Conditions: Non-Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: no

Brief summary:
The purpose of this study is to find out what effects a new drug, selumetinib, has on lung cancer when receiving standard chemotherapy with pemetrexed and platinum-based chemotherapy.

Detailed description:
This research is being done to see whether selumetinib improves the results of standard chemotherapy. The standard or usual treatment for this disease is treatment with chemotherapy alone.

Arms:
arm 1: Selumetinib: 75mg/ bid PO given on days 2-19 Pemetrexed: 500mg/m\^2 \& Cisplatin or Carboplatin\*: AUC6: 75mg/m\^2 given on day 1 Schedule = q 21 days

\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG arm 2: Selumetinib: 75mg/ bid PO given on days 1-21 (continuous) Pemetrexed: 500mg/m\^2 \& Cisplatin\*: 75mg/m\^2 or carboplatin AUC 6 given on day 1 Schedule = q 21 days

\*\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG arm 3: Selumetinib: NOT GIVEN Pemetrexed: 500mg/m\^2 \& Cisplatin\*: 75mg/m\^2 or carboplatin AUC6 given on day 1 Schedule = q 21 days

\*Must be specified at time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin only after discussion with CCTG

Interventions: intervention 1: Selumetinib intervention 2: Pemetrexed intervention 3: Cisplatin intervention 4: Carboplatin
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.219 
 
 
CONFIDENTIAL 
CONFIDENTIAL 
 
HEALTH CANADA SUBMISSION 
 
ADMINISTRATIVE UPDATE #1: 2015-APR-29 
 
AMENDMENT #1: 2015-OCT-29 
 
 
AMENDMENT #2: 2016-APR-12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CANADIAN CANCER TRIALS GROUP (CCCTG) 
 
A RANDOMIZED PHASE II TRIAL OF SELUMETINIB IN PATIENTS RECEIVING STANDARD 
PEMETREXED AND PLATINUM-BASED CHEMOTHERAPY FOR THE TREATMENT OF  
ADVANCED OR METASTATIC KRAS WILDTYPE OR UNKNOWN  
NON-SQUAMOUS NON-SMALL CELL LUNG CANCER 
 
CCTG Protocol Number: IND.219 
 
 
 
STUDY CHAIRS: 
Barbara Melosky 
 
 
Penelope Bradbury 
 
 
SENIOR INVESTIGATOR: 
Grzegorz (Greg) Korpanty 
 
 
SENIOR BIOSTATISTICIAN: 
Dongsheng Tu 
 
 
STUDY COORDINATOR: 
Pamela Brown-Walker 
 
 
SPONSOR: 
CCTG 
 
 
SUPPORTED BY: 
AstraZeneca 
 
(For contact information of study personnel see Final Page.) 
 


 
PROTOCOL DATE: 2014-DEC-03 
 
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AMEND #2: 2016-APR-12 
TABLE OF CONTENTS 
 
STUDY ACKNOWLEDGMENT/DISCLOSURE ............................................................................................... 1 
 
TREATMENT SCHEMA ..................................................................................................................................... 2 
 
1.0 
OBJECTIVES ......................................................................................................................................... 5 
1.1 
Primary Objective ................................................................................................................................... 5 
1.2 
Secondary Objectives .............................................................................................................................. 5 
1.3 
Exploratory Objective ............................................................................................................................. 5 
 
2.0 
BACKGROUND INFORMATION AND RATIONALE ...................................................................... 6 
 
3.0 
BACKGROUND THERAPEUTIC INFORMATION............................................................................ 8 
3.1 
Name and Chemical Information ............................................................................................................ 8 
3.2 
Chemical Structure .................................................................................................................................. 8 
3.3 
Mechanism of Action .............................................................................................................................. 8 
3.4 
Experimental Anti-tumour Activity ........................................................................................................ 8 
3.5 
Animal Toxicology ................................................................................................................................. 9 
3.6 
Studies in Humans ................................................................................................................................... 9 
3.7 
Pharmaceutical Data .............................................................................................................................. 11 
3.8 
Standard Chemotherapy Agents ............................................................................................................ 11 
 
4.0 
TRIAL DESIGN ................................................................................................................................... 12 
4.1 
Starting Doses ....................................................................................................................................... 12 
4.2 
Randomization ...................................................................................................................................... 12 
4.3 
Stratification .......................................................................................................................................... 12 
 
5.0 
STUDY POPULATION ....................................................................................................................... 13 
5.1 
Eligibility Criteria ................................................................................................................................. 13 
5.2 
Ineligibility Criteria ............................................................................................................................... 15 
 
6.0 
PRE-TREATMENT EVALUATION ................................................................................................... 17 
 
7.0 
ENTRY/RANDOMIZATION PROCEDURES .................................................................................... 18 
7.1 
Entry Procedures ................................................................................................................................... 18 
7.2 
BSA Calculation .................................................................................................................................... 18 
7.3 
Stratification .......................................................................................................................................... 18 
7.4 
Randomization ...................................................................................................................................... 18 
 
8.0 
TREATMENT PLAN ........................................................................................................................... 20 
8.1 
Drug Administration ............................................................................................................................. 20 
8.2 
Premedication ........................................................................................................................................ 21 
8.3 
Dose Adjustments ................................................................................................................................. 21 
8.4 
Duration of Protocol Treatment ............................................................................................................ 26 
8.5 
Concomitant Therapy ............................................................................................................................ 26 
 
9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT .............................................. 28 
9.1 
Evaluation During Protocol Treatment ................................................................................................. 28 
9.2 
Evaluation After Protocol Treatment ..................................................................................................... 29 


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS ......................................................... 30 
10.1 
Definitions ............................................................................................................................................. 30 
10.2 
Response and Evaluation Endpoints ..................................................................................................... 30 
10.3 
Response Duration ................................................................................................................................ 32 
10.4 
Stable Disease Duration ........................................................................................................................ 32 
10.5 
Methods of Measurement ...................................................................................................................... 33 
 
11.0 
SERIOUS ADVERSE EVENT REPORTING ..................................................................................... 34 
11.1 
Definition of a Reportable Serious Adverse Event ............................................................................... 34 
11.2 
Serious Adverse Event Reporting Instructions ..................................................................................... 34 
11.3 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting ................................................... 35 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada .................................. 36 
11.5 
CCTG Reporting Responsibility to AstraZeneca and Lilly .................................................................. 36 
11.6 
AstraZeneca Reporting Responsibilities ............................................................................................... 36 
11.7 
Reporting Safety Reports to Investigators ............................................................................................. 37 
 
12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING ............ 38 
12.1 
Criteria for Discontinuing Protocol Treatment ..................................................................................... 38 
12.2 
Duration of Protocol Treatment ............................................................................................................ 38 
12.3 
Therapy After Protocol Treatment is Stopped ...................................................................................... 38 
12.4 
Follow-up Off Protocol Treatment ........................................................................................................ 38 
 
13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION ............................................... 39 
13.1 
Central Radiology Review .................................................................................................................... 39 
13.2 
Central Pathology Review ..................................................................................................................... 39 
13.3 
Correlative Studies ................................................................................................................................ 39 
 
14.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 40 
14.1 
Objectives and Design ........................................................................................................................... 40 
14.2 
Primary Endpoints and Analysis ........................................................................................................... 40 
14.3 
Sample Size and Duration of Study ...................................................................................................... 40 
14.4 
Interim Analysis .................................................................................................................................... 41 
14.5 
Safety Monitoring ................................................................................................................................. 41 
 
15.0 
PUBLICATION POLICY ..................................................................................................................... 42 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. ..................................................................................... 42 
15.2 
Responsibility for Publication ............................................................................................................... 42 
 
16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES ...................................................... 43 
16.1 
Regulatory Considerations .................................................................................................................... 43 
16.2 
Inclusivity in Research .......................................................................................................................... 43 
16.3 
Obtaining Informed Consent ................................................................................................................. 44 
16.4 
Discontinuation of the Trial .................................................................................................................. 45 
16.5 
Retention of Patient Records and Study Files ....................................................................................... 45 
16.6 
Centre Performance Monitoring ............................................................................................................ 45 
16.7 
On-Site Monitoring/Auditing ................................................................................................................ 45 
16.8 
Case Report Forms ................................................................................................................................ 46 
 
17.0 
CORRELATIVE STUDIES .................................................................................................................. 47 
17.1  
Laboratory Correlative Studies ............................................................................................................. 47 
 
18.0 
REFERENCES ...................................................................................................................................... 48 


 
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APPENDIX I - PATIENT EVALUATION FLOW SHEET .............................................................................. 50 
APPENDIX II - PERFORMANCE STATUS SCALES/SCORES .................................................................... 51 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL .......................................................... 52 
APPENDIX IV - DOCUMENTATION FOR STUDY ...................................................................................... 53 
APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS ......................... 54 
 
 
LIST OF CONTACTS ........................................................................................................................... Final Page 
 


 
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AMEND #2: 2016-APR-12 
STUDY ACKNOWLEDGMENT/DISCLOSURE 
 
I understand that this protocol contains information that is confidential and proprietary to CCTG and 
AstraZeneca. 
 
I have read the protocol and agree that it contains all necessary details for carrying out the study as 
described. I will conduct this protocol as outlined therein, and according to Good Clinical Practice and 
any applicable local regulations. I will make a reasonable effort to complete the study within the time 
designated. I confirm that I and study personnel participating under my supervision have adequate 
resource to fulfill their responsibilities as outlined in this protocol. I will maintain documentation of any 
investigator responsibilities assigned to participating study personnel. I confirm that all data will be 
submitted in a timely manner and will be accurate, complete and supported by source documents. I will 
complete any protocol specific training required by the sponsor and that I understand the requirement to 
inform additional site personnel with delegated duties of this information. 
 
I will provide copies of the protocol and access to all information furnished by CCTG and AstraZeneca to 
study personnel under my supervision. I will discuss this material with them to ensure that they are fully 
informed about the investigational product and the study.  
 
I understand that this trial will be registered on a public trial registry and that my contact information and 
site name will be included in the registry listing. 
 
I will provide protocol information to my Research Ethics Board (REB), Institutional Review Board(s) 
[IRB(s)] or Independent Ethics Committee(s) [IEC(s)], subject to the following condition: The contents of 
this protocol may not be used in any other clinical trial and may not be disclosed to any other person or 
entity without the prior written permission of AstraZeneca and CCTG. The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, I will give prompt notice to 
AstraZeneca and CCTG of any such disclosure. 
 
I understand that I may terminate or suspend enrolment of the study at any time if it becomes necessary to 
protect the best interests of the study subjects, however I will give prompt notice to CCTG. The study 
may be terminated at any time by CCTG or AstraZeneca with or without cause. 
 
Any supplemental information that may be added to this document is also confidential and proprietary to 
AstraZeneca and CCTG and must be kept in confidence in the same manner as the contents of this 
protocol. I will retain all furnished information in confidence, prevent its disclosure to third parties and 
will not use it, other than for the purposes of the study, during the study and for a period of five years 
from the expiration or termination of the study. I will ensure that all study personnel receiving this 
information are informed of the obligations of confidentiality under this agreement and are made subject 
to these same obligations of confidentiality. 
 
 
___________________________________________________ 
_________________________ 
Qualified/Principal Investigator 
Date 
(printed name and signature) 
 
Protocol Number: CCTG IND219 
 
CENTRE: ___________________________________________ 


 
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AMEND #1: 2015-OCT-29; AMEND #2: 2016-APR-12 
TREATMENT SCHEMA 
 
This is an open-label, randomized phase II clinical study of selumetinib (intermittent or continuous) in 
patients with advanced or metastatic KRAS wildtype or unknown KRAS status, non-squamous non-small 
cell lung cancer (NSCLC) who are receiving pemetrexed/platinum chemotherapy doublet as a first line 
palliative treatment. 
 
Sample Size 
 
The total sample size is 140 patients. The estimated accrual is 8-10 patients per month. It is anticipated 
that the duration of accrual will be 12-15 months. 
 
Eligibility 
 
• 
Histologically and/or cytologically confirmed stage IIIB or IV non-squamous, KRAS wildtype or 
unknown NSCLC 
• 
Tumour sample available for correlative studies; patient must have provided informed consent for the 
release of the block. 
• 
At least one measurable lesion as per RECIST 1.1. 
• 
Age > 18 years. 
• 
ECOG performance status 0 or 1. 
• 
Previous major surgery is permitted provided > 14 days prior to randomization. 
• 
Prior radiation is permitted provided > 4 weeks has elapsed between the last dose and randomization. 
• 
Prior adjuvant chemotherapy or combined chemoradiotherapy permitted provided completed at least 
one year prior to enrolment. 
• 
No prior cytotoxic chemotherapy for advanced/metastatic disease. 
• 
Prior therapy with ALK inhibitors is permitted. No prior treatment with MEK inhibitors or any other 
tyrosine kinase inhibitor (including EGFR inhibitors of any kind). Patients may have received 
vaccines, immunotherapy or other agents that are not MEK/tyrosine kinase inhibitors in the adjuvant 
setting or for advanced or metastatic disease. 
• 
Laboratory tests: 
− 
Neutrophils  
> 1.5 x 109/L  
− 
Platelets  
> 100 x 109/L  
− 
Creatinine Clearance  > 50 ml/min  
− 
Total bilirubin  
< 1.5 x ULN  
− 
AST and ALT  
< 2.5 x ULN 
(if liver metastases < 5x ULN permissible providing 
ALP also ≤ 6 x ULN )  
• 
No history of other untreated malignancies or malignancies requiring therapy within the past 2 years. 
• 
No symptomatic brain metastases or spinal cord compression. Patients with asymptomatic 
brain/spinal cord metastasis who are not planned for radiation, or who have been treated and are 
stable off steroids (or on a decreasing dose) and anticonvulsants are eligible. 
• 
No significant cardiac disease (including uncontrolled hypertension); LVEF ≥ 50% for patients with 
cardiac disease. 


 
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AMEND #1: 2015-OCT-29; AMEND #2: 2016-APR-12 
• 
No evidence of: 
− 
severe or uncontrolled systemic disease; 
− 
active infection, active bleeding diatheses or renal transplant; 
− 
significant GI disease or inability to swallow capsules; 
− 
neuropathy > grade 1; 
− 
central serous retinopathy or retinal vein occlusion, high intraocular pressure (> 21 mm) or 
uncontrolled glaucoma. 
• 
No contraindications to treatment with standard cisplatin/carboplatin + pemetrexed chemotherapy 
regimen.  
• 
No: 
− 
potent inducers or inhibitors of CYP 3A4/5, CYP 2C19 or CYP1A2; 
− 
large amounts of grapefruit and Seville oranges and other products containing these fruits; 
− 
vitamin E or multivitamin supplements; 
− 
excessive sun exposure (must use adequate sunscreen protection). 
• 
Oral anticoagulants permitted with increased INR monitoring if patient cannot be switched to low 
molecular weight heparin. 
• 
No pregnant or lactating women; women of childbearing potential must have negative urine 
pregnancy test; use of adequate method of birth control if not sterile. 
• 
Risk benefit for Asian patients must be evaluated (increased exposure and or adverse events possible). 
 
