Double-Blind Randomized Phase II Trial of Carboplatin and Pemetrexed With or Without OGX-427 in Patients With Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer (The Spruce Clinical Trial)
Phase: PHASE2
Conditions: Non Squamous Non Small Cell Lung Cancer
Sponsor: SCRI Development Innovations, LLC

 
LUN 229 
Double-Blind Randomized Phase II Trial of Carboplatin and 
Pemetrexed with or without OGX-427 in Patients with Previously 
Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer  
(The Spruce Clinical Trial) 
 
SARAH CANNON RESEARCH INSTITUTE  
DEVELOPMENT INNOVATIONS 
PROTOCOL NUMBER: 
 
 
 
LUN 229 
STUDY DRUG: 
OGX-427 
  
SPONSOR: 
Sarah Cannon Research Institute (SCRI) 
Development Innovations (SCRI Innovations) 
3322 West End Avenue , Suite 900  
Nashville, TN  37203 
877-MY-1-SCRI 
 
 
STUDY CHAIR: 
David R. Spigel, M.D. 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900  
Nashville, TN  37203 
877-MY-1-SCRI 
asksarah@scresearch.net 
 
MEDICAL MONITOR: 
John D. Hainsworth, M.D. 
Sarah Cannon Research Institute  
3322 West End Avenue , Suite 900  
Nashville, TN  37203 
877-MY-1-SCRI 
 
 
DATE FINAL: 
14 February 2013 (Version 1.0) 
AMENDMENT 1 DATE: 
21 March 2013 (Version 2.0) 
AMENDMENT 2 DATE: 
9 July 2013 (Version 3.0)   
AMENDMENT 3 DATE: 
05 November 2014 (Version 4.0)   

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Clinical Trial Statement of Compliance 
 
This clinical trial shall be conducted in compliance with the protocol, as referenced 
herein, and all applicable local, national, and international regulatory requirements to 
include, but not be limited to: 
 
 International Conference on Harmonisation (ICH) Guidelines on Good 
Clinical Practice (GCP) 
 Ethical principles that have their origins in the Declaration of Helsinki  
 Food and Drug Administration (FDA) Code of Federal Regulation 
(CFR): 
o 
Title 21CFR Part 50 & 45 CFR Part 46, Protection of Human 
Subjects 
o 
Title 21CFR Part 54, Financial Disclosure by Clinical Investigators 
o 
Title 21CFR Part 56, Institutional Review Boards 
o 
Title 21CFR Part 312, Investigational New Drug Application 
 Title 45 CFR Parts 160, 162, and 164, Health Insurance Portability and 
Accountability Act (HIPAA)    
 
As the Principal Investigator (PI), I am in agreement and understand my 
responsibilities as a PI to conduct the clinical trial in accordance to the protocol and 
applicable regulations.  Furthermore, I understand and agree that any changes I initiate 
without prior agreement in writing from the Sponsor, shall be defined as a deviation 
from the protocol, and shall be formally documented as such. 
 
 

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Clinical Trial History of Amendments 
Double-Blind Randomized Phase II Trial of Carboplatin and Pemetrexed with or without 
OGX-427 in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell 
Lung Cancer  
(The Spruce Clinical Trial) 
 
Amd #/ Amd Date 
Refer to this Section 
Summary 
 
3 – 05 Nov 2014 
 
Synopsis Inclusion and 
3.1 Inclusion Criteria 
 
2.  Recurrent Stage IV Metastatic disease at the time of 
study entry (according to American Joint Committee 
on Cancer (AJCC) staging system, v7.0). 
3.  No prior systemic chemotherapy, immunotherapy, 
targeted therapy, or biological therapy for metastatic 
disease.  Previous adjuvant or neoadjuvant therapy 
for Stage I, II, or III disease is allowed as long as the 
interval from the end of treatment adjuvant therapy 
until disease progression was >12 months. 
4.  No prior radiation therapy to the whole pelvis or to 
≥25% of the total bone marrow area.  Other radiation 
therapy must be completed at least 2 weeks prior to 
study entry randomization.  Must have recovered 
from acute adverse effects prior to study entry 
randomization. 
 
 
Section 3.2 
Exclusion Criteria 
8.  Active second malignancy (except non-melanomatous 
skin or superficial bladder cancer) defined as requiring 
current need for cancer therapy or at high risk of 
recurrence (>350%) during the study. 
 
Section 5.1 
Treatment Plan 
 • a corticosteroid (dexamethasone 8-12 mg or 
corticosteroid equivalent) 
Carboplatin, at a dose calculated to produce an AUC of 6 
will be administered by intravenous infusion according to 
institutional standards beginning approximately 30 
minutes after the end of the pemetrexed infusion.   
 
  
Section 6.1 
Hematologic Toxicity 
Blood counts will be obtained at the beginning of each 
cycle.  To start a new treatment cycle, the patient must 
have the following blood counts:  ANC ≥1500/μL and 
platelet count ≥100,000/μL.  Hematologic dose 
modifications apply only to Day 1 values of each cycle.  
Dose reductions are not based on nadirs occurring 
during the previous treatment cycle. 
Table 5 Title change:  Day 1 Hematologic Dose 
Modifications 

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Amd #/ Amd Date 
Refer to this Section 
Summary 
 
Section 6.2 
Table 6  Non-
Hematologic Toxicity 
Dose Modifications  
Creatinine Clearance as calculated by Cockcroft-Gault 
method for Grades 2-4 toxicity criteria inserted. 
 
 
Section 8.1.3 
Precautions and Risks 
Associated with OGX-427  
Very likely:   
 
On rare occasions, infusion reactions can be 
life-threatening. 
Rare: 
 
Anaphylaxis or severe infusion reaction 
 
Section 10.2.2 
Stratification Factors  
Smoking Status:  Patients will be stratified as smokers or 
non-smokers.  Patients with a lifetime history of <100 
cigarettes are stratified as non-smokers.  Patients with >10 
pack/year history of smoking who but have not smoked 
for >15 years are also considered non-smokers.  All 
others will be classified as smokers. 
 
Minor edits 
A 7 day window has been added to restaging after every 2 
treatment cycles during initial treatment and maintenance. 
Innovation has been corrected to Innovations throughout.  
Previous protocols mentioned in the document have been 
labeled with their version numbers. 

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Clinical Trial Principal Investigator Signature Form 
Double-Blind Randomized Phase II Trial of Carboplatin and Pemetrexed with or 
without OGX-427 in Patients with Previously Untreated Stage IV Non-Squamous-
Non-Small-Cell Lung Cancer  
(The Spruce Clinical Trial) 
 
SCRI INNOVATIONS PROTOCOL NUMBER: LUN 229 
TRIAL DRUG:  
 
OGX-427  
 
DATE FINAL PROTOCOL: 
14 February 2013 (Version 1.0) 
AMENDMENT 1 DATE: 
21 March 2013 (Version 2.0) 
AMENDMENT 2 DATE: 
9 July 2013 (Version 3.0) 
AMENDMENT 3 DATE: 
05 November 2014 (Version 4.0) 
 
________________________________ 
____________________________  
_____________ 
Principal Investigator Name 
 
Principal Investigator Signature  
Date 
(Name Printed or Typed) 
 
 

 
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LUN 229 Synopsis 
 
 
Title of Study: 
Double-Blind Randomized Phase II Trial of Carboplatin and Pemetrexed with or 
without OGX-427 in Patients with Previously Untreated Stage IV Non-Squamous-
Non-Small-Cell Lung Cancer (The Spruce Clinical Trial) 
SCRI Innovations 
Protocol Number: 
LUN 229 
Sponsor: 
SCRI Development Innovations  
Study Duration:  
The duration of the study through the 
last patient  treated including  follow-up: 
32 months 
 
Phase of Trial: II 
Number of Subjects:  
The total number of patients expected to be accrued is 155. 
Objectives: 
Primary Objective 
 
To compare the progression-free survival (PFS) of OGX-427 plus 
carboplatin/pemetrexed therapy versus placebo plus 
carboplatin/pemetrexed in previously untreated patients with advanced 
non-squamous NSCLC.   
Secondary Objectives 
 
To compare the objective response rate (ORR) in each treatment arm. 
 
To compare overall survival (OS) in each treatment arm. 
 
To evaluate safety     
Exploratory Objectives 
 
Correlative analyses of serum levels of Hsp27. 
 
Correlative analysis of treatment outcomes with specific biomarkers. 
Study Design: 
This is a randomized, double-blind, placebo-controlled, Phase II study comparing 
pemetrexed and carboplatin plus OGX-427 followed by maintenance pemetrexed 
and OGX-427 versus pemetrexed and carboplatin plus placebo followed by 
maintenance pemetrexed and placebo in patients with previously untreated advanced 
non-squamous NSCLC.  The patients, investigator, study team members, (except for 
the mixing pharmacist/nurse), and anyone involved with the conduct of the trial 
from the time of randomization until database lock for the primary endpoint analysis 
will be blinded to the identity of the treatment assignment (OGX-427 or placebo).  
The primary endpoint of the trial is PFS.   
A total of 155 patients will be randomized in a 1:1 ratio.  Randomization will be 
stratified by histology (adenocarcinoma vs. large cell carcinoma) and smoking status 
(smoker vs. non-smoker) for the purpose of balance of enrollment and exploratory 
analysis. 
 

 
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LUN 229 Synopsis (continued) 
Study Drug(s), 
Dose, and Mode 
of 
Administration: 
 
  
 
 

 
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LUN 229 Synopsis (continued) 
Inclusion Criteria: 
Patients must meet the following criteria in order to be included in the clinical study: 
1. Histologic or cytologic diagnosis of advanced NSCLC, excluding squamous 
cell and small cell histology.  Tumors with mixed NSCLC histologies are 
eligible, as long as the predominant histology is not squamous.  If small-cell 
elements are present or not otherwise specified (NOS) histologically, the 
patient is not eligible. 
2. Metastatic disease at the time of study entry (according to American Joint 
Committee on Cancer (AJCC) staging system, v7.0). 
3. No prior systemic chemotherapy, immunotherapy, targeted therapy, or 
biological therapy for metastatic disease.  Previous adjuvant or neoadjuvant 
therapy is allowed for Stage 1, II, or III disease as long as the interval from 
end of treatment until disease progression was >12 months. 
4. No prior radiation therapy to the whole pelvis or to >25% of the total bone 
marrow area.  Other radiation therapy must be completed at least 2 weeks 
prior to study entry.  Must have recovered from acute adverse effects prior 
to study entry.  
5. At least one measurable lesion according to Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1 (see Section 9). 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
score of 0 or 1 (See Appendix A). 
7. Baseline laboratory values as follows: 
 
Absolute neutrophil count (ANC) ≥1500/μL 
 
Hemoglobin (Hgb) ≥10 g/dL 
 
Platelets ≥100,000/μL 
 
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤3.0 x the upper limit of normal (ULN); 5 x ULN if known hepatic 
metastases. 
 
Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease  
 
Serum creatinine ≤1.5 x ULN.  If creatinine is >1.5, calculate creatinine 
clearance ≥45 mL/min by the Cockcroft-Gault method: 
GFR =  (140-age) x (weight/kg) x (0.85 if female) 
                                                          (72 x serum creatinine mg/dL)                         
8. Fertile male patients willing to use adequate contraceptive measures (see 
Appendix B). 
9. Female patients who are not of child-bearing potential (see Appendix B), 
and fertile female patients of child-bearing potential who agree to use 
adequate contraceptive measures (see Appendix B), who are not 
breastfeeding, and who have a negative serum or urine pregnancy test 
within 72 hours prior to start of randomization. 
10. Life expectancy ≥ 12 weeks. 
11. Must be ≥18 years of age at the time of consent. 
12. Willingness and ability to comply with trial and follow-up procedures. 
13. Ability to understand the nature of this trial and give written informed 
consent 

 
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LUN 229 Synopsis (continued) 
 
Exclusion Criteria:  
  
Patients who meet any of the following criteria will be excluded from study entry: 
1. Known ALK translocation and EGFR “activating” mutations where first-
line treatment with targeted kinase inhibitor therapy is more appropriate. 
2. Known central nervous system (CNS) disease other than neurologically 
stable, treated brain metastases – defined as metastasis having no evidence 
of progression or hemorrhage after treatment and no ongoing requirements 
for corticosteroids, (e.g., dexamethasone) for at least 2 weeks.   
3. Any of the following cardiac diseases currently or within the last 6 months 
as defined by New York Heart Association [NYHA] ≥ Class 2 [See 
Appendix C]: 
 
Unstable angina pectoris 
 
Congestive heart failure  
 
Acute myocardial infarction 
 
Conduction abnormality not controlled with pacemaker or medication 
 
Significant ventricular or supraventricular arrhythmias (Patients with 
chronic rate-controlled atrial fibrillation in the absence of other cardiac 
abnormalities are eligible). 
4. Patients currently receiving therapeutic anticoagulation.    
5. Pregnant or lactating women. 
6. Any serious, active underlying medical condition that would impair the 
ability of the patient to receive study treatment, such as diabetes mellitus or 
infection. 
7. Unable or unwilling to take folic acid or vitamin B12.  
8. Active second malignancy (except non-melanomatous skin or superficial 
bladder cancer) defined as requiring current need for cancer therapy or at 
high risk of recurrence (>30%) during the study. 
9. Psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol.  
10. Inability or unwillingness to comply with trial and/or follow-up procedures 
outlined in the protocol. 
 
 

 
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LUN 229 Synopsis (continued) 
Statistical 
Methodology: 
Sample size considerations are based on progression-free survival (PFS) and follow-
up considerations are based on overall survival (OS).  The median PFS in the 
control group (carboplatin with pemetrexed plus placebo) is estimated to be 
approximately 5 months.  A PFS target hazard ratio (HR) of 0.60, corresponding to 
a median PFS in the experimental group (carboplatin with pemetrexed plus OGX-
427) of 8.3 months is hypothesized.  The study will have 85% power to test this 
hypothesis using a one-sided log-rank at the 5% level of significance.  Based on a 
uniform 15-month accrual period, a minimum of approximately 12 months follow-
up period for PFS and a loss to follow-up/non-evaluability for PFS assessment rate 
of approximately 10% per year, a total of 155 subjects will be randomized in a 1:1 
manner to achieve the targeted number of events in the scheduled PFS follow-up 
time.  Sample size and power calculations were performed using PASS 2008 
software. 
Descriptive statistics and statistical methods such as survival analysis and regression 
analysis will be used to assess the correlation of treatment outcomes with results 
from correlative testing. 
Correlative Testing: 
Blood samples will be collected from all patients and assessed for serum Hsp27 
levels at baseline, prior to the initial loading dose, and during treatment.  At these 
time points, approximately 7 mL of blood (red topped tube) will be collected for 
serum Hsp27.   
Hsp27 and AKT exist in complex with p38 MAPK and MK2 in the cytoplasm 
(Zheng et al. 2006).  Studies have shown Hsp27 regulates AKT activation and 
promotes cell survival by scaffolding MK2 to the AKT signal (Zheng et al. 2006, 
Wu et al. 2007).  The anti-tumor effect of Hsp27 inhibition might be associated with 
a decrease in AKT or other signaling pathway.  Therefore, the status of PTEN loss 
and mutation status of a panel of genes are suggested to be explored to investigate 
whether specific biomarker status has predictive value for Hsp27 inhibition.  
Available archival tissues will be collected from patients and may be assessed for 
PTEN (protein expression by IHC) and mutations in a panel of genes including, but 
not limited to: ABL1, AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, 
FGFR1, FGFR2, FGFR3, FGFR4, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, 
KIT, KRAS, MAP2K1, MET, MPL, MYC, NPM1, NRAS, PDGFRA, PIK3CA, 
PIK3R1, PTCH1, RUNX1, RET, SMO, STK11, and WT1. 

 
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LUN 229 Contact Information 
 
SCRI Innovations Contact Information: 
Sarah Cannon Research Institute 
Development Innovations 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
877- MY-1-SCRI 
asksarah@scresearch.net 
Study Chair: 
David R. Spigel, MD 
Sarah Cannon Research Institute 
3322 West End Avenue, Suite 900 
Nashville, TN  37203 
877-MY-1-SCRI 
asksarah@scresearch.net 
Medical Monitor: 
John D. Hainsworth, MD 
Sarah Cannon Research Institute 
3322 West End Avenue , Suite 900  
Nashville, TN  37203 
877-MY-1-SCRI 
 
Safety Dept. Phone # / Fax #:   
615-329-7358 /866-807-4325 
Regulatory Phone # / Fax #: 
877-MY-1-SCRI /615-524-4518 
SCRI Innovations Central Enrollment Email: 
CANN.SCRIInnovationsEnr@scri-
innovations.com 
Central Pharmacy Fax #: 
Central Pharmacy Email:  
866-325-9364 
centralpharmacy@scresearch.net 

 
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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CMP 
comprehensive metabolic profile 
CrCl 
creatinine clearance 
CR 
complete response 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group (Performance Status) 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HIPAA 
Health Insurance Portability and Accountability Act 
Hsp27 
heat shock protein 27 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
MRI 
magnetic resonance imaging 
NE 
not evaluable 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small-cell lung cancers 
NYHA 
New York Heart Association 
OS 
overall survival 
PD 
progressive disease 
PET 
positron-emission tomography 
PFS 
progression-free survival 
PR 
partial response 

 
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List of Abbreviations 
 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RR 
response rate 
SAE 
serious adverse event 
SCRI 
Sarah Cannon Research Institute 
SD 
stable disease 
ULN 
upper limit of normal 

 
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TABLE OF CONTENTS 
1 
INTRODUCTION .............................................................................................................. 20 
1.1 
Background ................................................................................................................. 20 
1.1.1 
OGX-427 ............................................................................................................... 20 
1.2 
Rationale for the Study ................................................................................................ 22 
2 
STUDY OBJECTIVES ...................................................................................................... 23 
2.1 
Primary Objective ....................................................................................................... 23 
2.2 
Secondary Objectives .................................................................................................. 23 
2.3 
Exploratory Objectives ................................................................................................ 23 
3 
TRIAL PATIENT POPULATION AND WITHDRAWAL .............................................. 23 
3.1 
Inclusion Criteria ......................................................................................................... 23 
3.2 
Exclusion Criteria ........................................................................................................ 24 
3.2.1 
Discontinuation from Study Treatment ..................................................................... 25 
3.2.2 
Pregnancy .............................................................................................................. 26 
4 
STUDY REGISTRATION ................................................................................................. 26 
5 
STUDY DESIGN ............................................................................................................... 26 
5.1 
Treatment Plan ............................................................................................................ 29 
5.2 
Restaging During the Treatment Phase ....................................................................... 31 
5.3 
Maintenance Phase ...................................................................................................... 31 
5.3.1 
Correlative Testing ................................................................................................. 31 
5.4 
Concomitant Medications ........................................................................................... 32 
5.4.1 
Palliative Radiotherapy ........................................................................................... 32 
5.4.2 
Leucovorin ............................................................................................................. 32 
5.4.3 
Medications and Non-Drugs Prohibited During the Trial ........................................... 32 
5.5 
Treatment Assignment Unblinding Procedures .......................................................... 33 
6 
DOSE MODIFICATIONS ................................................................................................. 33 
6.1 
Hematologic Toxicity .................................................................................................. 35 
6.2 
Non-Hematologic Toxicity Dose Modifications ......................................................... 37 
6.2.1 
Specific Non-Hematologic Toxicities....................................................................... 39 
6.3 
Dose Modifications for Infusion Reactions ................................................................ 39 
7 
TRIAL ASSESSMENTS AND EVALUATIONS ............................................................. 41 

