Conditions: Lungcancer
Keywords: Lung cancer Non small cell lung cancer non squamous pemetrexed carboplatin binimetinib chemotherapy combination chemotherapy Phase 1 Princess Margaret Cancer Centre carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These data suggest that MEK162 may provide a potential benefit in cancer indications harboring these mutations. MEK162 is currently being investigated in phase I clinical testing and has been well tolerated up to an MTD of 45mg BID in cancer patients.

There has been little change in survival benefit for patients with non-small cell lung cancer in recent years. Emerging new treatment options relying on molecular and genetic markers are being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer with molecular targeted therapies in combination with standard chemotherapy. This study will be targeting patients with KRAS mutations.

Detailed description:
OBJECTIVES

1.1 Primary Objectives

* To assess the safety of MEK162 administered in combination with carboplatin and pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).
* To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a continuous dosing schedule together with pemetrexed and carboplatin administered on a 3-weekly schedule as first line treatment in advanced NSCLC.
* To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.

1.2 Secondary Objectives

* To characterize the population pharmacokinetics of MEK162 administered in combination with carboplatin and pemetrexed (Phase I).
* To explore relationships between KRAS mutation (and sub-types) and additional genomic mutations and objective clinical response.

1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined in section 4.3) as measured with NCI CTC AE v4.

Phase Ib

• Objective response rate (ORR) as per RECIST v1.1.

Secondary Phase I • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs.

Phase Ib

* Evaluation of response rate (RR), progression-free survival (PFS) and disease control rate (DCR) for patients with and without KRAS mutation in tumor tissue.
* Exploratory analysis of KRAS mutation sub-type.

Exploratory end-points

• A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.

Arms:
arm 1: This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed.

Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma.

Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype.

The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.

Interventions: intervention 1: Binimetinib intervention 2: Pemetrexed intervention 3: Carboplatin
Intervention descriptions: intervention 1: Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease.

MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule. intervention 2: 4-6 cycles given intravenously in combination with carboplatin as per standard therapy. intervention 3: 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.

Protocol document:
Prot_SAP_000.pdf: 
Protocol #: CMEK162ACA02T 
Version Date: 31-May-2018 
1 
 
 
 
 
Cover Page 
 
 
TITLE: A Phase I/Ib Study of MEK162, a MEK inhibitor, in combination with 
carboplatin and pemetrexed in patients with non-squamous carcinoma of the lung. 
 
Protocol #: CMEK162ACA02T  
Version Date: 31-May-2018  
Protocol Number: CMEK162ACA02T  
Protocol Version/ Date: Amendment 6/31 May 2018 
NCT02185690 
 
 
 


Protocol #: CMEK162ACA02T 
Version Date: 31-May-2018 
2 
 
 
Protocol Number: CMEK162ACA02T 
Protocol Version/ Date: Amendment 6/31 May 2018 
 
 
TITLE:  A Phase I/Ib Study of MEK162, a MEK inhibitor, in combination with carboplatin and 
pemetrexed in patients with non-squamous carcinoma of the lung 
 
 
Coordinating Center: 
 
 
Princess Margaret Cancer Centre, University Health Network, 
Toronto, Ontario, Canada 
 
*Sponsor-Investigator: 
Dr. Natasha Leighl 
 
Division of Medical Oncology 
 
700University Avenue 
Toronto, ON M5G 1X6 
 
Telephone: 416-946-4645 
 
Fax: 416-946-6546 
 
E-mail: natasha.leighl@uhn.ca 
 
 
Institutions: 
Dr. Scott Laurie 
 
The Ottawa Hospital Regional Cancer Centre 
 
Ottawa, ON K1H 8L6 
 
Telephone: 613-737-7700 x70175 
 
Fax: 613-247-3511  
 
E-mail: slaurie@ottawahospital.on.ca 
 
 
Dr. Peter Ellis 
 
Juravinski Cancer Centre 
 
Hamilton, ON L8V 5C2 
 
Telephone: 905-387-9711 x64609  
 
Fax: 905-575-6326  
 
E-mail: Peter.Ellis@jcc.hhsc.ca 
 
 
Dr. Quincy Chu  
 
 
 
Cross Cancer Institute 
11560 University Avenue  
Edmonton, AB T6G 1Z2 
Telephone: 780-432-8248 
E-mail: quincy.chu@albertahealthservices.ca 
 
 
*A study can have only one Principal Investigator.  The Principal Investigator must be a 
physician and is responsible for all study conduct.   
 
Statistician: 
 
Lisa Wang 
 
Princess Margaret Cancer Centre  


Protocol #: CMEK162ACA02T 
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610 University Avenue 
Toronto, ON M5G 2M9 
Telephone: 416-946-4501 x4883 
Fax: 416-946-2154 
 
E-mail: lisawang@uhnresearch.ca 
 
 
Central Office Coordinator: 
Stephanie Effendi 
 
Princess Margaret Cancer Centre 
 
700 University Ave 
 
Toronto, ON M5G 1X6 
 
Telephone: 416-946-4501 x 5185 
 
Fax: 416-946-2016 
 
Email: Stephanie.effendi@uhn.ca 
 
Investigational Agent: MEK162 
Commercial Agents: Carboplatin and Pemetrexed 
 
 
 
Coordinating Centre: Princess Margaret Cancer Centre Drug Development Program 
 
Health Canada Control Number: 173681, 199168 
CR File Number: HC6-24-c173681 
 
 
 
 


Protocol #: CMEK162ACA02T 
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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SYNOPSIS 
 
Title of study: A Phase I/Ib Study of MEK162, a MEK inhibitor, in combination with 
carboplatin and pemetrexed in patients with non-squamous carcinoma of the lung 
Objectives:  
Primary 
 To assess the safety of MEK162 administered in combination with carboplatin 
and pemetrexed as first line chemotherapy treatment in advanced non-small cell 
lung cancer (NSCLC). 
 To determine the recommended phase II dose (RP2D) of MEK162 to be used 
when given in a continuous dosing schedule together with pemetrexed and 
carboplatin administered on a 3-weekly schedule in advanced NSCLC. 
 To explore the efficacy (as measured by tumor response in the Phase Ib portion) 
of the combination of MEK162 in addition to pemetrexed and carboplatin in 
chemotherapy-naïve patients with EGFR wild-type, ALK-rearrangement 
negative NSCLC of the lung. 
Secondary 
 To characterize the population pharmacokinetics of MEK162 administered in 
combination with carboplatin and pemetrexed (Phase I). 
 To explore relationships between KRAS mutation (and sub-types) and additional 
genomic mutations and objective clinical response. 
Study Design: This is a Phase I/Ib, open-label, dose-escalation, multi-center, non 
randomized study designed to evaluate the safety and tolerability of oral MEK162 
 
administered as BID dosing in combination with carboplatin and pemetrexed.  
Number of patients: 
Phase I: Standard 3+3 dose-escalation design consisting of up to two independent dose-
escalation treatment groups and one dose de-escalation group 
Phase Ib: 30 patients (including those treated at the same dose combination in the dose-
Stage IV 
Nonsquamous 
carcinoma of 
lung 
EGFR mut (-) 
ALK (-) 
Treatment-naïve 
Genomic  
Profiling 
(6-8 weeks) 
4-6 cycles 
Carboplatin 
+ 
Pemetrexed 
+ 
Continuous MEK162 
Dose escalation to RP2D 
4-6 cycles 
Carboplatin 
+ 
Pemetrexed 
+ 
Continuous MEK162 
At RP2D 
 
Phase I 
Phase Ib 
Maximum  
12 patients 
 Approximately 30 patients 
(inclusive of 6 patients  
at RP2D of Phase I component) 


Protocol #: CMEK162ACA02T 
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escalation phase of the study who are eligible for the safety set) 
Main criteria for Inclusion/Exclusion: 
Inclusion Criteria: 
- 
histologically confirmed stage IV non-squamous lung carcinoma (dose 
escalation), EGFR/ALK wild type (dose expansion) 
- 
tissue available for KRAS genotyping (unless known) 
- 
presence of measurable disease (RECIST version 1.1) 
- 
 no prior chemotherapy treatment for advanced NSCLC 
- 
Eastern Cooperative Oncology Group performance status 0 or 1 
- 
Life expectancy > 3 months 
- 
Treated stable CNS metastases permitted 
Exclusion Criteria: 
- 
History of significant ocular disease including retinal vein occlusion, central 
serous retinopathy, uncontrolled glaucoma, uncontrolled diabetes or 
hypertension 
- 
History of clinically significant interstitial lung disease or pneumonitis 
- 
QTc prolongation or clinically significant risk for prolonged QT interval  
- 
Active viral infection (hepatitis B, C or HIV) 
- 
Uncontrolled hypertension, recent acute coronary syndromes, other 
uncontrolled medical illness 
 
Intervention: 
- 
Cycle 1 (28 days): MEK162 days 1-5, then pemetrexed plus carboplatin IV on 
day 8, resume MEK162 days 8-26 
- 
Cycles 2 – 6 (21 days): pemetrexed plus carboplatin IV day 1, MEK162 days 1-
19 
- 
Subjects may receive up to 6 cycles of treatment 
Correlatives: 
- 
archival tissue will be analyzed for KRAS mutation status 
- 
for the dose escalation phase, this will be initiated at study enrolment 
- 
for the Phase Ib cohort expansion, this will initiated at study enrolment until one 
exploratory cohort is full (10 patients each in KRAS WT, G12C mutant, non-
G12C mutant cohorts); thereafter it will be required prior to study enrolment  
Statistics: 
After determination of RP2D, summary statistics will be used to report response rate, 
toxicity, progression-free survival (Kaplan-Meier), disease control rate. Analysis of 
outcome and toxicity by KRAS mutation subtype will be explored.  
 
 
 
 
 
Table outlining dose escalation schedule for study 


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Dose Escalation Schedule 
Dose Level 
Dose* 
MEK162** 
(mg) 
Carboplatin (AUC) 
 
Pemetrexed 
(mg/m2) 
Level -1 
30 BID*** 
5 
500 
Level 1 
30 BID 
5 
500 
Level 2 
45 BID 
5 
500 
*Doses are stated as exact dose in units (e.g., mg/m2, mcg/kg, etc.) rather than as a percentage. 
**Cycle 1: continuous dosing until day 5. Omit doses for 2 days prior to chemotherapy 
administration (cycle 1 days 6 and 7 and days 27 and 28; for additional cycles omit doses day 
20 and 21). Chemotherapy is to be administered cycle 1 day 8 and day 1 of every cycle 
thereafter. Cycle 1 has 28-day duration with subsequent cycles having 21-day duration. 
***Dose Level -1: MEK162 will be given in Cycle 1 as continuous dosing days 1-5, then days 
8-21 in the 28 day cycle; subsequent cycles will include MEK162 continuous dosing days 1-14 
in each 21 day cycle.  
 
In addition to dose levels noted above, intermediate dose levels or non-daily dosing of MEK 
162 (e.g. alternate dosing schedule of 2 weeks on/1 week off) may be implemented dependent 
on toxicity or emergent findings from this and other trials. 
 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................4 
SYNOPSIS .......................................................................................................................................4 
1. OBJECTIVES ............................................................................................................................10 
1.1 
Primary Objectives.................................................................................................10 
1.2 
Secondary Objectives.............................................................................................10 
1.3 
Exploratory Objectives ..........................................................................................10 
2. 
BACKGROUND ...............................................................................................................10 
2.1 
Study Disease .........................................................................................................10 
2.2 
Investigational Agent .............................................................................................13 
2.3 
Other Agents ..........................................................................................................17 
2.4 
Rationale ................................................................................................................19 
2.5 
Correlative Studies Background ............................................................................20 
3. 
PATIENT SELECTION ....................................................................................................21 
3.1 
Eligibility Criteria ..................................................................................................21 
3.2 
Exclusion Criteria ..................................................................................................24 
3.3 
Inclusion of Women and Minorities ......................................................................25 
4. 
REGISTRATION PROCEDURES ...................................................................................26 
4.1 
General Guidelines.................................................................................................26 
4.2 
Registration Process ...............................................................................................27 
5. 
TREATMENT PLAN ........................................................................................................27 
5.1 
Agent Administration.............................................................................................27 
5.2 
Trial Design ...........................................................................................................30 
5.3 
Definition of Dose-Limiting Toxicity ....................................................................32 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................34 
5.5 
Duration of Therapy ...............................................................................................35 
5.6 
Duration of Follow Up ...........................................................................................35 
5.7 
Criteria for Removal from Study ...........................................................................36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................36 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................44 
7.1 
List of Adverse Events and Reporting Requirements ............................................44 
7.2 
Adverse Event Characteristics ...............................................................................46 
7.3 
Serious Adverse Event Reporting ..........................................................................48 
7.4 
Routine Adverse Event Reporting .........................................................................50 
7.5 
Documentation of Adverse Events ........................................................................50 
7.6 
Follow-Up of AEs and SAEs .................................................................................50 
7.7 
Pregnancy ...............................................................................................................51 
7.8 
Investigator Notifications.......................................................................................51 


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7.9 
Data Safety and Monitoring Board ........................................................................51 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................51 
8.1 
Investigational Agent .............................................................................................51 
8.2 
Non-Investigational Agents ...................................................................................53 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................55 
9.1 
Pharmacokinetics ...................................................................................................55 
9.2 
Biomarker Studies ..................................................................................................57 
9.3 
Laboratory Correlative Studies ..............................................................................58 
10. 
STUDY CALENDAR .......................................................................................................58 
10.1 
Baseline/Pre-Study Evaluations .............................................................................60 
10.2 
Treatment ...............................................................................................................60 
10.3 
Specific guidance related to blood pressure...........................................................61 
10.4 
End of Study Drug Administration and Follow-Up Evaluations ...........................62 
11. 
MEASUREMENT OF EFFECT........................................................................................62 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................62 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................67 
12.1 
Data Collection and Reporting...............................................................................67 
12.2 
Source Documents .................................................................................................67 
12.3 
Retention of Patient Records and Study Files........................................................68 
12.4 
Site and Study Closure ...........................................................................................68 
13. 
STATISTICAL CONSIDERATIONS...............................................................................69 
13.1 
Study Design/Endpoints.........................................................................................69 
13.2 
Sample Size/Accrual Rate ......................................................................................70 
13.3 
Analysis of Primary Endpoints ..............................................................................70 
13.4 
Stratification Factors ..............................................................................................70 
13.5 
Analysis of Secondary Endpoints ..........................................................................70 
13.6 
Analysis of Exploratory Endpoints ........................................................................71 
REFERENCES ..............................................................................................................................71 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................75 
APPENDIX B 
 DATA MANAGEMENT GUIDELINES .................................................76 
APPENDIX C 
PATIENT DIARY (CYCLE 1) .................................................................78 
APPENDIX D 
PATIENT DIARY CYCLE 2+ ..................................................................80 
APPENDIX E 
INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................82 
APPENDIX F 
LISTING OF AGENTS INTERACTING WITH CYTOCRHOME P45086 


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APPENDIX G 
MANAGEMENT OF DRUG-INDUCED TOXICITY .............................88 
APPENDIX H 
BLOOD PRESSURE DIARY TEMPLATE .............................................92 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
 To assess the safety of MEK162 administered in combination with carboplatin and 
pemetrexed as initial chemotherapy in advanced non-small cell lung cancer (NSCLC). 
 To determine the recommended phase II dose (RP2D) of MEK162 to be used when given 
in a continuous dosing schedule together with pemetrexed and carboplatin administered 
on a 3-week schedule as initial chemotherapy in advanced NSCLC. 
 To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the 
combination of MEK162 in addition to pemetrexed and carboplatin in chemotherapy-
naïve patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung. 
 
1.2 
Secondary Objectives 
 
 To characterize the population pharmacokinetics of MEK162 administered in 
combination with carboplatin and pemetrexed (Phase I). 
 To explore relationships between KRAS mutation sub-types and objective clinical 
response. 
 
1.3 Exploratory Objectives 
 
 A limited sampling strategy pharmacokinetic model will be used to ensure that the 
clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-
based chemotherapy. 
 
2. BACKGROUND 
 
2.1 
Study Disease 
 
Non-small cell lung cancer (NSCLC) remains the most common and lethal malignancy in the 
world for both men and women (Canadian Cancer Society, 2013). Over 1 million cases are 
diagnosed each year (Juergens, 2006) and there are more than 900,000 NSCLC-related deaths 
annually (Jemal, 2011). The majority of patients are diagnosed with advanced disease at 
presentation or experience disease recurrence after initial curative approach. In spite of a wealth 
of translational and clinical research in recent years, there has been little change in overall survival 
(OS) with five-year survival rates of 18% for all stages combined (Canadian Cancer Society, 
2013). Although lung cancer rates have decreased in developed countries in the last decade, the 
incidence of lung adenocarcinoma continues to rise both in men and women worldwide for reasons 
that are not fully understood (Charloux 1997, Devesa, 2005, Jemal 2011). Thus, emerging new 
therapeutic modalities relying on distinct molecular and genetic changes within the lung cancer 
genome are being extensively studied as targets for new drugs for their potential to improve the 
outcome for patients with NSCLC (Maione, 2006).  
 


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First-line therapy for advanced NSCLC consists of platinum-based doublet chemotherapy 
(Schiller, 2002). The combination of cisplatin and pemetrexed has yielded greater benefits in the 
adenocarcinoma subgroup (40-60% of NSCLC). In a trial investigating first-line treatment with 
this combination compared with cisplatin and gemcitabine, a 2.5-month improvement in overall 
survival was seen for this group (12.6 v 10.9 months) with the pemetrexed-based regimen with a 
response rate of 30.6% in patients treated in this arm (Scagliotti 2008). The observation of 
improved efficacy of pemetrexed plus platinum in the adenocarcinoma population and inferior 
efficacy in squamous cell carcinoma led to the label change in pemetrexed to treat only those 
patients with non-squamous histology lung cancers. Subsequently, the combination of pemetrexed 
and carboplatin has been assessed in a number of phase II and III trials (Gervais, 2013; Schuette, 
2013; Zukin, 2013; Okamoto, 2013). Response rates have been favorable (20-35.8%) with this 
combination and toxicity was manageable with many of the populations for these trials being 
elderly or having reduced performance status. 
 
Subsequently, there has been a paradigm shift in the management of NSCLC with targeted therapy 
demonstrating proven benefit in patients with activating mutations of the tyrosine kinase domain 
of the epidermal growth factor receptor (EGFR) (Mok, 2009) and translocations in the ALK gene 
(Kwak, 2010). These drugs are now routinely utilized in the front-line setting to treat biomarker 
positive tumors. Somatic abnormalities in the EGFR and ALK genes are found in less than 20% of 
adenocarcinomas. Classification of lung cancer is becoming increasingly focused on genomic 
abnormalities. This renders the term non-small cell lung cancer less clinically useful and highlights 
the true molecular and genetic diversity of this disease allowing personalised and patient-centered 
care. 
 
Within the adenocarcinoma subtype, up to 30% of tumors will harbor activating mutations in KRAS 
(Bos 1989). Because the RAS-RAF-MEK-ERK signaling pathway is activated as a consequence of 
KRAS or BRAF mutations in human cancer (Davies, 2002), it is an attractive target for small 
molecule intervention (Ding, 2008). Given the critical location of MEK in this signaling pathway, 
it has been recognized as an important target for anti-cancer therapy. Drug development efforts to 
inhibit MEK demonstrated clinical benefit, although with limited overall success. For example, 
PD-0325901, CI-1040, and AZD6244, have achieved objective responses in melanoma, pancreatic 
cancer, and non-small cell lung cancer (Tzekova, 2008), but none have demonstrated significant 
single-agent activity in these tumor types. 
Recently published data confirm clinical efficacy with the combination of MEK inhibition 
(selumetinib) and docetaxel chemotherapy in the treatment of patients with KRAS-mutant NSCLC 
with improved response rate, progression-free survival and quality of life compared with docetaxel 
alone (Jänne, 2012). In this study, median progression-free survival was 5∙3 months (95% CI 4∙6–
6∙4) in the selumetinib group and 2∙1 months (1∙4–3∙7) in the placebo group (HR for progression 
with selumetinib 0∙58, 80% CI 0∙42–0∙79; one-sided p=0∙014). There was a 37% response rate in 
the selumetinib arm and no response in the docetaxel arm (two-sided p<0∙0001). Grade 3–4 
neutropenia, febrile neutropenia, and asthenia were more common in the selumetinib group than 
in the placebo group; by contrast, grade 3–4 dyspnea was more common in the placebo group than 
the selumetinib group. 
MEK inhibition with trametinib has also been combined with pemetrexed in a second-line phase 
I/Ib trial with patients stratified by KRAS status (Kelly, 2013). In this study, 42 patients were 


Protocol #: CMEK162ACA02T 
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treated with the combination. While no difference in response rate was seen between these groups 
(16% vs. 17%), these response rates compare favourably with historical data for pemetrexed 
treatment (Hanna, 2004) and support the absence of any negative interaction between these agents. 
In addition, the most common grade 3/4 toxicites were neutropenia (21%), anaemia (14%), 
asthenia (10%), nausea (7%) and dyspnea (7%). Diarrhoea is a known side effect of MEK 
inhibition and was present at grade 3/4 in 5% of cases. On review of all MEK-inhibitor trials, there 
is an increased incidence of neutropenia and febrile neutropenia when MEK inhibitors are added 
to chemotherapy. In the phase I/Ib trial combining docetaxel and trametinib supportive granulocyte 
colony-stimulating factor (GCSF) was used and the regimen was tolerable with disease control 
rate of 61% (Gandara, 2013). 
MEK162 (binimetinib), previously named ARRY-438162, is an oral, ATP non-competitive, 
highly selective inhibitor of MEK1/2 that has nanomolar activity against purified MEK enzyme 
(IC50 = 12 nM) and inhibits both basal and induced levels of ERK phosphorylation in numerous 
cancer cell lines with IC50s as low as 5 nM. MEK162 is especially potent at inhibiting the cell 
proliferation of mutant BRAF and RAS human cancer cell lines in vitro. In vivo, MEK162 has 
demonstrated dose-dependent tumor growth inhibition in various subcutaneous tumor transplants 
harboring BRAFV600E or RAS mutations, including HT29, MIA PaCa2, A549, LoVo, Calu6, 
DU145 and COLO 205. MEK162 has also shown significant inhibition of tumor growth as a single 
agent in NSCLC xenograft models in mice (KRAS mutant A549, EGFR mutant Calu-6, H1975) 
(Winski, 2010). These data suggest that MEK162 may provide a potential therapeutic benefit in 
cancer indications, harboring these mutations. MEK162 is currently investigated in phase I clinical 
testing and has been well tolerated up to a MTD of 45mg bid in cancer patients (Bendell, 2011). 
Studies in advanced or metastatic solid tumors are ongoing in combination with RAF and PI3K 
inhibitors (www.clinicaltrials.gov). In ongoing Phase I trials, in combination with other agents, 
MEK162 has been escalated to MTD of 45mg BID and appears tolerable at this dose. However, 
due to prior incidence of neutropenia and febrile neutropenia with continuous dosing of MEK-
inhibitors in combination with chemotherapy, intermittent dosing schedules are being explored in 
this setting. 
Standard of care in NSCLC at present involves all lung adenocarcinoma samples having 
immunohistochemical staining for ALK rearrangement and EGFR mutation testing (both results 
return in <10 days) to guide treatment decisions. These patients will be commenced on appropriate 
targeted therapies. The remainder of patients with adenocarcinoma will have platinum-based 
chemotherapy as their initial therapy or enroll in a clinical trial.  
 