Pre-Treatment Evaluations 
• 
History, physical exam, adverse events / baseline symptoms, hematology, biochemistry, coagulation, 
pregnancy test, EKG, LVEF (if applicable) and ophthalmology exam (if clinically indicated) within 7 
days prior to randomization. 
• 
Chest CT including upper abdomen and other scans / x-rays to document disease within 28 days (35 
days if negative). 
 
Treatment 
 
Arm 
Selumetinib 
75 mg bid PO 
Pemetrexed: 500mg/m2 
Cisplatin*: 75mg/m2 or 
Carboplatin*: AUC=6 
Schedule 
A 
Days 2-19 
Day 1 
q 21 days 
B 
Days 1-21 (continuous) 
C 
Not given 
* 
Must be specified at the time of randomization. Patients who start on treatment with cisplatin may switch to carboplatin 
only after discussion with CCTG. 
• 
Standard chemotherapy administered for 4-6 cycles; should continue with pemetrexed maintenance 
thereafter. 
• 
May continue with selumetinib alone in absence of disease progression providing that further 
chemotherapy is not planned. 


 
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On Treatment Evaluations 
• 
History and physical exam (weight, performance status, clinical tumour measurements, heart rate and 
tobacco use): Day 1 each cycle. 
• 
Blood pressure: Weekly in cycle 1, then Day 1 each cycle and as clinically indicated. 
• 
Hematology and biochemistry: Day 1, 8 and 15 for cycles 1 and 2, then Day 1 each cycle. 
• 
INR (if on oral anticoagulants), EKG and ophthalmology exam: As clinically indicated. 
• 
LVEF: Every 12 weeks if performed at baseline; additional assessments as per Section 8.3.2.3. 
• 
Radiology (chest CT including upper abdomen; other scans / x-rays as necessary to follow disease): 
Every 6 weeks regardless of treatment delays. 
• 
Adverse events: Evaluated continuously. 
 
Duration Of Treatment 
 
Treatment will continue until: 
• 
Patient experiences progression as defined in Section 10. 
• 
Unacceptable toxicity as defined in Section 8. 
• 
Intercurrent illness. 
• 
Patient refuses to continue treatment. 


 
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1.0 
OBJECTIVES 
 
1.1 
Primary Objective 
 
To determine the efficacy, as determined by objective response rate, of selumetinib (intermittent 
or continuous) in patients with NSCLC not known to have KRAS mutation receiving standard 
pemetrexed and platinum-based chemotherapy compared to chemotherapy alone. 
 
1.2 
Secondary Objectives 
 
1.2.1 
To assess the tolerability of selumetinib in patients receiving pemetrexed and platinum-based 
chemotherapy. 
 
1.2.2 
To assess the progression free survival of patients receiving selumetinib with pemetrexed and 
cisplatin to those receiving pemetrexed and platinum-based chemotherapy alone. 
 
1.2.3 
To assess whether KRAS mutation, other common mutations, or tumour based molecular 
signatures are predictive of selumetinib effect. 
 
1.3 
Exploratory Objective 
 
1.3.1 
To explore the feasibility of KRAS mutation testing in circulating tumour DNA (ctDNA) and 
concordance of KRAS mutation status between ctDNA and archival tumour tissue. 
 


 
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2.0 
BACKGROUND INFORMATION AND RATIONALE 
 
Lung cancer is the leading cause of cancer related mortality worldwide [Jemal 2008]. Non-small 
cell lung cancer (NSCLC) accounts for approximately 80% of lung cancer cases [Rankin 1986]. 
Approximately 40% of patients present with advanced NSCLC [Ramalingam 2008], and for patients 
who present with earlier stage of disease, relapse is common due to early micrometastatic spread 
[Winton 2005]. In this setting the disease is incurable and treatment is palliative in intent. Although 
the number of treatment options for patients with advanced disease has increased over the past 
decade, prognosis remains poor, and there is a pressing need for additional therapeutic options 
[Shepherd 2002; Schiller 2002; Hanna 2004; Shepherd 2005; Sandler 2006]. 
 
Cytotoxic chemotherapy is standard of care for patients with advanced NSCLC, and good 
performance status. In the first line setting, cisplatin based chemotherapy is associated with an 
absolute increase in overall survival of 10% at one year versus best supportive care (BSC) [NSCLC 
Collaborative Group 1995]. More recently, an additional modest benefit over that of standard 
combination chemotherapy, with the addition of the anti-angiogenic agent bevacizumab [Sandler 
2006] or the epidermal growth factor (EGFR) inhibitor cetuximab has been reported [Pirker 2008]. 
In the second line, single agent docetaxel is associated with a superior overall survival (OS) 
versus BSC (median OS 7.0 months versus 4.6 months, log-rank p=0.047 respectively). 
Pemetrexed or the EGFR tyrosine kinase inhibitor (TKI) gefitinib provide alternative treatment 
options to docetaxel, with equivalent survival [Shepherd 2005; Hanna 2004; Kim 2008]. In the second or 
third line setting, the EGFR TKI, erlotinib, has been demonstrated to provide OS and quality of 
life (QOL) benefits over that of BSC, after one or two lines of chemotherapy (Hazard ratio (HR) 
0.70 p<0.001) [Shepherd 2005; Bezjak 2006]. More recently, studies have shown platinum based 
pemetrexed combinations offer superior outcomes for patients with adenocarcinoma, as does 
pemetrexed maintenance therapy [Ciuleanu 2009; Paz-Ares 2012; Scagliotti 2014]. For patients with 
EGFR mutation positive disease, first line therapy with an EGFR TKI (gefitinib or erlotinib) is 
associated with a superior progression free survival compared with first line cytotoxic 
chemotherapy and has become a standard first line approach [Fukuoka 2011; Rosell 2012]. Despite 
these advances, the majority of patients with NSCLC die of their disease. 
 
Chemotherapy agents may invoke compensatory activation of the ras-raf-mek pathway and this is 
postulated to contribute to the emergence of drug resistance (for example, through regulation of 
downstream transcription factor such as GATA-1 which controls the transcription of genes such 
as XRCC1 and ERCC1, promoting proliferation and preventing apoptosis). Treatment of drug 
resistant cells with mitogen activated protein kinase (MEK) inhibitors, or combined treatments 
consisting of a chemotherapeutic drug and a MEK inhibitor, may be an effective approach to 
prevent drug resistance.  
 
Conversely, while combinations of paclitaxel and MEK inhibitors have been reported to be 
synergistic, some data suggest antagonism when MEK inhibitors and platins are given in 
combination. Cisplatin-induced apoptosis was associated with increased levels of both p53 and 
the downstream Bax protein as well as activated ERK1/ERK2 levels in a study with 
neuroblastoma cells. MEK inhibitors blocked apoptotic cell death, which prevented the cisplatin-
induced accumulation of p53 and Bax proteins. Other nonclinical data suggest strong schedule 
dependence suggesting that combined treatment with chemotherapy and MEK inhibitors would 
be more active following a 48 hour interruption in dosing with a MEK inhibitor, rather than 
dosing concurrently. 


 
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AMEND #2: 2016-APR-12 
Selumetinib (AZD6244, ARRY-142886) is a potent and selective allosteric MEK inhibitor. A 
randomized phase II study in patients with KRAS mutation-positive NSCLC has been conducted 
which compared selumetinib plus docetaxel to placebo plus docetaxel. There was a numerically 
greater increase (not statistically significant) in the primary endpoint of survival. The secondary 
endpoints of progression-free survival, objective response rate, and patients alive and progression 
free at 6 months each showed a statistically significant improvement in favour of selumetinib plus 
docetaxel [Janne 2012]. Further, while preclinical studies with selumetinib in combination with 
docetaxel suggested that intermittent scheduling (docetaxel followed by selumetinib) was active, 
the randomized phase II study in NSCLC showed activity with continuous administration with 
intermittent docetaxel. 
 
A candidate predictive gene expression signature for MEK inhibitors in NSCLC has been 
identified that detects activated KRAS/MEK signaling [Loboda 2010; Dry 2010; Brant 2013]. Signature 
scores indicating high pathway activity were consistently found in both KRAS mutant and 
wildtype tumours. Further testing of the gene expression signature in both of these tumour types 
may provide evidence of possible benefit for treatment with selumetinib in additional or 
alternative populations. The assay has been demonstrated to be robust using formalin fixed 
paraffin embedded (FFPE) tumour tissue [Brant 2013] which makes it feasible to test the signature 
as part of a clinical trial of selumetinib.  
 
In recent years, circulating tumour DNA (ctDNA) has emerged as a minimally invasive 
biomarker for profiling the tumour genome in multiple solid malignancies, including NSCLC, 
and as a potential alternative source of tumour DNA for genomic analysis [Schwarzenbach 2011; 
Francis 2015; Freidin 2015; Diaz 2014]. KRAS mutations have been detected successfully in ctDNA in 
patients with advanced NSCLC with > 90% concordance between ctDNA and the tumour tissue 
[Saik 2014]. We are planning to explore feasibility of KRAS mutation analysis from ctDNA and its 
concordance with tumour tissue. 
 
CCTG has undertaken a phase I trial (NCIC CTG IND.215) of selumetinib combined with 
pemetrexed and cisplatin to evaluate the recommended phase II dose of both an intermittent 
schedule (selumetinib given on days 2-19 of a 21 day cycle) and continuous selumetinib 
(continuous selumetinib daily in a 21 day cycle). CCTG is interested in the further exploration of 
the efficacy in patients with KRAS wildtype or unknown NSCLC and toxicity of these two 
schedules versus standard pemetrexed/cisplatin (carboplatin) chemotherapy in patients with 
previously untreated advanced or metastatic non-squamous NSCLC.  
 


 
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3.0 
BACKGROUND THERAPEUTIC INFORMATION 
 
3.1 
Name and Chemical Information 
 
Selumetinib (AZD6244, ARRY-142886) is a potent, selective, allosteric non-ATP competitive 
inhibitor of MEK. 
 
Chemical Information 
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid 
(2-hydroxy-ethoxy)-amide: AZD6244 free-base. 
 
3.2 
Chemical Structure 
 
Molecular formula C17H15BrClFN4O3 
Relative molecular mass 457.7 
 
3.3 
Mechanism of Action 
 
In cancer cells, signaling through the RAS/RAF/MEK/ERK pathway is frequently deregulated 
due to enhanced mitogenic stimulation at the level of growth factor receptors or activating 
mutations in RAS or RAF oncogenes. Inhibition of MEK, which lies downstream from these 
over-activated targets blocks inappropriate signal transduction in the pathway and is anticipated 
to arrest cancer cell proliferation and growth, offering a promising anti-cancer therapeutic 
strategy. 
 
AZD6244 inhibits the activity of isolated MEK to phosphorylate ERK2 in enzyme assays with an 
IC50 of approximately 10 to 14 nM. It is an uncompetitive inhibitor with respect to ATP. 
 
AZD6244 was inactive or only minimally active at 10 μM when tested against EGF receptor, 
erbB2, p38α, ERK2 and mitogen-activated protein kinase kinase. No significant activity for either 
AZD6244 or N-desmethyl AZD6244 was detected in a diverse panel of 305 and 336 enzymes, 
receptors, ion channels and transporters, respectively, at 10 μM. The potency of AZD6244 in 
inhibiting ERK1 and ERK2 phosphorylation in a diverse panel of cell lines was consistent 
ranging from 0.0018 to 0.0408 μM. In cell viability assays, IC50 values ranged from < 10 nM to 
> 10 μM and most of the cell lines that were sensitive to AZD6244 contained either a BRAF or 
RAS gene mutation [Davies 2007; Dry 2010]. 
 
3.4 
Experimental Anti-tumour Activity 
 
AZD6244 has demonstrated potent inhibition of BRAF or KRAS mutation-positive cell line 
viability and inhibition of xenograft growth, both as monotherapy and in combination with a 
number of cytotoxic and targeted anti-cancer agents, including docetaxel. In three xenograft 
models of a KRAS mutation-positive tumour (SW620 colorectal cancer, HCT-116 colorectal 
cancer and A549a NSCLC), a beneficial effect of the combination of AZD6244 with cytotoxic 
drugs (e.g. docetaxel and temozolomide) or targeted anti-cancer agents (e.g. gefitinib) was 
observed when compared with either agent as monotherapy. 


 
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3.5 
Animal Toxicology 
 
AZD6244 free-base has been acutely dosed as single oral doses up to 300 mg/kg in rats and as bid 
doses up to 100 mg/kg/dose in cynomolgus monkeys and for up to 29 days, once daily at doses of 
up to 100 mg/kg/day in rats and bid at doses up to 30 mg/kg/dose in cynomolgus monkeys. 
However, there appeared to be dose-limited absorption due to the limited solubility of AZD6244.  
 
AZD6244 Hyd-Sulfate has been dosed to mice and monkeys for 6 months bid at doses of up to 20 
and 4 mg/kg/dose, respectively. AZD6244 Hyd-Sulfate enhances systemic exposure (3- to 6-fold) 
to AZD6244 and clear dose-related increases in exposure in mice and monkeys over the dose 
range studied were seen.  
 
In a battery of safety pharmacology studies with AZD6244 free-base (hERG channel assay and 
behavioural, cardiovascular, pulmonary and gastrointestinal function/tolerability studies), there 
were no toxicologically significant findings. While there was some evidence of gastric irritation 
following a 100 mg/kg dose of AZD6244 in rats in the safety pharmacology study, there was no 
histopathological evidence of gastric irritation in rats in the 1-month study at this dose level. 
While minor increases in airway resistance were seen at 100 mg/kg AZD6244 in the respiratory 
safety pharmacology study, no respiratory abnormalities were apparent in the rat 1-month study at 
this dose level. 
 
The following have been observed during administration of AZD6244 in toxicology studies: 
diarrhea, dehydration and electrolyte imbalance; gastrointestinal tract toxicity; inflammatory 
changes in the liver; tissue mineralization (gastrointestinal mucosa, cornea, kidney, liver, 
myocardium, skeletal muscle, glandular tissue) associated with changes in plasma inorganic 
phosphate, calcium and/or albumin; hematopoietic atrophy, anemia, and an associated 
reticulocytosis. There was evidence of reversibility of most changes, with the exception of tissue 
mineralization. In vitro assays indicate a potential for phototoxicity (enhanced cytotoxicity in the 
presence of ultraviolet light). 
 
Reproductive toxicology studies indicate that AZD6244 can affect embryofetal development and 
survival at dose levels that do not induce maternal toxicity. AZD6244 showed no evidence of 
mutagenic or clastogenic potential in vitro. AZD6244 produced an increase in micronucleated 
immature erythrocytes in mouse micronucleus studies, predominantly via an aneugenic mode of 
action. 
 
3.6 
Studies in Humans 
 
As of 31 January 2014, approximately 1940 patients with cancer have received treatment with 
selumetinib. Full details are described in the current selumetinib investigator brochure.  
 