 
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7.1 
Overview ..................................................................................................................... 41 
7.2 
Baseline Trial Assessments ......................................................................................... 41 
7.3 
Study Treatment Assessments ..................................................................................... 41 
7.3.1 
OGX-427 (or Placebo) Loading Dose Period Assessments ........................................ 41 
7.4 
Treatment Phase Assessments ..................................................................................... 42 
7.4.1 
Cycle 1 Day 1 ........................................................................................................ 42 
7.4.2 
Cycle 1 Days 8 and 15 (±72 hours) .......................................................................... 42 
7.4.3 
Cycles 2 – 4, Day 1 (±72 hours)............................................................................... 42 
7.4.4 
Cycles 2 – 4 Days 8 and 15 (±72 hours) ................................................................... 42 
7.5 
Every 2 Cycles (6 Weeks) ........................................................................................... 42 
7.6 
Maintenance Treatment Assessments ......................................................................... 43 
7.6.1 
Day 1 Every 21 Days (±72 hours) ............................................................................ 43 
7.6.2 
Maintenance Days 8 and 15 (±72 hours) .................................................................. 43 
7.6.3 
Every 2 Cycles (6 Weeks) During Maintenance (±7 days) ......................................... 43 
7.7 
End of Study Treatment .............................................................................................. 43 
7.8 
Follow-Up ................................................................................................................... 44 
7.8.1 
Progression-Free Survival Follow-Up ...................................................................... 44 
7.8.2 
Survival Follow-Up ................................................................................................ 44 
7.9 
Comprehensive Metabolic Profile Assessments ......................................................... 44 
8 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION AND TOXICITY 
INFORMATION........................................................................................................................ 45 
8.1 
Study Drug (OGX-427 or Placebo) ............................................................................. 45 
8.1.1 
Labeling, Packaging and Supply .............................................................................. 45 
8.1.2 
Preparation and Administration of Study Drug ......................................................... 45 
8.1.3 
Precautions and Risks Associated with OGX-427 ..................................................... 46 
8.2 
Pemetrexed .................................................................................................................. 48 
8.2.1 
Labeling, Packaging and Supply .............................................................................. 48 
8.2.2 
Preparation and Administration of Pemetrexed ......................................................... 48 
8.2.3 
Precautions and Risks Associated with Pemetrexed .................................................. 48 
8.3 
Carboplatin .................................................................................................................. 48 
8.3.1 
Labeling, Packaging and Supply .............................................................................. 49 
8.3.2 
Preparation and Administration of Carboplatin ......................................................... 49 

 
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8.3.3 
Precautions and Risks Associated with Carboplatin .................................................. 49 
9 
RESPONSE EVALUATIONS AND MEASUREMENTS ................................................ 49 
9.1 
Patients with Measurable Disease ............................................................................... 49 
10 STATISTICAL CONSIDERATIONS ............................................................................... 49 
10.1 
Analysis Population..................................................................................................... 49 
10.2 
Sample Size Considerations ........................................................................................ 49 
10.2.1 
Demographic and Baseline Characteristics ............................................................... 49 
10.2.2 
Stratification Factors ............................................................................................... 49 
10.2.3 
Efficacy Analyses ................................................................................................... 50 
10.2.4 
Primary Efficacy Endpoint ...................................................................................... 50 
10.2.5 
Secondary Efficacy Endpoints ................................................................................. 50 
10.2.6 
Safety Analyses ...................................................................................................... 50 
10.3 
Analysis Populations ................................................................................................... 51 
10.4 
Planned Interim Analysis ............................................................................................ 51 
10.5 
Data Safety Monitor .................................................................................................... 51 
11 SAFETY REPORTING AND ANALYSES ...................................................................... 52 
11.1 
Adverse Events ............................................................................................................ 52 
11.1.1 
Definitions of Adverse Events ................................................................................. 52 
11.1.2 
Recording and Reporting of Adverse Events ............................................................ 53 
11.1.3 
Handling of Adverse Events .................................................................................... 53 
11.2 
Serious Adverse Events ............................................................................................... 54 
11.2.1 
Definitions of Serious Adverse Events ..................................................................... 54 
11.2.2 
Serious Adverse Event Reporting by Investigators .................................................... 54 
11.2.3 
Sponsor Serious Adverse Event Reporting Requirements .......................................... 56 
11.2.4 
Sponsor Reporting for Trials under an Investigational New Drug Assignment ............ 56 
11.3 
Recording of Adverse Events and Serious Adverse Events ........................................ 57 
11.3.1 
Diagnosis vs. Signs and Symptoms .......................................................................... 57 
11.3.2 
Persistent or Recurrent Adverse Events .................................................................... 57 
11.3.3 
Abnormal Laboratory Values .................................................................................. 57 
11.3.4 
Deaths ................................................................................................................... 57 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery ............................................. 58 
11.3.6 
Pre-Existing Medical Condition ............................................................................... 58 

 
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11.3.7 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies ........................................ 58 
11.3.8 
New Cancers .......................................................................................................... 58 
11.4 
Protocol-Defined Events of Special Interest ............................................................... 58 
12 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS ......................... 59 
12.1 
Institutional Review Board Approval ......................................................................... 59 
12.2 
Regulatory Approval ................................................................................................... 59 
12.3 
Insurance and Indemnity ............................................................................................. 60 
12.4 
Informed Consent ........................................................................................................ 60 
12.4.1 
Confidentiality ....................................................................................................... 60 
12.4.2 
Subject Confidentiality ........................................................................................... 60 
12.4.3 
Investigator and Staff Information ........................................................................... 61 
12.5 
Financial Information .................................................................................................. 61 
13 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL ........................... 61 
13.1 
Amendments to the Protocol ....................................................................................... 61 
13.2 
Documentation Required to Initiate Study .................................................................. 62 
13.3 
Trial Documentation and Storage ............................................................................... 63 
13.4 
Data Collection ............................................................................................................ 64 
13.5 
Trial Monitoring, Auditing, and Inspecting ................................................................ 64 
13.6 
Quality Assurance and Quality Control ...................................................................... 65 
13.7 
Disclosure and Publication Policy .............................................................................. 65 
14 REFERENCES ................................................................................................................... 66 
15 APPENDICES .................................................................................................................... 67 
15.1.1 
Guidelines for Evaluation of Measurable Disease ..................................................... 74 
15.1.2 
Response Criteria ................................................................................................... 76 
 

 
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LIST OF TABLES 
Table 1. 
Premedications for Pemetrexed/Carboplatin .................................................................... 29 
Table 2. 
Pemetrexed Dose Level Modifications ............................................................................ 34 
Table 3. 
Carboplatin Dose Level Modifications ............................................................................ 34 
Table 4. 
OGX-427 Dose Level Modifications .............................................................................. 34 
Table 5. 
Hematologic Dose Modifications ................................................................................... 36 
Table 6. 
Non-Hematologic Toxicity Dose Modifications .............................................................. 38 
Table 7. 
Dose Modifications for Infusion Reaction for OGX-427/Placebo ..................................... 40 
 
LIST OF FIGURES 
Figure 1: 
Enhanced Pemetrexed Effects After OGX-427 Treatment in A549 Cells ........................... 21 
Figure 2: 
Pemetrexed Increases Apoptotic Rates After OGX-427 Treatment in A549 Cells .............. 22 
Figure 3 
LUN 229 Treatment Schema .......................................................................................... 28 
 
LIST OF APPENDICES 
Appendix A: 
ECOG Performance Status Criteria 
67 
Appendix B: 
Guidelines for Women of Child-Bearing Potential 
68 
Appendix C: 
New York Heart Association (NYHA) Classification of Cardiac Disease 
70 
Appendix D: 
LUN 229 Schedule of Assessments 
71 
Appendix E: 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
73 
 

 
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1 
INTRODUCTION 
Lung cancer is the leading cause of cancer-related mortality worldwide (Pazdur et al 2004).  
Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of these cases.  The 
majority of patients present with unresectable locally advanced or metastatic disease.  
Patients with advanced disease rarely survive 5 years, and over half die within the first year 
of diagnosis.   
1.1 
Background 
Combination chemotherapy can extend survival, palliate symptoms of progressive disease, 
and improve the quality of life in patients with advanced NSCLC.   
Pemetrexed is a novel, multi-targeted antifolate, antimetabolite agent that initially was 
approved by the US Food and Drug Administration (FDA) for the treatment of unresectable 
malignant pleural mesothelioma in combination with cisplatin after demonstrating superior 
response rates, time to progression (TTP), and survival compared with cisplatin alone 
(Vogelzang et al. 2003).   
Scagliotti completed a multicenter, randomized, Phase III study of previously untreated 
locally advanced NSCLC patients, comparing pemetrexed (500 mg/m2) plus cisplatin 
(75 mg/m2)  Day 1 every 21 days versus gemcitabine (1250 mg/m2) Day 1 and Day 8 plus 
cisplatin (75 mg/m2) Day 1 every 21 days.  Overall survival (OS) with pemetrexed and 
cisplatin was statistically non-inferior to that achieved by gemcitabine and cisplatin 
(Scagliotti et al. 2008).    
Pemetrexed and carboplatin were compared in a large Phase III study with standard 
gemcitabine and carboplatin as first-line chemotherapy for patients with advanced NSCLC 
(Gronberg et al. 2009).  Of the 423 patients analyzed for toxicity the patients receiving 
pemetrexed and carboplatin had less hematologic toxicity and need for supportive care than 
the patients receiving gemcitabine and carboplatin.   
Maintenance treatment with pemetrexed following induction chemotherapy has been tested 
in a randomized, double-blind, placebo-controlled study (Ciuleanu et al. 2008).  Patients in 
the trial received 1 of 6 standard regimens (gemcitabine, paclitaxel, or docetaxel) with 
cisplatin or carboplatin.  Treatment selection was at the discretion of the investigator.  
Responders after 4 cycles (complete response [CR], partial response [PR], or stable disease 
[SD]) were randomly assigned maintenance therapy with either pemetrexed or best 
supportive care (BSC) plus placebo until progression.  Improvement in the non-squamous 
NSCLC patient population was significant.  OS was 14.4 months for the pemetrexed-treated 
patients and 9.4 months for the patents receiving placebo.  In the same group, median 
progression-free survival (PFS) for pemetrexed versus placebo was 4.4 months versus 1.8 
months.   
1.1.1 
OGX-427 
OGX-427 is an antisense oligonucleotide (ASO) designed to bind to heat shock protein 27 
(Hsp27) mRNA, resulting in the inhibition of the production of Hsp27 protein.  Hsp27 is 
over-expressed in many cancers including prostate, breast, lung, and bladder.  Increased 

 
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expression has been associated with inhibition of chemotherapy-induced apoptosis, increased 
cytoprotection and the development of treatment resistance.  OGX-427 is an inhibitor of 
Hsp27 that effectively targets and down-regulates Hsp27 mRNA and has been shown to 
increase apoptosis, inhibit tumor growth, and sensitize cells to various chemotherapy 
regimens in a variety of malignancies.  Gleave and his colleagues have shown enhanced 
antitumor effects with pemetrexed after treatment with OGX-427 in A549 cells (unpublished 
results see Figure 1).  
Figure 1: 
Enhanced Pemetrexed Effects After OGX-427 Treatment in A549 Cells 
 
To evaluate cell cytotoxicity, A549 cells were treated with 50nM OGX-427 for 2 consecutive 
days and incubated with indicated concentration of Pemetrexed for 72 h ; 72 h later, cell 
viability was determined by crystal violet assay; ScrB = scrambled oligonucleotide 
Increased apoptotic rates were also observed with pemetrexed after OGX-427 treatment in 
A549 Cells (Figure 2). 