We plan to offer the combination of carboplatin, pemetrexed and MEK162 to patients with lung 
adenocarcinoma as initial chemotherapy, where no ALK translocation or EGFR mutation are 
identified (after dose escalation phase). We will review the outcomes of the treatment combination 
with a planned review of KRAS mutation status, with particular interest in subtypes thereof. 
 
The following factors including the relative frequency of KRAS mutant NSCLC adenocarcinoma, 
along with an overall poorer prognosis and the lack of an established treatment option makes this 
an attractive option for these patients. This will be the first study combining MEK162 with 
carboplatin and pemetrexed for patients with advanced lung adenocarcinoma. 
 


Protocol #: CMEK162ACA02T 
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13 
 
2.2 
Investigational Agent 
 
2.2.1 MEK162 (binimetinib) 
 
 
Chemical name 
5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-n-(2-hydroxyethoxy)-1-methyl-1h-benzimidazole-
6-carboxamide. 
 
Molecular formula 
C17H15BrF2N4O3 
 
Relative molecular mass 
441.23 
Mechanism of action 
MEK162, previously named ARRY-438162, is an oral, ATP non-competitive, highly selective 
inhibitor of MEK1/2 that has nanomolar activity against purified MEK enzyme (IC50 = 12 nM) 
and inhibits both basal and induced levels of ERK phosphorylation in numerous cancer cell lines 
with IC50s as low as 5 nM. 
 
In vitro efficacy studies 
The biological activity of MEK162 has been evaluated in vitro (enzymatic and cell culture) and in 
vivo mouse xenograft studies. 
In biochemical studies, MEK162 has been shown to be a potent and highly selective inhibitor of 
MEK. In cellular assays, MEK162 has been shown to markedly inhibit the phosphorylation of 
ERK in human cell lines as well as human whole blood. In human MALME-3M melanoma cells 
and in HT29 colorectal cancer cells, MEK162 significantly inhibited proliferation and viability, 
respectively. The ability of MEK162 to inhibit cancer cell growth in culture was evaluated using 
a 
standard 
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-
tetrazolium (MTS) assay. In the human HT-29 colorectal cell viability assay, the IC50 of cell 
growth was observed at a concentration of 163 nM MEK162. In the human melanoma Malme-3M 
cell proliferation assay, the IC50 of cell growth was observed at a concentration of 30 nM 
MEK162. 
 
In vivo efficacy studies 


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In vivo studies were performed to evaluate the activity of MEK162 with respect to inhibiting tumor 
growth and tumor ERK phosphorylation. In the HT29 and in the COLO 205 colon carcinoma 
models, dose-dependent inhibition of tumor growth (up to 75% tumor growth inhibition [TGI]) 
was observed at doses ranging from 3 to 30 mg/kg, qd, by mouth (PO) for 21 days. In the sensitive 
COLO 205 colon carcinoma model, MEK162 treatment resulted in 84% TGI with significant 
tumor regressions at a dose of 30 mg/kg. In the BxPC3 pancreatic carcinoma model (which does 
not harbor either RAS or RAF mutations, but harbors MAP2K4 mutation), significant tumor 
regressions (59%) were seen at doses of 30 mg/kg. In the BxPC3 pancreatic carcinoma model 
(which does not harbor either RAS or RAF mutations, but harbors MAP2K4mutation), ~70% TGI 
and 13% PRs were seen at doses of 30 mg/kg, qd, PO for 21 days. Consistent with the mechanism 
of action for MEK162, TGI correlates with decreased phospho-ERK levels in tumor xenografts. 
Overall, MEK162 has demonstrated potent activity against MEK1/2 and broad anti-proliferative 
activity in vitro and in vivo. 
Non-clinical pharmacokinetics and metabolism of MEK162 
PK studies were conducted with MEK162 in rats, dogs and monkeys. After oral administration, 
the AUC and Cmax values for MEK162 increased in a nearly dose-proportional manner in rats 
and monkeys. The mean bioavailability was lowest in monkeys, higher in dogs, and highest in rats 
at equivalent doses (range across species: 13% to 72%). Following intravenous (IV) 
administration, the plasma clearance (CL) values were low-to-moderate (range: ~2 to 8 
mL/min/kg) and tended to increase across species such that monkey > dog > rat. Mean plasma t1/2 
values showed a similar trend where monkey > dog > rat (range: ~2 to 9 hrs.). The volume of 
distribution at steady state (Vss) values ranged from 0.189 to 1.57 L/kg. 
In vitro experiments in Caco-2 and LLC-PK1 cells indicated that MEK162 had moderate 
membrane permeability and is a substrate for P-gp. MEK162 exhibited high plasma protein 
binding in vitro (> 96%, except dog 84%) and is predicted to have good stability with respect to 
hepatic metabolism. Nonclinical in vitro and in vivo data indicate that there are multiple pathways 
of metabolism for MEK162 including oxidation and glucuronidation. MEK162 is metabolized by 
CYP3A and CYP1A2 with some involvement of CYP2C isoforms. In human plasma, major 
entities include glucuronides of MEK162, as well as the primary active metabolite, AR00426032, 
which is equipotent to MEK162. Formation of AR00426032 that has been monitored in clinical 
studies was found to be mediated primarily by CYP1A2 with minor contributions from other 
cytochrome P450 enzymes. MEK162 did not significantly inhibit (IC50> 25μM) the major CYP 
isoforms. MEK162 was not a time-dependent inhibitor of CYP3A. 
Following single- and repeat-dose administration of MEK162 to Sprague-Dawley rats for up to 6 
months, females were found to have approximately 2-fold higher exposure than males at 
equivalent doses. The values for Cmax and area under the plasma concentration-time curve for a 
dosing interval from time 0 extrapolated to infinity (AUCinf) increased with dose, although the 
increase in exposure was less than dose proportional. Cynomolgus monkeys receiving MEK162 
for 28 days or 9 months showed no consistent differences in exposure between females and males. 
There were no significant changes in exposure versus day. 
 


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Toxicity and safety studies with MEK162 
The toxicological evaluations of MEK162 include single-dose, and 28-day and 6-month repeat-
dose studies in Sprague Dawley rats and 28-day and 9-month repeat-dose studies in cynomolgus 
monkeys, all of which were conducted in accordance with international regulatory guidelines for 
nonclinical toxicity studies and in adherence to current GLP guidelines. These studies were 
supplemented with 3 genotoxicity assays (bacterial mutagenicity, mouse lymphoma assay and 
mouse micronucleus assay), local tolerance, 9 safety pharmacology studies (hERG channel assay 
and behavioral, cardiovascular, renal, pulmonary and 2 gastrointestinal function/tolerability 
studies as well as 2 non-GLP studies evaluating wound healing and immune function) and 3 
developmental toxicity studies in the rat and the rabbit. 
In all of the GLP toxicology studies conducted, there was no significant effect of MEK162 on vital 
signs, coagulation parameters, complement, organ weights or urinalysis parameters in doses up to 
100 mg/kg in rats and 10 mg/kg in monkeys. Administration of MEK162 to rats by oral gavage 
was associated with skin lesions (inflammation/scabbing), microscopic findings of soft tissue 
mineralization (which did not occur with the 26-week dosing regimen) and reversible minimal to 
mild clinical pathology changes. 
Safety pharmacology studies were conducted to assess the effects of MEK162 on key organ 
systems (cardiovascular, respiratory, neurobehavioral, renal and gastrointestinal function). Rats 
received single oral doses of 10, 30 or 100 mg/kg and monkeys were given single oral doses of 1, 
3 and 10 mg/kg. There were no significant in vivo safety findings at doses up to 100 mg/kg in rats 
and 10 mg/kg in monkeys in any of these studies. 
Clinical experience with MEK162 
MEK162 has been previously tested in a single-dose, first-in-human study in healthy subjects 
[ARRY-162-0601], a multiple ascending dose (MAD) study for 14 days in healthy subjects 
[ARRY-162-0602], a single-dose relative bioavailability and food effect study in healthy subjects 
[ARRAY-162-104], a study in patients with rheumatoid arthritis with dosing up to 4 weeks 
[ARRY-162-0603] and a phase 2 study evaluating 12 weeks of MEK162 in combination with 
methotrexate in patients with rheumatoid arthritis [ARRAY-162-201]. A Phase 1 dose-escalation 
study in patients with advanced solid tumors, followed by an expansion phase with cohorts in 
patients with advanced or metastatic biliary cancer and in patients with KRAS- or BRAF-mutant 
metastatic colorectal cancer [ARRAY-162-111], was initiated in August 2009.  
Clinical safety 
Safety data have been evaluated from 5 completed clinical studies in which MEK162 was 
administered qd or bid for up to 12 weeks at total daily doses ranging from 5 mg to 80 mg. In the 
completed studies, 235 subjects/patients received at least 1 dose of MEK162 and have been 
evaluated for safety, including 70 healthy subjects and 165 patients with rheumatoid arthritis. 
In the ongoing clinical study [ARRAY-162-111], a total of 64 cancer patients have received at 
least 1 dose of MEK162 (as of 23rd November 2010). In the dose-escalation phase, 4 dose levels 
were explored: 30 mg bid, 45 mg bid, 60 mg bid, and 80 mg bid. 2 out of 3 evaluable patients 
receiving 80 mg bid experienced DLTs. One patient had CTCAE Grade 3 rash despite maximal 


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treatment measures and one patient had CTCAE Grade 3 central serous retinopathy (CSR). Thus, 
80 mg bid was declared a non-tolerated dose. Six evaluable patients were enrolled at 60 mg bid 
and no DLTs were observed; therefore 60 mg bid was declared the MTD for the dose-escalation 
phase and the dose moved forward to the expansion phase. Subsequently, the MTD has been 
reduced to 45mg BID. 
The most commonly reported AEs reported to date have been rash, diarrhea, nausea, peripheral 
edema, fatigue, and vomiting. Of the patients who developed rash, most occurred within 5-8 days 
of initiation of study drug, were mild-to-moderate in severity, and responded to treatment (topical 
antibiotics, topical or oral steroids) or dose reduction. As noted above, 1 patient developed a 
CTCAE Grade 3 rash which required dose reduction of MEK162. The rash initially presented as 
CTCAE Grade 1 on Study Day 3 and progressed to CTCAE Grade 3 by Study Day 10. However, 
in the majority of cases, study drug was continued throughout treatment of the rash. 
Elevations in creatine kinase (CK) have been observed, but no other apparent trends in clinical 
laboratory parameters, vital signs, or electrocardiograms (ECGs) were associated with 
administration of MEK162. 
Of 41 patients in [ARRAY-162-111] dosed at 60mg bid (as of 13-Oct 2010), a total of 10 patients 
(1 patient in dose escalation, 6 patients in biliary expansion and 3 patients in the CRC expansion) 
have developed ocular findings, consistent with CSR, such as retinal edema and retinal detachment 
during the treatment phase of the study. CSR is a known adverse effect of allosteric MEK-
inhibitors. All reported events of retinopathy have been CTCAE Grade 1 or 2, and consistently 
resolved with holding study drug. Two patients have had a recurrence of retinopathy with re-
challenge of 45 mg bid. One of the patients was in the dose escalation portion of the study and 
discontinued the study due to retinopathy, while the other is being re- challenged with 30 mg bid. 
No retinal events have been reported for 4 patients treated at 45 mg bid during dose escalation. 
The CSR has been reversible following a drug holiday in all affected patients. To establish the 
safety profile of MEK162 at 45mg bid, future patients in the CRC expansion phase of study 
[ARRAY-162-111] are currently enrolled at this dose level. 
Clinical pharmacokinetics 
In healthy subjects, MEK162 exposure (as quantified by Cmax and AUC) tended to increase in a 
dose-proportional manner following single and multiple doses over a dose range of 5 to 80 mg for 
single dose and 60 mg for multiple doses (80 mg was not evaluated in the multiple dose study). 
The single-dose and multiple-dose studies yielded comparable mean values for MEK162 apparent 
terminal elimination half-life (t1/2; 8.40 hrs and 7.35 hrs, respectively; all doses included), and 
each study had a mean apparent time of Tmax of 1.18 hrs. The metabolite- to-parent exposure 
ratios for AR00426032 and urinary excretion profiles were consistent in the single-dose and 
multiple-dose studies in healthy subjects with the metabolite representing ~ 7 to 10% of the parent 
in plasma and < 10% of the parent drug being excreted renally. Accumulation in healthy subjects 
during 14 days of dosing was < 2-fold for all regimens. Administration of MEK162 with a high-
fat meal increased AUC and Cmax by 18% and 26%, respectively. 
Interpretation of PK data collected from the multiple-dose study in patients with rheumatoid 
arthritis was difficult, as the number of patients in each group was small and patients were not 


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pooled for calculation of overall mean PK values. Over a dose range of 10 to 40 mg, MEK162 
plasma exposure when MEK162 was administered concomitantly with methotrexate (MTX; 7.5 
to 22 mg weekly) appeared to be comparable to exposure observed when MEK162 was 
administered as monotherapy. Therefore, it was concluded that no clinically significant drug- drug 
interaction occurred. 
Initial evaluation of the PK of MEK162 in the cancer patient population indicated that there was a 
slight (1 to 2 hrs) delay in Tmax with the remainder of the plasma concentration-time profile 
appearing very similar to healthy subjects. Observed exposure has been approximately dose 
proportional in the doses evaluated to date (30 to 80 mg bid) and comparable to healthy subjects 
at equivalent doses. The inter-subject variability for AUC and Cmax as measured by coefficient 
of variation (CV) was ~40%. The active metabolite-to-parent ratio was consistent across the dose 
range studied, but slightly higher (~10 to 15%) than in the healthy subject population (~7 to 10%). 
As this is the first-in-human combination of MEK162 with carboplatin and pemetrexed, the dose 
will commence at 30mg BID. There will be an initial treatment phase for 5 days of continuous 
dosing and then a wash-out phase for 2 days prior to chemotherapy administration on day 8 for the 
first cycle. This is to minimize toxicity by allowing a washout period prior to chemotherapy 
administration with the aim of not compromising benefit from standard chemotherapy. 
Pharmacokinetic data will be collected by obtaining samples on cycle 1 day 5, and cycle 1 day 15 
to capture steady-state data. 
 
2.3 
Other Agents 
 
2.3.1 Pemetrexed 
 
 
 
Chemical name 
N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-
glutamic acid  
 
Molecular formula 
C20H19N5Na2O6 7H2O 
 
Mechanism of action 
Pemetrexed is an antifolate antimetabolite that targets multiple enzymes in the synthesis of 
pyrimidines and purines. It is a structural analog of lometroxol, an inhibitor of glycinamide 
ribonucleotide formyl transferase (GARFT). Its primary mechanism of action is via inhibition of 
thymidilate synthetase (TS), thereby decreasing the thymidine available for DNA synthesis. It 


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also inhibits dihydrofolate reductase (DHFR), blocking the synthesis of tetrahydrofolate. In 
addition, it blocks GARFT activity as well as other enzymes involved in biosynthesis of purines.  
The drug is transported into cells via the reduced folate carrier, and is subsequently 
polyglutamated (folylpolyglutamate synthase), with potent inhibitory ability of TS. This process 
of glutamation enhances both the exposure time and intracellular concentrations of the drug (Paz 
Ares, 2003). Pemetrexed induces G1/S cell cycle arrest and cell death, independent of P53. 
Preclinical activity has been demonstrated against multiple tumour types. In dog toxicology 
studies, predominant toxicities included gastrointestinal and hematologic adverse events. The 
most favourable toxicity profile was determined to be with weekly dosing compared to daily 
dosing.  
 
In phase I studies in humans, daily, weekly and 3-weekly schedules were explored (McDonald, 
1998; Rinaldi 1996; Rinaldi, 1999). Dose-limiting toxicities included neutropenia, 
thrombocytopenia and fatigue. Recommended doses were 4 mg/m2/day, 40 mg/m2/week and 600 
mg/m2 every 3 weeks. Other toxicities included diarrhea, mucositis, rash, and transaminitis. 
Plasma concentration-time functions followed a two-compartment model, with a mean half-life 
of 3.1 hours (range, 2.2–7.2 hours), and pemetrexed is highly protein bound (81% in plasma). 
Clearance is via renal excretion, with 78% of drug excreted unchanged in the urine within 24 
hours after administration.  
 
Subsequent development in lung cancer used the dose of 500 mg/m2 every 3 weeks, which is 
now standard of care second-line as a single agent or in combination with cisplatin or carboplatin 
first-line in advanced non-squamous NSCLC (Hanna 2004, Scagliotti 2008).  
 
Carboplatin 
 
 
Chemical name 
cis-diammine [1,1-cyclobutane-dicarboxylato(2-)platinum(II)] 
 
 
Molecular formula 


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C6H12N2O4Pt-2 
 
Mechanism of action 
Carboplatin, an analogue of cisplatin, is a platinum salt that complexes with DNA, yielding 
interstrand cross-links and intrastrand DNA adducts (Go, 1999). It differs from cisplatin with 
respect to toxicity profile, but has a similar structure and mechanism of action. While cisplatin 
has two chloride groups, carboplatin has a cyclobutane group, and requires an approximately ten-
fold higher concentration of drug and over seven-fold increase in exposure time to yield similar 
DNA effects as cisplatin.  
 
Platinum clearance is triphasic; the distribution, elimination and terminal half-lives are 22 
minutes, 116 minutes and 5.8 days respectively for carboplatin. Primary excretion of carboplatin 
is through the urine, with 90% clearance 24 hours after administration; renal clearance of 
carboplatin is similar to the glomerular filtration rate (GFR), and accounts for almost all 
elimination of the drug. Given the linear relationship between carboplatin clearance and GFR, 
the Calvert formula has been derived to calculate the dose of carboplatin required for a specific 
area under the curve of the drug. Carboplatin efficacy appears optimal between 5 and 7.5 
mg/mL/min. Recommended dosing in lung cancer as part of combination therapy ranges from an 
AUC of 5 to 6 mg/mL/min.  
 
Calvert Formula: Dose (mg) = Target AUC (mg/mLxmin) x [GFR (ml/min) + 25] 
  
2.4 
Rationale 
 
Today, the most common type of lung cancer is adenocarcinoma or non-squamous NSCLC, with 
most patients presenting with advanced incurable disease. For those patients without EGFR 
mutations or ALK rearrangements in their tumour, the optimal first-line chemotherapy treatment 
for non-squamous NSCLC is pemetrexed/platinum combination chemotherapy (Scagliotti 2008). 
Despite this, median survival times remain less than 12 months, with response rates of only 30% 
and median progression-free survival of 5 months. Approximately 30% of lung adenocarcinomas 
harbour KRAS mutations. Despite being the largest molecular subgroup of lung cancer patients, 
there is no available targeted therapy that improves outcome beyond chemotherapy.  
 
Recently, studies of MEK inhibitors suggest the potential to improve outcomes in KRAS mutant 
NSCLC when added to second-line chemotherapy (Janne 2013). However the value of MEK 
inhibition combined with first-line chemotherapy remains undefined.  Furthermore, our 
understanding of the effects of MEK inhibition in KRAS wild type NSCLC as well as in different 
KRAS mutant genotypes is limited.  
 
The current study proposes to combine MEK162, a highly potent MEK inhibitor with optimal 
first-line chemotherapy in advanced non-squamous NSCLC, pemetrexed and carboplatin, a 
recognized standard in North America (NCCN, 2015). This study is an initial step towards 
improving current therapy of advanced non-squamous NSCLC and to increasing our current 
understanding of the role of MEK inhibition in differing molecular subgroups of lung cancer.   
 


