condition being treated, including if the 
SAE is a primary outcome measure, and whether there has been a clear agreement 
with regulators not to consider these as SAEs, provided the information is collected 
elsewhere 
 
17.2.1 Re porting 
 
Reporting requirements to Array: 
 
All events must be reported, by FAX (303-386-1516), to Array Drug Safety within 24 hours of 
learning of its occurrence. This includes serious, related, labeled (expected) and serious, 
related, unlabeled (unexpected) adverse experiences. All deaths during treatment or within 
30 days following completion of active protocol therapy must be reported within 24 hours. 
 
Any serious adverse event occurring after the patient has provided informed consent and 
until  4 weeks  after  the  patient  has  stopped  study  participation  must  be reported.  This 
includes the period in which the study protocol interferes with the standard medical treatment 
given to a patient (e.g. treatment withdrawal during washout period, change in treatment to a 
fixed dose of concomitant medication). 
 
Serious adverse events occurring more than 4 weeks after study discontinuation need only 
be reported if a relationship to the Array study drug (or therapy) is suspected. 
 
Follow-up information is sent to the same person to whom the original SAE Report Form was 
sent, using a new SAE Report Form stating that this is a follow -up to the previously reported 
SAE  and  giving  the  date  of  the  original  report.  Each  re-occurrence,  complication,  or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
 
If the SAE is not previously documented  in the Investigator’s  Brochure or Package Insert 
(new  occurrence)   and  is  thought  to  be  related  to   MEK162,  an  Array  Drug  Safety 
representative  may  urgently  require  further  information  from  the  investigator  for  Health 
Authority reporting.  Array may need to issue an Investigator  Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported 
to the competent  authorities  and relevant ethics committees  in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries. 
 
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
To ensure patient safety, each pregnancy in a patient on study drug 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. 

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IRB Number: 13-004 A(11) 
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Page 42 of 46
 
 
 
 
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form  and reported by the 
investigator to Array Drug Safety. 
 
 
Ethics and Good Clinical Practice 
 
This study must be carried out in compliance with the protocol and the principles of Good 
Clinical Practice, as described in: 
 
1. 
ICH  Harmonized  Tripartite  Guidelines  for  Good  Clinical  Practice  1996.  Directive 
91/507/EEC, The Rules Governing Medicinal Products in the European Community. 
 
2. 
US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
 
3. 
Declaration of Helsinki and amendments,  concerning medical research in humans 
(Recommendations Guiding Physicians in Biomedical Research Involving Human 
Subjects). 
 
The investigator agrees to adhere to the instructions and procedures described in it 
and thereby to adhere to the principles of Good Clinical Practice that it conforms to. 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior 
to their inclusion in the study. Participants will also be informed that they are free to withdraw 
from the study at any time. All participants must sign an IRB/PB-approved consent form 
indicating their consent to participate. This consent form meets the requirements of the Code 
of Federal Regulations and the Institutional Review Board/Privacy Board of this Center. The 
consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form. 
 
 
19.0 
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IRB Number: 13-004 A(11) 
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20.0 
APPENDICES 
 
APPENDIX A: Gene List for Analysis 

Memorial Sloan Kettering Cancer Center
IRB Number: 13-004 A(11) 
Approval date: 25-Oct-2017 
Page 46 of 46
 
 
 
 
 
APPENDIX B: RECIST 1.1: 
 
APPENDIX C: SOP for pERK Phosphoflow studies 
 
APPENDIX D: Amsler grid test 
 
APPENDIX E: ECOG-KPS Conversion Table