3.6.1 
Phase I Trials 
 
Study ARRY-0401 – free-base suspension formulation of AZD6244 
Dose-limiting toxicities (DLTs) included grade 3 diarrhea and rash as well as hypoxia. The most 
frequently reported adverse events (AEs) were rashes (74.2%), diarrhea (58.1%), nausea (54.8%), 
fatigue (54.8%) and edema peripheral (48.4%). A trend towards elevated serum transaminase 
levels was observed, and AEs of alanine aminotransferase or aspartate aminotransferase were 
reported in 19.3 and 33.3%, respectively, of patients across all doses. Adverse events of 
hypertension were reported in 8.9% of patients, including 7.0% with hypertension or other 
cardiac conditions at entry to the study. No clinically significant trends in ECG parameters, 
including QTc, were observed. 


 
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Study D1532C00005 – Hyd-Sulfate capsule formulation of AZD6244 
DLTs included rash, fatigue and pleural effusion and the 75 mg bid dose was determined to be the 
maximum tolerated dose of the AZD6244 Hyd-Sulfate capsule formulation. 
 
The most frequently reported adverse events were fatigue (65.7%), dermatitis acneiform (60.0%), 
diarrhea (54.3%), nausea (48.6%), and edema peripheral (48.6%). Small increases in blood 
pressure were observed within the first week of continuous treatment with AZD6244; maximal 
median increases were apparent at after 3 weeks treatment with AZD6244 75 mg bid (systolic 
+7 mmHg; diastolic +13 mmHg) with improvement within 4 weeks of continuing treatment (to 
median +1 mmHg and +2 mmHg). Adverse events of left ventricular dysfunction or ejection 
fraction decreased have been reported in 8.6% of patients receiving AZD6244 75 mg bid in Study 
D1532C00005. There were no clinically significant changes in pulse rate, blood oxygen 
saturation, ECG parameters (including QTc) or hematology assessments, and no new clinically 
significant effects on laboratory parameters were observed. 
 
3.6.2 
Phase II Trials 
 
Rashes (including the preferred terms dermatitis acneiform, rash, rash maculopapular, rash 
macular, rash papular, acne and folliculitis), were reported in approximately 70% of patients 
receiving treatment with AZD6244, and dermatitis acneiform was the most common AE term 
overall (53.9%). Other commonly reported AEs were diarrhea (49.4%), nausea (32.7%) and 
vomiting (23.8%). AEs of peripheral edema, periorbital edema or facial edema were reported in 
30.9%, 8.6% and 4.1% of patients, respectively. AEs of fatigue or asthenia were reported in 
approximately 30% of patients in this Phase II population. Dyspnea exertional or dyspnea was 
reported in 13% of patients and, in individual studies, dyspnea exertional was reported at a higher 
incidence in the AZD6244 groups than in the comparator chemotherapy groups. 
 
Serious AEs were reported in 23.8% of patients receiving AZD6244 monotherapy. The most 
frequently reported serious AEs were vomiting (1.5%), diarrhea, erysipelas and pulmonary 
embolism (in 1.1% patients each). Serious AEs of infections (bacterial sepsis, sepsis, infection, 
bacterial arthritis) were reported in 2.2% of patients. 
 
3.6.3 
Pharmacokinetic Studies 
 
The first-in-human study of AZD6244 was conducted using a free-base suspension formulation. 
The maximum tolerated dose (MTD) was determined as 100 mg bid and subsequent phase II 
monotherapy studies conducted by AstraZeneca used this dose level and formulation. The 
pharmacokinetics of the AZD6244 Hyd-Sulfate capsule formulation was explored in Study 
D1532C00005; a MTD of AZD6244 75 mg bid was determined.  
 
In Study D1532C00005 the estimated oral bioavailability of the Hyd-Sulfate capsule relative to 
the free-base suspension based on dose-normalized AUC0-24 was determined to be 263% (90% 
CI = 214 to 322%).  
 
AZD6244 plasma pharmacokinetic parameters were similar after single and multiple dosing, 
suggesting minimal accumulation over time after bid dosing, consistent with the pharmacokinetic 
(PK) profile observed. The AZD6244 parameters were approximately dose proportional across 
the 25 to 100 mg dose range studied. 


 
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Circulating plasma concentrations of two metabolites, N-desmethyl AZD6244 and AZD6244 
amide, were measured. The mean ratio of N-desmethyl AZD6244 to AZD6244 was < 15%, and 
N-desmethyl AZD6244 was found to be 3- to 5-fold more potent than AZD6244 in an in vitro 
assay of cell-based ERK phosphorylation. Therefore N-desmethyl AZD6244 is likely to be 
contributing to pharmacodynamic effects. An investigation of the plasma PK of the AZD6244 
amide metabolite was included in Study D1532C00005 in order to further characterize the plasma 
PK profile and to investigate the concentrations of circulating AZD6244 amide relative to 
AZD6244. In an in vitro assay of cell-based ERK phosphorylation, the AZD6244 amide 
metabolite was approximately 40- to 50-fold less active than AZD6244, and is therefore unlikely 
to contribute significantly to biological activity. Concentrations of the AZD6244 amide increased 
after multiple dosing, with a mean ratio of AZD6244 amide to AZD6244 after multiple dosing of 
< 8% (maximum 22%). 
 
A food effect study (D1532C00020) involving administration of AZD6244 to patients with 
advanced solid malignancies under fasting conditions and with a high-fat meal indicated a 
statistically significant effect of food on the exposure of AZD6244. Glsmean Cmax and AUC were 
reduced by 62 and 19%, respectively, under fed conditions.  
 
There is no evidence of a PK interaction between AZD6244 and docetaxel, dacarbazine, erlotinib 
or temsirolimus. 
 
3.7 
Pharmaceutical Data 
 
Supplied: 
The drug product consists of a series of plain, blue hydroxypropylmethylcellulose (HPMC) 
capsules containing 25 mg of AZD6244 (expressed as free-base) for oral administration. 
AZD6244 capsules are supplied in white high-density polyethylene (HDPE) bottles with foil-
lined, induction-sealed, child-resistant closures. The container includes a desiccant canister. 
 
Selumetinib will be supplied as 25 mg blue capsules in bottles of 60 capsules. 
 
Storage: 
The capsules should be stored in their original packaging until use. For further information, 
Investigators should refer to the investigational product label. 
 
3.8 
Standard Chemotherapy Agents 
 
Standard chemotherapy agents are used in this protocol but are not supplied. Centres should 
consult the manufacturers’ guidelines for further details. 
 
Participating centres who are not able to access pemetrexed due to provincial funding constraints 
should contact CCTG for details on assistance from Lilly Canada. 


 
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4.0 
TRIAL DESIGN 
 
This is an open-label, randomized, phase II clinical study of selumetinib (intermittent or 
continuous) in patients with advanced or metastatic KRAS wildtype or unknown KRAS status, 
non-squamous non-small cell lung cancer (NSCLC) who are receiving pemetrexed/cisplatin or 
pemetrexed/carboplatin as a first line palliative treatment. This study is being conducted by the 
Canadian Cancer Trials Group (CCTG), with support from AstraZeneca. 
 
4.1 
Starting Doses 
 
The starting doses of pemetrexed and cisplatin  or pemetrexed and carboplatin are the standard 
doses recommended for clinical practice. Dose de-escalation will be permitted in the event of 
unacceptable toxicity. 
 
Selumetinib starting dose is 75mg bid. 
 
4.2 
Randomization 
 
Patients will be randomly assigned to a treatment arm as follows: 
 
Arm 
Selumetinib 
Pemetrexed/Cisplatin (Carboplatin) 
A 
Days 2-19 
Day 1 q 21 days 
B 
Days 1-21 (continuous) 
C 
Not given 
 
4.3 
Stratification 
 
Patients will be stratified by the type of planned platinum treatment (cisplatin vs. carboplatin). 
 


 
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5.0 
STUDY POPULATION 
 
Patients will have histologically and/or cytologically confirmed non-squamous NSCLC with 
wildtype KRAS or unknown KRAS status that is metastatic or unresectable and for which standard 
curative measures do not exist.  
 
This study is designed to include women and minorities as appropriate, but is not designed to 
measure differences in intervention effects. 
 
5.1 
Eligibility Criteria 
 
There will be NO EXCEPTIONS to eligibility requirements at the time of randomization. 
Questions about eligibility criteria should be addressed prior to randomization. 
 
The eligibility criteria for this study have been carefully considered. Eligibility criteria are 
standards used to ensure that patients who enter this study are medically appropriate candidates 
for this therapy. For the safety of the patients, as well as to ensure that the results of this study can 
be useful for making treatment decisions regarding other patients with similar diseases, it is 
important that no exceptions be made to these criteria for admission to the study. 
 
Patients must fulfill all of the following criteria to be eligible for admission to the study: 
 
5.1.1 
Patients must have histologically and/or cytologically confirmed non-squamous, KRAS wildtype 
or unknown, non-small cell lung cancer that is stage IIIB or IV, metastatic or unresectable and for 
which standard curative measures do not exist. 
 
5.1.2 
All patients must have a formalin fixed paraffin embedded tumour block (from primary or 
metastatic tumour) available for correlative studies and must have provided informed consent for 
the release of the block for correlative studies.  
 
5.1.3 
Patients must have at least one site of disease which is unidimensionally measurable as follows:  
 
Measurable disease defined as at least one target lesion that has not been irradiated or has 
progressed after radiation and can be accurately measured in at least one dimension by 
RECIST 1.1 criteria. 
 
Chest X-ray  
> 20 mm  
 
CT/MRI scan (with slice thickness of < 5 mm)  > 10 mm  
longest diameter  
 
Physical exam (using calipers)  
> 10 mm  
 
Lymph nodes by CT scan  
> 15 mm  
measured in short axis  
 
5.1.4 
Presence of clinically and/or radiologically documented disease (marker positive only patients are 
not eligible).  
 
All radiology studies must be performed within 28 days prior to randomization (within 35 days if 
negative). 
 
5.1.5 
Age > 18 years. 
 
5.1.6 
ECOG performance status 0 or 1 (Appendix II). 


 
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5.1.7 
Previous Therapy 
 
Surgery: 
Previous major surgery is permitted provided it has been at least 14 days prior to patient 
randomization and that wound healing has occurred. 
 
Radiation: 
Prior external beam radiation is permitted provided a minimum of 4 weeks has elapsed between 
the last dose and enrollment to the trial. Exceptions may be made for low dose, non-
myelosuppressive radiotherapy after consultation with CCTG. 
 
Chemotherapy and systemic therapy: 
Prior therapy with ALK inhibitors is permissible. Patients may not have received prior MEK 
inhibitors or any other tyrosine kinase inhibitor (including EGFR inhibitors of any kind). Patients 
may have received vaccines, immunotherapy or other agents that are not MEK/tyrosine kinase 
inhibitors in the adjuvant setting or for advanced or metastatic disease. 
 
Prior adjuvant platinum-based chemotherapy or combined chemoradiotherapy with curative 
intent is permissible provided completed at least one year prior to enrolment.  
 
No prior cytotoxic chemotherapy for advanced / metastatic disease is permissible. 
 
5.1.8 
Laboratory Requirements  
(must be done within 7 days prior to randomization) 
 
Hematology: 
Neutrophils 
> 1.5 x 109/L  
Platelets  
> 100 x 109/L 
 
Biochemistry: 
Creatinine Clearance* > 50 ml/min 
Total bilirubin 
< 1.5 x ULN 
AST and ALT 
< 2.5 x ULN 
(if liver metastases < 5x ULN permissible providing 
ALP also ≤ 6 x ULN) 
 
* Creatinine clearance to be measured directly by 24 hour urine sampling or as calculated by 
appropriate formula below: 
 
Females: GFR = 1.04 x (140-age) x weight in kg 
 
 
serum creatinine in μmol/L 
 
Males: GFR  
= 1.23 x (140-age) x weight in kg 
 
 
serum creatinine in μmol/L 
 
5.1.9 
Patient consent must be appropriately obtained in accordance with applicable local and regulatory 
requirements. Each patient must sign a consent form prior to enrollment in the trial to document 
their willingness to participate.  
 
Patients who cannot give informed consent (i.e. mentally incompetent patients, or those 
physically incapacitated such as comatose patients) are not to be recruited into the study. Patients 
competent but physically unable to sign the consent form may have the document signed by their 
nearest relative or legal guardian. Each patient will be provided with a full explanation of the 
study before consent is requested. 


 
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5.1.10 Patients must be accessible for treatment and follow-up. Patients randomized on this trial must be 
treated and followed at the participating centre. This implies there must be reasonable 
geographical limits (for example: 1 ½ hour's driving distance) placed on patients being 
considered for this trial. (Call the CCTG office (613-533-6430) if questions arise regarding the 
interpretation of this criterion.) Investigators must assure themselves the patients randomized on 
this trial will be available for complete documentation of the treatment, response assessment, 
adverse events, and follow-up. 
 
5.1.11 In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization. 
 
 
5.2 
Ineligibility Criteria 
 
Patients who fulfill any of the following criteria are not eligible for admission to the study: 
 
5.2.1 
Patients with a history of other untreated malignancies or malignancies which required therapy 
within the past 2 years. Patients with other malignancies of a nature that do not require treatment 
may be eligible after consultation with the CCTG.  
 
5.2.2 
Symptomatic brain metastases or spinal cord compression. Patients with asymptomatic 
brain/spinal cord metastasis who are not planned for radiation, or who have been treated and are 
stable off steroids (or on a decreasing dose) and anticonvulsants are eligible.  
 
5.2.3 
Patients with significant cardiac disease, including: 
 
any factors that increase the risk of QTc prolongation or risk of arrhythmic events (e.g. heart 
failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome or 
unexplained sudden death under 40 years of age) or mean resting corrected QT interval (QTc) 
> 470 msec 
 
uncontrolled hypertension (BP > 150/95 mmHg despite medical therapy) 
 
acute coronary syndrome within 6 months prior to starting treatment 
 
angina Canadian Cardiovascular Society Grade II-IV (despite medical therapy) 
 
symptomatic heart failure (NYHA II-IV) 
 
prior or current cardiomyopathy including but not limited to known hypertrophic 
cardiomyopathy or known arrhythmogenic right ventricular cardiomyopathy 
 
atrial fibrillation with a ventricular rate > 100 bpm at rest 
 
severe valvular heart disease 
 
Patients with cardiac disease, who do not meet the exclusion criteria above, must have a baseline 
LVEF > 50%. 
 
5.2.4 
Any evidence of severe or uncontrolled systemic disease, active infection, active bleeding 
diatheses or renal transplant, including any patient known to have hepatitis B, hepatitis C or 
human immunodeficiency virus (HIV). 
 
5.2.5 
Patients who have neuropathy > grade 1 or other conditions precluding treatment with the 
standard chemotherapy regimen planned. Consult CCTG for patients with localised neuropathies 
as such patients may be eligible. 


 
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5.2.6 
Patients who have significant gastrointestinal disease and who are unable to swallow capsules. 
 
5.2.7 
Patients on potent inhibitors or inducers of CYP3A4/5, CYP2C19 and CYP1A2 (must have 
discontinued within 2 weeks prior to randomization or 3 weeks for St. John’s Wort). Patients who 
do not agree to avoid the ingestion of large amounts of grapefruit and Seville oranges (and other 
products containing these fruits, e.g. grapefruit juice or marmalade) and not take vitamin E 
supplements or multivitamin supplements. 
 