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2.5 
Correlative Studies Background 
   
It is postulated that mutations in the RAS-RAF-MEK-ERK pathway, particularly in KRAS, may 
increase sensitivity to MEK inhibition in combination with chemotherapy (see section 2.1). For 
this reason, we will be conducting KRAS genotyping in addition to standard diagnostic molecular 
and pathologic assessment of NSCLC tissue of participating subjects.  
 
KRAS mutations are seen in approximately 30% of all lung adenocarcinoma cases. The prognostic 
impact of these mutations remains unclear, but may be associated with less benefit from EGFR 
TKI therapy (Martin, 2013). While there is no approved targeted therapy for KRAS mutant 
adenocarcinoma of the lung, the combination of a MEK inhibitor, selumetinib, and second-line 
chemotherapy with docetaxel in advanced KRAS mutant lung cancer may improve response and 
progression-free survival (Janne, 2013). In a small randomized phase II trial, there was even a 
signal of improved survival with the addition of the MEK inhibitor. Early phase trials of other 
MEK inhibitors in lung cancer suggest that there may be higher response rates in selected KRAS 
mutations, such as codon 12 mutations G12C and G12V. There may also be incremental activity 
in KRAS wild type tumours compared to chemotherapy alone (Gandara, 2014).  
 
We hypothesize that the response rate of MEK162 plus pemetrexed/carboplatin will be highest in 
the cohort with G12C mutation, and that the response rate in the wild type and other KRAS mutant 
populations will be similar.  
 
Following macro-dissection of formalin-fixed archival tumor tissue, all genotyping assays will be 
performed in the CAP/CLIA-certified Advanced Molecular Diagnostics Laboratory (AMDL) by 
licensed technologists. This facility routinely performs Sanger sequencing and PCR-based analysis 
(ABI 7900, ABI 3100/3130) on targeted DNA regions to detect specific mutations that may predict 
outcome or response to therapy (Kamel-Reid, 2012). This will be the method used for KRAS 
genotyping in this study. 
 
The results of this assessment will not be used prospectively in the phase I part of the study but 
will be utilized for stratification for the phase Ib component. 
 
Any correlations with response will be determined at the end of the trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria  
Subjects eligible for enrolment on the study must meet all of the following criteria: 
3.1.1 For dose escalation, patients with histologically confirmed non-squamous carcinoma of 
lung. This includes patients with EGFR or ALK positive lung carcinoma previously 
treated with standard TKIs. For dose expansion, patients must have histologically 
confirmed EGFR wild-type, ALK-rearrangement negative non-squamous lung carcinoma. 
Patients with neuroendocrine carcinoma, mixed small and non-small cell carcinoma or 
squamous carcinoma are not eligible in dose escalation or expansion.  
3.1.2 Tissue available for KRAS mutation status analysis, unless KRAS genotype is already 
known. 
3.1.3 Patients must have metastatic disease (incurable stage IIIB/stage IV). 
3.1.4 Patients must have clinically and/or radiographically documented measurable disease, 
defined as at least one lesion that can be accurately measured in at least one dimension 
(longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as 
>10 mm with CT scan, MRI, or calipers by clinical exam. See Section 11 for the 
evaluation of measurable disease. Patients must have radiographic evidence of disease 
progression following the most recent line of treatment.  Areas of previous radiation may 
not serve as measurable disease unless there is evidence of progression post radiation.   
3.1.5 At time of registration, if the patient has had previous treatment it must have been at least 
4 weeks since major surgery or radiation therapy (two weeks from small field short course 
palliative RT e.g. to bone), and the patient must have recovered from side effects; four 
weeks from any other previous anti-cancer therapy including biologics, and 7 days from 
TKIs (permitted in dose escalation only).  
3.1.6 Patients with treated stable CNS metastases are permitted if stability of disease is 
documented with imaging ≥28 days after treatment completion, and if patients are off 
corticosteroids for at least 7 days prior to starting study treatment. 
3.1.7 Patients may have had prior malignancy if definitively treated and/or, in the opinion of the 
investigator, the only active malignancy is NSCLC. Patients with mixed small cell lung 
cancer histology are excluded. Patients who have received radiotherapy to >30% bone 
marrow are excluded. Consult PI if unsure whether second malignancies meet requirements 
specified above. 
3.1.8 Patients treated for another malignancy, must have recovered from all prior treatment-
related toxicities (CTCAE v4.0 ≤ grade 1) at the time of registration (with the exception 
of alopecia or skin depigmentation). 
3.1.9 Able to swallow and retain oral medication and does not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome 
or major resection of the stomach or bowels. This includes ulcerative disease, uncontrolled 
nausea, vomiting, diarrhea, small bowel resection or other malabsorptive syndrome.  
 
3.1.10 Patients receiving medications or substances that are inhibitors or inducers of CYP1A2, 


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CYP2C19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs 
must be used with caution (Appendix E).  Because the lists of these agents are constantly 
changing, it is important to regularly consult a frequently-updated list such as 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the 
Physicians’ Desk Reference may also provide this information.  As part of the 
enrollment/informed consent procedures, the patient will be counseled on the risk of 
interactions with other agents, and what to do if new medications need to be prescribed or 
if the patient is considering a new over-the-counter medicine or herbal product. 
3.1.11 Age ≥18 years.  As no dosing or adverse event data are currently available on the use of 
MEK162 in combination with pemetrexed and carboplatin in patients <18 years of age, 
children are excluded from this study, but will be eligible for future pediatric trials. 
3.1.12 Eastern Cooperative Group (ECOG) performance status ≤1 (Karnofsky >60%, see 
Appendix A). 
3.1.13 Within 7 days of the proposed start date of treatment, patients must have normal organ and 
marrow function as defined below: 
Absolute granulocytes 
≥1.5 × 109/L 
Hemoglobin  
≥100 g/L without transfusion support 
Platelets 
        
≥100 × 109/L without transfusion support 
 
Bilirubin 
≤1.25 × institutional upper limit of normal 
AST(SGOT) / ALT(SGPT) 
≤2.5 × institutional upper limit of normal or 
≤5 × institutional upper limit of normal in the 
presence of liver metastases 
 
 
 
Creatinine clearance  
 
 
 ≥50 mL/min/1.73 m2 
    Cardiac function 
Left Ventricular Ejection Fraction (LVEF) 
≥50% determined by multi-gated acquisition 
scan  (MUGA) or echocardiogram 
3.1.14 Ability to understand and willing to sign a written informed consent document.  Patients 
must be able to provide Informed Consent based on the details below: 
 Absence of any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule; those 
conditions should be discussed with the patient before registration in the trial 
 Before patient registration/randomization, written informed consent must be given 
according to ICH/GCP, and national/local regulations. 
3.1.15 Life expectancy of greater than 3 months. 
3.1.16 No evidence of active uncontrolled infection (patients on antibiotics are eligible). 


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3.1.17 Female patients of child bearing potential must have a negative serum or urine pregnancy 
test within 72 hours prior to the first dose of study drug and four weeks following the last 
dose of MEK162.  
 Women of child-producing potential must agree to use effective contraceptive 
methods prior to study entry, during study participation, and for at least 120 days 
after the last administration of study medication.  These methods include: 
 Total abstinence when this is in line with the preferred and usual lifestyle 
of 
the 
subject. 
Periodic 
abstinence 
(e.g., 
calendar, 
ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception. 
 2 barrier methods: condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/vaginal suppository. 
 A barrier method plus hormonal method from visit 1 to 120 days after the 
last dose of treatment.  In case of use of oral contraception, women should 
have been stable on the same pill for a minimum of 3 months before taking 
study treatment.  
 Men treated or enrolled on this trial must agree to use adequate contraception prior 
to and for 120 days after completion of treatment (see above for adequate 
contraception methods). 
Note: Female patients of childbearing age are defined as follows:  
 
• Patients with regular menses  
 
• Patients, after menarche with amenorrhea, irregular cycles, or using a contraceptive 
method that precludes withdrawal bleeding  
 
• Women who have had tubal ligation  
 
Female patients may be considered to NOT be of childbearing potential for the following 
reasons:  
 
• The patient has undergone total abdominal hysterectomy with bilateral salpingo-
oophorectomy or bilateral oophorectomy  
 
• The patient is medically confirmed to be menopausal (no menstrual period) for 24 
consecutive months  
 
• Pre-pubertal females. The parent or guardian of young female patients who have not yet 
started menstruation should verify that menstruation has not begun. If a young female 
patient reaches menarche during the study, then she is to be considered as a woman of 
childbearing potential from that time forward.  
 
 
 
 
 
 


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3.2 
Exclusion Criteria 
3.2.1 History or current evidence/risk of retinal vein occlusion (RVO) or predisposing factors 
to RVO (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic 
disease such as hypertension, diabetes mellitus, or history of hyperviscosity or 
hypercoagulability syndromes).  Patients with prior deep venous thrombosis or 
pulmonary embolism are permitted. 
3.2.2 History of retinal degenerative disease. 
3.2.3 History of Gilbert’s syndrome. 
3.2.4 Any serious and/or unstable pre-existing medical (aside from malignancy exception), 
psychiatric disorder, or other conditions that could interfere with subjects’ safety, 
obtaining informed consent or compliance to the study procedures, in the opinion of the 
PI.  
3.2.5 History of interstitial lung disease or pneumonitis. 
3.2.6 Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated 
respiratory, hepatic, renal metabolic or cardiac disease). 
3.2.7 Any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. 
congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or 
baseline QTcB interval >480 msec (calculated using Bazett’s formula).  
3.2.8 History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary artery bypass grafting, angioplasty, or stenting within the past 6 months 
prior to screening or cardiac metastases. 
3.2.9 History or evidence of current clinically significant uncontrolled arrhythmias.  
3.2.10 History or evidence of current ≥Class II congestive heart failure as defined by New York 
Heart Association (NYHA).  
3.2.11 History of neuromuscular disorders associated with elevated creatine phosphokinase 
(CK), such as inflammatory myopathies, muscular dystrophy, amyotrophic lateral 
sclerosis, spinal muscular atrophy. 
3.2.12 Patients planning to embark on a new strenuous exercise regimen after the first dose of 
study treatment, (muscular activities such as strenuous exercise, that can results in 
significant increases in plasma CK levels should be avoided while on MEK162 
treatment). 
3.2.13 Known positivity for Hepatitis B surface antigen or Hepatitis C antibody.  
3.2.14 Known Human Immunodeficiency Virus (HIV) positive patients on combination 
antiretroviral therapy are ineligible because of the potential for pharmacokinetic 
interactions with MEK162.  In addition, these patients are at increased risk of lethal 
infections when treated with marrow-suppressive therapy.  Appropriate studies will be 
undertaken in patients receiving combination antiretroviral therapy when indicated. 
3.2.15 Treatment refractory hypertension defined as a blood pressure systolic >140 mmHg 
and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy.  
3.2.16 Subjects with intra-cardiac defibrillators or permanent pacemakers.  
3.2.17 Pregnant or nursing (lactating) women are excluded from this study because MEK162 is 
a small molecule kinase inhibitor with the potential for teratogenic or abortifacient 
effects.  Because there is an unknown but potential risk for adverse events in nursing 
infants secondary to treatment of the mother with MEK162, breastfeeding should be 
discontinued if the mother is treated with MEK162.  These potential risks may also apply 


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to other agents used in this study.  
3.2.18 Patients who have had chemotherapy or radiotherapy within 4 weeks of registration (2 
weeks for small field short course palliative RT), and patients who have received 
radiotherapy to >30% of their bone marrow for malignancy. 
3.2.19 Patients who have received any prior chemotherapy for metastatic NSCLC. Patients who 
have received adjuvant treatment or chemoradiation therapy for stage III disease should 
have completed this ≥12 months prior to study enrollment. 
3.2.20 Patients who have had prior treatment with a MEK inhibitor. 
3.2.21 Patients who are receiving any other investigational agents. 
3.2.22 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to MEK162, Pemetrexed or Carboplatin. 
3.2.23 Uncontrolled inter-current illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.2.24 Any other condition that would, in the Investigator’s judgment, contraindicate the 
patient’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to 
swallow medication, social/psychological issues, medical, psychiatric, cognitive or other 
conditions that may compromise the patient’s ability to understand the patient 
information, give informed consent , comply with the study protocol or complete the 
study. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all ethnic groups are eligible for this trial. The intent is to 
recruit subjects from racial/ethnic/gender groups in close approximation to the incidence of the 
disease in these groups. We anticipate the study population will be reflective of the population 
treated at Canadian tertiary cancer centres with advanced NSCLC with respect to gender and ethnic 
mix. However, the trial is not designed to measure differences in intervention effects. The 
population of Southern Ontario is ethnically diverse. The proportion of different ethnic groups in 
the community is provided in the table below. Universal access to health care will ensure that there 
is no discrimination on the basis of gender or race (Guide to Canadian Human Rights Act: 
www.chrc-ccdp.ca/public/guidechra.pdf). Individual hospital registries and databases do not 
routinely collect racial data, under the direction of the Canadian Human Rights Code. The 
population demographics and distribution of minorities in Southern Ontario is included in the 
following table. 
 
The population demographics and distribution of minorities in Canada is included in the 
following table: 
 


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26 
 
Table: Visible minority population by Consortium Provinces  (2001 Census)  
 
British Columbia Alberta 
Ontario 
Nova Scotia 
Total 
Total population of province 3,868,870 
2,941,150 
11,285,550 
897,570 
18,993,140 
Visible Minorities 
Population % 
Population % 
Population % 
Population % 
Population % 
Black 
25,465 
1% 
31,390 
1% 
411,095 
4% 
19,670 
2% 
487,620 
3% 
Asian 
768,435 
20% 268,660 
9% 
1,513,825 
13% 12,630 
1% 
2,563,550 
13% 
Latin American (Hispanic) 
23,880 
1% 
18,745 
1% 
106,835 
1% 
520 
0% 
149,980 
1% 
Visible minority, not included 
elsewhere 
4,195 
0% 
4,220 
0% 
78,915 
1% 
1,170 
0% 
88,500 
0% 
Multiple visible minority 
14,465 
0% 
6,910 
0% 
42,375 
0% 
535 
0% 
64,285 
0% 
Total Visible minority 
population 
836,440 
22% 329,925 
11% 2,153,045 
19% 34,525 
4% 
3,353,936 
18% 
Source: Statistics Canada, Census of Population.  
 
Data from our consortium has been compiled regarding the representation of minorities on 
previous clinical trials, and the distribution is as follows: 
 
Population Percentage of Minority and Gender of entering PMHC Trials 
 
2010 
2011 
2012 
Visible Minorities 
 
 
 
Black 
0.9 
2.3 
1.2 
Asian 
10.1 
10.9 
11.6 
Hispanic 
10.1 
2.3 
3.5 
Total  
21.1 
15.5 
16.3 
Women 
59.6 
56.6 
44.2 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
The Study Coordinator at the Drug Development Program office will enter eligible patients on 
study centrally.  All sites should call the Study Coordinator to verify dose level availabilities.  
The required forms (Registration Checklist) will be provided upon site activation.   
 
Following registration, patients should begin protocol treatment within 3 calendar days.  Issues 
that would cause treatment delays should be discussed with the Principal Investigator (cc the 
central office study coordinator).  If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be cancelled.  The Study Coordinator 
should be notified of cancellations as soon as possible.   
 
 


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27 
 
4.2 
Registration Process 
 
Prior to registering a patient, each institution must have submitted all necessary regulatory 
documentation to the Drug Development Program Central Office.  The registration checklist will 
only be sent once this has been received.   
 
No patient can receive protocol treatment until registration with the Central Office has taken 
place.  All eligibility criteria must be met at the time of registration.  There will be no exceptions.  
Any questions should be addressed with the Central Office prior to registration.   
 
To register a patient, the following documents are to be completed by the research nurse or data 
manager and sent / faxed to the Central Office Study Coordinator: 
• 
Signed patient consent form 
• 
Registration Checklist signed by the investigator  
 
To complete the registration process, central office will review the checklist and once eligibility 
has been confirmed: 
• 
Assign a patient study number 
• 
Assign the patient a dose 
• 
Register the patient on the study 
• 
Fax or e-mail the confirmation worksheet with the patient study number and dose to the 
participating site 
 
To ensure immediate attention is given to the faxed checklist, each site is advised to also call the 
study coordinator listed on the front sheet. Patient registration will be accepted between the hours 
of 9am to 5pm Monday to Friday, excluding Canadian statutory holidays when the central office 
will be closed. 
 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 7.  Appropriate dose modifications are described in Section 6.  No 
investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy. 
 
 
 
 
 
 
 
 


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28 
 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
MEK162 
Take with water 
not later than 
30mins after 
breakfast in 
morning 
15mg  
tablet**   
PO in the a.m. 
and p.m.  
Doses should be 
12±2 hrs apart. 
Daily, continuous dosing. 
Omit dosing for 2 days 
prior to chemotherapy 
administration: 
cycle 1 day 6 & 7, cycle 1 
day 27 & 28, cycle 2+ day 
20 & 21 (see section 5.1.3). 
28 days (4 
weeks) for 
cycle 1 only 
 
21 days  
(3 weeks) 
for cycle 2 
onward 
 
 
 
Pemetrexed Pre-medicate with 
dexamethasone 
before and after 
dosing. Ensure 
vitamin B12 and 
folic acid 
supplementation 
ongoing. 
**In 
100ml NS 
IV over 10 
minutes 
For cycle 1, day 8, and day 
1 of each subsequent cycle.  
Carboplatin Take 8 glasses 
water for 2 days 
prior to dosing. 
**In 250 
ml 5% 
glucose 
IV over 30 mins 
For cycle 1, day 8, and day 
1 of each subsequent cycle. 
**Doses as appropriate for assigned dose level. 
 
5.1.1 MEK162 
 
MEK162 tablets will be taken orally, twice daily, with a glass of water.  An intermittent dosing 
schedule will be employed as outlined in section 5.1.  Doses will be administered for 5 days 
followed by a 2-day omission prior to commencing chemotherapy: for cycle 1, continuous dosing 
until day 5; omit doses for 2 days prior to chemotherapy administration (cycle 1 days 6 and 7, and 
cycle 1 days 27 and 28). For cycles 2+, omit doses on day 20 and 21. 
 
The prescribed bid doses for MEK162 should be taken 12 ± 2 hours apart.  Each morning daily 
dose of MEK162 should be taken at approximately the same time each day, and must be taken no 
later than 30 minutes after the start of the patients’ normal breakfast.  The second dose of MEK162 
should be taken together with a glass of water and irrespective of food, 12 ± 2 hours after the 
morning dose (except for the pharmacokinetic sampling days on cycle 1 day 5 and cycle 1 day 15 
when the patients should take their morning dose at the clinic, and skip the evening dose of 
MEK162).   
Patients must avoid consumption of grapefruit or grapefruit jucie during the entire study and 
preferably 7 days before the first dose of study medications, due to potential CYP3A4 interaction 
with the study medications. Orange juice is allowed.  
Patients should be instructed to swallow the tablets as a whole and not to chew or crush them. 
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the 
next scheduled dose. 


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29 
 
Any doses that are missed should be skipped and should not be replaced or made up during the 
evening dosing (in the case of MEK162) or on a subsequent day, whichever applies. 
If, for any reason, a breakfast was not consumed, then the patient should still take the scheduled 
morning dose of MEK162 with a glass of water. If this happens on days of PK sampling, it should 
be documented in source documentation and/or the electronic CRFs. 
The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course. 
 
5.1.2 Pemetrexed 
 
Intravenous pemetrexed will be administered once every 21 days (1 complete cycle) over a 10-
minute (±5min) infusion.  Subjects will be pre-medicated with folic acid and vitamin B12 
supplements in order to reduce the incidence and severity of hematologic and gastrointestinal 
toxicities as well as cutaneous hypersensitivity reactions. Recommendations for pre-medication 
are as follows: 
 
 350-1000µg folic acid, once daily, by mouth for 5 days preceding the first dose of 
pemetrexed, during treatment, and for 21 days following the last dose of pemetrexed 
 1000µg vitamin B12 by intramuscular injection in the week preceding the first dose of 
pemetrexed and every nine weeks thereafter (subsequent vitamin B12 injections may be 
given on the same day as pemetrexed). 
 4 mg dexamethasone (or equivalent), twice daily, by mouth the day before, the day of, and 
the day after pemetrexed administration. 
 
Additional information can be found in the prescribing information for pemetrexed 
[Alimta Package Insert, 2012]. 
 
5.1.3 Carboplatin 
 
IV carboplatin will be administered once every 21 days (1 cycle) over a 30-minute (± 10min) 
infusion. 
 
Carboplatin dosing by BSA is not recommended as it does not take into account the patient’s renal 
function and/or desired platelet nadir, which may result in overdosing (i.e. patients with poor renal 
function) or underdosing (i.e. with above average renal function).  Several methods have been 
proposed for calculating carboplatin doses, considering the area under the curve (AUC) and its 
subsequent hematologic toxicity, and also the direct relationship between glomerular filtration and 
carboplatin clearance. 
Calvert Formula (Calvert, 1994): Most commonly used method 
Dose (mg) = Target AUC (mg/mL per min) x [CrCl (mL/min) + 25] 
To avoid toxicity, FDA recommends capping the carboplatin dose for a desired AUC.  The 
maximum dose is based on a GFR estimate that is capped at 125 mL/min for patients with 
normal renal function: 


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30 
 
Maximum Carboplatin Dose (mg) = Target AUC (mg/mL per min) x (125 mL/min + 25) 
(See FDA communication on carboplatin dosing) 
 Adequate hydration and urinary output should be maintained during the 24 hours 
following carboplatin dosing.  
 Magnesium and potassium supplementation should be given as per institutional 
guidelines. 
 