 
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Figure 2: 
Pemetrexed Increases Apoptotic Rates After OGX-427 Treatment in 
A549 Cells 
 
To evaluate cell apoptosis, A549 cells were treated with 50nM OGX-427 for 2 consecutive 
days and incubated with indicated concentration of Pemetrexed for 72 h ; 72 h later, total 
protein was extracted and analyzed by immunoblotting; ScrB = scrambled oligonucleotide. 
Similar synergistic results have been observed with OGX-427 in combination with platinum 
(please refer to the OGX-427 Investigator Brochure for more detailed information). 
1.2 
Rationale for the Study 
Modern doublet chemotherapy improves survival in patients with advanced NSCLC 
compared with supportive care alone.  Recently, histology has emerged as a predictive 
marker for first-line treatment.  Patients with non-squamous NSCLC treated with 
platinum/pemetrexed lived longer than patients treated with platinum/gemcitabine.    
Moreover, pemetrexed resulted in a survival advantage in patients with non-squamous lung 
cancer when used as a maintenance therapy in the first-line setting compared with patients 
treated only at progression.  Despite these recent advantages, overall survival for patients 
with advanced disease remains relatively poor. 
OGX-427 is a 2’-methoxyethyl (MOE) oligonucleotide analogue which targets Hsp27.  
Hsp27 is a stress-activated ATP-independent cytoprotective chaperone which mediates 
treatment resistance in cancer.  Preclinical models demonstrate that OGX-427 is a potent 
Hsp27 inhibitor across solid tumors.  A phase I study of OGX-427 as monotherapy or in 
combination with docetaxel could not identify a maximum tolerated dose.  There was a 
single dose-limiting toxicity of cerebral hemorrhage; however, infusion reactions were 
common.  These reactions were largely low-grade and rarely (<1.5%) resulted in treatment 
modification.  Several patients at varying dose levels had evidence of tumor shrinkage, 
including patients with NSCLC. 

 
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This randomized phase II study will compare the combination of carboplatin/pemetrexed 
with and without OGX-427 in patients with previously untreated advanced non-squamous 
NSCLC.  The multicenter study will be conducted through the Sarah Cannon Research 
Institute network. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
 To compare the progression-free survival (PFS) of OGX-427 plus 
carboplatin/pemetrexed therapy versus placebo plus carboplatin/pemetrexed in 
previously untreated patients with advanced non-squamous NSCLC.   
2.2 
Secondary Objectives 
 To compare the objective response rate (ORR) in each treatment arm. 
 To compare overall survival (OS) in each treatment arm. 
 To evaluate safety     
2.3 
Exploratory Objectives 
 Correlative analyses of serum levels of Hsp27. 
 Correlative analysis of treatment outcomes with specific biomarkers 
3 
TRIAL PATIENT POPULATION AND WITHDRAWAL 
3.1 
Inclusion Criteria 
Patients must meet the following criteria in order to be included in the study: 
1. Histologic or cytologic diagnosis of advanced NSCLC, excluding squamous cell and 
small cell histology.  Tumors with mixed NSCLC histologies are eligible, as long as 
the predominant histology is not squamous.  If small-cell elements are present or not 
otherwise specified (NOS) histologically, the patient is not eligible. 
2. Metastatic disease at the time of study entry (according to American Joint Committee 
on Cancer (AJCC) staging system, v7.0). 
3. No prior systemic chemotherapy, immunotherapy, targeted therapy, or biological 
therapy for metastatic disease.  Previous adjuvant or neoadjuvant therapy for Stage I, 
II, or III disease is allowed as long as the interval from the end of treatment until 
disease progression was >12 months. 
4. No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow 
area.  Other radiation therapy must be completed at least 2 weeks prior to study entry.  
Must have recovered from acute adverse effects prior to study entry. 
5. At least one measurable lesion according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 (see Section 9). 
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 
1 (see Appendix A). 

 
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7. Baseline laboratory values as follows: 
 Absolute neutrophil count (ANC) ≥1500/μL 
 Hemoglobin (Hgb) ≥10 g/dL 
 Platelets ≥100,000/μL 
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x 
the upper limit of normal (ULN); 5 x ULN if known hepatic metastases. 
 Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert’s disease  
 Serum creatinine ≤1.5 x ULN.  If creatinine is >1.5, calculate creatinine clearance 
(CrCl) ≥45 mL/min by the Cockcroft-Gault method: 
GFR =  (140-age) x (weight/kg) x (0.85 if female) 
(72 x serum creatinine mg/dL)                            
 
8. Fertile male patients willing to use adequate contraceptive measures (see Appendix 
B). 
9. Female patients who are not of child-bearing potential (see Appendix B), and fertile 
female patients of child-bearing potential who agree to use adequate contraceptive 
measures (see Appendix B), who are not breastfeeding, and who have a negative 
serum or urine pregnancy test within 72 hours prior to start of randomization. 
10. Life expectancy ≥ 12 weeks. 
11. Must be ≥18 years of age at the time of consent. 
12. Willingness and ability to comply with trial and follow-up procedures. 
13. Ability to understand the nature of this trial and give written informed consent. 
3.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
1. Known ALK translocation and EGFR “activating” mutations where first-line 
treatment with targeted tyrosine kinase inhibitor therapy is more appropriate. 
2. Known central nervous system (CNS) disease other than neurologically stable, treated 
brain metastases – defined as metastasis having no evidence of progression or 
hemorrhage after treatment and no ongoing requirements for corticosteroids, (e.g., 
dexamethasone) for at least 2 weeks.    
3. Any of the following cardiac diseases currently or within the last 6 months as defined 
by New York Heart Association [NYHA] ≥ Class 2 [see Appendix C]: 
 Unstable angina pectoris 
 Congestive heart failure  
 Acute myocardial infarction 
 Conduction abnormality not controlled with pacemaker or medication 

 
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 Significant ventricular or supraventricular arrhythmias (Patients with chronic rate-
controlled atrial fibrillation in the absence of other cardiac abnormalities are 
eligible). 
4. Patients currently receiving therapeutic anticoagulation. 
5. Pregnant or lactating women. 
6. Any serious, active underlying medical condition that would impair the ability of the 
patient to receive study treatment, such as diabetes mellitus or infection. 
7. Unable or unwilling to take folic acid or vitamin B12.  
8. Active second malignancy (except non-melanomatous skin or superficial bladder 
cancer) defined as requiring current need for cancer therapy or at high risk of 
recurrence (>30%) during the study. 
9. Psychological, familial, sociological, or geographical conditions that do not permit 
compliance with the protocol.  
10. Inability or unwillingness to comply with trial and/or follow-up procedures outlined 
in the protocol. 
3.2.1 
Discontinuation from Study Treatment 
Patients will be discontinued from any phase of study treatment for one or more of the 
following reasons: 
 Disease progression 
 Irreversible or intolerable toxicity or abnormal laboratory values requiring 
treatment discontinuation according to Section 6, Dose Modifications 
 Unable to complete at least 3 cycles of at least one chemotherapy agent 
 Patient requests to withdraw from the trial and discontinue treatment 
 Conditions requiring therapeutic intervention not permitted by the protocol 
 Intercurrent illness or safety concerns which, per the investigator, prevent 
continuation of study treatment 
 Non-compliance/lost to follow-up 
 Global or severe deterioration of health status such that it requires discontinuation 
of protocol treatment without objective evidence of disease progression 
After discontinuation from study treatment, patients must be followed for adverse events 
(AEs) for 30 calendar days after their last dose of study drug(s).  All new AEs occurring 
during this period must be reported and followed until resolution, unless, in the opinion of 
the investigator, these values are not likely to improve because of the underlying disease.  In 
this case, the investigator must record his or her reasoning for this decision in the patient’s 
medical record and as a comment on the Case Report Form (CRF). 
All patients who have Grade 3 or 4 laboratory abnormalities (Common Terminology Criteria 
for Adverse Events [CTCAE] v4.0 [http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE]) at the time 
of discontinuation must be followed until the laboratory values have returned to Grade 1 or 2, 
unless it is, in the opinion of the investigator, not likely that these values are to improve.  In 

 
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this case, the investigator must record his or her reasoning for making this decision in the 
patient’s medical record and as a comment on the CRF. 
3.2.2 
Pregnancy 
During the course of the study, all female patients of childbearing potential (the definitions of 
“women of childbearing potential” are listed in Appendix B)  must contact the treating 
investigator immediately if they suspect that they may be pregnant (a missed or late 
menstrual period).   
If an investigator suspects that a patient may be pregnant prior to administration of study 
drug(s), the study drug(s) must be withheld until the result of the pregnancy test is confirmed.  
If a pregnancy is confirmed, the patient must not receive any study drug(s), and must be 
discontinued from the study.   
If an investigator suspects that a patient may be pregnant after the patient has been receiving 
study drug(s), the study drug(s) must immediately be withheld until the result of the 
pregnancy test is confirmed.  If a pregnancy is confirmed, the study drug(s) must be 
immediately and permanently stopped, the patient must be discontinued from the study, and 
the investigator must notify the Sarah Cannon Research Institute (SCRI) Study Chair as soon 
as possible.  If a patient becomes pregnant while enrolled in the study, a Pregnancy Form (a 
paper report form) should be completed and faxed to SCRI Innovations Safety Department.  
For more details regarding handling and reporting of pregnancies that occur during treatment, 
see Section 11.4.   
4 
STUDY REGISTRATION 
The patient must willingly consent after being informed of the procedures to be followed, the 
experimental nature of the treatment, potential benefits, alternatives, side-effects, risks, and 
discomforts.  Human protection committee approval of this protocol and consent form is 
required.  Eligible patients who wish to participate in the study will be randomly assigned to 
treatment. 
Registration and randomization must occur prior to the initiation of study therapy.  For 
information regarding the study registration process, please refer to the study reference 
materials. 
5 
STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled, Phase II trial comparing pemetrexed  
and carboplatin plus OGX-427 followed by maintenance pemetrexed and OGX-427 versus 
pemetrexed and carboplatin plus placebo followed by maintenance pemetrexed and placebo 
in patients with previously untreated advanced non-squamous NSCLC.  The patients, 
investigator, study team members, (except for the mixing pharmacist/nurse), and anyone 
involved with the conduct of the trial from the time of randomization until database lock for 
the primary endpoint analysis will be blinded to the identity of the treatment assignment 
(OGX-427 or placebo).  The primary endpoint of the trial is PFS.   