Patients who require oral anticoagulants (Coumadin) are eligible provided there is increased 
vigilance with respect to INR monitoring upon initiation of dosing with selumetinib (see Sections 
6 and 9). If medically appropriate and treatment available, the investigator should consider 
switching these patients to LMW heparin. 
 
5.2.8 
Patients with current or past history of central serous retinopathy or retinal vein occlusion, high 
intraocular pressure (> 21mm) or uncontrolled glaucoma (irrespective of IOP). Patients with 
visual symptoms should undergo ophthalmologic examination prior to randomization. 
 
5.2.9 
Pregnant or lactating women. Women of childbearing potential must have a urine pregnancy test 
proven negative within 7 days prior to randomization. Men and women of childbearing potential 
must agree to use adequate contraception as described in Section 11.3.1. 
 
5.2.10 Patients who do not agree to avoid excessive sun exposure and use adequate sunscreen protection. 
 
5.2.11 Selumetinib-specific precautions for patients of Asian ethnicity: 
 
Plasma exposure of selumetinib (Cmax and AUC) is higher, at a population level, in subjects of 
Asian descent by approximately 1.5- to 2-fold in non-Japanese Asians and Japanese subjects, 
compared with Western subjects. However, there is overlap in the range of exposure experienced 
by Asian and Western subjects and the higher average plasma exposure was not associated with a 
change in the tolerability profile of single dose selumetinib. 
 
Investigators should make a clinical judgment as to whether the potential risk of experiencing 
higher selumetinib plasma exposure and potential adverse events outweighs the potential benefit 
of treatment with selumetinib. 


 
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6.0 
PRE-TREATMENT EVALUATION 
(See Appendix I) 
 
Investigations 
Timing 
History and Physical 
Exam including: 
• history, height, weight, BSA, performance 
status, tobacco use 
• vital signs (blood pressure and heart rate) 
• documentation of all measurable and non-
measurable disease 
• clinical tumour measurements (if applicable) 
within 7 days prior to 
randomization 
Hematology 
• CBC, ANC, platelets 
Biochemistry 
• serum creatinine 
• creatinine clearance 
• bilirubin 
• alkaline phosphatase 
• AST, ALT 
• LDH 
• total protein 
• calcium, phosphate 
• albumin 
• CPK 
Coagulation1 
• INR (if applicable) 
Other Investigations 
• pregnancy test2 
• EKG 
• LVEF (if applicable) 
• ophthalmology exam (if clinically indicated) 
Radiology3 
• chest CT including upper abdomen (must 
include adrenals) 
• other scans/x-rays as necessary to document 
disease 
within 28 days (35 days if 
negative) prior to randomization 
Correlative Studies 
• Archival tissue4 (Mandatory) 
must be confirmed available prior 
to randomization 
• Whole blood and plasma 
after registration but before first 
dose of study treatment  
Adverse Events5 
Baseline adverse event evaluation (to document 
residual adverse events from previous therapy 
and baseline symptoms) 
within 7 days prior to 
randomization 
1 Required only if taking oral anticoagulants (i.e. Coumadin). 
2 For women of childbearing potential only. 
3 To ensure comparability, the baseline scans and subsequent scans to assess response must be performed using identical 
techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, 
the identical contrast agent, and preferably the same scanner). 
4 See Section 17 and laboratory manual(s) for details. 
5 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) (Appendix V). 


 
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7.0 
ENTRY/RANDOMIZATION PROCEDURES 
 
7.1 
Entry Procedures 
 
All randomizations will be done through the CCTG web-based, password-operated Electronic 
Data Capture (EDC) system. Complete details regarding obtaining a password, accessing the 
system and randomizing patients will be provided at the time of study activation and will also be 
included in the “EDC Data Management Guidebook”, posted on the IND.219 trial specific web-
site. If sites experience difficulties accessing the system and/or randomizing patients please 
contact the help desk (link in EDC) or the IND.219 Study Coordinator. 
 
All eligible patients enrolled on the study by the participating treatment centre will be assigned a 
serial number which must be used on all documentation and correspondence with CCTG. 
 
The following information will be required: 
• 
trial code (CCTG IND.219) 
• 
patient's initials (may be coded)  
• 
informed consent version date, date signed by patient, name of person conducting consent 
discussion and date signed 
• 
confirmation of the requirements listed in Section 5.0, including dates of essential tests and 
actual laboratory values 
• 
BSA, height and weight 
• 
Stratification factors: KRAS known WT vs. unknown KRAS status and the type of planned 
platinum treatment (cisplatin vs. carboplatin) 
 
7.2 
BSA Calculation 
 
In calculating surface areas, actual heights and weights should be used, that is, there will be no 
downward adjustment to "ideal" weight. This principle applies to individuals whose calculated 
surface area is 2.2 m2 or less. In those rare cases where a patient's surface area is greater than 2.2, 
the actual surface area or 2.2 may be used.  
 
All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting randomization. 
 
7.3 
Stratification 
 
Subjects will be stratified by KRAS status (known WT versus unknown) and the type of planned 
platinum treatment (cisplatin vs. carboplatin). 
 
7.4 
Randomization 
 
Randomization will be provided electronically. 
 
Note: The validity of results of the trial depends on the authenticity of the data and the follow up of all 
patients entered into the trial. Under no circumstances, therefore, may an allocated patient’s data 
be withdrawn prior to final analysis, unless the participant withdraws from the trial and requests 
that data collection/submission cease from the point in time of withdrawal. 


 
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All eligible patients admitted to the trial will be followed by the coordinating centre. It is the 
responsibility of the physician in charge to satisfy himself or herself that the patient is indeed 
eligible before requesting registration/randomization. 
 
All randomized patients are to be followed until death or until sites are informed by CCTG that 
further follow-up is no longer required.  


 
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8.0 
TREATMENT PLAN 
 
Although the Canadian Cancer Trials Group acts as the coordinating agency for the trial, the 
responsibility for treatment of patients rests with the individual investigator. 
 
In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient 
randomization.  
 
8.1 
Drug Administration 
 
NB: For reporting purposes, each three week period of treatment will be considered “one cycle” 
and the date of chemotherapy administration is considered “Day 1”. 
 
Arm 
Selumetinib 
75 mg bid PO 
Pemetrexed: 500mg/m2 plus 
Cisplatin*: 75mg/m2 
or 
Carboplatin*: AUC 6 
Schedule 
A 
Days 2-19 
Day 1 
q 21 days 
B 
Days 1-21 (continuous) 
C 
Not given 
* Must be specified at the time of randomization.  Patients who start on treatment with cisplatin may switch to 
carboplatin only after discussion with CCTG. 
 
Selumetinib is to be taken on an empty stomach - no food or drink other than water for 2 hours 
prior to dosing and 1 hour after dosing (i.e. take at least 2 hours after a meal and 1 hour before the 
next meal) with water. The bid doses should be taken approximately 12 hours apart. 
 
Guidelines recommend that first line chemotherapy be administered for no more than 4-6 cycles. 
All patients receiving standard chemotherapy are considered on study until criteria in Section 
12.1 are met. Patients should continue with pemetrexed maintenance (with selumetinib for Arms 
A and B). Patients who discontinue standard chemotherapy for reasons other than disease 
progression, may continue with selumetinib alone providing that further chemotherapy is not 
planned. When further chemotherapy (other than pemetrexed maintenance) or systemic therapy is 
planned, selumetinib must be discontinued.  
 
Total carboplatin dose (mg) will be calculated according to the Calvert formula: 
Carboplatin dose (mg) = (target AUC) x (GFR +25);  
GFR = glomerular filtration rate (see Section 5.1.8) 
 
The maximum dose based on a GFR estimate is capped at 125 mL/min for patients with normal 
renal function. No higher estimated GFR values should be used. Please refer to the following link 
for more information: 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm
228974.htm 


 
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8.2 
Premedication 
 
Patients should receive standard premedication according to the product monograph and local and 
provincial formulary guidelines: 
• 
Antiemetics (for highly emetogenic chemotherapy) 
• 
Hydration (for cisplatin) 
• 
Vitamin supplementation (for pemetrexed) 
 
Alternatively, standard protocols are available on the Cancer Care Ontario website: 
https://www.cancercare.on.ca/toolbox/drugformulary. 
 
Initially, premedication for nausea and/or vomiting related to selumetinib is not required, as it is 
usually self-limiting but can be easily managed with anti-emetic medication such as 
prochlorperazine or 5-HT3 receptor antagonists at the treating investigator’s discretion. 
 
8.3 
Dose Adjustments 
 
Dose adjustments for each drug should be performed for toxicity related to that drug.  
 
8.3.1 
Dose Adjustments for Standard Pemetrexed Plus Cisplatin/Carboplatin 
 
Doses will be reduced for hematologic and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity. Adverse events will be graded 
using the NCI Common Terminology Criteria for Adverse Events (CTCAE) (see Appendix V). 
 
Investigators must consult the product monographs for each chemotherapy agent, or follow their 
local or provincial formulary guidelines for dose modifications.  
 
Alternatively, standard protocols are available on the Cancer Care Ontario website: 
https://www.cancercare.on.ca/toolbox/drugformulary. 
 
8.3.2 
Dose Adjustments for Selumetinib ONLY 
 
The major adverse events which have been described with selumetinib are diarrhea, nausea, 
vomiting, stomatitis, rash, fatigue, fever, dyspnea, pneumonitis, edema, hypertension, CPK 
increases, phosphate increases, falls in LVEF, transaminitis and visual symptoms. The guidelines 
which follow outline dose adjustments for several of these toxic effects.  
 
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. If the patient has 
several adverse effects which are related to both standard chemotherapy and selumetinib, use the 
recommended dose adjustment that reduces to the lowest level for both standard chemotherapy 
and selumetinib.  
 
Dose levels of selumetinib are provided below. A maximum of two dose reductions for toxicity is 
permitted; if a third is required, the patient must discontinue protocol therapy. If a patient 
discontinues selumetinib for more than 4 weeks (or more than 6 weeks for asymptomatic 
reductions in LVEF and for RPED/central serous retinopathy), they are no longer eligible to 
re-start treatment. 


 
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Selumetinib  
0 (starting dose) 
Dose level-1 
Dose level -2 
Arm A Intermittent  
75 mg bid day 2-19 
50 mg bid day 2-19 
50 mg od day 2-19 
Arm B Continuous  
75 mg bid continuously 
50 mg bid continuously 
50 mg od continuously 
 
8.3.2.1 Management of New or Worsening Dyspnea Not Related to NSCLC 
 
 
New AE of dyspnea* or worsening of  
pre-existing dyspnea* > 1 CTC Grade 
The following should be considered based on clinical examination: 
Chest x-ray, PA and lateral view. Consider ECHO, ECG, BNP, 
Troponin I, sputum, blood, urine culture (bacterial antigens and PCR), 
WBC, Hb and urea. 
No obvious underlying cause of 
dyspnea or suspected ILD 
Perform HRCT scan. 
Consider respiratory 
consultation. 
HRCT does not show 
interstitial lung 
disease/pneumonitis 
ILD/pneumonitis 
diagnosed by HRCT 
Dyspnea AE resolved 
to < grade 1 or baseline 
Continue selumetinib 
Dyspnea AE not resolved 
to < grade 1 or baseline 
Seek cardiology and/or 
respiratory consult if not 
already performed. 
Consider selumetinib dose 
interruption/reduction. 
Consider selumetinib dose 
interruption and/or 
discontinuation.  
Treat according to local 
practices. 
If test results indicate diagnosis other 
than ILD/pneumonitis, treat according to 
local practices. 
Consider selumetinib dose interruption  
and/or discontinuation. 
BNP:  Brain Natriuretic Peptide 
ILD:  
Interstitial Lung Disease 
CTC:  National Cancer Institute common toxicology criteria 
PA:  
Posteroanterior 
Echo:  Echocardiography 
PCR:  Polymerase chain reaction 
Hb: 
Hemogloblin 
WBC: White blood cells 
HRCT: High resolution computerized tomography 
* For investigating events of dyspnea that are not considered to be due to disease under study. 


 
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AMEND #2: 2016-APR-12 
8.3.2.2 Management of Diarrhea  
 
 
 
Diarrhea 
Loperamide: 4 mg 
initially then 2 mg every 
4 hours or after each 
unformed stool.  
Dietary management. 
CTC Grade 1 or 2 
uncomplicated diarrhea. 
Grade 1 or 2 complicated 
diarrhea* or Grade 3 or 4  
at any time. 
Consider hospitalization. 
Treat as per local practices (IV hydration, 
electrolytes, octreotide, iv antibiotics). 
Selumetinib dose interruption.** 
Diarrhea resolving or 
resolved after 12 hrs of 
loperamide treatment 
Continue loperamide for 
12 hours after diarrhea 
resolved. 
Adjust diet. 
Patient should: Contact the centre and increase to  
high dose loperamide (2 mg every 2 hours;  
possibly 4 mg every 4 hours at night). 
Additional treatment may be considered according to local practice. 
Diarrhea resolving or resolved 
after 24 hours of high dose 
loperamide treatment. 
Persistent diarrhea not resolved after  
12 hours of loperamide and remains 
uncomplicated CTC grade 1 or 2. 
Persistent diarrhea not 
resolved after 24 hours of 
high dose loperamide. 
Full examination 
Treat as per local practices 
(Rehydration, electrolytes, 
octreotide, antibiotics, 
hospitalization) 
Consider selumetinib dose 
interruption** 
Continue loperamide for 12 
hours after diarrhea resolved. 
Adjust diet. 
* 
Diarrhea becomes complicated by associated vomiting or inability to take oral fluids; marked abdominal distension or cramping; 
bloody stools, fever or symptoms of hypotension 
** Consider interruption or delay of pemetrexed/cisplatin (carboplatin). 