Additional information can be found in the prescribing information for carboplatin [Paraplatin] 
Package Insert, 2010]. 
 
 
5.2 
Trial Design 
 
Phase I  
A standard 3+3 dose-escalation design consisting of up to two independent dose-escalation 
treatment groups and one dose de-escalation group will be used to determine the maximum 
administered dose (MAD) and the RP2D for the combination in subjects with advanced non-
squamous lung carcinoma. The cohort will be expanded to 6 patients at the recommended Phase 
II dose level (RP2D). The MAD is the dose of MEK162 in which ≥2/3 or ≥2/6 patients 
experience dose-limiting toxicity (Section 5.3). The overall safety and tolerability of each 
treatment combination will be evaluated independent of the other treatment groups. 
 
Phase Ib  
Once RP2D has been identified, an expansion cohort will be opened.  The RP2D will be 
expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients 
eligible for the safety set (including those treated at the same dose combination in the dose-
escalation phase of the study who are eligible for the safety set) to be evaluated for safety, 
tolerability, pharmacokinetics and biologic activity of MEK162. 
  
Stratification of patients by KRAS genotype aims for the targets detailed below: 
Wild-type KRAS: N=10 
KRAS mutant non-G12C: N=10 
KRAS mutant G12C: N=10 
 
During the expansion cohort, subjects who do not complete at least one post-baseline disease 
assessment (clinic or radiologic evaluation) may be replaced.  Refer to Section 13 (Statistical 
Considerations) for specific details. 
 
Dosing for Phase Ib will begin at the RP2D and patients will be stratified by KRAS status as 
detailed above. 
5.2.1 Dose Escalation 
 
The dose of MEK162 will be escalated in fixed increments according to the dose escalation 
scheme outlined in Section 5.2.1. The starting dose will be 30 mg BID.  This dose is based on 
animal toxicology studies in humans (see Section 2) when given as a single agent and in 


Protocol #: CMEK162ACA02T 
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31 
 
combination with other agents.  An intermittent dosing schedule of MEK162 is proposed in order 
to minimize toxicity. 
 
Treatment with MEK162 will commence as a single agent, 1 week prior to administration of 
cycle 1 of chemotherapy. Doses will be administered for 5 days followed by a 2-day omission 
prior to commencing chemotherapy. Patients who have completed 4-6 cycles of chemotherapy 
may continue to receive MEK162 until excess toxicity or disease progression.  
 
Dose Escalation Schedule 
Dose Level 
Dose* 
MEK162 
(total daily dose) 
Carboplatin 
(every 3 weeks) 
Pemetrexed 
(every 3 weeks) 
Minimum 
number of 
patients 
Level -1 
30mg bid*+ 
 (60mg total) 
AUC 5 
500mg/m2 
3 
Level 1 
(starting) 
30mg bid* 
(60mg total) 
AUC 5 
500mg/m2 
3 
Level 2 
45mg bid*  
(90mg total) 
AUC 5 
500mg/m2 
3 
*For cycle 1, continuous dosing until day 5.  Omit doses for 2 days (days 6 and 7, and days 27 
and 28) prior to chemotherapy administration.  For cycles 2+, omit doses on days 20 and 21.  
Chemotherapy is to be administered on day 8 of cycle 1, and day 1 of every cycle thereafter. 
Cycle 1 has 28-day duration with subsequent cycles having 21-day duration. 
+ In the event of MEK162 dose reduction or accrual to Dose Level -1, the schedule of 
MEK162 will be modified to: cycle 1 daily dosing day 1-5, omit days 6 and 7 (2 days prior to 
chemotherapy) and then daily dosing days 8-21, omit days 22-28. For cycles 2+, daily dosing 
days 1-14 and omit days 15-21. Cycle 1 is 28 days, subsequent cycles are 21 days.  
 
The rate of subject entry and escalation to the next dose level will depend upon assessment of the 
safety profile of patients entered at the previous dose level. Toxicity will be evaluated according 
to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. 
 
A minimum of three patients will be entered on each dose level.  All three will be followed for 
one completed cycle of therapy (28 days in cycle 1) and subsequent enrollment of new cohorts 
will be based on the toxicity assessment in that first cycle and the documentation of any dose 
limiting toxicities (for definitions see below). 
 
 
 
5.2.2 Maximum Administered Dose (MAD) 
 
If 0/3 patients exhibit dose limiting toxicity at this dose level: 
 Dose escalation to the next dose level may begin in a new cohort of patients 
 
If 1/3 patients exhibit dose limiting toxicity at this dose level: 


Protocol #: CMEK162ACA02T 
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32 
 
 Expand dose level to a total of 6 patients. 
 If no further DLT events are seen, dose escalation to the next dose level may begin in a 
new cohort of patients. 
 If further DLT events are seen (2 or more out of 6 patients), this dose level will be 
considered the maximum administered dose (MAD).  
 
If ≥2/3 patients exhibit dose limiting toxicity: 
 This dose level will be considered the maximum administered dose (MAD).  
 Before opening the next higher dose level all toxic effects at the preceding dose level will 
be reviewed and expansion or escalation will be undertaken as appropriate.  Conference 
calls between investigators will be organized as required. 
 
5.2.3 Recommended Phase II Dose 
 
As described above the MAD is that dose in which ≥2/3 or ≥2/6 patients experience dose-limiting 
toxicity. 
 
Normally one dose level below that dose will be considered the recommended phase II dose 
(RP2D).  If the MAD is seen at the starting dose level, then dose level “-1” will be the 
recommended dose if tolerated. In the event that the MAD (as defined above) is not reached by 
dose level 2, this will be deemed the RP2D.  
 
If clinically appropriate, intermediate dose levels may be studied to assure that the recommended 
dose is the highest tolerable.   
 
Up to a total of 6 patients may be treated at the recommended dose to assure information on the 
safety profile at that dose is complete. 
 
 
5.2.4 Patient Replacement During Dose Escalation Phase 
 
Three patients within a dose level must be observed for the first cycle (28 days) without 
experiencing a DLT before accrual to the next higher dose level may begin.  If a patient is 
withdrawn from the study prior to completing 15 days of therapy without experiencing a DLT 
prior to withdrawal, an additional patient may be added to that dose level.  Patients missing 7 or 
more doses due to toxicity will not be replaced since these patients will be considered to have 
experienced a dose limiting toxicity. 
The patient will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each course and reviewed by the study 
staff.    The subject diary template can be found in Appendix C and Appendix D. 
 
 
5.3 
Definition of Dose-Limiting Toxicity 
 


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33 
 
Toxicity will be graded using the Common Terminology Criteria for Adverse Events version 4.0 
(CTCAE).  Any dose limiting toxicity must be a toxicity that is considered related to study drug 
in cycle 1 (first 28 days of treatment on study).  Dose limiting toxicity is defined as follows: 
 
 The inability to administer MEK162 on ≥75% of scheduled treatment days during cycle 1 
due to an unresolved adverse event related to the study drug 
 Any ≥ grade 3 non-hematological toxicity (except for abnormalities of AST, electrolyte 
disturbance responsive to correction within 24 hours, or diarrhea, nausea, vomiting, 
stomatitis, rash or photosensitivity that respond to standard medical care within 48 hours, or 
fatigue lasting < 7 days) 
 Grade 4 neutropenia persisting for ≥ 7 days, or grade ≥3 febrile neutropenia 
 Grade 4 thrombocytopenia 
 Retinopathy:  
o Grade 2 central serous retinopathy (CSR) for > 14 consecutive days confirmed by 
ophthalmologic exam 
o Grade ≥3 central serous retinopathy confirmed by ophthalmologic exam 
o Other retinal disorders grade ≥3 confirmed by ophthalmologic examination 
 Treatment delay of ≥ 14 days due to unresolved toxicity 
 QTc interval ≥ 501 ms, on at least two separate electrocardiograms (ECGs) 
 Serum creatinine > 2X ULN 
 Any ≥ grade 2 non-hematological toxicity described in the CTCAE v4.0, which in the 
judgment of the Principal Investigator, is considered dose-limiting 
 
Management and dose modifications associated with the above adverse events are outlined in 
Section 6. 
 
Dose escalation will proceed within each cohort according to the following scheme.  Dose-
limiting toxicity (DLT) is defined above.   
 
Number of Patients with DLT at a 
Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter 3 patients at the next dose level. 
≥2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter at least 3 more patients at this dose level. 
 If 0 of these 3 patients experience DLT, proceed to 
the next dose level. 
 If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  Three (3) additional 


Protocol #: CMEK162ACA02T 
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34 
 
patients will be entered at the next lowest dose level 
if only 3 patients were treated previously at that dose. 
≤1 out of 6 at highest dose level 
below the maximally administered 
dose 
This is generally the recommended phase 2 dose. At 
least 6 patients must be entered at the recommended 
phase 2 dose. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 MEK162 
 
MEK162 is a substrate for many CYP isoforms (CYP3A and 1A2 with some involvement of 
CYP2C isoforms). Although the risk of metabolic interaction caused by an effect on an individual 
isoform is minimized for MEK162, caution should be used in patients receiving concomitant 
treatment with other drugs that are either potent inhibitors or inducers of CYP3A, CYP2B6, 2C8, 
2C9, 2C19, and 1A2.  
 
Because there is a potential for interaction of MEK162 with other concomitantly administered 
drugs through the cytochrome P450 system, the case report form must capture the concurrent use 
of all other drugs, over-the-counter medications, or alternative therapies.  The Principal 
Investigator should be alerted if the patient is taking any agent known to affect or with the potential 
to affect selected CYP450 isoenzymes. Appendix F presents guidelines for identifying 
medications/substances that could potentially interact with the study agent(s). 
 
Patients who require agents on the provided list in Appendix F will be excluded from enrolling in 
the study.  Patients who require such an agent during participation in the study may be allowed to 
continue if the following apply: they have stable or responding disease; no alternative treatment is 
available; and they have close clinical monitoring while they are enrolled in the clinical trial. 
 
Any other medication which is considered necessary for the patient’s welfare, and which is not 
expected to interfere with the evaluation of the study drug, may be given at the discretion of the 
Investigator.   
 
No other anti-cancer or investigational agents are permitted during the entire duration of treatment 
with study drug. 
 
 
5.4.2 Pemetrexed 
 
 350-1000µg folic acid, once daily, by mouth for 5 days preceding the first dose of 
pemetrexed, during treatment, and for 21 days following the last dose of pemetrexed 
 1000µg vitamin B12 by intramuscular injection in the week preceding the first dose of 
pemetrexed and every three cycles thereafter (subsequent vitamin B12 injections may be 
given on the same day as pemetrexed). 
 4 mg dexamethasone (or equivalent), twice daily, by mouth the day before, the day of, 
and the day after pemetrexed administration. 


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35 
 
 
5.4.3 Carboplatin 
 
Standard antiemetic protocols should be followed for administration of carboplatin (as per 
institutional anti-emetic guidelines). Note that ondansetron may be used with caution. Zolasetron 
is excluded because of interaction with cytochrome P450.  
5.4.4 Additional supportive medications 
 
Supportive and other palliative measures are permitted.  
 
Radiotherapy is permitted after cycle 1 for symptomatic bone metastases which pre-dated study 
enrollment. MEK162 and chemotherapy should be held for the duration of this treatment. New 
bone metastases requiring radiotherapy are considered to be indicative of disease progression and 
patients will have to come off study for this. 
 
Management of diarrhea and skin toxicity is outlined in Appendix G. 
 
5.5 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), carboplatin and pemetrexed 
chemotherapy may continue for a maximum of 6 cycles.  After the 6th cycle, it is under the 
Investigator’s discretion to continue with pemetrexed alone.  
 
MEK162 treatment may continue until one of the following criteria applies: 
 
Disease progression, 
 
Intercurrent illness that prevents further administration of treatment, 
 
Unacceptable adverse event(s), 
 
Clinical progression 
 
Patient decides to withdraw from the study, or 
 
General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
 
Significant noncompliance with the protocol schedule in the opinion of the investigator 
 
5.6 
Duration of Follow Up 
 
Patients will be followed from the end of study drug administration until adverse event 
stabilization or resolution, disease progression, or until death.  Patients removed from study for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event.  Patients who withdraw consent will no longer be followed. 
Follow-Up Period 
Safety Follow-Up: 
28 days from the 
End of Study 
Drug 
Administration 
120 days after End of 
Study Drug 
Administration visit* 
and then every 120 
days until disease 
Until resolution 
or stabilization 
of adverse 
event(s)*** 


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36 
 
 
* All study participants are expected to maintain contraceptive practices until 120 days after the end of study drug administration. 
** Must be documented radiologically and as per RECIST guidelines. 
*** Follow for AEs until all other follow-up requirements are met. Refer to section 7.6 for guidance in the following of ongoing 
or new AEs or SAEs. Note that disease progression must be demonstrated per RECIST.  
 
5.7 
Criteria for Removal from Study 
 
Patients will be removed from study when any of the criteria listed below applies: 
 Patient death 
 Withdrawal of consent 
 Disease progression (radiological or clinical) 
 Termination of study by Sponsor-Investigator or Regulatory Authority 
 
The reason for study removal and the date the patient was removed must be documented in the 
Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Doses will be reduced for haematological and other adverse events.  Dose adjustments are to be 
made according to the greatest degree of toxicity.  Adverse events will be graded using the NCI 
Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE). 
 
The major adverse effects of MEK162 which limit dose is/are:  
 Ocular (retinal) toxicity 
 Skin rash 
 Persistent fatigue 
 Nausea 
Neutropenia (when administered with chemotherapy)  
 
Other frequent treatment-related adverse events in patients receiving MEK 162 (binimetinib) 
include: 
 Vomiting 
progression** 
Reason Patients 
Removed from Study 
Objective Disease 
Progression** 
X 
 
X (monthly FU) 
Clinical Progression/ 
Symptomatic 
Deterioration 
X 
 
X (monthly FU) 
Adverse Events or 
clinically significant lab 
value 
X 
X 
X (weekly FU for 
4 weeks, then 
monthly) 
All other patients 
X 
X 
X (monthly FU) 


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37 
 
 Diarrhea 
 Peripheral edema 
 Creatine phosphokinase (CPK) elevation 
 
Other relevant toxicities include: 
 Retinal events 
 Blood pressure increase 
 Cardiac ejection fraction decrease 
 Pneumonitis 
 
The guidelines which follow outline dose adjustments for several of these toxic effects.  
Carboplatin and pemetrexed dose modifications are based on CCO Regimen Monograph (CCO, 
2012 and CCO, 2013). 
 
If a patient experiences several adverse events and there are conflicting recommendations, please 
use the recommended dose adjustment that reduces the dose to the lowest level.  
Once a dose has been reduced it will not be increased at a later time even if there is no toxicity.   
 
Recommended Dose Modifications for MEK162, Carboplatin and Pemetrexed 
Worst toxicity 
CTCAE v4.0 
Grade (unless 
otherwise 
specified*) 
Recommended Dose Modifications any time  
during a cycle of therapy 
MEK162 
Carboplatin 
Pemetrexed 
Blood and lymphatic system disorder 
Anaemia 
≤Grade 2 
Maintain dose levels of all drugs. 
Grade 3 
Omit dose until resolved 
to ≤grade 1. 
Hold until ≤grade 1, 
then dose reduction 
by 1 AUC. 
Hold until ≤grade 1, 
then reduce dose by 
100 mg/m2 
Grade 4 
Discontinue all drugs 
Neutrophil count (ANC) decreased (Neutropenia) 
Grade 1 
Maintain dose levels of all drugs 
Grade 2 
Maintain dose level  
Hold carboplatin and pemetrexed for 1 week 
or until resolved to ≤grade 1 and then 
administer at same dose as previous. 
Grade 3 
Omit dose until ≤grade 1, 
and then resume at same 
dose.  
If resolved in >7 days, 
then treat with G-CSF. 
At the second 
occurrence, reduce dose 
by 1 dose level**  
Hold until ≤grade 1; 
and then treat with G-
CSF. At the second 
occurrence,  dose 
reduce by 1 AUC. 
Hold until ≤grade 1. 
Then recommence at 
same dose. 
Grade 4 
Omit dose until resolved 
Hold until ≤grade 1, 
Hold until ≤grade 1 


Protocol #: CMEK162ACA02T 
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38 
 
to ≤grade 1, and then 
maintain dose level.  
If resolved in >7 days, 
then treat with G-CSF. 
At the second 
occurrence,  reduce dose 
by 1 dose level**  
then treat with G-
CSF. At the second 
occurrence, dose 
reduce by 1 AUC. 
and then treat with 
G-CSF. At the 
second occurrence, 
reduce dose by 100 
mg/m2  
Febrile Neutropenia 
 
Grade 3  
Omit dose. If resolved in 
≤7 days, treat with G-
CSF. At the second 
occurrence, reduce dose 
by 1 dose level.  
 
If not resolved in ≤7 
days, discontinue. 
Hold both drugs until ≤grade 2, then treat 
with G-CSF. 
At the second occurrence, dose reduce 
pemetrexed by 100 mg/m2  and carboplatin 
by 1 AUC. 
Grade 4 
Discontinue all drugs 
Platelet count decreased (Thrombocytopenia) 
Grade 1 
Maintain dose level 
Maintain doses of both drugs 
Grade 2 
Hold both drugs until ≤grade 2 (plt ≥100). 
Then recommence both drugs at same dose. 
Grade 3 
Omit dose until resolved 
to ≤grade 1, then 
maintain dose level. 
If resolved in >7 days, 
then discontinue.  
Hold both drugs until ≤grade 2 (plt ≥100). 
Then recommence both drugs with 
pemetrexed dose reduction of 100 mg/m2 and 
carboplatin dose reduction of 1 AUC. If 
bleeding, discontinue both drugs. 
Grade 4 
Omit dose until resolved 
to ≤grade 1, then 
maintain dose level. 
If resolved in >7 days, 
then discontinue. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs with 
pemetrexed dose reduction of 100 mg/m2 and 
carboplatin dose reduction of 1 AUC. If 
bleeding, discontinue both drugs. 
Investigations  
Serum creatinine 
Grade 1 
Maintain dose level  
See ***Table for dose modifications of 
chemotherapy agents based on creatinine 
clearance 
Grade 2 
Omit dose until resolved 
to <grade 1 or baseline, 
and then maintain dose 
level. 
Grade 3 
Omit dose and 
discontinue from study 
treatment. 
 
Grade 4 
Creatinine phosphokinase (CK/CPK) 
Grade 1 or 2 
Maintain dose level of all drugs 
Grade 3 
Omit dose until resolved 
Hold both drugs until ≤grade 2. 


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to <grade 1. 
If resolved in ≤7 days, 
reduce dose level by 1 
dose level**. 
If resolved in >7 days 
discontinue.  
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin, or if bleeding, 
discontinue both drugs. 
Grade 4 
Discontinue all drugs 
Bilirubin 
Grade 1 
Maintain dose level of all drugs 
Grade 2 
Omit dose until resolved 
to <grade 1. 
If resolved in 7 days, 
then maintain dose level.  
If resolved in >7 days, 
then reduce by 1 dose 
level** 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at same dose. 
Grade 3 
Discontinue  
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue all drugs 
AST or ALT 
Grade 1 
Maintain dose level of all drugs 
Grade 2 
Omit dose until resolved 
to <grade 1 (or ≤grade 2 
in case of liver 
metastases).  
If resolved in ≤7 days, 
maintain dose level. 
If resolved in > 7 days, 
reduce dose by 1 dose 
level** 
Hold both drugs until ≤grade 2. Then 
recommence both drugs at same dose. 
Grade 3 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue all drugs 
Cardiac Disorders 
LV systolic dysfunction* 
Grade 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade > 4 
Discontinue 
Discontinue 
Other cardiac disorders 
Grade 1 and 2 
Maintain dose level 
Grade ≥ 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 


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Grade > 4 
Discontinue 
If Grade 4, discontinue. Obtain formal 
cardiology evaluation and discuss with PI. 
Persistent Hypertension 
Grade 3 requiring >1 
drug or more 
intensive therapy 
than previously 
Omit dose until resolved 
to ≤grade 1, then reduce 
by 1 dose level**  
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 requiring >1 
drug or more 
intensive therapy 
than previously 
Discontinue 
Discontinue both drugs. 
Medical Management as required. 
Discuss with PI. 
Asymptomatic Amylase and /or Lipase elevation 
< Grade 2 
Maintain dose level of all drugs 
Grade 3 
Omit until resolved to 
≤grade 2, then 
recommence at same 
dose. 
25% dose reduction of pemetrexed, and 1 
AUC dose reduction of carboplatin. 
Perform CT scan/US to assess pancreas, liver 
and gallbladder within 1 week of 1st 
occurrence of grade 3 amylase/lipase. 
Grade 4 
Discontinue all drugs 
Creatine Kinase (CK) elevation 
Grade 1 and 2 
Maintain dose level of all drugs. 
If total CK ≥ 3 x ULN, measure isoenzymes and myoglobin in blood and 
urine. 
Grade 3 
(>5-10 x ULN) 
If asymptomatic: 
Maintain dose. Monitor 
closely and measure 
isoenzymes and 
myoglobin in blood and 
urine. 
If symptomatic (muscle 
pain/spasms): interrupt 
dose until resolved to 
≤grade 1 and monitor 
closely. Then: 
- If resolved in ≤ 14 days, 
reduce 1 dose level**   
- If resolved in > 28 days, 
permanently discontinue. 
Maintain dose level 
Grade 4 
If asymptomatic, 
interrupt dose and 
monitor closely. 
- If resolved in ≤ 14 days, 
reduce 1 dose level**  
- If resolved in > 28 days, 
permanently discontinue. 
If symptomatic, 
Maintain dose level 


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permanently discontinue. 
Diarrhoea 
Grade 1 
Maintain dose but initiate 
anti-diarrhoea treatment 
Maintain dose level of both drugs 
Grade 2 
Omit dose until resolved 
to ≤ grade 1, then 
recommence at same 
dose. 
For 2nd occurrence at 
grade 2, omit dose until 
resolved to ≤grade 1, then 
reduce dose by 1 dose 
level** 
Hold both drugs until ≤grade 2. 
Maintain dose level of both drugs. 
 