 
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A total of 155 patients will be randomized in a 1:1 ratio.  Randomization will be stratified by 
histology (adenocarcinoma vs. large cell carcinoma) and smoking status (smoker vs. non-
smoker) for the purpose of balance of enrollment and exploratory analysis. 

 
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Figure 3 
LUN 229 Treatment Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stratification 
Adenocarcinoma vs. Large Cell Carcinoma 
Smoker vs. Non-Smoker 
OGX-427 
3 loading doses at 600 mg IV 
Days -9 to -1 
Randomized Double-Blind 
1:1 Ratio 
Placebo 
3 loading doses 
Days -9 to -1 
Follow-Up 
Follow-Up 
OGX-427 
600 mg IV weekly 
Days 1, 8, 15 
Pemetrexed 
500 mg/m2 IV Day 1 q 21d 
Placebo 
IV weekly  
Days 1, 8, 15 
Pemetrexed 
500 mg/m2 IV Day 1 q 21d 
Group 1 
Group 2 
Maintenance Phase 
Continue until disease 
progression or 
unacceptable toxicity 
All patients will receive premedication for study drug (OGX-427 or placebo) with an antihistamine and an 
H2 antagonist, and a corticosteroid as described in Section 5.1.  All patients will receive premedication for 
pemetrexed with folic acid, vitamin B12, and dexamethasone as described in Table 1.  Anti-emetics may be 
administered according to institutional standards. 
OGX-427 
600 mg IV weekly 
Days 1, 8, 15 
Pemetrexed 
500 mg/m2 IV on Day 1 
Carboplatin 
AUC 6 IV Day 1 
Continue therapy if stable 
disease or better;  
restage every 2 cycles  
Placebo 
IV weekly 
Days 1, 8, 15 
Pemetrexed 
500 mg/m2 IV on Day 1 
Carboplatin 
AUC 6 IV Day 1 
Treatment Phase  
(Cycle = 21 days) 
Maximum 4 Cycles 
Loading Doses   

 
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5.1 
Treatment Plan 
Pre-medications for Study Drug (OGX-427/Placebo)  
To reduce the potential of known potential allergic reactions occurring with OGX-427, 
patients will receive the following pre-medications 30-60 minutes prior to OGX-427/placebo 
administration during the loading doses and Cycle 1 (Days 1, 8 and 15).    
 an antihistamine (diphenhydramine 25-50 mg or equivalent antihistamine)  
 an H2 antagonist (ranitidine 50 mg or H2 antagonist equivalent) 
 a corticosteroid (dexamethasone 8-12 mg or corticosteroid equivalent) 
If the patient has not manifested signs or symptoms of an infusion reaction during the loading 
doses and Cycle 1, the patient may be treated in subsequent cycles without some or all of the 
pre-medications.  However, should Grade 2 or greater reactions occur, the patient should 
resume pre-medications, including dexamethasone, prior to study drug for the duration of 
treatment. 
Table 1. 
Premedications for Pemetrexed/Carboplatin  
Patients will receive premedications for pemetrexed/carboplatin as shown in Table 1. 
Premedications 
Dosing 
Folic acid 
350-1000 µg PO daily 
Beginning ≤1 week before the first 
infusion of pemetrexed and 
continuing until 3 weeks after 
discontinuation of pemetrexed 
Vitamin B12 
1000 mcg IM Q9W 
Beginning ≤1 week before the first 
infusion of pemetrexed and 
continuing until 3 weeks after 
discontinuation of pemetrexed 
Dexamethasone 
8-12 mg IV Day 1 of each 
Cycle (Recommended) 
May substitute institutional equivalent   
NOTE:  If equivalent dexamethasone 
has been administered on Day 1 of a 
cycle prior to the study drug, 
additional dexamethasone prior to 
pemetrexed/carboplatin is at the 
discretion of the treating investigator.   
Prophylactic Anti-emetics 
Administered per local institutional guidelines. 

 
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Study Drug - OGX-427 (or Placebo) Loading Doses:  
Treatment will be initiated within 5 days from randomization with a Loading Dose Period 
(Day -9 to Day -1) followed by 21-day (3 week) study treatment cycles.   
Three separate administrations of study drug will be given during the 9-day Loading Dose 
Period.  The 3 loading doses (600 mg OGX-427 or placebo) must be administered with at 
least one “non-treatment” day between each dose (i.e. every other day).  This 9-day period 
for the loading doses allows for variations in the treatment schedule due to holidays and 
clinic schedules.  There must also be a minimum of 1 and no more than 7 days between the 
third loading dose and Cycle 1, Day 1. 
Study Treatment Phase: 
Patients will receive the study drug, 600 mg OGX-427 or placebo, prior to the administration 
of pemetrexed and carboplatin administration on Day 1 of each cycle.  A maximum of 4 
cycles will be given.  Study drug will also be administered on Day 8 and Day 15 during each 
cycle (i.e., weekly).  
Study Drug:  
OGX-427 or placebo will be administered intravenously, after preparation in D5W.  OGX-
427 or placebo should be added to 250 mL D5W as close to the time of administration as 
possible.  The dose will be administered intravenously as an infusion over approximately 
2 hours using either a peripheral or central indwelling catheter.  Refer to Section 8.1 for 
preparation and administration instructions for OGX-427 or placebo. 
Pemetrexed: 500 mg/m2 IV Day 1 q 21d  
Infuse over approximately 10 minutes or according to institutional standards within 
approximately 30 minutes after the end of the Study Drug infusion 
Carboplatin:  Area Under the Curve (AUC) 6 IV Day 1 q 21d   
Carboplatin, at a dose calculated to produce an AUC of 6 will be administered by intravenous 
infusion according to institutional standards beginning after the end of the pemetrexed 
infusion.   
The carboplatin dose will be calculated using the Calvert Formula based on the patient’s 
glomerular filtration rate (GFR) which is estimated by using the CrCl.   
 
Calvert Formula:  Carboplatin dose (mg) = target AUC x (GFR + 25) 
 
The Food and Drug Administration (FDA) has recommended that physicians consider 
capping the dose of carboplatin for the desired exposure (AUC) to avoid potential toxicity 
due to overdosing for all laboratories using the IDMS-derived serum creatinine 
measurements.  Therefore the maximum dose of carboplatin should be based on a CrCl no 
greater than 125 mL/min for patients with normal renal function.  In these, carboplatin can be 
safely dosed according to the instructions in the drug’s labeling.  Refer to US FDA, Center 
for Drug Evaluation and Research website:  

 
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http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/
ucm228974.htm  for more specific guidelines. 
Cockcroft-Gault Formula:  
  CrCl (GFR) = [(140 – age) x (wt in kg)] x (0.85 if female) 
                        (72 x serum creatinine [mg/dL]) 
5.2 
Restaging During the Treatment Phase 
Restaging by CT scans per RECIST version 1.1 (see Appendix E) will occur after Cycle 2 
and Cycle 4 (see Section 7.5).  A maximum of 4 treatment cycles will be given.  If there is no 
evidence of progressive disease or irreversible toxicity, patients will begin weekly 
maintenance therapy as described in Section 5.3.    
5.3 
Maintenance Phase 
Patients who have been discontinued from the Study Treatment Phase for disease 
progression, unacceptable toxicity, voluntarily withdrew from further treatment in the study 
or were removed from the Study Treatment Phase before receiving a minimum of 3 cycles 
containing at least one chemotherapy agent are not eligible for the Maintenance Phase.  
Patients who have objective response or stable disease after four cycles of therapy (minimum 
of three cycles) will then move to the Maintenance Phase of the trial.  Patients will receive 
pre-medications with folic acid, vitamin B12 and dexamethasone as described in Table 1.   
During maintenance therapy patients will receive pemetrexed 500 mg/m2 IV and Study Drug 
on Day 1 every 21 days followed by Study Drug on Days 8 and 15 of every cycle.   
There will be no crossover of drug treatments. 
During the Maintenance Phase, patients will be reevaluated by CT scans (per RECIST 
version 1.1; see Section 9) every 6 weeks (after every 2 treatment cycles).  Patients will be 
eligible to continue maintenance treatment as long as they are benefiting and have no 
evidence of disease progression, and do not meet any criteria for discontinuation or 
withdrawal (see Section 3.2.1). 
5.3.1 
Correlative Testing 
Blood samples will be collected from all patients and assessed for serum Hsp27 levels at 
baseline, prior to the initial loading dose, and during treatment.  At these time points, 
approximately 7 mL of blood (red topped tube) will be collected for serum Hsp27.   
Hsp27 and AKT exist in complex with p38 MAPK and MK2 in the cytoplasm (Zheng et al. 
2006).  Studies have shown Hsp27 regulates AKT activation and promotes cell survival by 
scaffolding MK2 to the AKT signal complex (Zheng et al. 2006, Wu et al. 2007).  The anti-
tumor effect of Hsp27 inhibition might be associated with a decrease in AKT or other 
signaling pathway.  Therefore, the status of PTEN loss and mutation status of a panel of 
genes are suggested to be explored to investigate whether specific biomarker status has 
predictive value for Hsp27 inhibition.  