 
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ADMIN UPDATE #1: 2015-APR-29 
8.3.2.3 Management of LVEF Changes (if LVEF done at baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.3.2.4 Management of Visual Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
LVEF > 20 percentage points 
lower than baseline 
LVEF > 50%  
Continue selumetinib. 
Repeat LVEF in 3 
weeks. 
[If LVEF stable, 
consider 3-monthly 
LVEF] 
LVEF < 39% 
Discontinue 
selumetinib. 
Manage according to 
local policy. 
Refer to cardiology. 
Follow until recovery. 
LVEF 40-49% 
Hold selumetinib for up to 6 weeks 
Manage according to local policy 
If recovers to ≥ 50% and within 
10 percentage points of baseline may 
restart at 1 DL reduction AND follow 
LVEF q3w until stable for 
> 2 assessments. 
If no recovery, discontinue. 
LVEF: Left ventricular ejection fraction 
LVEF > 10 percentage points 
lower than baseline 
Visual Symptoms 
Ophthalmic assessment: include best corrected visual acuity, intraocular pressure, slit 
lamp fundoscopy (photograph if abnormal); consider optical coherence tomography 
No diagnosis of 
RPED / CSR or RVO 
Diagnosis of RPED / CSR 
Diagnosis of RVO 
Manage according to 
local practice 
Discontinue selumetinib 
Best corrected 
visual acuity 
20/40 or better 
Best corrected 
visual acuity 
worse than 20/40 
Continue selumetinib 
Selumetinib dose 
interruption 
Repeat ophthalmic assessments 
every 3 weeks until resolution 
On resolution to 20/40 or better 
selumetinib may be restarted 
 
Consider selumetinib 
dose reduction 
CSR:  Central serous retinopathy 
RVO:  Retinal vein occlusion 
RPED:  Retinal pigment epithelial detachment 
 


 
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8.3.2.5 Management of Rash 
 
Recommendations to start on day 1 of treatment with selumetinib  
and for the duration of treatment  
• 
Use skin moisturizer (thick, alcohol-free) at bedtime 
• 
Avoid excessive exposure to sunlight 
• 
Use sunglasses/sunscreen (PABA-free, SPF ≥15; UVA and UVB protection) as needed 
• 
Use of topical retinoids or benzoyl peroxide is not recommended 
 
Grade 1 rashes 
Mild or moderate strength topical steroid  
and/or topical antibiotic 
 
Grade 2 rashes 
Moderate strength topical steroid  
and oral antibiotic 
 
Grade ≥ 3 rashes or 
Grade 2 rashes considered by the patient to be intolerable 
• 
Moderate strength topical steroid and oral antibiotic 
• 
(consider broad spectrum/gram negative cover if infection suspected) 
• 
Consider referral to a dermatologist: manage rash per recommendation 
• 
Interrupt selumetinib until rash improves to grade 2 or less 
Selumetinib may be restarted at original dose or reduced at the discretion of the investigator 
 
8.3.2.6 Oral care guidelines 
• 
Patients should be encouraged to take responsibility for their own oral care whenever possible 
to help maintain a clean and pain-free mouth. 
• 
Oral health assessment prior to anti-cancer treatment may be beneficial for dentate patients 
with poor oral/ dental health. 
• 
Prevention, early diagnosis and management of stomatitis may help reduce the need for dose 
modification. 
− 
Smoking and high alcohol intake should be discouraged. 
− 
Avoidance of painful stimuli (such as spicy food, hot food and drink) may be beneficial. 


 
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AMEND #1: 2015-OCT-29; AMEND #2: 2016-APR-12 
Recommended Dental Care 
 
Management of Stomatitis 
• Brush teeth twice daily twice daily using a fluoride 
toothpaste and soft toothbrush 
• in the morning before breakfast 
• before bedtime, at least 30 minutes after evening meal 
• the tongue can be gently brushed, if not sore 
 
• Consider treatment at Grade 1 or as 
soon as the patient experiences sore 
mouth 
• Use dental floss once daily (caution in patients with 
coagulopathies) 
 
• Saline (0.9% sodium chloride) 
mouthwash recommended 
• Use at times other than after tooth 
brushing 
• Use non-alcoholic mouthwash (in patients with a healthy 
mouth) 
• Immediately after selumetinib intake 
• Several times daily according to the instructions 
 
• The following may be considered 
depending on the patient’s clinical 
condition and local medical practice 
• oral topical analgesic anaesthesia 
• topical steroids 
• antiviral and/or antifungal medication 
• Clean dentures thoroughly using a soft toothbrush and a 
mild denture-soaking solution 
• in the morning, after overnight soaking 
• after every meal 
• before soaking overnight 
• Dentures should be left out while resting 
 
8.3.2.7 Management of Other Toxicity 
 
Grade of 
Toxicity 
Action 
Dose Modification 
Grade 2 
Treat symptomatically. If persistent and 
symptomatic, consider short selumetinib 
dosing holiday of 2-4 days.  
None  
Grade 3 
Hold selumetinib.* 
When resolved to < grade 2, restart 
selumetinib at a one dose level reduction 
Grade 4** 
Discontinue selumetinib permanently. 
 
*  
Discontinue if not recovered within 21 days. 
** Discuss with CCTG if isolated hematologic toxicity  
 
8.4 
Duration of Protocol Treatment 
 
Treatment will continue until the criteria for removal from protocol treatment have been met (see 
Section 12). 
 
8.5 
Concomitant Therapy 
 
Permitted: 
 
Patients may receive ongoing supportive and palliative care (e.g. pain control - avoid NSAIDs 
while receiving pemetrexed) as clinically indicated throughout the study. All supportive 
medications must be recorded on the electronic case report form as appropriate. 


 
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ADMIN UPDATE #1: 2015-APR-29 
Not Permitted: 
• 
Other anti-cancer treatment. 
• 
Other investigational therapy. 
• 
Patients should avoid the ingestion of large amounts of grapefruit and Seville oranges (and 
other products containing these fruits (e.g. grapefruit juice or marmalade)). 
• 
Patients should not take vitamin E supplements. 
• 
Patients should avoid excessive sun exposure and use adequate sunscreen protection. 
• 
Potent inhibitors or inducers of CYP3A4/5, CYP2C19 and CYP1A2 are not permitted unless 
clinically indicated and no alternate therapies are available. Corticosteroids as part of anti-
emetic regimens are permitted. 
 


 
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9.0 
EVALUATION DURING AND AFTER PROTOCOL TREATMENT 
 
All patients entered on study must be evaluated according to the schedule outlined in Appendix I 
with documentation submitted according to the schedule in Appendix IV. 
 
9.1 
Evaluation During Protocol Treatment 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• 
history 
• 
weight 
• 
ECOG performance status 
• 
clinical tumour measurements 
• 
blood pressure 
• 
heart rate 
• 
tobacco use 
Day 1 Each Cycle. 
Blood pressure weekly cycle 1 and 
then day 1 each cycle and as clinically 
indicated. 
Hematology1 
• 
CBC, ANC, platelets 
Day 1, 8 and 15 for cycles 1 and 2; 
thereafter day 1 each cycle. 
Biochemistry1 
• 
serum creatinine 
• 
creatinine clearance 
• 
bilirubin 
• 
alkaline phosphatase 
• 
AST, ALT 
• 
LDH 
• 
total protein 
• 
calcium, phosphate 
• 
albumin 
• 
CPK 
Day 1, 8 and 15 for cycles 1 and 2; 
thereafter day 1 each cycle. 
Coagulation2 
• 
INR (if applicable) 
As clinically indicated. 
Other 
Investigations 
• 
LVEF 
Every 12 weeks if required at baseline. 
See section 8 for additional 
assessments. 
• 
EKG 
• 
Ophthalmology exam3 
If clinically indicated. 
Radiology4 
• 
Chest CT including upper abdomen 
(must include adrenals) 
• 
Other scans as necessary to follow 
known disease 
Every six weeks, regardless of any 
treatment delays. 
Adverse Events5 
Patients must be evaluated continuously for adverse events  
1 
Timing of Day 1 Assessments: Pre-treatment blood draws, physical exams, weight and performance status may be done one 
working day prior to treatment if necessary (e.g. Friday for treatment on Monday, or to accommodate holidays). NOTE: Labs 
do NOT need to be repeated on day 1 cycle 1. 
2 
Required only if taking oral anticoagulants (i.e. Coumadin). 
3 
If visual symptoms. 
4 
To ensure comparability, the baseline x-rays/scans and subsequent x-rays/scans to assess response must be performed using 
identical techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of 
contrast, the identical contrast agent, and preferably the same scanner). 
5 
Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(Appendix V). 


 
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AMEND #2: 2016-APR-12 
9.2 
Evaluation After Protocol Treatment 
 
All patients will be seen at the end of the last cycle and then 4 weeks after the end of the last 
cycle date. Thereafter, continued follow-up is not required for patients who go off protocol 
treatment with progressive disease, except to document ongoing toxicities (until resolved to 
< grade 2; repeat LVEF and/or ophthalmological assessments may be required) and late toxicities 
(including second malignancies) and death. For patients who go off protocol treatment with CR, 
PR, or SD ongoing, follow-up will be required every 3 months until progression (see Appendix I 
for investigations to be performed). A Death Report will be required for all patients and is due 
within 2 weeks of knowledge of death (see Appendix IV - Documentation for Study). 
 
Investigations 
Timing 
History and 
Physical Exam 
including: 
• 
ECOG performance status 
• 
clinical tumour measurements (if 
applicable) 
• 
blood pressure 
• 
heart rate 
Four weeks after completion of 
protocol treatment 
Hematology 
• 
CBC, differential, platelets 
Four weeks after completion of 
protocol treatment 
Thereafter repeat abnormal labs related 
to selumetinib until ≤ grade 2 or 
baseline 
Biochemistry 
• 
serum creatinine 
• 
creatinine clearance 
• 
bilirubin 
• 
alkaline phosphatase 
• 
AST, ALT 
• 
LDH 
• 
total protein 
• 
calcium, phosphate 
• 
albumin 
• 
CPK 
Coagulation1 
• 
INR (if applicable) 
As clinically indicated. 
Other 
Investigations 
• 
LVEF2 
Every three months until resolution of 
protocol related toxicity 
• 
EKG 
• 
ophthalmology exam3 
If clinically indicated. 
Radiology4 
• 
chest CT including upper abdomen 
(must include adrenals) 
• 
other scans as necessary to follow 
known disease 
Only for patients with CR, PR or SD 
ongoing: every 3 months until PD. 
Adverse Events5 
Four weeks after completion of protocol treatment. All protocol related adverse 
events must be followed (every 3 months) until resolution to ≤ grade 2 or baseline. 
Every 3 months thereafter only if ongoing protocol related toxicity until resolved 
≤ grade 2. 
1. Required only if taking oral anticoagulants (i.e. Coumadin). 
2. Only if done at baseline or if patient experienced cardiac toxicity. 
3. If visual symptoms. 
4. To ensure comparability, the baseline x-rays/scans and subsequent x-rays/scans to assess response must be performed using 
identical techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of 
contrast, the identical contrast agent, and preferably the same scanner). 
5. Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
(Appendix V). 


 
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10.0 
CRITERIA FOR MEASUREMENT OF STUDY ENDPOINTS 
 
10.1 
Definitions 
 
10.1.1 Evaluable for adverse events. All patients will be evaluable for adverse event evaluation from the 
time of their first treatment. 
 
10.1.2 Evaluable for response. All patients who have received at least one cycle of therapy and have 
their disease re-evaluated will be considered evaluable for response (exceptions will be those who 
exhibit objective disease progression prior to the end of cycle 1 who will also be considered 
evaluable). Patients on therapy for at least this period and who meet the other listed criteria will 
have their response classified according to the definitions set out below [Eisenhauer 2009]. 
 
10.2 
Response and Evaluation Endpoints 
 
Response and progression will be evaluated in this study using the revised international criteria 
(1.1) proposed by the RECIST (Response Evaluation Criteria in Solid Tumors) committee. 
 
10.2.1 Measurable Disease. Measurable tumour lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with chest x-ray 
and as ≥ 10 mm with CT scan or clinical examination. Bone lesions are considered measurable 
only if assessed by CT scan and have an identifiable soft tissue component that meets these 
requirements (soft tissue component ≥ 10 mm by CT scan). Malignant lymph nodes must be ≥ 
15mm in the short axis to be considered measurable; only the short axis will be measured and 
followed. All tumour measurements must be recorded in millimetres (or decimal fractions of 
centimetres). Previously irradiated lesions are not considered measurable unless progression has 
been documented in the lesion. 
 
10.2.2 Non-measurable Disease. All other lesions (or sites of disease), including small lesions are 
considered non-measurable disease. Bone lesions without a measurable soft tissue component, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, 
inflammatory breast disease, lymphangitic involvement of lung or skin and abdominal masses 
followed by clinical examination are all non-measurable. Lesions in previously irradiated areas 
are non-measurable, unless progression has been demonstrated. 
 
10.2.3 Target Lesions. When more than one measurable tumour lesion is present at baseline all lesions 
up to a maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be 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. Note that pathological nodes must meet the 
criterion of a short axis of ≥ 15 mm by CT scan and only the short axis of these nodes will 
contribute to the baseline sum. All other pathological nodes (those with short axis ≥ 10 mm but 
< 15 mm) should be considered non-target lesions. Nodes that have a short axis < 10 mm are 
considered non-pathological and should not be recorded or followed (see 10.2.4). At baseline, the 
sum of the target lesions (longest diameter of tumour lesions plus short axis of lymph nodes: 
overall maximum of 5) is to be recorded. 
 
After baseline, a value should be provided on the CRF for all identified target lesions for each 
assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are too 
small to measure and indeed are believed to be absent, a default value of 0 mm may be used. 


 
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10.2.4 Non-target Lesions. All non-measurable lesions (or sites of disease) plus any measurable lesions 
over and above those listed as target lesions are considered non-target lesions. Measurements are 
not required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”. 
 
10.2.5 Response. 
 
All patients will have their BEST RESPONSE from the start of study treatment until the end of 
treatment classified as outlined below: 
 
Complete Response (CR): disappearance of target and non-target lesions and normalization of 
tumour markers. Pathological lymph nodes must have short axis measures < 10mm (Note: 
continue to record the measurement even if < 10mm and considered CR). Residual lesions (other 
than nodes < 10mm) thought to be non-malignant should be further investigated (by cytology or 
imaging) before CR can be accepted. Confirmation of response is only required in non-
randomized studies.  
 
Partial Response (PR): at least a 30% decrease in the sum of measures (longest diameter for 
tumour lesions and short axis measure for nodes) of target lesions, taking as reference the 
baseline sum of diameters. Non target lesions must be non-PD. Confirmation of response is only 
required in non-randomized studies. 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study. Minimum duration of 
stable disease is 4 weeks. 
 
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured lesions 
taking as references the smallest sum of diameters recorded on study (including baseline) AND 
an absolute increase of ≥ 5mm. Appearance of new lesions will also constitute progressive 
disease (including lesions in previously unassessed areas). In exceptional circumstances, 
unequivocal progression of non-target disease may be accepted as evidence of disease 
progression, where the overall tumour burden has increased sufficiently to merit discontinuation 
of treatment or where the tumour burden appears to have increased by at least 73% in volume. 
Modest increases in the size of one or more non-target lesions are NOT considered unequivocal 
progression. If the evidence of PD is equivocal (target or non-target), treatment may continue 
until the next assessment, but if confirmed, the earlier date must be used. 
 


 
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Table:  
Integration of Target, non-Target and New Lesions into Response Assessment: 
Target Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this  
Category also Requires 
Target lesions ± non target lesions 
 
 
 
CR 
CR 
No 
CR 
tumour nodes <10mm 
CR 
Non-CR/Non-PD 
No 
PR 
 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least once > 4 wks. 
from baseline  
Not all evaluated 
Non-PD 
No 
NE 
 
PD 
Any 
Any 
PD 
 
Any 
PD 
Any 
PD 
 
Any 
Any 
Yes 
PD 
 
Non target lesions ONLY 
 
 
 
No Target 
CR 
No 
CR 
tumour nodes < 10mm 
No Target 
Non-CR/non-PD 
No 
Non-CR/ 
non-PD 
 
No Target 
Not all evaluated 
No 
NE 
 
No Target 
Unequivocal PD 
Any 
PD 
 
No Target 
Any 
Yes 
PD 
 
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”. This is a reason 
for stopping therapy, but is NOT objective PD. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
10.3 
Response Duration 
 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded on study (including 
baseline). 
 