Follow guidelines in Appendix G for 
management of diarrhea. 
Grade 3  
Omit dose until resolved 
to ≤grade 1, then reduce 
dose by 1 dose level** 
For 2nd occurrence at 
grade 3, discontinue. 
Hold both until ≤grade 2. 
Recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Follow guidelines in Appendix G for 
management of diarrhea. 
Grade 4 
Discontinue all drugs.  Follow guidelines in Appendix G for management 
of diarrhea. 
ECG QTc-Interval prolonged 
Grade 1 and 2 
Maintain dose level of all drugs 
Grade 3 
Omit dose until returned 
to ≤grade 1 or baseline, 
then reduce 1 dose 
level** following 
consultation with PI. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue all drugs 
Eye disorders 
Central serous retinopathy 
Grade 1 
Maintain dose level. 
Perform eye 
examinations every 15 
days until resolution. 
Maintain dose level of both drugs 
Grade 2 
Omit dose until resolved 
to ≤grade 1. 
If resolved in <14 days, 
then dose reduce by 1 
dose level**. 
If resolved in >14 days, 
discontinue patient from 
study drug treatment.  
Hold both drugs until ≤grade 2. 
Then recommence both drugs at same dose. 
Grade 3  
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 


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reduction of carboplatin. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 
Retinopathy, retinal detachment, tear or retinal vascular disorder (including RVO) – other 
than CSR 
Grade 1 and 2 
Discontinue 
 
Grade 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 
Uveitis 
Grade 1 
Maintain dose level of all drugs 
Grade 2 
Maintain dose level. If 
unresolved in >14 days, 
discontinue. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at same dose. 
Grade 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 
Visual disturbance without retinal changes 
Grade 1 
Maintain dose level for all drugs 
Grade 2 
Maintain dose level. If 
unresolved in >14 days, 
discontinue. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at same dose. 
Grade 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 
Visual disturbances without retinal changes 
Grade 1 and 2 
Maintain dose level for all drugs 
Grade 3 
Omit dose until resolved 
to ≤grade 1. 
If resolved in <14 days, 
then dose reduce by 1 
dose level**. 
If resolved in >14 days, 
discontinue patient from 
study drug treatment. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 


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Eye disorders – other 
Grade 1 and 2 
Maintain dose level of all drugs 
Grade 3 
Discontinue 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction of pemetrexed, and 1 AUC dose 
reduction of carboplatin. 
with PI. 
Grade 4 
Discontinue 
Discontinue. Obtain formal ophthalmology 
evaluation and discuss with PI. 
Skin and subcutaneous disorders 
Rash/Photosensitivity 
Grade 1 
Maintain dose level of all drugs but consider initiating skin toxicity 
therapy according to guidelines (Appendix G). 
Grade 2 
Maintain dose of all drugs but initiate skin toxicity therapy according to 
guidelines (Appendix G). 
Grade 3, despite skin 
toxicity therapy 
 Asymptomati
c lasting >48 
hours 
 Symptomatic 
Omit dose until resolved 
to ≤grade 1, then if 
resolved in ≤48 hours, 
reduce by 1 dose level** 
If resolved >48 hours, 
discontinue. 
Hold both drugs until ≤grade 2. Then if 
resolved in ≤48 hours, recommence both 
drugs at same dose. If resolved >48 hours, 
recommence both drugs at 25% dose 
reduction. 
Grade 4, despite skin 
toxicity therapy 
Discontinue all drugs 
General disorders 
Fatigue 
Grade 1 or 2 
Maintain doses of all drugs 
Grade 3 
Omit dose until resolved 
to ≤grade 1, then if 
resolved in ≤7 days, 
reduce by 1 dose level** 
If resolved >7 days, 
discontinue. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction. 
Edema 
Grade 1 or 2 
Maintain doses of all drugs 
Grade 3 
Omit dose until resolved 
to grade ≤1, then if 
resolved in ≤14 days, 
reduce by 1 dose level** 
If resolved >14 days, 
discontinue. 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction. 
Other adverse events 
Grade 1 or 2 
Maintain doses of all drugs 
Grade 3 
Omit dose until resolved 
to grade ≤1, then reduce 
by 1 dose level** 
Hold both drugs until ≤grade 2. 
Then recommence both drugs at 25% dose 
reduction. 
Grade 4 
Discontinue 


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44 
 
*If a patient requires a dose delay of >14 days from the intended day of the next scheduled dose of MEK162, the 
patient must be discontinued from study treatment.  Patients who discontinue from the study for a study-related adverse 
event or an abnormal laboratory value must be followed at least once a week for 4 weeks and subsequently at 4 week 
interval, until resolution or stabilization of the event, whichever comes first, except specifically mentioned. 
**Patients requiring more than two dose reductions of MEK162 will be discontinued from study drug treatment. 
***Table for dose modifications of chemotherapy agents based on creatinine clearance: 
Creatinine Clearance 
Carboplatin (% previous dose) 
Pemetrexed (% previous dose) 
61-79 
 
Use Calvert formula 
100%, but use NSAIDS with 
extreme caution 
45-60 
30-<45 
Discontinue 
<30 
Discontinue 
Discontinue 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An adverse event is any untoward medical occurrence (including any abnormal laboratory 
finding), symptom, or disease temporarily associated with the use of a medicinal (investigational 
product) in a patient administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with treatment. 
 
7.1 
List of Adverse Events and Reporting Requirements 
 
7.1.1 Expected Adverse Events for MEK162 
 
The major adverse effects of MEK162 which limit dose is/are (as referenced in Table 17, 
MEK162 IB Edition 15):  
 Ocular (retinal) toxicity 
 Skin rash 
 
Very common treatment-related adverse events in patients receiving binimetinib include: 
 Constipation 
 Decreased appetite 
 Dyspnoea 
 Alopecia 
 Pruritus 
 Abdominal pain 
 Fatigue 
 Oedema peripheral 
 Pyrexia 
 Alanine aminotransferase increased 
 Myalgia 
 Dry skin (Xerosis) 
 Rash 
 Hypertension 
 
Other relevant toxicities include: 
 Other ocular events including raised eye pressure, visual changes 


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 Blood pressure increase 
 Cardiac ejection fraction decrease 
 Pneumonitis 
 Itching 
 Vomiting 
 
Additional risks associated with MEK162 
 Among all patients treated with MEK162, a patient experienced acute liver failure (the 
liver rapidly lost its ability to function normally) leading to death. Due to this case and 
the observed increase in the value of liver enzymes, your liver function will be evaluated 
frequently. 
 As mentioned above, a decrease of left ventricular ejection fraction has been reported in 
studies with MEK162. This means the heart may have difficulty pumping enough blood 
throughout the body. This adverse event has also been described with other similar 
compounds. Your cardiac function will be evaluated before and during the study. Patients 
with severe and recent cardiac abnormalities or events should not receive MEK162. 
 Bleeding events including bleeding in the stomach, intestines, and brain have been reported 
in patients treated with MEK162. Please contact your doctor to seek immediate medical 
attention for any unusual signs or symptoms that might indicate bleeding, e.g. bruising, 
blood in vomit, black tarry stools, difficulty speaking or walking 
 MEK162 has caused mild to moderate visual changes in some patients, which include 
floaters, swelling and/or inflammation in and around the eyes and changes in the retina. 
While this type of visual impairment may resolve, there is a risk that the visual changes 
may continue. Blurred vision and, in some cases, loss of vision might be observed with 
MEK162. There is the possibility that these changes could affect the activities of your daily 
life (i.e. driving a car or operating machinery). It is important to tell your doctor about any 
pre-existing eye problems you have and visual changes that occur while taking the study 
drug as your doctor may decide to change or stop your treatment with the study drug. 
 Hypertensive crisis was described in a single agent study with MEK162. Increase of 
blood pressure may be a potential risk when receiving MEK162. Patients at risk for high 
blood pressure will be monitored closely and according to the discretion of the 
investigator and if necessary these patients will receive specific treatment for 
hypertension. 
 Cases of serious adverse events of inflammation of the lung tissue (Interstitial Lung 
Disease or Non-Infectious Pneumonitis) have been reported in clinical studies of 
MEK162. Difficulty breathing, often accompanied by a cough and fever, is the most 
common symptom of pneumonitis. Please inform your doctor should you experience any 
of the symptoms described above. 
 Blood clots have been reported in patients treated with MEK162 including blood clots in 
veins in the legs (deep vein thrombosis), in veins of the eyes (retinal vein occlusion) and 
in arteries of the lungs (pulmonary embolism).  Please contact your doctor right away if 
you have symptoms that may be caused by blood clots such as swelling, increased 
warmth, redness or pain in your leg, loss of vision, or cough, shortness of breath or chest 
pain. 
 A severe skin reaction including serious illness with blistering of the skin, mouth, eyes 


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and genitals has been reported in a patient who received Binimetinib (MEK162) in 
combination with another investigational drug (known as BYL719). It is possible that one 
of these drugs may have caused this reaction; however, because the patient started both 
drugs at the same time, it is unknown which of the two drugs may have contributed to the 
skin reaction. Please contact your physician immediately in case of such symptoms. 
 A small number of patients and subjects in clinical trials developed hives and/or swelling 
in the throat, also known as angioedema, which can be a sign of an allergic reaction.  Your 
doctor should be notified immediately if you experience tightness in your throat which may 
be associated with difficulty breathing. 
 Severe muscle damage with breakdown of muscle tissue (rhabdomyolysis) which may 
result in organ damage such as kidney failure.   
 
Please refer to the binimetinib investigator’s brochure for a comprehensive list of adverse events 
(Edition 15, 20-Mar-2018, Section 6 Reference Safety Information and Section 7.1 Identified 
and Potential Risks).  
 
7.1.2 Expected Adverse Events for Carboplatin 
 
The adverse events most likely to occur from carboplatin include: 
 myelosuppression 
 fatigue 
 peripheral neurotoxicity 
 audiologic toxicity 
 rash 
 
Please refer to the PARAPLATIN package insert for a comprehensive list of adverse events.  
 
7.1.3 Expected Adverse Events for Pemetrexed 
  
The adverse events most likely to occur from pemetrexed in combination with platinum agents 
include: 
 myelosuppression 
 stomatitis/pharyngitis 
 constipation 
 nausea, vomiting 
 
As a single agent, the most likely adverse events of pemetrexed include: 
 fatigue 
 nausea 
 anorexia 
 
Please refer to the ALIMTA package insert for a comprehensive list of adverse events. 
 
7.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 


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in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for AE reporting.  All appropriate treatment areas should 
have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can 
be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Associated with the use of the drug: There is a reasonable possibility that the experience may 
have been caused by the drug/biologic. 
 
Life threatening adverse drug experience: Any adverse drug/biologic experience that places 
the subject, in the view of the investigator, at immediate risk of death from the reaction as it 
occurred. 
 
Serious adverse drug experience: Any event is an AE occurring at any dose that results in any 
of the following outcomes: 
 
Death 
 
A life-threatening AE (The patient was, in the view of the Investigator, at immediate risk 
of death from the event as it occurred.  It does not mean that the event, had it occurred in 
a more severe form, might have caused death). 
 
Hospitalization or prolongation of existing hospitalization (Complications that occur 
during hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other   serious criteria, the event is   serious. Hospitalization for elective treatment of a 
pre-existing condition that did not worsen from baseline is not considered to be an AE). 
 
A persistent or significant disability/incapacity (A substantial disruption of a person’s 
ability to conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated headache, 
nausea, vomiting, diarrhea, influenza, accidental trauma (i.e., sprained ankle) that may 
interfere or prevent everyday life functions but do not constitute a substantial disruption). 
 
A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition (Examples include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in hospitalization or the development of 
drug dependency or drug abuse). 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported 
as an SAE.  A second malignancy is one unrelated to the treatment of a prior malignancy (and is 


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NOT a metastasis from the initial malignancy). 
 
Events not considered to be serious adverse events are:  
 hospitalizations for the routine treatment or monitoring of the studied indication, not 
associated with any deterioration in condition,  
 treatment, which was elective or pre-planned, for a pre-existing condition that is 
unrelated to the indication under study and did not worsen,  
 admission to a hospital or other institution for general care, not associated with any 
deterioration in condition, or  
 treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission.  
 
Any SAE occurring from the start of study medication administration and until 4 weeks after the 
patient has stopped study participation must be reported. This includes the phase in which the study 
protocol interferes with the standard medical treatment given to a patient (e.g. treatment 
withdrawal during screening phase, change in treatment to a fixed dose of concomitant 
medication). Serious adverse events occurring more than 4 weeks after the end of study drug 
administration need only be reported if a relationship to MEK162 is suspected.  
 
Unexpected adverse drug experience: Any adverse drug experience, the nature, frequency, or 
severity of which is not consistent with the product monographs and investigator brochure, or not 
consistent with the risk information described above as expected adverse events. 
 
7.3 
Serious Adverse Event Reporting 
 
7.3.1 Sponsor Notification 
 
Any serious adverse event must be reported to the Central Office within 24 hours of the 
Investigator at the site learning of the event by a completed SAE form. The adverse event must be 
completely described in the case report form. 
 
The Central Office will provide expedited reports of on-study SAEs to Health Canada and Array 
BioPharma Inc. (Array) for those events which meet regulatory requirements for expedited 
reporting, i.e. events which are BOTH serious AND unexpected (as determined by reference to the 
Investigator Brochure), AND which are thought to be related to protocol treatment (or for which 
a causal relationship with protocol treatment cannot be ruled out).  
 
All adverse signs and symptoms which occur during or following the course of drug administration 
must be reported in detail on the subject’s case report form.  This description is to include the 
nature of the sign or symptom, time of onset in relation to drug application, duration, severity, and 
possible relationship to drug, required therapy, and outcome.  The subject should be followed until 
the adverse reaction is resolved, or until in the opinion of the Principal Investigator, reversal of the 
reaction is not likely to occur.  
 
7.3.2 SAE Follow-up 
 


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Follow-up SAE reports is subject to the same timelines as the initial report, and is sent to the same 
parties to whom the original Serious Adverse Event Form was sent. A new serious adverse event 
form is completed for the follow-up, stating that this is a follow-up to the previously reported 
serious adverse event 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. The follow-up 
information should describe whether the event has resolved or continues, if and how it was treated, 
and whether the patient continued or discontinued study participation.  
 
The Sponsor-Investigator and Institution will assist Array in investigating any SAE and will 
provide any follow-up information reasonably requested by Array. 
 
7.3.3 REB Notification of SAEs 
 
Investigators must notify their Research Ethics Boards (according to their local REB policies) and 
file the report in their study files. Documentation as outlined below must be maintained for 
reportable SAEs.  Documentation that serious adverse events (SAEs) have been reported to REB 
must be forwarded to the DDP and kept on file at the Centre. Documentation can be any of the 
following:  
 
letter or email from the REB acknowledging receipt  
 
stamp from the REB, signed and dated by REB chair, acknowledging receipt 
 
letter demonstrating the SAE was sent to the REB 
 
email submission to REB by site 
 
7.3.4 Health Canada SAE Reporting 
 
All serious, unexpected adverse drug reactions must also be reported by the Princess Margaret 
Cancer Centre DDP Central Office to Health Canada within 15 days if the reaction is neither fatal 
nor life threatening, and within 7 days if the reaction is fatal or life threatening. 
 
The Central Office will be responsible for reporting all serious unexpected adverse events to Health 
Canada. The Central Office will generate SUSAR reports for all SAEs deemed Health Canada 
reportable.  
 
7.3.5 SAE Reporting to Array BioPharma Inc.  
 
To ensure patient safety, each serious adverse event must also be reported to Array (in English) 
within 15 calendar days of learning of its occurrence, even if it is not felt to be treatment-related.  
Follow-up information about a previously reported serious adverse event must also be reported 
within 15 calendar days of the Investigator-sponsor receiving it. The SAE Report Form must 
indicate the relationship to study treatment and be signed by the investigator. The Princess 
Margaret Cancer Centre DDP Central Office will report the SAE to Array:  
 
Attention:  
Drug Safety 
drugsafety@arraybiopharma.com  
Fax: (303)-386-1516 


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50 
 
 
A summary of SUSARs (see Section 7.3.4) from this study will be generated every 6 months, 
and submitted to Array Biopharma. 
 
7.4 
Routine Adverse Event Reporting 
 
For abnormal laboratory values, it is the responsibility of the Principal Investigator or delegate 
to assess the clinical significance of each abnormality. Only abnormal laboratory values that can 
be assessed for grade using CTCAE version 4.0 will be documented. The Investigator will 
determine whether abnormal laboratory values are considered clinically significant and represent 
AEs based on their medical judgment.  
 
Data on all adverse experiences/toxicities regardless of seriousness must be collected for 
documentation purposes only.   
 
7.4.1 Clinical Laboratory Abnormalities: 
 
All abnormal laboratory values should be captured on source documentation and assessed for 
clinical significance by the Investigator at the site.  Only abnormal laboratory values deemed 
clinically significant should be listed as AEs in source and CRFs.  All clinically significant 
abnormal laboratory results will be followed up until the related AE resolves, returns to < grade 2 
or baseline value in the follow-up period.  Clinically significant laboratory abnormalities will be 
dictated in the clinic notes.  Additionally, laboratory abnormalities resulting in an intervention are 
considered to be clinically significant. 
 
7.5 
Documentation of Adverse Events 
 
All AEs must be captured in the source documents, as well as reported in electronic document 
capture (EDC) system.  AEs reported using SAE forms must also be reported in EDC system. 
 
All serious and non-serious AEs occurring from the start of study medication administration to 
the end of study drug administration visit must be recorded as AEs on the CRF. The Investigator 
should review all documentation (e.g., hospital progress notes, laboratory, or diagnostic reports) 
relative to the event being reported.  
 
7.6 
Follow-Up of AEs and SAEs 
 
SAEs and AEs should be followed for 28 days after the last dosing of study drug or until they are 
resolved (return to normal or baseline values), stabilized, improve to < Grade 2, or the patient is 
lost to follow-up and cannot be contacted.  Additional investigations (e.g., laboratory tests, 
diagnostic procedures, or consultation with other healthcare professionals) may be required to 
completely investigate the nature and/or causality of an AE or SAE.  If the patient dies during the 
study or within 28 days following the last dose of study medication, any postmortem findings 
(including histopathology) should be provided to the Sponsor.  CRF data should be updated with 
any new information as appropriate. 
 


Protocol #: CMEK162ACA02T 
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51 
 
7.7 
 
Pregnancy 
 
Any pregnancy of a study subject or of a study subject’s partner that occurs during study 
participation should be reported for pregnancies that occur up to 30 days after the last dose of study 
medication. If the study subject is the father, then two forms should be completed, one for the 
father and the other for the mother and neonate. To ensure patient safety each pregnancy must also 
be reported to Array within 15 days of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
birth, and the presence or absence of any birth defects, congenital abnormalities or maternal and 
newborn complications.  
 
7.8 
Investigator Notifications 
 
The Sponsor-Investigator will receive Investigator Safety Letters (ISLs) issued by Array for 
suspected, unexpected serious adverse reactions which have occurred in Array-sponsored studies 
with the study drug. The Sponsor-Investigator is responsible for forwarding these ISLs to all sub-
investigators participating in the study, as well as to the Research Ethics Boards, according to local 
practice. 
 
7.9 
Data Safety and Monitoring Board 
 
A Data Safety and Monitoring Board, an independent group of experts, through the Princess 
Margaret Cancer Centre Drug Development Program will be reviewing the data from this research 
throughout the study to see if there are unexpected or more serious side effects than described in 
the consent. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
 
8.1 
Investigational Agent 
 
8.1.1 MEK162 
 
MEK162 is currently supplied as film-coated tablets in dosage strength of 15mg. The film-coated 
tablets consist of MEK162 drug substance, lactose monohydrate, microcrystalline cellulose, 
colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and a commercial film 
coating.  
The tablets are yellow to dark yellow capsule-shaped.  
As development continues additional strengths of similar formulation may be developed. 
Investigational agent Manufacturing 


Protocol #: CMEK162ACA02T 
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52 
 
 
Array manufactures MEK162 for clinical use. 
 
Investigational Agent Packaging and Labeling 
 
MEK162 will be packaged and labeled by a contract manufacturing organization and stored by 
Array.  Study drug labeling will contain the following information in English and French: 
 
Protocol Code: MEK162 
Investigational Drug name and formulation (mg): MEK162 
Lot Number: DP-ARR16-118-A 
Contents: 15mg tablets  
Store at 25°C 
Investigational drug:  To be used by qualified investigators only.   
Sponsor: Princess Margaret Cancer Centre 
 
Investigational Agent Handling and Storage 
 
Investigational agent will be stored under secure (with limited access), temperature-controlled 
conditions for the duration of the study. Investigational agent bottles will be stored at ambient 
temperature (i.e.15-25C) and protected from light, in an area accessible only to authorized staff.  
Patients will be asked to store their one-month supply of drug at ambient temperature and protected 
from light.  Packaging is in plastic bottles acceptable for pharmaceutical use. The Investigator, or 
designee will keep study drug inventory forms. 
 