 
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Available archival tissues will be collected from patients and may be assessed for PTEN 
(protein expression by IHC) and mutations in a panel of genes including, but not limited to:  
ABL1, AKT1, ALK, B-Raf, CTNNB1, DDR2, EGFR, HER2, FGFR1, FGFR2, FGFR3, 
FGFR4, GNA11, GNAQ, GNAS, HRAS, IDH1, IDH2, KIT, K-Ras, MEK1, c-Met, MPL, 
Myc, NPM1, NRas, PDGFRA, PI3KCA, PI3KR1, RUNX1, SMO, PTCH1, LKB-1, RET, 
and WT1. 
A paraffin-embedded tumor tissue block (from the primary tumor or metastasis) obtained at 
diagnosis may be used.  In the absence of paraffin-embedded tissue, 15 unstained paraffin-
embedded tumor slides are acceptable. 
5.4 
Concomitant Medications 
Patients will be instructed to notify the investigator of any additional medications taken 
(including over-the-counter products) during the course of the study.   
The use of granulocyte colony-stimulating factor (G-CSF) should follow the American 
Society for Clinical Oncology guidelines.  All other supportive care may be administered as 
per institutional standard protocol.  
5.4.1 
Palliative Radiotherapy 
Patients may receive palliative therapy during the trial only for local pain control, and only if 
in the opinion of the treating Investigator the patient does not have progressive disease.  The 
radiation field cannot encompass a target lesion.  Radiation to a target lesion is considered 
progressive disease and the patient should be removed from study treatment. 
5.4.2 
Leucovorin 
Folic acid and vitamin B12 supplementation has significantly reduced the number of episodes 
of grade 4 hematologic and grade 3 or 4 non-hematologic toxicities associated with 
pemetrexed therapy; a need for leucovorin as a rescue agent is not anticipated.  However, this 
section provides information should rescue be necessary.  
In clinical trials, leucovorin was permitted for grade 4 leukopenia that lasted 3 days, grade 
4 neutropenia that lasted 3 days, and was immediately permitted for grade 4 
thrombocytopenia, bleeding associated with grade 3 thrombocytopenia, or grade 3 or grade 4 
mucositis.  The doses and schedules of leucovorin recommended for IV use are 100 mg/m2 
IV once, followed by 50 mg/m2 leucovorin IV every 6 hours until recovery of counts.  
However, institutional standards may be followed.  
5.4.3 
Medications and Non-Drugs Prohibited During the Trial 
At each visit, the investigator will ask the patient about any new medications he/she has 
taken after the start of study treatment. 
All concomitant medications/significant non-drug therapies taken ≤30 days prior to start and 
after start of study treatment, including physical therapy and blood transfusions, should be 
recorded. 
The following restrictions apply during the entire duration of the trial: 

 
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 No other investigational therapy should be given to patients.   
 Concomitant cancer treatment (e.g., biologic, hormonal therapy, immunotherapy, 
chemotherapy, and radiation therapy for disease progression) is prohibited.  If such 
treatment is required, then the patient must first be withdrawn from the trial.   
 No chronic treatment with systemic steroids (at a dose equivalent of greater than 20 
mg prednisone per day) other than those used for premedication per protocol or 
treatment with immunosuppressive agents.  Topical or inhaled corticosteroids are 
allowed. 
 Patients requiring therapeutic warfarin or coumarin-derivative anticoagulants will be 
monitored with INR and Prothrombin Time as clinically indicated. 
 Caution should be used when administering nonsteroidal anti-inflammatory drugs 
(NSAIDs) concurrently with pemetrexed to patients with mild to moderate renal 
insufficiency (creatinine clearance 45-79 mL/min).  NSAIDs with short elimination 
half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of 2 days 
before, the day of, and 2 days following administration of pemetrexed.  NOTE:  No 
dose adjustment of pemetrexed is needed with concomitant NSAIDs in patients with 
normal renal function. 
In the absence of data regarding potential interaction between pemetrexed and 
NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these 
NSAIDs should interrupt NSAID dosing for at least 5 days before, the day of, and 2 
days following pemetrexed administration.  If concomitant administration of NSAIDs 
is necessary, patients should be monitored closely for toxicity, especially myeloid, 
renal, and gastrointestinal toxicity. 
Ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed; 
however, it can be administered with pemetrexed in patients with normal renal 
function (creatinine clearance ≥80 mL/min).     
5.5 
Treatment Assignment Unblinding Procedures 
There is no intention to routinely unblind individual patients at any time.  Individual requests 
for urgent safety unblinding require the approval of the Medical Monitor.   
There also may be instances where unblinding of a patient(s) may be required for a safety 
review at the request of the SCRI Innovations Medical Monitor or DSM or for Regulatory 
Authority reporting requirements. 
After all patients have completed protocol treatment and the database has been locked, the 
trial will be unblinded for analysis of the safety and efficacy outcomes. 
6 
DOSE MODIFICATIONS 
All toxicities will be graded utilizing the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) version 4.0 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE).  If toxicity occurs, the toxicity will be graded, 
and appropriate supportive care treatment will be administered to decrease the signs and 

 
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symptoms thereof.  Dose adjustments will be based on the organ system exhibiting the 
greatest degree of toxicity.  A maximum of two dose reductions for the Study Drug or either 
chemotherapy will be allowed.  Patients requiring >2 dose reductions will be discontinued 
from the offending study drug/chemotherapy but will be allowed to continue on other 
agent(s) if appropriate.   
Doses of pemetrexed and carboplatin as well as Study Drug if indicated will be modified 
based on hematologic and non-hematologic toxicity.  If dose reductions are necessary they 
will be permanent for the remainder of the treatment.  Doses will be adjusted according to the 
dose modification tables that follow.  Any patient requiring a toxicity-related dose delay of 
more than 21 days from the intended day of the next scheduled dose must be discontinued 
from the offending agent(s). 
Table 2. 
Pemetrexed Dose Level Modifications   
Dose Level 
Pemetrexed (IV mg/m2) 
0 (starting dose) 
500 
-1 
400 
-2 
300 
Table 3. 
Carboplatin Dose Level Modifications 
Dose Level 
Carboplatin (AUC) 
0 (starting dose) 
6 
-1 
5 
-2 
4 
Table 4. 
OGX-427 Dose Level Modifications 
Dose Level 
OGX-427(IV mg) 
0  
600 mg 
-1 
500 mg 
-2 
400 mg 
To maintain study blinding, the volume for OGX-427/placebo will be adjusted to ~ 290 mL for each 
administration.  
 

 
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6.1 
Hematologic Toxicity 
Blood counts will be obtained at the beginning of each cycle.  To start a new treatment cycle, 
the patient must have the following blood counts:  ANC ≥1500/μL and platelet count 
≥100,000/μL.   Hematologic dose modifications apply only to Day 1 values of each cycle.  
Dose reductions are not based on nadirs occurring during the previous treatment cycle.  
Dose level modifications for pemetrexed, carboplatin, and Study Drug due to hematologic 
toxicity are shown in Table 5.  For toxicities that lead to a dose reduction, the dose will not 
be re-escalated during subsequent cycles.  If hematologic parameters do not recover within 
≤3 weeks (21 days), the patient should be removed from the Study Treatment Phase and start 
the Maintenance Phase if appropriate (see Section 5.3).   
Grade 3 and 4 anemia should be treated along ASCO and Institutional Guidelines.

 
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Table 5. 
Day 1 Hematologic Dose Modifications   
Blood Counts 
Pemetrexeda 
Carboplatina 
Study Drug 
ANC ≥1500/µL;  
Platelets ≥100,000/µL 
No dose modification 
No dose modification 
No dose modification 
ANC 1500/µL and/or;  
Platelets <100,000/µL 
Delay doseb and resume 
with a reduction of 1 
dose level (Table 2) 
Delay doseb and resume 
with a reduction of 1 
dose level (see Table 3) 
Delay doseb and resume 
with a reduction of 1 
dose level only for the 
second or subsequent 
occurrence (see Table 4) 
Grade 3 neutropenic 
fever (ANC <1000/µL + 
Temperature ≥101F 
(38.5C)) or neutropenic 
infection 
 
Documented infection 
with Grade 3 
neutropenia (ANC 
<1000/µL)  
Grade 4 neutropenia 
(ANC <1000/µL 
>7 days)  
Grade 4 
thrombocytopenia 
(platelet count <25 
x 109/L >7 days 
Treat neutropenic fever 
or infection according 
to institutional 
guidelines.  Resume with 
reduction of 1 dose level 
(see Table 2) 
 
With recurrence of any 
of these toxicities, the 
patient should be 
removed from study 
treatment. 
Resume with reduction 
of 1 dose level.  
Consider G-CSF 
(see Table 3) 
 
 
With recurrence of any  
of these toxicities, the 
patient should be 
removed from study 
treatment. 
 
Delay doseb and resume 
with a reduction of 1 
dose level 
 
 
 
With recurrence of any  
of these toxicities, the 
patient should be 
removed from study 
treatment. 
Grade 4 febrile 
neutropenia or grade 4 
infection with 
neutropenia (both 
defined as septic shock). 
Thrombocytopenic 
hemorrhage (gross not 
occult bleeding) 
associated with a platelet 
count <50 x 109/L 
Remove patient from 
study treatment and 
follow for disease 
progression 
Remove patient from 
study treatment and 
follow for disease 
progression 
Remove patient from 
study treatment and 
follow for disease 
progression 
a 
No more than two dose reductions will be allowed for any patient.  Patients requiring additional dose 
modifications due to toxicity will discontinue protocol treatment. 
b 
Hold chemotherapy cycle until hematologic parameters return to adequate levels (i.e., ANC 1500/µL, 
platelets 100,000/µL).  If hematologic parameters have not recovered within 21 days (3 weeks), the 
patient will be removed from the study treatment. 
Note:  Hematologic dose modifications apply only to Day 1 values of each cycle.  Dose reductions are not 
based on nadirs occurring during the previous treatment cycle. 

 
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6.2 
Non-Hematologic Toxicity Dose Modifications 
Dose modifications for non-hematologic toxicities should be based on toxicities occurring during 
the previous cycle.  Most dose modifications below, but not all, are for both chemotherapies.  If 
grade 3 or 4 non-hematologic toxicity (other than nausea, vomiting, fatigue, malaise, anorexia, 
lethargy, or alopecia) occurs, treatment with  pemetrexed,  carboplatin, and possibly Study Drug 
(see below) should be held, and should be resumed at a one level dose reduction (see Table 2 and 
Table 3) once toxicity recovers to ≤ grade 1.  If the toxicity is clearly attributable to one drug, 
then dose reduction of only that drug is necessary.  For example, if the toxicity is known to occur 
with only one of the chemotherapeutic agents (e.g. neurotoxicity with carboplatin but not 
pemetrexed or diarrhea with pemetrexed but not carboplatin) the patient may remain on study 
treatment and only the offending chemotherapy will be held, dose adjusted, or discontinued.  
Although there is little evidence that OGX-427 increases toxicity above that of chemotherapeutic 
agent(s) it is administered with, except for infusion reactions, whether Study Drug is held, 
adjusted, or discontinued is up to the discretion of the treating Investigator.  For toxicities that 
lead to a dose reduction, the dose will not be re-escalated during subsequent cycles.  Any patient 
who develops grade 3 or 4 toxicity (in the Study Treatment Phase or the Maintenance Phase) that 
does not resolve to ≤ grade 1 within 3 weeks should be removed from the study treatment. 
 