10.4 
Stable Disease Duration 
 
Stable disease duration will be measured from the time of randomization until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
 


 
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10.5 
Methods of Measurement 
 
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. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy, which may be treatment 
arm dependent. While on study, all lesions recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. For lesions which fragment/split add 
together the longest diameters of the fragmented portions; for lesions which coalesce, measure the 
maximal longest diameter for the “merged lesion”. 
 
10.5.1 Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10mm 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. If feasible, imaging is preferred. 
 
10.5.2 Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. 
However, lesions > 20 mm on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
 
10.5.3 CT, MRI. CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on 
the assumption that CT slice thickness is 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). While PET scans are not 
considered adequate to measure lesions, PET-CT scans may be used providing that the measures 
are obtained from the CT scan and the CT scan is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast). 
 
10.5.4 Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
 
10.5.5 Endoscopy, Laparoscopy. The utilization of these techniques for objective tumour evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
10.5.6 Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumour types such as germ cell 
tumours, where known residual benign tumours can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumour has met criteria for response or stable 
disease is advised to differentiate between response or stable disease and progressive disease. 


 
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AMEND #2: 2016-APR-12 
11.0 
SERIOUS ADVERSE EVENT REPORTING 
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse 
Events (CTCAE) will be utilized for Adverse Event (AE) reporting (version can be found in 
Appendix V). All appropriate treatment areas should have access to a copy of the CTCAE. A 
copy of the CTCAE can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
All serious adverse events (SAE) defined as per ICH guidelines (see below) and other adverse 
events must be recorded on case report forms. In addition, all “reportable” serious adverse events 
are subject to expedited reporting using the CCTG SAE form. The term ‘reportable SAE’ is used 
in the definitions which follow to describe those SAEs which are subject to expedited reporting to 
CCTG.  
 
11.1 
Definition of a Reportable Serious Adverse Event 
 
• 
All serious adverse events, regardless of whether they are unexpected or related to protocol 
treatment, occurring during the treatment period and within 30 days after the last protocol 
treatment administration, must be reported in an expedited manner. Any late deaths related to 
protocol treatment or other serious adverse event occurring after this 30-day period which is 
unexpected and related to protocol treatment must also be reported in an expedited manner 
(see Section 11.2 for reporting instructions). 
• 
A serious adverse event (SAE) is any adverse event that at any dose: 
− 
results in death 
− 
is life-threatening 
− 
requires inpatient hospitalization or prolongation of existing hospitalization (excluding 
hospital admissions for study drug administration, transfusional support, scheduled 
elective surgery and admissions for palliative or terminal care) 
− 
results in persistent or significant disability or incapacity 
− 
is a congenital anomaly/birth defect 
 
Medical and scientific judgement should be exercised in deciding whether expedited reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
intervention to prevent one of the events listed above. 
 
11.2 
Serious Adverse Event Reporting Instructions 
 
All reportable serious adverse events must be reported using a web-based Electronic Data 
Capture (EDC) system being used for this trial. For details about accessing the EDC system and 
completing the on-line SAE report form, please refer to the CCTG Generic Data Management 
Guidebook for EDC Studies posted on the IND.219 section of the CCTG website 
(www.ctg.queensu.ca). 
 
Within 24 hours: 
Complete preliminary Serious Adverse Event Report and submit to 
CCTG via EDC system. 
 
Within 7 days: 
Update Serious Adverse Event Report as much as possible and submit 
report to CCTG via EDC system. 


 
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AMEND #2: 2016-APR-12 
EDC SAE web application interruption: 
In the rare event that internet connectivity to the EDC SAE system is disrupted, please print and 
complete a paper copy of the SAE Report, available from the trial specific website. 
 
FAX paper SAE Report to: 
 
IND.219 Study Coordinator 
Canadian Cancer Trials Group 
Fax No.: 613-533-2411 
 
Please use the same timelines for submission as for direct EDC reporting. 
 
Once internet connectivity is restored, the information that was FAXED to CCTG on the paper 
SAE Report must also be entered by the site into the EDC SAE web application.  
 
Local internet interruption: 
If you are unable to access the EDC SAE system, and cannot access a paper copy of the SAE 
Report from the trial website, please phone the IND.219 trial team (613-533-6430) to obtain a 
copy of the SAE Report by FAX. Once completed, the report must be FAXED back to CCTG as 
indicated above. Once internet connectivity is restored, the information that was FAXED to 
CCTG on the paper SAE Report must also be entered by the site into the EDC SAE web 
application.  
 
In cases of prolonged internet interruptions, please contact the CCTG Safety Desk for further 
instructions (613-533-6430).  
 
11.3 
Other Protocol Reportable Events – Pregnancy/Exposure Reporting 
 
11.3.1 Pregnancy Prevention 
 
Women of childbearing potential (WOCBP) and males who are enrolled in the trial must be 
informed of the requirement to use contraception as outlined in eligibility criterion 5.2.9. 
Investigators are advised to inform the female partners of male participants when appropriate and 
compliant with local policy.  
 
11.3.2 Pregnancy Reporting 
 
The investigator is required to report to the sponsor any pregnancy occurring in female 
participants and female partners of male participants. Pregnancies occurring up to 6 months after 
the completion of treatment with selumetinib and pemetrexed and cisplatin must also be reported. 
 
The investigator should report the pregnancy in a timely manner, within 24 hours of learning of 
the pregnancy, using the CCTG Pregnancy Reporting Form available from the trial webpage.  
 
Once informed consent has been obtained, the form should be updated to provide further 
pregnancy information and to reflect the outcome of the pregnancy. All follow-up reports must be 
submitted to CCTG in a timely manner. For pregnant partner of trial participant (and pregnant 
participants, if required by local policy), a copy of the signed signature page of the pregnancy 
follow-up consent must be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812 / safety-desk@ctg.queensu.ca). 


 
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If the pregnancy results in death, is life-threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or 
is a congenital anomaly/birth defect, then an SAE report must be additionally submitted as 
described above. Please note, hospitalization for labour/delivery alone does not constitute an 
‘inpatient hospitalization’ for the purposes of pregnancy reporting. 
 
11.3.3 Exposure Reporting (non-study participants) 
 
The investigator is required to report to CCTG any incidence of exposure to study agent(s). 
Exposure is defined as significant, direct, contact/inhalation/consumption of agent(s) by non- 
study participant (an individual who is not otherwise participating in this clinical trial). An 
example of an exposure includes a non-study participant swallowing study medication. The 
investigator is responsible for determining significance, based on the agent to which the 
individual is exposed. 
 
The investigator should report the exposure in a timely manner, within 24 hours of learning of the 
exposure, using the CCTG Exposure Reporting Form available from the trial webpage. 
 
Once informed consent has been obtained, the form should be updated to provide further 
exposure information and to reflect the outcome of the exposure as the information becomes 
available upon appropriate follow-up of the exposed individual. All follow-up reports must be 
submitted to CCTG in a timely manner. A copy of the signed exposure follow-up consent 
signature page must also be submitted to CCTG. 
 
Documents outlined above (including updates) must be sent to the CCTG safety desk (613-533-
2812 / safety-desk@ctg.queensu.ca). 
 
If the exposure results in death, is life-threatening, requires inpatient hospitalization or 
prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or 
is a congenital anomaly/birth defect, then an SAE report must be additionally submitted as 
described above. 
 
11.4 
CCTG Responsibility for Reporting Serious Adverse Events to Health Canada 
 
The CCTG will provide expedited reports of SAEs to Health Canada (Office of Clinical Trials) 
for those events which meet regulatory requirements for expedited reporting, i.e. events which are 
BOTH serious AND unexpected, AND which are thought to be related to protocol treatment (or 
for which a causal relationship with protocol treatment cannot be ruled out). 
 
11.5 
CCTG Reporting Responsibility to AstraZeneca and Lilly 
 
AstraZeneca and Lilly will be notified of all serious adverse events reported to Health Canada for 
selumetinib and pemetrexed respectively. CCTG as sponsor will determine regulatory 
reportability in Canada.  
 
11.6 
AstraZeneca Reporting Responsibilities 
 
AstraZeneca will report all selumetinib regulatory reportable serious adverse events from non-
CCTG trials (Safety Updates) to Health Canada and also provide to CCTG within the timelines 
outlined in the contract. CCTG will review these events to determine which meet the criteria 
(serious, unexpected, drug related) for IND.219 investigator distribution.  


 
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11.7 
Reporting Safety Reports to Investigators 
 
CCTG will notify Investigators of all Safety Reports (Serious Adverse Events (SAEs) from this 
trial and Safety Updates (SUs) from other clinical trials) that are reportable to regulatory 
authorities in Canada. This includes all serious events that are unexpected and related (i.e. 
possibly, probably, or definitely) to protocol treatment. The reports will be posted to the CCTG 
trial IND.219 web-based safety monitoring utility. 
 
Investigators must notify their Research Ethics Boards (REBs) of events which involve corrective 
action(s) to be taken as a result of the event(s) such as protocol and/or informed consent changes. 
The date of REB Submission for these SAEs and SUs will need to be entered into the CCTG trial 
IND.219 web based safety monitoring utility and documentation of REB submission must be 
retained in the study binder on site. The REB submission template provided by CCTG can be 
used to assist with tracking, submission, filing and monitoring. 
 
The submission of events to your ethics board should be done as soon as possible (we suggest 
within 30 days). REB submissions greater than 90 days from the date of notification will be 
regarded as delinquent and a major deficiency will be assigned. These safety reports are to be 
filed in the trial files on site. 


 
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12.0 
PROTOCOL TREATMENT DISCONTINUATION AND THERAPY AFTER STOPPING 
 
12.1 
Criteria for Discontinuing Protocol Treatment 
 
Patients may stop protocol treatment in the following instances: 
• 
Intercurrent illness which would, in the judgement of the investigator, affect assessments of 
clinical status to a significant degree, and require discontinuation of protocol therapy. 
• 
Unacceptable toxicity as defined in Section 8.0. 
• 
Tumour progression as defined in Section 10.0. 
• 
Request by the patient. 
 
Efforts should be made to maintain the investigations schedule and continue follow-up, even if 
patients discontinue protocol treatment prematurely and/or no longer attend the participating 
institution. 
 
12.2 
Duration of Protocol Treatment 
(see Section 10.0 for response definition) 
• 
Patients who progress (treatment failure) will go off all study agents at the time progression is 
documented clinically and/or radiographically. 
• 
All other patients should continue treatment with standard pemetrexed chemotherapy (with 
selumetinib for Arm A and B) in the absence of unacceptable toxicity.  
 
12.3 
Therapy After Protocol Treatment is Stopped 
 
At the discretion of the investigator. 
 
12.4 
Follow-up Off Protocol Treatment 
 
See Section 9.2. 


 
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13.0 
CENTRAL REVIEW PROCEDURES AND TISSUE COLLECTION 
 
13.1 
Central Radiology Review 
 
At the conclusion of the trial, a central review of x-rays and/or scans may be carried out if any 
responses have been claimed. For purposes of reporting, the results of both local and central 
radiology reviews will be included. 
 
13.2 
Central Pathology Review 
 
There will be no central pathology review for this study. 
 
13.3 
Correlative Studies 
 
Details of tissue collection for this study are found in Section 17. 


 
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14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Objectives and Design 
 
This is an open-label, randomized, phase II clinical study of selumetinib (intermittent or 
continuous) in patients with advanced or metastatic KRAS wildtype or unknown status, non-
squamous non-small cell lung cancer (NSCLC) who are receiving pemetrexed/cisplatin or 
pemetrexed/carboplatin as a first line palliative treatment. A minimization procedure will be used 
to allocate patients after stratification by KRAS status (wildtype versus unknown) and planned 
platinum treatment (cisplatin versus carboplatin). Before the interim analysis, patients will be 
allocated with equal probability to one of three treatment arms: pemetrexed/cisplatin (or 
carboplatin) and intermittent selumetinib (Arm A), pemetrexed/cisplatin (or carboplatin) and 
continuous selumetinib (Arm B) or pemetrexed/cisplatin (or carboplatin) alone (Arm C). The trial 
may be stopped after interim analysis (see Section 14.4). If the trial is not stopped, subsequent 
patients will be randomized to the selected selumetinib arm and Arm C in a 3:1 ratio to ensure 
that the final analysis includes Arm A (or B) and Arm C in a 2:1 ratio. 
 
14.2 
Primary Endpoints and Analysis 
 
The primary endpoint is response rate, defined as proportion of patients with CR or PR among all 
patients evaluable for response (definition in 10.1.2). Sensitivity analysis will also be performed 
with response rate defined as proportion of patients with CR or PR among all patients 
randomized. A stratified Cochran–Mantel–Haenszel (CMH) test will be the primary method to 
compare the response rates between Arm B (or A) and Arm C in the final analysis. The lower 
80% asymptotic confidence limit (one-sided) for the difference of response rate between 
continuing selumetinib arm and Arm C will also be calculated based on asymptotic method. 
 
Secondary endpoints include toxicity, progression free survival and overall survival, gene 
expression signatures/profiles and/or KRAS codon subtypes in tumour that may influence 
response. Because of the small sample size, analyses for most of these secondary endpoints will 
be descriptive. Dose intensity and dose modifications will be calculated for each drug, and 
progression free survival and overall survival will be summarized by the median and associated 
confidence intervals and described by Kaplan-Meier curves. 
 
14.3 
Sample Size and Duration of Study 
 
The response rate of patients on the chemotherapy alone arm (Arm C) is expected to be 30%. 
Assuming that Arm B is chosen at the interim analysis, with 120 patients randomized overall, 
with 80 patients on Arm B and 40 on Arm C, we would be able to detect an 18% difference in 
response rate between two arms (from 30% to 48%) with a one-sided alpha = 0.2 and beta = 0.2.  
 
The 20 patients who are randomized to the Arm A (or B) discontinued at the interim analysis will 
not be included in the final analysis but will be summarized separately. Assuming the trial goes to 
full accrual, it is anticipated that 140 patients will be enrolled in approximately 12 months with 6 
months follow up time after the end of accrual before and after the interim analysis, it will take 24 
months to complete the trial.  


 
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14.4 
Interim Analysis 
 
An interim analysis will be performed at a total accrual of 60 patients (20 per arm). If both Arm A 
and Arm B have 4 or more responses (PR+CR), one arm will be chosen for further study based on 
response efficacy and toxicity data.  
 
If only one of Arm A or B have 4 or more responses, that arm with less than 4 responses will be 
discontinued. The remaining Arm will progress to full accrual. The data from the discontinued 
Arm will not be included in the final analysis.  
 
If both Arm A and Arm B have less than 4 patients with response, the trial shall stop because the 
chance to have a positive trial is low. 
 
The above decision rule was derived by testing the null hypothesis that the true response rate of a 
selumetinib arm is 10% or less versus the alternative hypothesis that the true response rate of a 
selumetinib arm is 30% or higher. Therefore, a selumetinib arm would be discontinued at interim 
analysis if its true response rate is much worse than expected. With 20 patients included in the 
analysis, the exact alpha and beta levels of the above stopping rule are 0.13 and 0.11, 
respectively. 
 