Availability 
 
MEK162 is provided under a Collaborative Agreement between the Sponsor and the agent 
manufacturer (Novartis/Array). 
 
Investigational Agent Ordering and Shipping 
 
Investigational agents may be ordered only after the initial REB approval and the site has been 
activated by the Drug Development Program Central Office. 
Array will supply MEK162 to the study site.  Study drugs must be received by a designated person 
at the study site, handled and stored safely and properly, and kept in a secured location to which 
only the investigator and designated assistants have access. The Principal Investigator, or 
authorized study personnel, upon receipt of the study medication supplies, will conduct an 
inventory and acknowledge receipt to Array, or designee. The study drugs should be stored 
according to the instructions specified on the drug labels. 
 
Study medication should only be dispensed once a patient has (1) signed an informed consent form 


Protocol #: CMEK162ACA02T 
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53 
 
(ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and 
continuing eligibility requirements, and (4) been assigned a patient identification number. 
 
Agent Accountability 
 
The Investigator is responsible for study medication accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or 
designated study personnel must maintain study medication accountability records throughout the 
study.   
 
The accountability records maintained during the study will be used to support patient dosing data.  
Site personnel are responsible for reconciling and resolving discrepancies in study medication 
accountability.    
 
Missing study medication must be recorded along with an explanation of the discrepancy.  At the 
conclusion of the study, all unused study medication and all medication containers will be returned 
to Array or designee, unless other arrangements have been approved by Array. 
 
Agent Inventory Records  
 
The investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received using their site-specific Drug 
Accountability Record Form (DARF). 
 
8.2 
Non-Investigational Agents 
 
8.2.1 Carboplatin 
 
Carboplatin is a cisplatin derivative and shares the same mechanism of action. Highly reactive 
platinum complexes are formed intracellularly. These complexes inhibit DNA synthesis through 
covalent binding of DNA molecules to form intrastrand and interstrand DNA crosslinks. 
Carboplatin is considered to be cell cycle phase-nonspecific, but recent studies have shown 
complex and variable effects on the cell cycle.  
Availability 
 
Paraplatin AQ® (Brand Discontinued), Generic brands available 
 
Reconstituted in 250ml normal saline 0.9% or glucose 5%. Carboplatin is physically incompatible 
with any IV set, needle or syringe containing aluminum. Carboplatin solutions are stable for 8 
hours at room temperature (25°C). Intravenous administration over 30 minutes. 
 
Ordering and Shipping 
 
Carboplatin will be sourced locally by the study site and reimbursed through provincial drug 
funding mechanisms.  The Principal Investigator, or authorized study personnel, upon receipt of 
the study medication supplies, will conduct an inventory. 


Protocol #: CMEK162ACA02T 
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54 
 
 
Study medication should only be dispensed once a patient has (1) signed an informed consent form 
(ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and 
continuing eligibility requirements, and (4) been assigned a patient identification number. 
 
Accountability 
The Investigator is responsible for study medication accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or 
designated study personnel must maintain study medication accountability records throughout the 
study.   
 
The accountability records maintained during the study will be used to support patient dosing data.  
Site personnel are responsible for reconciling and resolving discrepancies in study medication 
accountability.   
 
Missing study medication must be recorded along with an explanation of the discrepancy.  At the 
conclusion of the study, all unused study medication and all medication containers will be returned 
to the clinical trials pharmacy, unless other arrangements have been approved by the sponsor.  
 
8.2.2 Pemetrexed 
 
Pemetrexed is a pyrrolopyrimidine antifolate that exerts its antineoplastic activity by inhibiting 
thymidylate synthase (TS), glycinamide ribonucleotide formyltransferase (GARFT) and 
dihydrofolate reductase, which are all folate-dependent enzymes involved in the de novo 
biosynthesis of thymidine and purine nucleotides. Pemetrexed is transported into cells by both the 
reduced folate carrier and membrane folate binding protein transport systems. Inhibition of TS 
appears to be the primary mechanism of action. Severe toxicity in early clinical studies (6% toxic 
death rate) led to the introduction of mandatory folate and vitamin B12 supplementation. 
 
Availability 
 
Commercial name Alimta® (Eli Lilly) 
 
Reconstituted in 100ml normal saline 0.9%. Pemetrexed is incompatible with calcium containing 
solutions and should not be co-administered with other drugs and diluents. Keep unopened vials 
at room temperature. Pemetrexed is not light sensitive. Intravenous administration over 10 
minutes. 
 
Ordering and Shipping 
 
Pemetrexed will be sourced locally by the study site, and reimbursed through provincial funding 
mechanisms.  The Principal Investigator, or authorized study personnel, upon receipt of the study 
medication supplies, will conduct an inventory. 
 
Study medication should only be dispensed once a patient has (1) signed an informed consent form 
(ICF), (2) met all eligibility criteria for entry into the study, (3) completed all screening and 


Protocol #: CMEK162ACA02T 
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55 
 
continuing eligibility requirements, and (4) been assigned a patient identification number. 
 
Accountability 
The Investigator is responsible for study medication accountability, reconciliation, and record 
maintenance.  In accordance with all applicable regulatory requirements, the Investigator or 
designated study personnel must maintain study medication accountability records throughout the 
study.   
 
The accountability records maintained during the study will be used to support patient dosing data.  
Site personnel are responsible for reconciling and resolving discrepancies in study medication 
accountability.   
 
Missing study medication must be recorded along with an explanation of the discrepancy.  At the 
conclusion of the study, all unused study medication and all medication containers will be returned 
to clinical trials pharmacy, unless other arrangements have been approved by the sponsor. 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
All participating sites will provide documentation of IATA training to the Central Office for all 
study staff delegated to the task of shipping and handling of specimens. 
 
9.1 
Pharmacokinetics  
The blood sampling regimens for determining the pharmacokinetics of MEK162 and its primary 
active metabolite AR00426032, are given in Table 9.1. Blood samples for MEK162/AR00426032 
plasma concentration measurements will be collected on all patients in the study. 
Pharmacokinetic (PK) testing will occur over a 24-hour period on each of cycle 1 day 5 and cycle 
1 day 15 (see Table 9.1). This will allow steady-state information to be obtained related directly 
to the chemotherapy dose and without chemotherapy. PK kits will be provided for this study. 
 
All samples are to be taken as closely as possible to the times specified above in Section 9.1. If 
samples are taken at times different from this schedule, they are still valuable provided the sample 
times are accurately recorded.  
Exact dates and clock times of drug administration and actual PK blood draw will be recorded on 
the appropriate CRF. The time of the last meal should be recorded on all post-dose PK sampling 
days. If a patient experiences an AE that results in an unscheduled visit or fits the criteria of 
a SAE as determined by the Investigator, a blood sample (4 mL) should be collected for 
measurement of plasma drug concentrations. Additionally, if a patient experiences an ocular 
event of any grade, a blood sample should be collected. 
If vomiting occurs within 4 hours following study-drug administration on the day of PK blood 
sampling, the time (using the 24 hour clock) of vomiting should be recorded on the transmittal 
forms, which accompanies the sample. No additional trial medication should be taken that day in 
an effort to replace the material that has been vomited. If a patient withdraws prematurely from 
the study, a PK blood sample (4 mL of sample) must be obtained whenever possible. Sample 


Protocol #: CMEK162ACA02T 
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56 
 
should be as soon as possible after the last dose of MEK162, and the date and time of last dose 
recorded. 
Intravenous cannulation of an antecubital or forearm vein may be performed prior to drug 
administration on serial PK sampling days to facilitate collection of blood specimens. The cannula 
will be kept patent by means of a heparin/saline lock. If a cannula is utilized, an initial 1 mL 
volume of blood will be collected and wasted prior to collection of each whole blood sample to 
assure the heparin/saline solution does not dilute the blood sample. Pharmacokinetic sample tubes 
will be clearly labeled with the drug name, study number, patient serial number, sample date, and 
sample collection time (relative to dosing). The date and time of sample collection will be captured 
on Pharmacokinetics Forms (Form PK). If for any reason a sample is not collected, the sample 
date and time should be recorded as not done (ND) on the Pharmacokinetics Form (Form PK). 
Complete instructions for sample collection, processing, handling and shipment will be provided 
in the lab manual.  
9.1.1 
PK Shipping Instructions  
A sample inventory detailing the number and identities of the samples sent must accompany each 
batch of samples dispatched. Samples should be shipped to avoid arrival at the laboratory during 
weekends. Please refer to the lab manual for complete instructions. 
All samples must be carefully packed in suitable material containing sufficient dry ice to keep 
them frozen during shipment. A list of samples, including the date, subject number, and the time 
of sampling should be included in the shipment. Any missing samples should be notified on the 
list. 
Any sampling problems should be noted on the CRF and on appropriate source documentation. 
 
 
 
 
 
 
 
 
 
Table 9.1. Pharmacokinetic sampling schedule 
 
Cycle 
Day 
Scheduled time for pharmacokinetic sampling 
relative to dosing 
1 
5 
Pre-dose 
1 
5 
0.5 hr post dose ± 15 min 


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57 
 
1 
5 
1.5 hr post dose ± 15 min 
1 
5 
3 hr post dose ± 30 min 
1 
5 
5 hr post dose ± 1 hr 
1 
5 
8 hr post dose ± 1 hr 
1 
15 
Pre-dose 
1 
15 
0.5 hr post dose ± 15 min 
1 
15 
1.5 hr post dose ± 15 min 
1 
15 
3 hr post dose ± 30 min 
1 
15 
5 hr post dose ± 1 hr 
1 
15 
8 hr post dose ± 1 hr 
N/A 
Safety follow-up  
(28 days from the End of 
Study Drug 
Administration) 
Post-dose, unspecified time point 
 
9.2 
Biomarker Studies 
 
The collection of a representative sample of tumor tissue is an important part of this trial and is 
mandatory for participation in the study for the evaluation of KRAS mutations, as well as KRAS 
codon subtypes. Tumor blocks will be the preferred material to collect. These will optimize the 
amount of tissue available to investigators and permit the preservation of the tumor block 
submitted. If tissue is obtained from another hospital and, at any time, the submitting hospital 
requires the block to be returned for medical or legal concerns, it will be returned by courier on 
request. The methodology for KRAS mutation testing is detailed in the lab manual. If KRAS 
analysis is already available, the patient will be eligible for the study.  
 
All patients will be approached for optional consent for tissue samples to be banked for future 
biomarker exploration.  
 
Patients will not be identified by name. The only identification of tissue will be by a patient 
study number assigned at the time of registration to the trial the surgical/histology number and/or 
patient initials.  
 
This information will be generated retrospectively in the dose escalation phase, but will also be 
used for stratification purposes for the phase Ib portion of the study. 


Protocol #: CMEK162ACA02T 
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58 
 
 
9.3 
Laboratory Correlative Studies 
 
N/A 
 
10. STUDY CALENDAR 
 
Baseline (pre-study) evaluations are to be conducted within 14 days prior to start of protocol 
therapy, unless specified differently in the study calendar.  Informed consent and scans and x-rays 
must be done within28 days prior to the start of therapy. In the event that the patient’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy.  The following schedule of assessments applies to all subjects.  More 
frequent assessments should be obtained if clinically indicated.  If pre-study physical exam, vital 
signs, weight, performance status, and blood assessments were done within 3 days prior to 
treatment initiation, they do not need to be repeated for cycle 1 day 1. For subsequent cycles 2+, 
day 1 assessments can be completed up to 72 hours prior to day 1.  A cycle is 28 days long for 
cycle 1 only, and 21 days for cycle 2 and onwards. 
 
 


Protocol #: CMEK162ACA02T 
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59 
 
 
Pre-
Study 
Day -
14 
Cycle  
1 
Cycle  
2 
Cycle  
3 
Cycle  
4 
Cycle  
5 
Cycle 
6 
Subsequent 
cycles 
End of 
Treatmentd 
Safety F/Ui 
Disease 
Progression FU 
D 
1 
D 
8
m 
D 
15 
m 
D 
21 
m 
D 
1 
D 
8 
D 
15 
D 
1 
D 
8 
D 
15 
D 
1 
D 
8 
D 
15 
D 
1 
D 
8 
D 
15 
D 
1 
MEK162 
A………………………………………………..……………………………………………..A 
Pemetrexed 
B 
B 
B 
B 
B* 
B* 
Carboplatin 
C 
C 
C 
C 
C* 
C* 
Informed 
consent 
X 
Demographics 
X 
Medical history 
X 
Inclusion/ 
Exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X……………………………………………………………………………..……….…………X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs ** 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
screen 
X 
 
X 
X 
X 
Serum 
chemistrya 
X 
Xl 
X 
X 
X 
X
l 
Xl 
Xl 
Xl 
Xl 
X 
X 
X 
ECGb  
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
 
Echocardiogram
/ MUGAc 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
 
Adverse event 
evaluation 
 
X………………..…………………………………………………………………………………X 
X 
 
 
Tumor 
measurements 
X 
Tumor measurements are repeated every 6-8 weekse.  Documentation (radiologic) must be provided 
for patients removed from study for progressive disease. 
Xn 
 
X 
Radiologic 
evaluation 
X 
Radiologic measurements should be performed every 6-8weekse. 
 
 
X 
 
X 
B-HCG 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Pharmacokinetic 
testing 
 
Xg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Ophthalmologic 
assessmenth 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
 
 
Audiogramj 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research blood 
sample k 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
Consent for 
genomic 
profiling 
X 


Protocol #: CMEK162ACA02T 
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60 
 
A:     MEK162:  Dose as assigned; administration schedule (omit dose for 2 days prior to each administration of chemotherapy). 
B:     Pemetrexed:  Dose as assigned; administration schedule.  
C:     Carboplatin: Dose as assigned; administration schedule.  
*:      Optional cycle 5 and 6 of chemotherapy. 
**:    Vital signs include heart rate, blood pressure, respiratory rate, temperature, oxygen saturation 
a) 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, magnesium, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium, creatine kinase (CK). 
b) 
ECG to be performed at baseline, Cycle 2 day 1 (prior to treatment), then every 6 weeks (± 7 days) irrespective of cycle until MEK162 discontinuation, and at end of 
treatment visit. 
c) 
LV assessment (echocardiogram or MUGA) to be performed at baseline, prior to cycle 3 (week 6 or 7), then every 9 weeks (± 7 days) irrespective of cycle until MEK162 
discontinuation. 
d) 
End of treatment evaluations 
e) 
Tumour measurements to be performed according to RECIST 1.1. 
f) 
Serum pregnancy test (women of childbearing potential)-3 days  
g) 
Pharmacokinetic testing:  Cycle 1 day 5 (0-8hr),  cycle 1 day 15 (0-8hr) and safety follow-up 
h) 
Ophthalmologic assessment at baseline, then in week 4 or 5 (prior to cycle 2 day 1 treatment), and then every 6 weeks ± 7 days irrespective of cycle. Exam includes slit 
lamp examination, visual acuity testing, visual field testing, intraocular pressure, and indirect fundoscopy 
i) 
Safety follow-up 28 days from the end of study drug administration (± 2 days). AEs (including concomitant medications taken for ongoing AEs) and ongoing anti-
neoplastic treatments will be collected for 28 days (±2 days) after the last dose of study drug. Note that pregnancy follow up is required at 120 days (± 2 days) for all 
subjects of child bearing potential. 
j) 
Patients with significantly impaired hearing must be made aware of potential ototoxicity and may choose not to participate in the study. If those with hearing impairment 
are included baseline audiograms are recommended and should be followed by repeat audiograms prior to treatment on cycle 2 day 1. 
k) 
Only for patients who sign optional consent. To be drawn prior to treatment and at specified timepoints. 
l) 
Amylase (to be completed within 72 hours prior to receiving treatment) 
m) Day 8, 15, and 21 assessments to be completed ± 1 day 
n) 
Only required when patient is taken off study treatment for reasons other than progressive disease and when a radiological scan was not completed within 3 weeks (± 7 
days) of this decision. 
 
 
10.1 
Baseline/Pre-Study Evaluations 
 
The study IRB/IEC/REB approved informed consent must be signed and dated before any 
screening procedures are performed (procedures which are part of the clinical routine during the 
initial diagnostic work-up of the patient may be performed before obtaining the ICF). A copy of 
the ICF must be given to the patient or to the person signing the form. Patients who sign the study 
informed consent but fail to be started on treatment for any reason will be considered a screen 
failure. 
Baseline (pre-study) evaluations are to be conducted within 14 days prior to start of protocol 
therapy, unless specified differently in the study calendar.  Scans and x-rays must be done <28 
days prior to the start of therapy. Patients who sign the study informed consent but fail to be 
started on treatment for any reason will be considered a screen failure. The reason for not being 
started on treatment will be entered on the Screening Log. 
10.2 
Treatment 
Carboplatin and pemetrexed are given intravenously on a 3-weekly schedule. Treatment with 
chemotherapy will start on cycle 1 day 8 following a week of treatment with MEK162 alone. 
MEK162 which will be taken orally bid, with the exception of Cycle 1 Day 5 and Cycle 1 Day 15, 
when only the morning dose of MEK162 will be taken (to allow for pharmacokinetic assessments). 
In addition, MEK162 will be omitted for 2 days prior to administration of chemotherapy for every 
cycle. This is to minimize toxicity by allowing a washout period prior to chemotherapy 
administration with the aim of not compromising benefit. All patients will receive the study drug 
on a continuous basis with these exceptions. There is no fixed treatment duration; patients may 
continue treatment with MEK162 until the development of any unacceptable toxicity that 
precludes any further treatment, disease progression, and/or treatment is discontinued at the 
discretion of the Investigator or by patient refusal. For details of assessments, refer to section 10.  
Patients with significant impaired hearing at baseline must be made aware of potential 


Protocol #: CMEK162ACA02T 
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61 
 
ototoxicity and may choose not to participate in the study.  If included, baseline audiograms are 
recommended and should be followed by repeat audiograms prior to treatment on cycle 2 day 1. 
Ophthalmologic examination will occur at baseline and if ophthalmologic symptoms occur. 
 Full ophthalmic examination including slit lamp examination, visual acuity testing, visual field 
testing, intraocular pressure (IOP) and indirect fundoscopy with attention to retinal 
abnormalities, especially RPED like events and RVO.  
 For patients with clinical suspicion of retinal abnormalities (i.e. photopsia, metamorphopsia, 
impairment of visual acuity, etc.) or RVO, additional assessments of optical coherence 
tomography (for RPED) and fluorescein angiography (for RVO) are mandatory.  
 Images of the ophthalmic exams (at a minimum, OCT and fluorescein angiography) should be 
sent to the investigative site along with the results of the exam and be maintained in the 
patient’s source document file.    
 Follow up for total creatine kinase (CK) ≥3 X ULN will include weekly assessment of 
isoenzymes and myoglobin in blood/or urine, and troponin as applicable. 
 
Tumor reassessments and CT Thorax, abdomen and pelvis will be performed every 6-8 weeks. 
10.3 
Specific guidance related to blood pressure 
 
Risk of hypertension has been highlighted on prior studies involving MEK162. Based on the 
analysis of current available data with MEK162 it appears this risk may be limited to patients with 
underlying risk factors for hypertension.  
 
Blood pressure must be carefully monitored during the first 2 cycles (49 days) in patients with 
known underlying risk factors for hypertension at screening. 
 
 Patients must monitor their blood pressure at home or at medical facility at day 10 and day 30 
following drug initiation if they meet the following criteria: 
o Patients with history of hypertension and/or 
o Patients receiving antihypertensive drugs before onset of study treatment and/or 
o Patients with a screening systolic blood pressure (SBP) of ≥140mmHg and/or 
o Patients with a screening diastolic blood pressure (DBP) of ≥90mmHg 
 
 The investigator should educate the patient on the signs and symptoms of hypertension and use 
of the home blood pressure monitor, if applicable. More frequent assessments during the study 
may also be performed at the discretion of the investigator and if medically indicated.  
 
 Measurements are to be taken at the same time on days 10 and 30 after taking any hypertensive 
medications and after being at rest for 5 minutes in a sitting position. If SBP ≥160mmHg, or 
DBP ≥100mmHg, the patient should contact his/her investigator to have an unscheduled visit. 
At this unscheduled visit, the patient’s blood pressure should be assessed formally for grading 
and these measurements must be documented in the appropriate section of the case report form 
(CRF). Clinical decisions will be based on the BP assessment performed in clinic. Early 


Protocol #: CMEK162ACA02T 
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62 
 
initiation of treatment and aggressive management of emergent hypertension must be 
implemented after its diagnosis. 
 
 For patients monitoring their blood pressure at home, it is suggested to develop a patient diary 
to record their self-assessed blood pressure measurements and present the collected data to the 
investigator for evaluation and appropriate management. This diary must be maintained with 
the patient’s source documentation. 
 