 
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Table 6. 
Non-Hematologic Toxicity Dose Modifications   
NCI CTCAE Grade 
Pemetrexed Dose  
Carboplatin Dose  
Study Drug  
Grade 0, 1, or 2 (except 
neurotoxicity) 
 
No modification 
No modification 
No modification 
Grade 3b,c, d, e (except 
transaminase elevation)    
Holda 
Holda 
Holda 
Grade 4b, e          
Toxicity resolves to 
grade ≤1 
Resume with a one level 
dose reduction 
Resume with a one level 
dose reduction 
Resume with a one level 
dose reduction 
Second repeat incidence 
of Grade 3 or 4 toxicity 
(except nausea, vomiting, 
fatigue/malaise/ 
lethargy, anorexia,  and 
alopecia) 
Discontinue treatment 
Discontinue treatment 
Discontinue treatment 
Grade 2  
Creatinine Clearance 
(calculated by Cockcroft-
Gault method)  
Hold  
No modification 
No modification 
Grade 3  
Creatinine Clearance 
(calculated by Cockcroft-
Gault method) 
Holda 
Holda 
Hold  
Grade 4 
Creatinine Clearance 
(calculated by Cockcroft-
Gault method) 
Once toxicity resolves to 
Grade ≤1 resume with a 
one level dose reduction 
Once toxicity resolves to 
Grade ≤1 resume with a 
one level dose reduction 
Once toxicity resolves to 
Grade ≤1 resume with a 
one level dose reduction 
Mucositis Grade 3 or 4  
Holda 
Holda 
Hold 
       Mucositis resolves to 
grade ≤1  
Resume with a one level 
dose reduction 
 No modification 
No modification 
Transaminase Elevation 
Grade 1-3 
No modification 
No modification 
No modification 
Transaminase Elevation 
Grade 4 
Holda 
Holda 
Holda 
Neurotoxicity 
Grade 1 or 2  
No modification 
Reduce with a two level 
dose reduction 
No modification 
Neurotoxicity Grade 3  
or 4  
Discontinue treatment 
Discontinue treatment 
Discontinue treatment 
Diarrhea Grade 3 or 4 
or requiring 
hospitalization  
Holda  
Holda  
Hold 
Toxicity resolves to 
grade ≤1 
Resume with a one level 
dose reduction 
No modification 
No modification 
 
 
 
 
a Both chemotherapy agents should be held until toxicity resolves to ≤ grade 1.  Any patients who develop irreversible grade 3/4 
non-hematologic toxicity, or toxicity that does not resolve to ≤ grade 1 within 3 weeks, should be removed from the study 
treatment.  No more than 2 dose reductions are allowed for either chemotherapy agent. 

 
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b Dose reduction for nausea and vomiting should be made only if grade 3 or grade 4 toxicity occurs in spite of maximum 
antiemetics. 
c No dose reduction is needed for grade 1-3 transaminase elevations. 
d    For a Grade 3 pulmonary embolism, the dose should be held but the subsequent doses do not have to be reduced one dose 
level, at the Investigator’s discretion.   
e   Patients who manifest a Grade 3 electrolyte value(s) i.e., hypokalemia, do not require a dose reduction once the electrolyte 
issue is resolved.  Patients who manifest a Grade 4 electrolyte value(s) do not have to be removed from protocol for a Grade 
4 electrolyte value, at the Investigator’s discretion; Example: Grade 4 elevated glucose in a patient with diabetes mellitus. 
 
6.2.1 
Specific Non-Hematologic Toxicities   
6.2.1.1 
Diarrhea 
In the event of grade 3 or 4 diarrhea, the following supportive measures are recommended:  
hydration, octreotide, and anti-diarrheals. 
If diarrhea is severe (i.e., requiring IV rehydration) and/or associated with fever or severe 
neutropenia (grade 3 or 4), broad-spectrum antibiotics must be prescribed.  Patients with severe 
diarrhea or any diarrhea associated with severe nausea or vomiting should be hospitalized for IV 
hydration and correction of electrolyte imbalances.  
6.2.1.2 
Febrile Neutropenia 
Patients experiencing febrile neutropenia with significant symptoms should be managed in a 
hospital setting according to standard procedures, with the urgent initiation of IV antibiotic 
therapy.  Patients with febrile neutropenia without symptoms should be managed according to 
standard guidelines. 
6.2.1.3 
Clinically Significant Effusions 
For patients who develop or have baseline clinically significant pleural or peritoneal effusions 
(on the basis of symptoms or clinical examination) before or during initiation of pemetrexed 
therapy, consideration should be given to draining the effusion prior to dosing.     
6.2.1.4 
Motor Neuropathy or Muscle Weakness 
Any onset of > grade 2 motor neuropathy or > grade 2 muscle weakness should be evaluated by 
an electromyogram (EMG) to rule out the possibility of chronic inflammatory demyelinating 
polyneuropathy (CIDP). With a diagnosis of CIDP the patient should be discontinued from study 
treatment.  
6.3 
Dose Modifications for Infusion Reactions 
Infusion reactions (e.g. rash, urticaria, erythema, pruritus, bronchospasm, and hypotension) can 
occur with the agents used in this study.  There is increased risk of a reaction with carboplatin.  
Carboplatin must be discontinued in patients experiencing a grade 3 or 4 infusion reaction during 
treatment. 
To identify the grade of a reaction, refer to the list below adapted for the General Disorders and 
Administration Site Conditions section of the NCI CTCAE Version 4.0: 

 
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 Grade 1:  Mild transient reaction; infusion interruption not indicated; intervention 
not indicated. 
 Grade 2:  Therapy or infusion interruption indicated but responds promptly to 
symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, IV fluids 
indicated for ≤24 hours). 
 Grade 3:  Prolonged (e.g., not rapidly responsive to symptomatic mediation and/or 
brief interruption of infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical sequelae.  Note:  any 
infusion that is interrupted and not resumed within the visit will be considered a 
Grade 3 reaction. 
 Grade 4:  Life-threatening consequences; urgent intervention indicated. 
If any of the agents are discontinued due to an infusion reaction, the other agent(s) may be 
continued. 
In the event of an infusion reaction, obtain vital signs, follow the institutional guidelines of each 
site and the recommendations shown in the tables below for OGX-427/placebo infusion reactions 
based on the grade of the reaction.   
Table 7. 
Dose Modifications for Infusion Reaction for OGX-427/Placebo  
Toxicity 
Dose Modification 
Any Grade 1 infusion reaction 
Slow the rate of infusion of the drug until resolution of symptoms, 
then resume at the planned infusion rate. 
Grade 2 or 3 infusion reaction 
in a patient not on steroid 
prophylaxis  
Stop the infusion.  Give dexamethasone 8 mg IV, diphenhydramine 
50 mg IV, and/or an H2 antagonist (e.g. Ranitidine 50 mg IV) after 
consultation with the attendant physician.  Resume after recovery of 
symptoms at a slower rate, and then increase incrementally toward the 
initial rate. 
Resume premedication regimen to include dexamethasone 8 mg, 
diphenhydramine 50 mg, and/or an H2 antagonist. 
Grade 2 or 3 infusion reaction 
in the presence of steroid 
prophylaxis (after initial 
loading doses) 
Stop the infusion. Give dexamethasone 8 mg IV, diphenhydramine 50 
mg IV, and/or an H2 antagonist (e.g. Ranitidine 50 mg IV) after 
consultation with the attendant physician.  Resume after recovery of 
symptoms at a slower rate, and then increase incrementally toward the 
initial rate.  
Reduce the OGX-427/placebo by one dose level for all subsequent 
doses.   
Grade 4 infusion reaction 
Stop the infusion.  Discontinue OGX-427/placebo.   
*There will be no dose reductions of OGX-427/placebo during the Loading Dose period.  Per protocol, all patients are given a 
lower dose of OGX-427/placebo and receive maximal prophylactic medication during the loading dose period in attempt to 
decrease the incidence and severity of any infusion reaction.  Grade 3 reactions have been uncommon in other OGX-427 trials. 

 
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7 
TRIAL ASSESSMENTS AND EVALUATIONS 
7.1 
Overview 
All patients should visit the trial center on the days specified within this protocol.  The baseline 
medical history, physical examination, ECOG PS, complete blood counts (CBC) with 3-part 
differential and platelets, and comprehensive metabolic profile (CMP), should be done ≤ 7 days 
prior to initiation of treatment.  However, if these initial examinations are obtained within 72 
hours prior to the initiation of treatment they do not have to be repeated.  Scans should be 
performed ≤ 4 weeks prior to initiation of treatment. 
7.2 
Baseline Trial Assessments 
 Informed consent form prior to any other study related procedures  
 Medical history and demographics  
 Smoking history 
 Physical examination including measurements of height (first visit) and weight   
 Vital signs (resting heart rate, blood pressure, respiratory rate, oral temperature) 
 ECOG PS (see Appendix A) 
 Concomitant medication review 
 CBC including 3-part differential and platelets   
 CMP (See Section 7.9) 
 7 mL blood (red top tube) for serum Hsp27  
 Serum or urine pregnancy test (must be performed within 72 hours prior to the 
initiation of treatment) 
 Archived tumor tissue (See Section 5.3.1) 
 Electrocardiogram (ECG) (repeat if clinically indicated) 
 Tumor Evaluation 
 
CT Scan of Chest to include adrenal glands  (CT Scan of Abdomen and 
Pelvis required if adrenal glands are not included on CT Scan of Chest)   
 
PET Scan or Bone scan   
 
CT Scan Head or MRI Brain 
7.3 
Study Treatment Assessments   
7.3.1 
OGX-427 (or Placebo) Loading Dose Period Assessments 
 Vital signs pre-dosing (resting heart rate, blood pressure, respiratory rate, oral 
temperature) 
 AE assessment   
 Concomitant medication review 
 7 mL blood (red top tube) for serum Hsp27 (prior to first loading dose)   

 
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7.4 
Treatment Phase Assessments  
7.4.1 
Cycle 1 Day 1  
 Physical examination including measurement of weight and vital signs    
 ECOG PS (see Appendix A)   
 AE assessment   
 Concomitant medication review    
 CBC, including 3-part differential and platelets   
 CMP (See Section 7.9) 
 7 mL blood (red top tube) for serum Hsp27 
7.4.2 
Cycle 1 Days 8 and 15 (±72 hours)  
 Vital signs pre-dosing 
 CBC, including 3-part differential and platelets (Day 8 and Day 15)   
 AE assessment  (Day 8 and Day 15) 
 Concomitant medication review 
 CMP (see Section 7.9) (Day 8 and Day 15) 
7.4.3 
Cycles 2 – 4, Day 1 (±72 hours) 
 Physical examination including measurement of weight and vital signs pre-dosing   
 ECOG PS (see Appendix A)   
 AE assessment  
 Concomitant medication review   
 CBC, including 3-part differential and platelets  
 CMP (See Section 7.9)   
 7 mL blood (red top tube) for serum Hsp27 
7.4.4 
Cycles 2 – 4 Days 8 and 15 (±72 hours) 
 Vital signs pre-dosing 
 CBC, including 3-part differential and platelets  
 AE assessment 
 Concomitant medication review   
7.5 
Every 2 Cycles (6 Weeks) 
Patients will be evaluated for response to treatment after every 2 cycles of treatment (end of 
Cycles 2 and 4).  The following assessments will be performed if abnormal at baseline or 
clinically indicated: 
 Tumor Evaluation 