14.5 
Safety Monitoring 
 
Adverse events will be monitored on an ongoing basis by the central office and their frequencies 
reported annually at investigator meetings. Toxic effects will be categorized using the CTCAE. 
The worst event for each patient in each category or subcategory will be described. Both events 
related and unrelated to treatment will be captured. 


 
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15.0 
PUBLICATION POLICY 
 
15.1 
Authorship of Papers, Meeting Abstracts, Etc. 
 
15.1.1 The results of this study will be published. Prior to trial activation, the chair will decide whether 
to publish the trial under a group title, or with naming of individual authors. If the latter approach 
is taken, the following rules will apply: 
• 
The first author will generally be the chair of the study. 
• 
A limited number of the members of the Canadian Cancer Trials Group and may be credited 
as authors depending upon their level of involvement in the study. 
• 
Additional authors, up to a maximum of 15, will be those who have made the most significant 
contribution to the overall success of the study. This contribution will be assessed, in part but 
not entirely, in terms of patients enrolled and will be reviewed at the end of the trial by the 
study chair. 
 
15.1.2 In an appropriate footnote, or at the end of the article, the following statement will be made: 
 
"A study coordinated by the Canadian Cancer Trials Group. Participating 
investigators included: (a list of the individuals who have contributed 
patients and their institutions)." 
 
15.2 
Responsibility for Publication 
 
It will be the responsibility of the Study Chair to write up the results of the study within a 
reasonable time of its completion. If after a period of six months following study closure the 
manuscript has not been submitted, the central office reserves the right to make other 
arrangements to ensure timely publication. 
 
Dissemination of Trial Results 
CCTG will inform participating investigators of the primary publication of this trial. The 
complete journal reference and, if where publicly available, the direct link to the article will be 
posted 
on 
the 
Clinical 
Trial 
Results 
public 
site 
of 
the 
CCTG 
web 
site 
(http://www.ctg.queensu.ca). 


 
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16.0 
ETHICAL, REGULATORY AND ADMINISTRATIVE ISSUES 
 
16.1 
Regulatory Considerations 
 
All institutions in Canada must conduct this trial in accordance with International Conference on 
Harmonization-Good Clinical Practice (ICH-GCP) Guidelines. 
 
This trial is being conducted under a Clinical Trial Application (CTA) with Health Canada. As a 
result, the conduct of this trial must comply with Division 5 of the Canadian Regulations 
Respecting Food and Drugs (Food and Drugs Act). 
 
16.2 
Inclusivity in Research 
 
CCTG does not exclude individuals from participation in clinical trials on the basis of attributes 
such as culture, religion, race, national or ethnic origin, colour, mental or physical disability 
(except incapacity), sexual orientation, sex/gender, occupation, ethnicity, income, or criminal 
record, unless there is a valid reason (i.e. safety) for the exclusion.  
 
In accordance with the Declaration of Helsinki and the Tri-Council Policy Statement (TCPS), it is 
the policy of CCTG that vulnerable persons or groups will not be automatically excluded from a 
clinical trial (except for incompetent persons) if participation in the trial may benefit the patient 
or a group to which the person belongs.  
 
However, extra protections may be necessary for vulnerable persons or groups. It is the 
responsibility of the local investigator and research ethics board (REB) to ensure that appropriate 
mechanisms are in place to protect vulnerable persons/groups. In accordance with TCPS, 
researchers and REBs should provide special protections for those who are vulnerable to abuse, 
exploitation or discrimination. As vulnerable populations may be susceptible to coercion or undue 
influence, it is especially important that informed consent be obtained appropriately.  
 
Centres are expected to ensure compliance with local REB or institutional policy regarding 
participation of vulnerable persons/groups. For example, if a vulnerable person/group would be 
eligible for participation in a CCTG clinical trial under this policy but excluded by local policy, it 
is expected that they would not be enrolled in the trial. It is the centre’s responsibility to ensure 
compliance with all local SOPs.  
 
It is CCTG’s policy that persons who cannot give informed consent (i.e. mentally incompetent 
persons, or those physically incapacitated such as comatose persons) are not to be recruited into 
CCTG studies. It is the responsibility of the local investigator to determine the subject’s 
competency, in accordance with applicable local policies and in conjunction with the local REB 
(if applicable).  
 
Subjects who were competent at the time of enrolment in the clinical trial but become 
incompetent during their participation do not automatically have to be removed from the study. 
When re-consent of the patient is required, investigators must follow applicable local policies 
when determining if it is acceptable for a substitute decision maker to be used. CCTG will accept 
re-consent from a substitute decision maker. If this patient subsequently regains capacity, the 
patient should be re-consented as a condition of continuing participation.  


 
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16.3 
Obtaining Informed Consent 
 
It is expected that consent will be appropriately obtained for each participant/potential participant 
in a CCTG trial, in accordance with ICH-GCP section 4.8. The centre is responsible for ensuring 
that all local policies are followed. 
 
Additionally, in accordance with GCP 4.8.2, CCTG may require that participants/potential 
participants be informed of any new information may impact a participant’s/potential 
participant’s willingness to participate in the study.  
 
Based upon applicable guidelines and regulations (Declaration of Helsinki, ICH-GCP), a 
participating investigator (as defined on the participants list) is ultimately responsible, in terms of 
liability and compliance, for ensuring informed consent has been appropriately obtained. CCTG 
recognizes that in many centres other personnel (as designated on the participants list) also play 
an important role in this process. In accordance with GCP 4.8.5, it is acceptable for the Qualified 
Investigator to delegate the responsibility for conducting the consent discussion. 
 
CCTG requires that each participant sign a consent form prior to their enrollment in the study to 
document his/her willingness to take part. CCTG may also require, as indicated above, that 
participants/potential participants be informed of new information if it becomes available during 
the course of the study. In conjunction with GCP 4.8.2, the communication of this information 
should be documented. 
 
CCTG allows the use of translators in obtaining informed consent. Provision of translators is the 
responsibility of the local centre. Centres should follow applicable local policies when procuring 
or using a translator for the purpose of obtaining informed consent to participate in a clinical trial.  
 
In accordance with ICH-GCP 4.8.9, if a subject is unable to read then informed consent may be 
obtained by having the consent form read and explained to the subject. 
 
16.3.1 Obtaining Consent for Pregnancy/Exposure Reporting 
 
Information from and/or about the subject (i.e. the pregnant female, the newborn infant, male 
partner) should not be collected about or from them unless or until they are a willing participant 
in the research. The rights and protections offered to participants in research apply and consent 
must be obtained prior to collecting any information about or from them.  
 
Trial-specific consent forms for “Pregnancy Follow-up” and “Exposure Follow-up” can be found 
on the trial webpage. The appropriate consent form must be used to obtain consent from any non-
trial participant (such as the pregnant partner or exposed individual). 
 
Participants will not be withdrawn from the main trial as a result of refusing or withdrawing 
permission to provide information related to the pregnancy/exposure. Similarly, male participants 
will not be withdrawn from the main study should their partner refuse/withdraw permission. 
 
Obtaining Consent for Research on Children 
In the case of collecting information about a child (i.e. the child resulting from a pregnant 
participant/partner or an exposed child), consent must be obtained from the parent/legal guardian. 


 
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For reporting an exposure, the parent/guardian is required to sign an “exposure follow-up” 
consent form (even if they are a participant in the main study) prior to collecting information about 
the child. 
 
16.4 
Discontinuation of the Trial 
 
If this trial is discontinued for any reason by the CCTG all centres will be notified in writing of 
the discontinuance and the reason(s) why. If the reason(s) for discontinuance involve any 
potential risks to the health of patients participating on the trial or other persons, the CCTG will 
provide this information to centres as well. 
 
If this trial is discontinued at any time by the centre (prior to closure of the trial by the CCTG), it 
is the responsibility of the qualified investigator to notify the CCTG of the discontinuation and 
the reason(s) why.  
 
Whether the trial is discontinued by the CCTG or locally by the centre, it is the responsibility of 
the qualified investigator to notify the local Research Ethics Board and all clinical trials subjects 
of the discontinuance and any potential risks to the subjects or other persons. 
 
16.5 
Retention of Patient Records and Study Files 
 
All essential documents must be maintained as per C.05.012 and in accordance with ICH-GCP.  
 
The Qualified Investigator must ensure compliance with the Regulations and the GCP Guideline 
from every person involved in the conduct of the clinical trial at the site.  
 
Essential documents must be retained for 25 years following the completion of the trial at the 
centre (25 years post final analysis, last data collected, or closure notification to REB, whichever 
is later), or until notified by CCTG that documents no longer need to be retained.  
 
In accordance with GCP 4.9.7, upon request by the monitor, auditor, REB or regulatory authority, 
the investigator/institution must make all required trial-related records available for direct access.  
 
CCTG will inform the investigator/institution as to when the essential documents no longer need 
to be retained.  
 
16.6 
Centre Performance Monitoring 
 
This study is eligible for inclusion in the Centre Performance Index (CPI).  
 
Forms are to be submitted according to the schedule in the protocol. There are minimum 
standards for performance. 
 
16.7 
On-Site Monitoring/Auditing 
 
CCTG site monitoring/auditing will be conducted at participating centres in the course of the 
study as part of the overall quality assurance program. The monitors/auditors will require access 
to patient medical records to verify the data, as well as essential documents, standard operating 
procedures (including electronic information), ethics and pharmacy documentation (if 
applicable). 


 
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As this trial is conducted under a CTA with Health Canada, your site may be subject to an 
inspection by the Health Canada Inspectorate. 
 
AstraZeneca has reserved the right to audit participating centres. Audits may only be conducted 
after consultation with CCTG. 
 
16.8 
Case Report Forms 
 
A list of forms to be submitted, as well as expectation dates, are to be found in Appendix IV. 
 
This trial will use a web-based Electronic Data Capture (EDC) system for all data collection. For 
details of accessing the EDC system and completing the on-line Case Report Forms please refer 
to the “EDC Generic Data Management Guidebook” posted on the IND.219 area of the CCTG 
web-site (www.ctg.queensu.ca). 


 
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17.0 
CORRELATIVE STUDIES 
 
17.1  
Laboratory Correlative Studies 
 
17.1.1 Tumour Tissue (Mandatory) 
 
The collection of representative tumour tissue is an important part of this trial and is mandatory 
for participation in the study for the evaluation of KRAS and other common mutations, as well as 
gene expression signatures/profiles and/or KRAS codon subtypes. Samples may be tested for 
gene fusions involving the ALK, ROS and RET genes. As the clinical relevance of these tests has 
not yet been determined and standard mutation assessment (e.g. EGFR mutations) is done as part 
of usual care, there are no plans to inform centres or patients of the results.  
 
Patients will not be identified by name. The only identification of tissue will be by a patient study 
number assigned at the time of randomization to the trial, and may also include patient initials or 
unique identifiers and the pathology identification number. 
 
Testing specifically for hereditary genetic defects predisposing to malignant disease will not be 
carried out without the expressed consent of the patient.  
 
All patients on whom tumour samples are collected will be aware of this retrieval and will have 
given their consent. 
 
17.1.2 Blood Samples (Mandatory) 
 
Whole blood and plasma for KRAS mutations analysis in ctDNA will be collected from all 
patients at baseline. Other mutations may also be evaluated. 
 
PLEASE REFER TO THE LABORATORY MANUAL FOR COMPLETE INSTRUCTIONS. 


 
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18.0 
REFERENCES 
Bezjak A, Tu D, Seymour L. Symptom improvement in lung cancer patients treated with erlotinib: quality of 
life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21 J Clin Oncol 24: 
3831-3837, 2006. 
Brant R, Liptrot T, Rooney C et al. Progress with candidate predictive gene expression signatures for MEK 
inhibitors in non-small cell lung cancer (NSCLC). J Thorac Oncol 2013; 8:2S (suppl; abstr P3.06-048).  
Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, Wu YL, Bover I, Begbie S, Tzekova 
V, Cucevic B, Pereira JR, Yang SH, Madhavan J, Sugarman KP, Peterson P, John WJ, Krejcy K, Belani CP. 
Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell 
lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374(9699):1432. 
Davies B, Logie A, McKay J, Martin P, Steele S, Jenkins R et al. AZD6244 (ARRY-142886), a potent 
inhibitor of mitogen-activated protein kinase/extracellular signal-related kinase kinase 1/2 kinases: mechanism 
of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical 
models. Mol Cancer Ther 2007;6:2209-19. 
Diaz LA Jr, Bardelli A. Liquid biopsies: genotyping circulating tumour DNA. J Clin Oncol 2014; 32:579-586. 
Dry JR, Pavey S, Pratilas CA, Harbron C, Runswick S, Hodgson D, et al. Transcriptional pathway signatures 
predict MEK addiction and response to selumetinib (AZD6244). Cancer Res. 2010 Mar 15;70(6):2264-73. 
Eisenhauer E, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation 
criteria in solid tumors: Revised RECIST guideline version 1.1. Eur J Can 45: 228-47, 2009. 
Francis G, Stein S. Circulating cell-free tumour DNA in the management of cancer. Int J Mol Sci. 
2015;16:14122-14142. 
Freidin MB, Freydina DV, Leung M e tal. Circulating tumour DNA outperforms circulating tumour cells for 
KRAS mutation detection in thoracic malignancies. Clin Chem. 2015;61:1299-1304. 
Fukuoka M, Wu YL, Thongprasert S, Sunpaweravong P, Leong SS, Sriuranpong V, Chao TY, Nakagawa K, 
Chu DT, Saijo N, Duffield EL, Rukazenkov Y, Speake G, Jiang H, Armour AA, To KF, Yang JC, Mok TS. 
Biomarker analyses and final overall survival results from a phase III, randomized, open-label, first-line study 
of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung 
cancer in Asia (IPASS). J Clin Oncol. 2011;29(21):2866 
Hanna N, Shepherd FA, Fosella FV et al. Randomized phase III trial of pemetrexed versus docetaxel in 
patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22: 1589-1597, 
2004. 
Jänne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, Franke FA, Grinsted L, Zazulina V, 
Smith P, Smith I, Crinò L. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: 
a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol. 2012 Nov 27. 
Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, Thun MJ. CA Cancer statistics, 2008. Cancer J Clin. 2008 
Mar-Apr;58(2):71-96. Epub 2008 Feb 20. 
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins CL, Sellers MV, Lowe ES, Sun 
Y, Liao ML, Osterlind K, Reck M, Armour AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus 
docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 
2008;372(9652):1809. 
Loboda A, Nebozhyn M, Klinghoffer R et al. A gene expression signature of RAS pathway dependence 
predicts response to PI3K and RAS pathway inhibitors and expands the population of RAS pathway activated 
tumors. BMC Med Genomics 2010; 3: 26. 
Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in NSCLC: a meta-analysis using updated 
data on individual patients from 52 randomised clinical trials. BMJ 311(7010): 899–909, 1995. 