10.4 
End of Study Drug Administration and Follow-Up Evaluations 
 
Patients who discontinue study treatment before completing the study should be scheduled for a 
visit as soon as possible, at which time all of the assessments listed for the end of treatment (EOT) 
visit will be performed. At a minimum, all patients who discontinue study treatment, including 
those who refuse to return for a final visit, will be contacted for safety evaluations during the 28 
days (+/- 2 days) following the last administration of study treatment. 
Patients who discontinue study treatment should be considered withdrawn from the study after the 
EOT assessments are performed or when it is clear that the patient will not return for these 
assessments. 
If a withdrawal occurs, or if the patient fails to return for visits, the investigator must determine 
the primary reason for a patient’s premature withdrawal from the study and record this information 
on the EOT CRF page.  EOT or premature patient withdrawal is not considered as the end of the 
study. 
Patients will be followed as per section 5.6 and the study calendar above. 
 
11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  For the purposes of this study, patients should be re-evaluated 
every 6-8 weeks.  In addition to a baseline scan, confirmatory scans will also be obtained 8 weeks 
following initial documentation of an objective response. 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6-8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 (not less than 4) weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (uni-dimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes 
are used in the RECIST criteria. 


Protocol #: CMEK162ACA02T 
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63 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their first 
treatment with MEK162. 
 
Evaluable for objective response.  Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified according 
to the definitions stated below.  (Note:  Patients who exhibit objective disease progression prior to 
the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that are 
evaluable but do not meet the definitions of measurable disease, have received at least one cycle 
of therapy, and have had their disease re-evaluated will be considered evaluable for non-target 
disease.  The response assessment is based on the presence, absence, or unequivocal progression 
of the lesions.  
 
11.1.2 Disease Parameters 
 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or as ≥10 mm 
with CT scan, MRI, or calipers by clinical exam.  All tumor measurements must be recorded in 
millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.   
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter < 10 mm or pathological lymph nodes with  10 to < 15 mm short axis) as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural/pericardial effusions, lymphangitic involvement of skin or lung, 
inflammatory breast disease, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 


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Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  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.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
11.1.3 Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  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.  
 
Clinical Lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and  10 mm diameter as assessed using calipers 
(e.g. skin nodules). For the case of skin lesions, documentation by colour photography including 
a ruler to estimate the size of the lesion is recommended.  When lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and 
may also be reviewed at the end of the study. 
 
Chest X-ray:  Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 
CT & MRI:  CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. CT should be performed with slice thickness of 5 mm or less.  When CT 
scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body scans). 
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised.   
 


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Cytology, Histology:  These techniques can be used to differentiate between PR and CR in rare 
cases. The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment can be considered if the measurable tumour has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and progressive disease.  
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study, including 
baseline. Overall response will not go from PR to SD. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a patient 
to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
 


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11.1.4.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
Note:  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. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 


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11.1.5 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
11.1.6 Progression-Free Survival 
 
Progression free survival (PFS) is defined as the duration of time from start of treatment to time 
of progression or death, whichever occurs first.  If such event is not observed after 6 months of 
follow up, patients are censored. 
 
11.1.7 Response Review 
 
All CR and PR responses will be reviewed by an expert independent of the study at the patient’s 
completion of the study by simultaneous review of patient files and radiologic images. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Collection and Reporting 
 
All data obtained in the clinical trial described in this protocol will be reported on eCRFs in the 
Medidata Electronic Document Capture system (Medidata).  Data reported on eCRFs should be 
consistent with the source documents and verifiable.  All data for the primary and secondary 
endpoints will source verified prior to publication.  The Investigator will review the data and 
electronically sign the eCRFs to acknowledge agreement with the data entered. Data will be 
entered into Medidata will be used for developing tables and listings for the final study report. 
 
Prior to the start of the study, the Investigator will complete a Site Participant’s Log showing the 
signatures and handwritten initials of all individuals who are authorized to make or change entries 
on source documents and eCRFs. 
 
 
12.2 
Source Documents 
 


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Source documents refer to the original documents, data, and records where the first recording of a 
data point occurred.  Examples of source documentation include, but are not limited to:  
 
Hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate copies, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories and at medico-technical departments involved in the clinical trial) 
 
Please ensure that source document entries are attributable, legible, contemporaneous, original, 
and accurate.  Note that sign-off of source documents should be attributable to a single record and 
“bracketing” multiple entries on source document pages for a single signature is not allowed.  
Corrections to source document entries should only be completed by drawing a single line through 
the previous entry and then recording the corrected data, initialing the change, and dating the 
change.  Only the individual that initially recorded the data should make any corrections.    
 
12.3 
Retention of Patient Records and Study Files 
 
The ICH guidance document, Good Clinical Practice: Consolidated Guidelines (ICH Guidance 
Document E6) (1997) states that the investigator and sponsor shall retain study records relating to 
the study until at least 2 years after the last approval of a marketing application and until there are 
no pending or contemplated marketing applications, or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  In the event of a 
trial discontinuation, sponsor records should also be kept for a minimum of 2 years.  Per Health 
Canada, all original records should be maintained for 25 years after the above requirements are 
satisfied and the final report has been issued.  Records contained in the Clinical Trial Application 
should be maintained on file for at least 25 years.  We will comply with these regulations.    The 
Sponsor will notify sites when documents are to be destroyed. 
 
12.4 
Site and Study Closure 
 
Upon completion of the study, the following activities, when applicable, will be completed by the 
Central Office in conjunction with the Investigator, as appropriate: 
 
 Collection of study materials (i.e., specimen collection kits, drug shippers, etc.) 
 Data clarifications and/or resolutions 
 Accounting, reconciliation, and final disposition of used and unused study medication 
 Review of site study records for completeness 
 
If the Sponsor or Investigator or appropriate regulatory officials identify conditions arising during 
the study that indicate that the study should be halted or that the study center should be terminated, 
this action may be taken after appropriate consultation among the Sponsor and Investigator. 
Conditions that may warrant termination of the study include, but are not limited to, the following: 
 
 The discovery of an unexpected, serious, or unacceptable risk to the patients enrolled in 
the study 


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 A decision on the part of the Sponsor to suspend or discontinue testing, evaluation, or 
development of the product  
 Failure of the Investigator to enroll patients into the study at an acceptable rate  
 Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
 Submission of knowingly false information to the Sponsor, or appropriate regulatory 
authority  
 Insufficient adherence to protocol requirements 
 Refusal of the Investigator to supply source documentation of work performed in this 
clinical trial 
 
Study termination and follow-up will be performed in compliance with the conditions set forth in 
the International Conference on Harmonisation (ICH) sixth efficacy publication (E6) on Good 
Clinical Practice, Section 4.12, ICH E6 4.13, ICH E6 5.20, and ICH E6 5.21. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Primary 
 
Phase I  
 Development of dose-limiting toxicity (DLT), (defined in section 4.3) as measured with 
NCI CTCAE v4.0 in cycle 1. 
 Adverse events, serious adverse events, changes in hematology and chemistry values, 
vital signs, ECGs. 
 
Phase Ib 
 Objective response rate (ORR) as per RECIST v1.1. ORR is defined as the percentage of 
patients that have achieved complete or partial response as the overall response.  
 Evaluation progression-free survival (PFS) and disease control rate (DCR) for patients 
with and without KRAS mutation in tumor tissue. PFS is defined as the time from start of 
treatment to disease progression or death. DCR is defined as the percentage of patients 
that have achieved either stable disease, partial or complete response as the overall 
response.  
 
Secondary 
 
Phase I   
 Pharmacokinetic profile of MEK162 when administered with carboplatin and 
pemetrexed. 
 
Phase Ib 
 Exploratory analysis of KRAS mutation sub-type. 
Exploratory  


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 A limited sampling strategy pharmacokinetic model will be used to ensure that the 
clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-
based chemotherapy. 
 
13.2 
Sample Size/Accrual Rate 
 
Final sample size will be dependent upon the number of dose levels required to reach the RP2D. 
Once the RP2D is established, at least 6 patients will be enrolled to further evaluate toxicity, 
response and translational research of this regimen. It is anticipated that 9 to 12 patients will be 
enrolled in the phase I part of this study. In phase Ib, a total of 30 patients will be enrolled. 
 
 
Accrual and Duration of Study 
It is expected that accrual for the phase I portion of this study will be completed in 36 weeks. For 
the phase Ib part, the estimated accrual for this study is 3-4 patients per month.  Thus, patient 
accrual for 30 patients is expected to be completed within another 9 months.  Additional time is 
required to allow the response data to mature.  
 
13.3 
Analysis of Primary Endpoints 
 
Baseline patient and tumour characteristics, safety and efficacy outcomes will be summarized by 
dose level and phase, and combined, using descriptive statistics. Time to progression will be 
estimated using the Kaplan-Meier method. No statistical testing will be performed, except in an 
exploratory fashion for tertiary analyses. Plots, tables, and listings will be used to improve 
understanding of the study results. 95% confidence intervals will be constructed for outcomes of 
interest. 
 
13.4 
Stratification Factors 
 
There are no stratification factors for the dose escalation portion of the study. Once RP2D has 
been identified, an expansion cohort will enrol additional patients stratified by KRAS genotype.   
  
Stratification of patients by KRAS genotype aims for the targets detailed below: 
Wild-type KRAS: N=10 
KRAS mutant non-G12C: N=10 
KRAS mutant G12C: N=10 
 
13.5 
Analysis of Secondary Endpoints 
 
Pharmacokinetic parameters will be summarized by dose level and phase, and combined using 
descriptive statistics. Exploratory analysis of response rate by KRAS genotype will be 
summarized using descriptive statistics.  
 
If responses are reported as a secondary objective, the following criteria will be used.  Every 
report should contain all patients included in the study.  For the response calculation, the report 
should contain at least a section with all eligible patients.  Another section of the report may 
detail the response rate for evaluable patients only.  However, a response rate analysis based on a 


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subset of patients must explain which patients were excluded and for which reasons. 95% 
confidence limits will be given. 
 
13.6 
Analysis of Exploratory Endpoints 
 
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood sample 
providing evaluable PK data. The PAS will be used for summaries of PK data (Tables and Figures) 
as well as for listings of derived parameters. 
Note: patients will be removed from the estimation of certain PK parameters on an individual basis 
depending on the number of available blood samples. These patients will be identified at the time 
of the analyses. 
Demographic and other baseline data including disease characteristics will be summarized for all 
patients in the PAS.  
Genomic analysis will be performed on the submitted tumor specimen for each patient and this 
will be retrospectively analysed for correlation with response data. 
 
The dose-determining set consists of all patients from the safety set who either meet the following 
minimum exposure criterion and have scheduled safety evaluations, or discontinue earlier due to 
DLT. A patient is considered to have met the minimum exposure criterion if having received at 
least 16 out of the 24 planned daily combination doses of MEK162 (bid) in the first 28 days of 
dosing. 
Patients who do not experience DLT during the first cycle are considered to have sufficient safety 
evaluations if they have been observed for ≥ 28 days following the first dose, and are considered 
by both the Sponsor and Investigators to have enough safety data to conclude that a DLT did not 
occur. 
Patients who do not meet these minimum safety evaluation requirements will be regarded as 
ineligible for the dose-determining set and will need to be replaced. 
Time to event will be estimated using the Kaplan Meier approach. Groups of different prognosis, 
in particular KRAS mutation status will be compared with the log rank test.  
All conclusions will be based on all eligible patients.  Subgroup analyses may be performed 
including by KRAS genotype. Patients may be excluded for major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, etc.).  
Subgroup analysis of efficacy will be exploratory only, and the reasons for excluding patients from 
the analysis will be clearly reported.  The 95% confidence intervals will be provided.  
 
 
 
 
REFERENCES 
 


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72 
 
Alimta Package Insert, 2012. 
 
Bendell J, Papadopoulos K, Jones S. A Phase 1 dose-escalation study of MEK inhibitor MEK162 
(ARRY-438162) in patients with advanced solid tumors. In: Proceedings of the 102nd Annual 
Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, Florida. 
Philadelphia (PA): AACR; 2011. Abstract B243. 
 
Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682-9. 
 
Calvert AH. Dose optimisation of carboplatin in adults. Anticancer Res 1994; 14(6A): 2273-8.  
Carboplatin dosing. FDA Office of Oncology Drug Products, October 10, 2010. 
Canadian Cancer Society, Canadian Cancer Statistics, 2013. 
http://www.cancer.ca/~/media/cancer.ca/CW/cancer%20information/cancer%20101/Canadian%
20cancer%20statistics/canadian-cancer-statistics-2013-EN.pdf 
 
Cancer Care Ontario, Carboplatin: Regimen Monograph. CCO Formulary. March 2012. 
 
Cancer Care Ontario, Pemetrexed: Regimen Monograph. CCO Formulary. October 2013. 
 
Charloux, A., E. Quoix, N. Wolkove, D. Small, G. Pauli, and H. Kreisman, The increasing 
incidence of lung adenocarcinoma: reality or artefact? A review of the epidemiology of lung 
adenocarcinoma. Int J Epidemiol, 1997. 26(1): p. 14-23. 
 
Davies H, Bignell GR, Cox C, et al (2002) Mutations of the BRAF gene in human cancer. 
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Ding L, Getz G, Wheeler DA, et al. Somatic mutations affect key pathways in lung 
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Eisenhauer EA, Therasseb P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (version 1.1). Eur J. Cancer. 2009;45:228-247  
Gandara DR, Hiret S, Blumenschein GR et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in 
combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase 
I/Ib trial. J Clin Oncol 31, 2013 (suppl; abstr 8028) 
 
Gervais R, Robinet G, Clément-Duchêne C, et al. Pemetrexed and carboplatin, an active option 
in first-line treatment of elderly patients with advanced non-small cell lung cancer (NSCLC): a 
phase II trial. Lung Cancer. 2013;80(2):185-90. 
 
Hanna N, Shepherd FA, Fossella FV et al. Randomized phase III trial of pemetrexed versus 


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docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J 
Clin Oncol. 2004 May 1;22(9):1589-97.  
 
Jänne PA, Shaw AT, Rodrigues Pereira J, et al. Selumetinib plus docetaxel for KRAS-mutant 
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Jemal, A., F. Bray, M.M. Center, J. Ferlay, E. Ward, and D. Forman, Global cancer statistics. CA 
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Juergens RA, Brahmer JR. Adjuvant treatment in non-small cell lung cancer: Where are we now? 
J. Natl Compr. Canc. Netw. 2006;4:595–600. 
 
Kelly K, Mazieres J, Leighl NB, et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in 
combination with pemetrexed for KRAS-mutant and  wild-type (WT) advanced NSCLC: A 
phase I/Ib trial. J Clin Oncol 31, 2013 (suppl; abstr 8027) 
 
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell 
lung cancer. N Engl J Med. 2010;363:1693–703. 
 
Maione, P., C. Gridelli, T. Troiani, and F. Ciardiello, Combining targeted therapies and drugs 
with multiple targets in the treatment of NSCLC. Oncologist, 2006. 11(3): p. 274-84. 
 
Mok, T.S., Y.L. Wu, S. Thongprasert, C.H. Yang, D.T. Chu, N. Saijo, et al., Gefitinib or 
carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009. 361(10): p. 947-57. 
 
Okamoto I, Aoe K, Kato T, et al. Pemetrexed and carboplatin followed by pemetrexed maintenance 
therapy in chemo-naïve patients with advanced nonsquamous non-small-cell lung cancer. Invest 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
 
Pao, W. and N. Girard, New driver mutations in non-small-cell lung cancer. Lancet Oncol 2011. 
12(2): p. 175-80. 
 
Paraplatin Package Insert, 2010 
 
Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine 
with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-
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Winski S, Anderson D, Bouhana K, et al. 162 MEK162 (ARRY-162), a novel MEK 1/2 inhibitor, 
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www.clinicaltrials.gov 
 
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Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 
10;31(23):2849-53. 
 
 


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


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APPENDIX B 
 DATA MANAGEMENT GUIDELINES 
 
Data Management Guidelines 
 
Case Report Form Submission Schedule 
 
The Registration Checklist will be a paper CRF that will be provided by the Drug Development 
Central Office and all other data required for the study will be collected in eCRFs in Medidata.  
The form submission schedule is outlined below. 
 
Case Report Form 
Submission Schedule 
Registration Checklist 
At the time of registration 
Baseline Folder 
Within 3 weeks of on study date 
Cycle Folder 
Within 3 weeks of the end of each cycle of 
treatment 
End of Treatment Folder 
Within 3 weeks of the patient coming off 
treatment 
Follow-up Folder(s) 
Within 3 weeks of the patient coming to clinic  
Final Report Folder 
Within 3 weeks of the follow-up period being 
complete or of the patient's death being known to 
the investigator unless this constitutes a 
reportable adverse event when it should be 
reported according to expedited guidelines in 
Section 7. 
 
Case Report Form Completion 
 
The paper Registration Checklist CRF must be completed using black or blue ink. Any errors 
must be crossed out so that the original entry is still visible, the correction clearly indicated and 
then initialed and dated by the individual making the correction.  Medidata Rave eCRFs will be 
completed according to the schedule noted above.  
 
All patient names or other identifying information will be removed prior to being sent to the 
Central Office and the documents labeled with patient initials, study number and the protocol 
number if applicable.  
 
Monitoring 
This is an investigator initiated study and study monitoring will be performed by the Drug 
Development Program Central Office or its designate. 
 
Data in the Medidata Rave eCRFs will be monitored on a regular basis (according to the 
monitoring plan) and quality assurance measures will be performed.  Electronic data queries as 
well as paper query letters may be issued to the site. 
 
Regulatory Requirements 
 
 Please submit all required documents to the DDP Central Office. 


Protocol #: CMEK162ACA02T 
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77 
 
 Canadian Principal Investigators must submit a completed Qualified Investigator 
Undertaking. The signed originals are to be submitted to the DDP Central Office. 
 All investigators must have an up-to-date CV (signed within 2 years) on file with the 
DDP Central Office. 
 Laboratory certification/accreditation and normal ranges are required 
 Investigators and site staff are required to complete Medidata eCRF training modules 
depending on delegated tasks  
 Consent forms must be reviewed by the Central Office before submission to the local 
ethics regulatory board (REB/IRB) and must include a statement that 1) information will 
be sent to and 2) medical records will be reviewed by the DDP Central Office. 
 A Membership list of the local ethics board is required. 
 A copy of the initial approval letter from the ethics board must be submitted to the DDP 
Central Office. 
 A completed Site Participant List/Training Log is required and must be submitted to DDP 
 Continuing approval will be obtained at least yearly until follow-up on patients is 
completed and no further data is being obtained for research purposes. 
 
Retention of Patient Records and Study Files 
 
ICH Good Clinical Practice guidelines apply to this study. It is the responsibility of the Drug 
Development Program Central Office to inform the investigator/institution as to when trial-related 
records are no longer need to be retained. The investigator/institution should take measures to 
prevent accidental or premature destruction of these documents.  
 
 
 
 


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78 
 
APPENDIX C 
PATIENT DIARY (CYCLE 1) 
 
Daily Drug Administration Diary: Cycle 1 
  
Today’s Date: _____________Patient Initials:_____________ Patient Study ID: _____________ 
 
 
INSTRUCTIONS  
1. 
Complete one form for the first cycle of treatment. 
2. 
You will take ____mg MEK162 tablet each day (____ mg total dose), twice a day, 1 hour before or 2 
hours after food, continuously, except on days 6, 7, 27, and 28 (no dose on these days). 
3. 
On days 5 and 15, you will take your AM dose in the clinic, so please bring your tablets with you. 
4. 
Record the date and time you took the tablet, try take the tablets at the same time each day.   
5. 
On day 8, take MEK162 after chemotherapy. 
6. 
If you vomit after taking a dose, do not take another tablet. 
7. 
Swallow each tablet whole.  Do not crush or chew the tablets. 
8. 
If you have any comments or notice any side effects, please record them in the comments column.   
9. 
Please bring this form and your bottle of MEK162 at the end of each cycle. 
10. In case of errors, please place a single slash mark through the error and initial it.  Please do not white 
out any error or scribble it out with ink.  Please do not write the correct information directly over the 
error, but on a separate line next to the error. 
Day 
Date 
Actual Dose 
Taken 
  AM            PM 
Time of Dose  
   
  AM         PM 
Comments 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
* 
 
* 
 
* you will take this dose in clinic, please 
bring tablets with you 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
Take dose AFTER chemotherapy (BID), 
please bring tablets with you.  
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
* 
 
* 
 
*you will take this dose in clinic, please 
bring tablets with you 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 


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18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Signature of Reviewer: ____________________________  Date of Review: ________________ 
 
 
 


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80 
 
 
APPENDIX D 
PATIENT DIARY CYCLE 2+ 
 
Daily Drug Administration Diary: Cycle ___ 
 
  
Today’s Date: _____________Patient Initials:_____________ Patient Study ID: _____________ 
 
 
INSTRUCTIONS  
1. 
Complete one form for each cycle of treatment. 
2. 
You will take ____mg MEK162 tablet each day (____ mg total dose), twice a day, 1 hour before or 2 
hours after food, continuously over a 19 day period. 
3. 
Record the date and time you took the tablet, try take the tablets at the same time each day.   
4. 
On day 1, take MEK162 after chemotherapy. 
5. 
If you vomit after taking a dose, do not take another tablet. 
6. 
Swallow each tablet whole.  Do not crush or chew the tablets. 
7. 
If you have any comments or notice any side effects, please record them in the comments column.   
8. 
Please bring this form and your bottle of MEK162 at the end of each cycle. 
9. 
In case of errors, please place a single slash mark through the error and initial it.  Please do not white 
out any error or scribble it out with ink.  Please do not write the correct information directly over the 
error, but on a separate line next to the error. 
Day 
Date 
Morning (AM) 
Evening (PM) 
Comments 
Time 
Number 
of pills 
Time 
Number 
of pills 
1 
 
 
 
 
 
 
Take dose AFTER chemotherapy 
(BID), please bring tablets with you. 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 


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14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
Signature of Reviewer: ____________________________  Date of Review: ________________ 
 
 
 
 


Protocol #: CMEK162ACA02T 
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APPENDIX E 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Permitted Concomitant Therapy requiring Caution and / or Action 
 
MEK162 is a substrate for many CYP isoforms (CYP3A and 1A2 with some involvement of 
CYP2C isoforms). Although the risk of metabolic interaction caused by an effect on an 
individual isoform is minimized for MEK162, caution should be used in patients receiving 
concomitant treatment with other drugs that are either potent inhibitors or inducers of CYP3A, 
2C8, 2C9, 2C19, and 1A2.  
In vitro data showed that MEK162 is a substrate for P-glycoprotein (P-gp) and breast cancer 
resistance protein (BCRP) and thus the use of drugs that are known to inhibit these transporters 
should be used with caution.  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#PgpTransport 
 
MEK162 potentially induces CYP3A4.  MEK162 may induce the metabolic clearance of co-
medications metabolized by CYP3A4, if sufficiently high concentrations are achieved in vivo.  
Caution should be used in patients receiving concomitant treatment with other drugs that are 
substrates of CYP3A4 as the efficacy of these drugs could be reduced when administered with 
MEK162.  
http://medicine.iupui.edu/clinpharm/ddis/table.asp  
 
Drugs with a conditional, possible or known risk to prolong the QT interval and/or induce 
Torsade de Pointes should be used with caution.  See the website from QTdrugs.org Advisory 
Board of the Arizona CERT. 
http://www.crediblemeds.org/everyone/composite-list-all-qtdrugs/ 
 
 
 


Protocol #: CMEK162ACA02T 
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83 
 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
[Note to investigators:  This appendix includes an “information sheet” to be handed to the 
patient at the time of enrollment.  Use or modify the text as appropriate for the study agent, so 
that the patient is aware of the risks and can communicate with their regular prescriber(s) and 
pharmacist.  A convenient wallet-sized information card is also included for the patient to clip 
out and retain at all times.] 
 