 
PROTOCOL DATE: 2014-DEC-03 
 
CCTG TRIAL: IND.219 
 
 
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49 
CONFIDENTIAL 
 
AMEND #2: 2016-APR-12 
Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, 
Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance 
therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction 
therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer 
(PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 13: 247-55, 2012. 
Pirker R, Szczesna A, von Pawel J, et al. FLEX: A randomized, multicenter, phase III study of cetuximab in 
combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with 
advanced non-small cell lung cancer (NSCLC). J Clin Oncol 26: (Suppl Abstr 3), 2008. 
Ramalingham S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances 
and future directions. Oncologist 13 (Suppl 1):5-13, 2008. 
Rankin EM. Non-small cell lung cancer. In: Slevin ML and Staquet MJ, eds. Randomised trials in cancer: a 
critical review. New York: Raven Press: 447-92, 1986. 
Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, Palmero R, Garcia-Gomez R, Pallares 
C, Sanchez JM, Porta R, Cobo M, Garrido P, Longo F, Moran T, Insa A, De Marinis F, Corre R, Bover I, 
Illiano A, Dansin E, de Castro J, Milella M, Reguart N, Altavilla G, Jimenez U, Provencio M, Moreno MA, 
Terrasa J, Muñoz-Langa J, Valdivia J, Isla D, Domine M, Molinier O, Mazieres J, Baize N, Garcia-Campelo 
R, Robinet G, Rodriguez-Abreu D, Lopez-Vivanco G, Gebbia V, Ferrera-Delgado L, Bombaron P, Bernabe R, 
Bearz A, Artal A, Cortesi E, Rolfo C, Sanchez-Ronco M, Drozdowskyj A, Queralt C, de Aguirre I, Ramirez 
JL, Sanchez JJ, Molina MA, Taron M, Paz-Ares L, Spanish Lung Cancer Group in collaboration with Groupe 
Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica Erlotinib versus standard 
chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-
cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 
2012;13(3):239. 
Saik EK, Freidin MB, Freydina DV et al. A comparative study of blood-based KRAS mutation analysis in circulating 
tumor cells versus circulating plasma DNA to predict primary tumor mutations in lung cancer. J Clin Oncol 32:5s, 2014 
(suppl; abstr 7563) 
Sandler A, Gray R, Parry MC. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung 
cancer. N Engl J Med 355 (24): 2542-2550, 2006. 
Scagliotti GV, Gridelli C, de Marinis F, Thomas M, Dediu M, Pujol JL, Manegold C, San Antonio B, Peterson 
PM, John W, Chouaki N, Visseren-Grul C, Paz-Ares LG. Efficacy and safety of maintenance pemetrexed in 
patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction 
treatment: A cross-trial comparison of two phase III trials. Lung Cancer 85: 408-14, 2014. 
Schiller JH, Harrington D, Belani CP et al. Comparison of four chemotherapy regimens for advanced non-
small-cell lung cancer. N Engl J Med 346:92–98, 2002. 
Shepherd FA, Dancey J, Ramlau R et al. Prospective randomized trial of docetaxel versus best supportive care 
in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy, J Clin Oncol 
18: 2095–2103, 2002. 
Shepherd FA, Rodrigues PJ, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N 
Engl J Med 353: 123-132, 2005. 
Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev 
Cancer. 2011;11:426-37 
Winton T, Livingston R, Johnson D, Rigas J, Johnston M, Butts C, Cormier Y, Goss G, Inculet R, Vallieres E, 
Fry W, Bethune D, Ayoub J, Ding K, Seymour L, Graham B, Tsao MS, Gandara D, Kesler K, Demmy T, 
Shepherd F; National Cancer Institute of Canada Clinical Trials Group; National Cancer Institute of the United 
States Intergroup JBR.10 Trial Investigators. Vinorelbine plus cisplatin vs. observation in resected non-small-
cell lung cancer. N Engl J Med. 352(25):2589-97, 2005. 


 
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ADMIN UPDATE #1: 2015-APR-29; AMEND #2: 2016-APR-12 
APPENDIX I - PATIENT EVALUATION FLOW SHEET 
 
Required Investigations 
Pre-study 
(within 7 days prior to 
randomization,  
or as noted) 
Day 1 
each 
cycle 
Weekly 
cycles 1 and 
2 then Day 1 
each cycle 
Every 6 weeks  
4 weeks after end of last 
treatment cycle, then 
every 3 months until PD / 
death 
History and Physical Exam1 
 
 
 
 
 
Weight 
X 
X 
 
 
 
Performance status 
X 
X 
 
 
4 weeks only 
Tobacco use 
X 
X 
 
 
 
Blood pressure 
X 
X 
X2 
 
4 weeks only 
Heart rate 
X 
X 
 
 
4 weeks only 
Clinical tumour measurements 
X 
 
 
X 
X 
(if applicable) 
Hematology and Biochemistry1 
 
 
 
 
 
CBC, ANC, platelets 
X 
X 
X 
 
X5 
Creatinine, creatinine clearance,  
bilirubin, ALP, AST, ALT, LDH, total 
protein, calcium, phosphate, albumin, CPK 
X 
X 
X 
 
X5 
Coagulation 
 
 
 
 
 
INR3 
X 
As clinically indicated 
Radiology4 
 
 
 
 
 
Chest CT including upper abdomen (must 
include adrenals) 
Other scans / x-rays as necessary to 
document disease 
X 
(within 28 days prior 
to randomization or 35 
if negative) 
 
 
X6 
Every 3 months if 
patient is off treatment 
with CR, PR or SD 
Other Investigations 
 
 
 
 
 
Pregnancy test7 
X 
 
 
 
 
EKG 
X 
As clinically indicated 
LVEF 
X8 
 
X9 
X10 
Ophthalmology exam (if clinically indicated) 
X 
As clinically indicated 
Correlative Studies 
 
 
 
 
 
Archival tissue (all pts) 
X 
 
 
 
 
Whole blood and plasma for ctDNA 
X 
 
 
 
 
Adverse Events 
 
 
 
 
 
Baseline symptoms/ adverse events11 
X 
Continuously 
X5 
1 Timing of Day 1 Assessments: Pre-treatment blood draws, physical exams, weight and performance status may be done one working day prior 
to treatment if necessary (e.g. Friday for treatment on Monday, or to accommodate holidays). NOTE: Labs do NOT need to be repeated on day 
1 cycle 1. 
2 Blood pressure weekly in Cycle 1, then Day 1 each cycle and as clinically indicated. 
3 Required only if taking oral anticoagulants (i.e. Coumadin). 
4 To ensure comparability, the baseline x-rays/scans and subsequent x-rays/scans to assess response must be performed using identical 
techniques (i.e. scans performed immediately following bolus contrast administration using a standard volume of contrast, the identical contrast 
agent, and preferably the same scanner). 
5 Required at 4 weeks. To be done additionally every three months thereafter (Follow-up Report)  if ongoing related grade > 2 adverse events 
even if patient came off treatment with progressive disease.  
6 Maintain schedule even if cycles are delayed. 
7 Women of childbearing potential only. 
8 Required for patients with cardiac disease. 
9 Required every 12 weeks if performed at baseline. See section 8 for additional assessments. 
10 Repeat every 3 months to follow toxicities even if patient came off treatment with progressive disease. 
11 Adverse events will be recorded and graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) (Appendix V). 


 
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APPENDIX II - PERFORMANCE STATUS SCALES/SCORES 
 
PERFORMANCE STATUS CRITERIA 
Karnofsky and Lansky performance scores are intended to be multiples of 10. 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
100 
Fully active, normal. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
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. 
80 
Active, but tires more quickly. 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
selfcare 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. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play; 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited 
selfcare; confined to bed or 
chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
4 
Completely disabled. Cannot 
carry on any selfcare. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
* The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 


 
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AMEND #1: 2015-OCT-29; AMEND #2: 2016-APR-12 
APPENDIX III - DRUG DISTRIBUTION, SUPPLY AND CONTROL 
 
Drug Distribution 
 
Selumetinib will be supplied by AstraZeneca and distributed by Bay Area Research Laboratory. 
 
All other agents are commercially available and should be dispensed from the centre’s pharmacy. (Note: 
Lilly Canada may provide assistance with pemetrexed if needed. Contact CCTG.) 
 
 
Drug Labelling 
 
Drug supplies for this study will be labelled in accordance with Health Canada regulations. 
 
 
Initial Drug Supply 
 
Once a centre is locally activated (following receipt and review of all required documentation), the CCTG 
will authorize start-up supplies of selumetinib to be shipped directly to the centre. Drug will be shipped to 
the centre within 3 working days of local activation. Drug accountability and drug re-order forms for each 
agent will be included with drug shipments and are also available on the trial website. 
 
 
Drug Ordering (Re-Supply) 
 
Fax a copy of the re-order form to the distributor. Please allow sufficient time for shipment of drug. 
 
 
Drug Accountability 
 
The investigational products are to be prescribed only by the investigator and co-investigators on the 
participants list. Under no circumstances will the investigator allow the drug to be used other than as 
directed by the protocol. Accurate records must be maintained accounting for the receipt of the 
investigational product and for the disposition of the product (Drug Accountability Log). 
 
 
Drug Destruction 
 
Expired/used study drug may be destroyed as per local standard operating procedures. Destruction of 
expired/used drug must be documented on the Drug Accountability Log and a copy of the destruction 
certificate kept on file in the pharmacy. Instructions for return or destruction of unused drug will be 
supplied at the time of expiry and at trial closure. 
 
** PLEASE NOTE** 
DRUG FROM THIS SUPPLY IS TO BE USED ONLY 
FOR PATIENTS RANDOMIZED ON THIS STUDY 
 
Study drug shipped to participating centres may be transferred from the main hospital pharmacy to a 
satellite pharmacy, provided separate drug accountability records are maintained in each pharmacy. 
Investigational agent may NOT however, be transferred to pharmacies or physicians outside the 
participating centre. 


 
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ADMIN UPDATE #1: 2015-APR-29; AMEND #2: 2016-APR-12 
APPENDIX IV - DOCUMENTATION FOR STUDY 
 
Follow-up is required for patients from the time of randomization and will apply to all eligible and 
ineligible patients. This trial will use a web-based Electronic Data Capture (EDC) system for all data 
collection including SAE reporting (see Section 11.0 for details regarding SAE reporting). For details 
about accessing the EDC system and completing the on-line Case Report Forms, please refer to the Data 
Management Guidebook posted on the IND.219 are of the CCTG web-site (www.ctg.queensu.ca). 
 
Electronic Case 
Report Form 
To be Completed/Submitted Electronically: 
Supporting Documentation to be 
submitted using Supporting Document 
Upload Tool2 
BASELINE 
REPORT 
Due within 2 weeks of patient randomization. 
 
Note: Eligibility Checklist must be completed at time of 
randomization to confirm eligibility.  
Copy of main consent signature page(s); 
relevant pathology and radiology reports. 
Documentation of KRAS status (if 
applicable). 
TREATMENT 
REPORT 
To be completed every 3 weeks (i.e. after each cycle). Due 
within 2 weeks of end of cycle. This form documents 
treatment, adverse events, investigations and response 
assessment for each cycle. 
Relevant radiology reports. 
Patient Diary. 
LVEF, EKG reports (if applicable). 
CORRELATIVE 
STUDIES 
See Section 17. To be completed and submitted with the 
tumour tissue at time of Baseline Folder completion.  
Archival Tissue Submission Forms and 
Request for Payment Form. 
END OF 
TREATMENT  
REPORT 
To be completed when patient permanently discontinues 
treatment. Due within 2 weeks of end of protocol treatment. 
 
4 WEEK POST 
TREATMENT 
REPORT 
To be completed once on all patients, 4 weeks after going 
off protocol treatment. Due within 2 weeks after contact 
with patient. 
Relevant radiology reports. 
FOLLOW-UP 
REPORT 
Continued follow-up is not required for patients who go off 
protocol treatment with progressive disease, except to 
document ongoing treatment related toxicities (until 
resolved to < grade 2; repeat LVEF and/or ophthalmological 
assessments may be required) and late toxicities (including 
second malignancies). For patients who go off protocol 
treatment with response or stable disease ongoing, Follow-
up Report to be completed every 3 months until 
relapse/progression. Due within 2 weeks after contact with 
patient. An additional follow-up report may be required at 
the time of final analysis to capture survival and therapy 
information since last report. Due within 2 weeks after 
contact with patient 
Relevant radiology reports. 
RELAPSE/ 
PROGRESSION 
REPORT 
To be completed at the time of disease relapse or 
progression. Due within 2 weeks after contact with patient. 
Relevant radiology reports. 
DEATH REPORT 
Required for all patients1. Due within 2 weeks of knowledge 
of death. 
Autopsy report, if done. 
SERIOUS 
ADVERSE EVENT 
(SAE) REPORT 
All reportable serious adverse events must be reported as 
described in Section 11.0. Preliminary CCTG Serious 
Adverse Event Report due within 24 hours. Updated CCTG 
Serious Adverse Event Report due within 7 days. 
All relevant test reports; admission, 
discharge summaries/notes. 
1 It is the investigator's responsibility to investigate and report the date/cause of death of any patient. Any death that is thought to be 
treatment related must also be reported as a Serious Adverse Event as described in Section 11. 
2 Supporting documents should be submitted using the Supporting Document Upload Tool. For instructions on this tool, see Power Point 
Presentation available on the IND.219 webpage. 


 
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APPENDIX V - NCI COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS  
 
The descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for Adverse Event (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. 
 
 


 
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CONFIDENTIAL 
Final Page 
CONFIDENTIAL 
 
AMEND #1: 2015-OCT-29 
LIST OF CONTACTS 
 
PATIENT RANDOMIZATION 
All patients must be randomized via the web-based, password-operated electronic data system at the CCTG web page 
before any treatment is given. 
 
 
Contact 
Tel. # 
Fax # 
STUDY SUPPLIES 
Data Management Guidebook, 
Protocol, Safety Information 
Electronic Case Report Forms. 
Available on CCTG Website: 
http://www.ctg.queensu.ca  
under: Clinical Trials 
613-533-6430 
613-533-2411 
PRIMARY CONTACTS FOR 
GENERAL PROTOCOL-
RELATED QUERIES 
(including eligibility questions 
and protocol management) 
Pamela Brown-Walker 
Study Coordinator 
CCTG 
Email: 
pbrown-walker@ctg.queensu.ca 
or: 
Dr. Greg Korpanty 
Email:  
gkorpanty@ctg.queensu.ca 
STUDY CO-CHAIRS 
Barbara Melosky 
Email: 
bmelosky@bccancer.bc.ca 
604-877-6000 
x 2017 
604-877-0585 
Penelope Bradbury 
Email: 
penelope.bradbury@uhn.ca 
416-946-4501 
 
SERIOUS ADVERSE EVENT 
REPORTING 
See protocol Section 11.0 for details 
of reportable events. 
Dr. Greg Korpanty 
Senior Investigator, CCTG 
613-533-6430 
613-533-2411 
or 
Pamela Brown-Walker  
Study Coordinator, CCTG 
DRUG ORDERING 
See Appendix III and trial website (www.ctg.queensu.ca) for details and 
contact information