The patient ____________________________ is enrolled on a clinical trial using the 
experimental agent MEK162. This form is addressed to the patient, but includes important 
information for others who care for this patient.  
 
MEK162  interacts with many drugs that are processed by your liver.  Because of this, it is very 
important to tell your study doctors about all of your medicine before you start this study.  It is 
also very important to tell them if you stop taking any regular medicine, or if you start taking a 
new medicine while you take part in this study.  When you talk about your medicine with your 
study doctor, include medicine you buy without a prescription at the drug store (over-the-counter 
remedy), or herbal supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet.  These are 
the things that you and they need to know:  
 
MEK162 interacts with certain specific enzymes in your liver.  
 The enzymes in question are CYP3A4 and 2C8, 2C9, 2C19, and 1A2. 
 MEK162 potentially inhibits CYP3A4 and may increase clearance of co-medication that is 
broken down by this enzyme.  
 MEK162 must be used very carefully with other medicines that need these liver enzymes to 
be effective or to be cleared from your system.   
 Other medicines may also affect the activity of the enzyme.   
o Substances that increase the enzyme’s activity (“inducers”) could reduce the 
effectiveness of the drug, while substances that decrease the enzyme’s activity 
(“inhibitors”) could result in high levels of the active drug, increasing the chance 
of harmful side effects. 
    
 You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
 Before you start the study, your study doctor will work with your regular prescriber to 
modify or change any medicines that are considered “strong inducers/inhibitors or 
substrates of  CYP3A4 and 2C8, 2C9, 2C19, and 1A2. 
 Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   


Protocol #: CMEK162ACA02T 
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84 
 
 Please be very careful!  Over-the-counter drugs have a brand name on the label—it is 
usually big and catches your eye.  They also have a generic name—it is usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
 Be careful:  
o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you drink grapefruit juice or eat grapefruit:  Avoid these until the study is over.  
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking MEK162. 
 
 
Other medicines can be a problem with your study drugs.  
 
 You should check with your doctor or pharmacist whenever you need to 
use an over-the-counter medicine or herbal supplement.  
 
 Your regular prescriber should check a medical reference or call your 
study doctor before prescribing any new medicine for you.  Your study 
doctor’s name is  
 
 
_____________________________________  
 
and he or she can be contacted at  
 
_____________________________________ 
 
 
 


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85 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INFORMATION ON POSSIBLE DRUG INTERACTIONS  
You are enrolled on a clinical trial using the experimental agent 
MEK162. MEK162 interacts with drugs that are processed by your 
liver.  Because of this, it is very important to: 
 Tell your doctors if you stop taking regular medicine or if you start 
taking a new medicine. 
 Tell all of your prescribers (doctor, physicians’ assistant, nurse 
practitioner, pharmacist) that you are taking part in a clinical trial. 
 Check with your doctor or pharmacist whenever you need to use 
an over-the-counter medicine or herbal supplement. 
 
 
 
MEK162 may interact with specific liver enzymes called CYP1A2, 2C 
and CYP3A4, and must be used very carefully with other medicines 
that interact with these enzymes.  
 Before you start the study, your study doctor will work with your 
regular prescriber to switch any medicines that are considered 
“strong inducers/inhibitors or substrates of CYP1A2, 2C and 
CYP3A4.” 
 Before prescribing new medicines, your regular prescribers should 
go to http://medicine.iupui.edu/clinpharm/ddis/table.aspx for a 
list of drugs to avoid, or contact your study doctor.   
 Your study doctor’s name is _____________________________ 
 and can be contacted at _________________________________.  


Protocol #: CMEK162ACA02T 
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86 
 
APPENDIX F 
LISTING OF AGENTS INTERACTING WITH CYTOCRHOME 
P450 
 
 
 
 
P450 
Enzyme 
Enzyme 
Reaction 
 
Substrates 
 
Inhibitors 
 
Inducers 
CYP1A2 
7-Ethoxyresorufin 
Acetaminophen 
Caffeine 
Imipramine 
Furafylline 
Charcoal - 
broiled beef 
 
0-dealkylation 
Acetanilide 
Estradiol 
Methoxyresofurin 
-Naphthoflavone 
Cigarette smoke 
 
 
Aromatic amines 
Ethoxyresorufin 
Phenacetin 
 
Cruciferous 
vegetables 
 
 
 
 
Theophylline 
 
Omeprazole 
 
 
 
 
Warfarin 
 
 
CYP2A6 
Coumarin 
Coumarin 
 
 
Diethyldithiocarbamate 
Barbiturates 
 
7-hydroxylation 
Butadiene 
 
 
-Methoxypsoralen 
 
 
 
Nicotine 
 
 
Tranylcypromine 
 
CYP2B6 
 
Cyclophosphamide 
Ifosfamide 
 
Orphenadrine 
Not known 
CYP2C8 
Taxol 6-hydroxylalation 
Carbamazepine 
Taxol 
 
Quercetin 
Not known 
CYP2C9 
Tolbutamide 
Diclofenac 
Tenoxicam 
Tolbutamide 
Sulfaphenazole 
Rifampin 
 
Methylhydroxylation 
Phenytoin 
Tetrahydrocannabinol 
Torsemide 
Sulfinpyrazone 
 
 
 
Piroxicam 
Tienilic acid 
S-Warfarin 
 
 
CYP2D19 
S-Mephenytoin 
Citalopram 
Imipramine 
Mephobarbital 
Tranylcypromine 
Rifampin 
 
4'-hydroxilation 
Diazepam 
Lansoprazole 
Pentamidine 
 
 
 
 
Diphenylhydantoin 
S-Mephenytoin 
Proguanil 
 
 
 
 
Hexobarbital 
Omeprazole 
Propranolol 
 
 
CYP2D6 
Dextromethorphan 
Amiflamine 
Encainide 
Nortriptyline 
Ajmaline 
Not known 
 
O-demethylation 
Amitriptyline 
Flecainide 
Ondansetron 
Chinoidine 
 
 
 
Aprodine 
Fluoxetine 
Paroxetine 
Corynanthe 
 
 
 
Brofaromine 
Flunarizine 
Perhexiline 
Fluoxetine 
 
 
 
Bufurolol 
Fluphenazine 
Perphenazine 
Lobelin 
 
 
 
Captopril 
Guanoxan 
Propafenone 
Propidin 
 
 
 
Cinnarizine 
Haloperidol (reduced) 
Propranolol 
Quinidine 
 
 
 
Citalopram 
Hydrocodone 
N-Propuylajmaline 
Trifluperidol 
 
 
 
Clomipramine 
Imipramine 
Remoxipride 
Yohimbine 
 
 
 
Clozapine 
Indoramin 
Sparteine 
 
 
 
 
Codeine 
Methoxyamphetamin
e 
Thioridazine 
 
 
 
 
Debrisoquine 
Methoxyphenamine 
Timolol 
 
 
 
 
Deprenyl 
Metoprolol 
Tomoxetine 
 
 
 
Dextromethorphan 
Desmethylcitalopram 
Mexiletine 
Trifluperidol 
 
 
 
O-demethylation 
Desipramine 
Mianserin 
Tropisetron 
 
 
 
 
Dextromethorphan 
Miniaprine 
 
 
 


Protocol #: CMEK162ACA02T 
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87 
 
 
APPENDIX F continued 
 
P450 
Enzyme 
Enzyme 
Reaction 
 
Substrates 
 
Inhibitors 
 
Inducers 
CYP2E1 
Chlorzoxazone 
Acetaminophen 
Enflurane 
Theophylline 
3-Amino-1,2,4-triazole 
Ethanol 
 
6-hydroxylation 
Alcohols 
Halogenated alkanes 
 
Diethyldithiocarbamate 
Isoniazid 
 
 
Aniline 
Isoflurane 
 
Dihydrocapsaicin 
 
 
 
Benzene 
Methylformamide 
 
Dimethylsulfoxide 
 
 
 
Caffeine 
Nitrosamines 
 
Disulfiram 
 
 
 
Chlorzoxazone 
p-Nitrophenol 
 
Phenethyl isothiocyanate 
 
 
 
Dapsone 
Styrene 
 
4-Methylprazole 
 
CYP3A4 
Testosterone 
Acetaminophen 
Etoposide 
Tacrolimus (FK506) 
Clotrimazole 
Carbamazepine 
 
6-hydroxylation 
Aldrin 
Flutamide 
Tamoxifen 
Ethinylestradiol 
Dexamethasone 
 
 
Alfentanil 
Hydroxyarginine 
Taxol 
Gestodene 
Phenobarbital 
 
 
Amiodarone 
Ifosfamide 
Teniposide 
Itraconazole 
Phenytoin 
 
 
Astemizole 
Imipramine 
Teniposide 
Ketoconazole 
Rifampin 
 
 
Benzphetamine 
Lansoprazole 
Terfenadine 
Miconazole 
Sulfadimidine 
 
 
Budesonide 
Lidocaine 
Tetrahydrocannabinol 
Naringenin 
Sulfinpyrazone 
 
 
Carbamazepine 
Loratadine 
Theophylline 
Troleandomycin 
Troleandomycin 
 
 
Cyclophosphamide 
Losartan 
Toremifene 
Activator:  -
Naphtoflavone 
 
 
 
Cyclosporin 
Lovastatin 
Triazolam 
Grapefruit juice 
 
 
 
Dapsone 
Midazolam 
Troleandomycin 
 
 
 
 
Digitoxin 
Nifedipine 
Verapamil 
 
 
 
 
Diazepam 
Quinidine 
Zalosetron 
 
 
 
 
Erythromycin 
Rapamycin 
Zonisamide 
 
 
 
 
Ethinylestradiol 
Retinoic Acid 
Diltiazem 
 
 
 
 
Omeprazole 
Steroids (e.g., 
cortisol) 
Warfarin 
 
 
 
 
 


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88 
 
 
APPENDIX G 
MANAGEMENT OF DRUG-INDUCED TOXICITY 
 
Patient history of diarrhea 
At screening, the patient’s history of diarrhea should be reviewed and the patient should be 
appropriately informed of chemotherapy-induced diarrhea and its’ management: 
 Review previous medical history of diarrhea within the last 12 months; laxative use, 
colon surgery, abdominal and pelvic irradiation, nocturnal diarrhea, pain, ulcerative 
colitis and other diarrhea-inducing diseases/conditions; 
 Stop all diarrheogenic agents at screening if possible, otherwise exclude from trial; 
 Instruct patients regarding risk of developing diarrhea; 
 Perform baseline clinical/laboratory studies according to the trial protocol (e.g. one could 
rule out carrier state of Salmonella spp., Clostridium difficile, Campylobacter spp., 
Proactively investigate for occurrence of diarrhea 
Educate patient 
1. Remind patients at each visit to contact the site upon signs of loose stool or symptoms of 
abdominal pain. Additionally, at the beginning of each cycle, each patient should be specifically 
questioned regarding any experience of diarrhea or diarrhea-related symptoms. If symptoms 
were experienced by the patient, then the site should question the patient regarding the actions 
taken for these symptoms and re-instruct as necessary.  
2. In addition to dietary modification, the patients should be instructed on early warning signs 
(e.g. severe cramping → severe diarrhea, fever with diarrhea → infection). Patients should be 
instructed on what to report to the investigator if possible (i.e. number of stools, stool 
composition, stool volume) and how to report symptoms of life-threatening sequelae (eg, fever 
or dizziness on standing).  
3. Contact the patient 2 times a week after the start of MEK162 treatment to detect diarrhea early 
during at least the first 2 cycles. If no problems occur, instruct the patient to call when a problem 
does arise.  
 Stop all lactose-containing products, alcohol 
 Stop laxatives, bulk fiber (like Metamucil®), and stool softeners (i.e, docusate sodium; 
Colace®) 
 Stop high-osmolar food supplements such as i.e, Ensure® Plus and i.e, Jevity® Plus (with 
fiber) 
 Drink 8 to 10 large glasses of clear liquids per day (like i.e, water, Pedialyte®, Gatorade®, 
broth) 
 Eat frequent small meals (i.e, bananas, rice, applesauce, toast)
 


Protocol #: CMEK162ACA02T 
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Loperamide supply 
t is recommended that patients are provided a sufficient supply of loperamide tablets with the 
administration of MEK162 at the start of each cycle in case the patient experiences diarrhea. 
When loperamide is provided to patients, it is mandatory that patients are instructed at each cycle 
in detail on the use of loperamide in order to manage signs or symptoms of diarrhea at home. 
The site should ensure that the patient understood the instructions. 
Patients should be instructed to start oral loperamide at the first sign of loose stool or symptoms 
of abdominal pain. 
Multiple events of diarrhea may occur throughout the duration of treatment. When each 
occurrence of diarrhea is first reported, the following steps to manage the event are 
recommended: 
Evaluate condition of patient 
 Obtain history of onset and duration of diarrhea including a description of the number of 
stools and stool composition (e.g. watery, blood or mucus in stool); 
 Assess patient for fever, abdominal pain/cramps, distension, bloating, nausea, vomiting, 
dizziness, weakness (i.e., rule out risk for sepsis, bowel obstruction, dehydration); 
 Obtain medication profile (i.e., to identify any diarrheogenic agents) and dietary profile 
(i.e., to identify diarrhea-enhancing foods). 
 For study drug dose adjustment see Table 5.3 in the study protocol. 
 Analyze the following: 
o Blood from stool;  
o C. difficile toxin;  
o Fecal cultures may be performed if infection is suspected. These may include: 
Shigella and pathogenic E.coli-enterotoxigenic, enterohemorrhagic etc., possibly 
Aeromonas, Pleisiomonas (if suspected exposure to contaminated water).  
 Administer intravenous hydration and electrolyte replacement as needed.
 Endoscopic examinations may be considered only if absolutely necessary. The bowel is 
likely to be fragile with evidence of colitis and thus great care and caution must be 
exercised in undertaking these invasive procedures. 

Loperamide is the recommended first-line treatment of diarrhea (any Grade).  
Persistent symptoms may require the administration of high dose loperamide followed by 
treatment with second-line agents such as opium tincture and octreotide acetate, based on 
severity and duration of diarrhea and related signs/symptoms.  
Upon treatment with any anti- diarrhea agents, the patient’s response to treatment should be 
observed and appropriately documented in the source document and eCRF. 
 


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Guidelines for the treatment of study drug combination induced skin toxicity 
Skin rash has been observed for MEK162 in the ongoing studies [ARRAY-162-111] and thus is 
recognized as potential overlapping toxicity associated with the concurrent use of both 
compounds. The majority of the rash was CTCAE Grade 1 or 2, but also dose-limiting as Grade 
3 at the 80mg bid dose for MEK162. 
The results of the STEPP study (Mitchell 2009, Piperdi 2009) support the use of pre-emptive 
skin treatment for patients at risk of treatment induced skin toxicity. In this study, the pre- 
emptive skin treatment regimen reduced the incidence of specific CTCAE Grade ≥ 2 skin 
toxicity by more than 50% as compared to the group who received only reactive skin toxicity 
treatment. 
In this study, patients will not initially receive prophylactic treatment for skin toxicity during 
cycle 1. However, prophylactic treatment for skin toxicity may be introduced in subsequent 
cycles of treatment and in new patients if at least one patient has experienced CTCAE Grade 3 or 
greater skin toxicity, or if at least two patients have experienced such toxicities that are CTCAE 
Grade ≥ 2. Prophylactic supportive therapy for skin toxicity (i.e. initiated 24 hrs prior to study 
drug combination) including skin moisturizers, sunscreen (PABA free, SPF ≥ 15, UVA/UVB 
protection), topical steroid (1% hydrocortisone cream), and doxycycline (100 mg BID) may be 
initiated in all patients at the dose levels where these toxicities have been observed and may be 
advised to all further patients. Effective medications also include antihistamines, topical 
corticosteroids and low-dose systemic corticosteroids (the latter should be used with caution due 
to risk of hyperglycemia). 
The treatment algorithm is as follows (See section 5.3): 
Mild rash (CTCAE Grade 1) 
 Treatment with MEK162 should be maintained at the current dose. 
 Topical hydrocortisone (1% or 2.5% cream) for macular rash and/or topical clindamycin 
(1%) for pustular rash is recommended. 
 The patient should be reassessed after 2 weeks. 
Moderate rash (CTCAE Grade 2) 
 Treatment with MEK162 should be maintained at the current dose, and the rash should be 
closely monitored for change in severity. 
 Doxycycline or minocycline are not recommended due to phototoxicity and should be 
replaced with oxytetracycline or lymecycline. However, if doxycycline or minocycline 
are used, precaution measurements should be taken (i.e., avoid direct exposure on sun, 
use of sunglasses, sunscreen, ect.). The recommendation is: topical clindamycin (1%) 
plus either hydrocortisone (2.5% cream) or pimecrolimus (1% cream) plus 


Protocol #: CMEK162ACA02T 
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91 
 
oxytetracycline (500 mg twice daily) or lymecycline (408 mg once daily). 
Severe rash (CTCAE Grade 3-4) CTCAE Grade 3
Asymptomatic 
The dose of MEK162 should be omitted until resolved to CTCAE Grade ≤ 1, in line with 
protocol recommendations, and the rash should be closely monitored for any change in severity. 
In addition to the interventions recommended for moderate rash, prednisolone (25 mg) may be 
given (with caution due to risk of hyperglycemia). 
If asymptomatic skin toxicity CTCAE Grade 3 is not resolved within 48 hrs, discontinue patient 
from study drug treatment
Symptomatic 
If symptomatic skin toxicity CTCAE Grade 3 occurs the dose of MEK162 should be omitted and 
patients discontinued from study drug treatment. 
CTCAE Grade 4 
If skin toxicity CTCAE Grade 4 occurs the dose of MEK162 should be omitted and patients 
discontinued from study drug treatment. 
 
  
 
 
 
 
 
 


Protocol #: CMEK162ACA02T 
Version Date: 31-May-2018 
92 
 
APPENDIX H 
BLOOD PRESSURE DIARY TEMPLATE 
 
Blood Pressure Diary 
 
Today’s Date _________________ Patient Initials_________ Patient Study ID _______________ 
 
INSTRUCTIONS: 
1. 
Complete blood pressure measurements on day 10 and day 30 of treatment and record on this form.  
2. 
Measurements are to be taken at the same time each day, after taking any hypertensive medications.  
3. 
Please bring this form with you at your clinic visits to review with your doctor/nurse.  
4. 
In case of errors, please place a single slash mark through the error and initial it.  Please do not white out any 
error or scribble it out with ink.  Please do not write the correct information directly over the error, but on a 
separate line next to the error. 
Day 
Date 
Time 
Systolic 
Diastolic 
Comments 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
 
6 
 
 
 
 
 
7 
 
 
 
 
 
8 
 
 
 
 
 
9 
 
 
 
 
 
10 
 
 
 
 
 
11 
 
 
 
 
 
12 
 
 
 
 
 
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14 
 
 
 
 
 
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16 
 
 
 
 
 
17 
 
 
 
 
 
18 
 
 
 
 
 
19 
 
 
 
 
 
20 
 
 
 
 
 
21 
 
 
 
 
 
22 
 
 
 
 
 
23 
 
 
 
 
 
24 
 
 
 
 
 
25 
 
 
 
 
 
26 
 
 
 
 
 
27 
 
 
 
 
 
28 
 
 
 
 
 
29 
 
 
 
 
 
30 
 
 
 
 
 
Physician’s Office will complete this section: 
Physician/Nurse reviewing diary: ______________________ 
Date reviewed: _____________________