 
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 
CT Scan of Chest with adrenal glands included.  (CT Scan of Abdomen and 
Pelvis required if adrenal glands are not included on CT Scan of Chest)   
7.6 
Maintenance Treatment Assessments 
7.6.1 
Day 1 Every 21 Days (±72 hours) 
 Physical examination including measurement of weight and vital signs pre-dosing 
 ECOG PS (see Appendix A)   
 AE assessment  
 Concomitant medication review   
  CBC, including 3-part differential and platelets  
 CMP (See Section 7.9)   
 7 mL blood (red top tube) for serum Hsp27 
7.6.2 
Maintenance Days 8 and 15 (±72 hours) 
 Vital signs pre-dosing 
 CBC, including 3-part differential and platelets 
 AE assessment 
 Concomitant medication review 
7.6.3 
Every 2 Cycles (6 Weeks) During Maintenance (±7 days)   
Patients will be re-evaluated for response to treatment after every 2 cycles during the maintenance 
portion.  The following assessments will be performed if abnormal at baseline or clinically indicated: 
 Tumor Evaluation 
 
CT Scan of Chest with adrenal glands included.  (CT Scan of Abdomen and 
Pelvis required if adrenal glands are not included on CT Scan of Chest)   
7.7 
End of Study Treatment  
Subjects will return to the study center within 30 days after treatment ends due to progressive 
disease, or discontinuation from trial treatment due to unacceptable toxicity or a decision to 
discontinue study treatment by the subject or the study physician.    
 Physical examination including measurement of weight and vital signs   
 ECOG PS (see Appendix A) 
 AE assessment 
 Concomitant medication review   
 CBC, including 3-part differential and platelets   
 CMP (See Section 7.9)  
 7 mL blood (red top tube) for serum Hsp27 
 Tumor Evaluation 

 
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 
CT Scan of Chest with adrenal glands included if not performed within last 
30 days.  (CT Scan of Abdomen and Pelvis required if adrenal glands are 
not included on CT Scan of  Chest)   
7.8 
Follow-Up 
7.8.1 
Progression-Free Survival Follow-Up 
Patients who discontinue trial treatment prior to the occurrence of disease progression will be 
followed every 6 weeks from the date of last dose of study drug until disease progression or for 
up to 2 years whichever comes first.  Assessments at these visits will be performed as described 
in Appendix D.  Any subsequent cancer therapy will be documented. 
7.8.2 
Survival Follow-Up 
After disease progression is documented, subjects will be followed every 2 months for survival 
(e.g., date and cause of death) for up to 2 years or death, whichever comes first.  Subjects may be 
contacted during outpatient visits or by telephone (contact with family member acceptable).  Any 
subsequent cancer therapy will be documented.    
7.9 
Comprehensive Metabolic Profile Assessments 
The CMP panel can sometimes vary by institution.  The following laboratory tests should be performed 
for each subject for assessment of CMP:   
 glucose 
 blood urea nitrogen (BUN) 
 creatinine 
 sodium 
 potassium 
 chloride 
 calcium 
 carbon dioxide (CO2) 
 alkaline phosphatase (ALP) 
 AST  
 ALT  
 total bilirubin 
 total protein 
 albumin 

 
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8 
DRUG FORMULATION, AVAILABILITY, ADMINISTRATION AND TOXICITY 
INFORMATION 
8.1 
Study Drug (OGX-427 or Placebo) 
This is a blinded study.  Access to treatment assignment codes will be restricted to one or more 
mixing pharmacists/nurses who will be responsible for maintaining assignment records and all 
Study Drug (OGX-427 or Placebo) preparation.  
OGX-427 will be provided by OncoGenex Technologies, Inc.  Placebo will be D5W supplied by 
the site pharmacy.  Trial sites will obtain OGX-427 per instructions provided by SCRI 
Innovations to the participating sites.  Once OGX-427 is shipped to a site, it may not be shipped 
or shared with another site or subject. 
8.1.1 
Labeling, Packaging and Supply 
All clinical trial material will be labeled in accordance with local and federal regulations, 
stipulating that the product is for investigational use only.  Vials of OGX-427 must be stored in a 
secure, temperature monitored refrigerator, at a temperature of 2 - 8° C (36-46° F) until the time 
of use.  Do not freeze.  The drug substance and active ingredient of OGX-427 is an antisense 
oligonucleotide (ASO).  Refer to the Investigator’s Brochure for complete information. 
OGX-427 dosing solutions will be administered intravenously preferably using an infusion 
pump.  Once mixed for administration, it is recommended that the OGX-427 dosing solution be 
administered within 24 hours if kept at room temperature or refrigerated (2-8° C, 36-46° F).  
Investigational drug accountability records will be maintained documenting the utilization of the 
study drug at the clinical site. 
Placebo will be D5W supplied by the site pharmacy.  An additional 40 mL of D5W will also be 
added to 250 mL of D5W so that the volume of placebo will be the same as the volume of OGX-
427 at each dose level to maintain the blind.  
8.1.2 
Preparation and Administration of Study Drug 
The OGX-427 drug dilution procedure should be performed according to the instructions below 
and following proper aseptic technique:  
OGX-427 should be stored between 2 - 8° C (36 – 46°F) prior to use. 
Once dose instructions have been received from the site Investigator, remove OGX-427 from the 
refrigerator and inspect the vials for particulate matter.  Vials containing particulate matter 
should not be used. 
Using proper aseptic technique withdraw the correct amount of OGX-427 from each vial using a 
syringe and a needle.  
To prepare Study Drug, begin with 250 mL of D5W, then add OGX-427, and additional D5W if 
required to the intravenous D5W solution, as shown in the table below.  For placebo add 40 mL 
of D5W to 250 mL of D5W.  
 

 
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Dose Period 
Dosage 
# of vials 
Volume of 
OGX-427 
Volume of D5W 
Loading Dose  
600 mg 
3 
24 mL 
16 mL 
Treatment Cycles 
600 mg 
3 
24 mL 
16  mL 
Maintenance 
600 mg 
3 
24 mL 
16  mL 
Attach the intravenous tubing to the bag and prime the IV line with the D5W solution. 
Label the bag with appropriate identification. 
Study Drug can be administered via a central venous line for continuous intravenous infusion or 
a secure peripheral line may be used.  This decision is at the discretion of the Investigator.  The 
infusion should be administered over 2 hours preferably using an infusion pump.  Dosing 
solutions and volumes for OGX-427 dose modifications are in the table below:   
Dose Solutions and Volumes for Study Drug for Dose Modifications 
Initial Dose 
Dosage 
Modification 
# of vials 
Volume of 
OGX-427 
Volume of D5W 
600mg  
500mg 
2.5 
20 mL 
20  mL 
 
400 mg 
2 
16 mL 
24 mL 
 
8.1.3 
Precautions and Risks Associated with OGX-427 
The risks and side effects that have been seen in patients who have been treated with OGX-427 
alone that have been felt to be possibly, probably, or definitely related to Study Drug are defined 
below.  
Very likely (greater than 20% of patients):  
 Infusion reactions, which occur during or soon after the infusion of OGX-427, 
have occurred in ~ 67% of patients, including cytokine release syndrome, when 
the loading dose was 600 mg and the patient was premedicated with an H2 
antagonist and antihistamine.  The most common symptoms have been chills, 
flushing, diarrhea, nausea, and vomiting.  The majority of reactions occurred with 
the first three loading doses and during the first weekly infusions of therapy.  
Reactions have continued to occur with further infusions in some patients.  
Reactions may require treatment or prophylaxis with corticosteroids.  On rare 
occasions, infusion reactions can be life-threatening. 
 Anemia    
 Lymphopenia  
 Decrease leukocytes  

 
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 Transient prolongation of PPT or elevated INR   
 Decrease in kidney function   
 Blood creatinine increased 
 Decrease in liver function (reversible)  
 Hyponatremia  
 Elevated ALT 
 Thrombocytopenia   
 Hypokalemia   
 Hyperglycemia   
 Nausea 
 Diarrhea  
 Fatigue  
_______________________________________________________________________  
Less likely (5-20% of patients):  
 Pyrexia  
 Decreased appetite  
 Vomiting  
 Pruritus  
 Peripheral neuropathy 
 Arthralgia  
 Dizziness  
 Hypertension  
 Neutropenia  
 Headache  
 Myalgia  
 Elevated bilirubin  
 Muscle weakness   
 Hematuria  
 Influenza like illness  
 Urticaria  
 Dyspnea  
 Abdominal pain  
 Erythema  
 Chest pain 
 Rash  
 Redness of the skin 
 Cytokine release syndrome, which occurs during or soon after the infusion of 
OGX-427.   
 Increased sweating or perspiration 
 Feeling of intense heat 
_____________________________________________________  
Rarely (but may be serious) (less than 5% of patients):  

 
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 Cerebral hemorrhage 
 Thrombosis  
 Pulmonary embolus  
 Vascular purpura 
 Hemolytic uremic syndrome (HUS) 
 Pancreatitis 
 Anaphylaxis or severe infusion reaction    
 Hemoptysis 
 Serious infection such as sepsis, pneumonia, abscess 
 Arrhythmia 
 Cardiac arrest 
 Gastrointestinal hemorrhage 
 Intestinal obstruction 
 Status epilepticus 
 Chronic inflammatory demyelinating polyneuropathy (CIDP)  
 Membranous nephropathy 
 Hypovolemic shock  
 Anasarca  
 Pyelonephritis 
 Sudden death 
8.2 
Pemetrexed 
Pemetrexed is FDA approved for NSCLC.  Commercials supplies will be used for this trial and 
the drug will not be provided.  Refer to the prescribing information for additional information. 
8.2.1 
Labeling, Packaging and Supply 
See full prescribing information for pemetrexed for complete details. 
8.2.2 
Preparation and Administration of Pemetrexed 
See full prescribing information for pemetrexed for complete details. 
8.2.3 
Precautions and Risks Associated with Pemetrexed 
See full prescribing information for pemetrexed for complete details. 
8.3 
Carboplatin 
Commercial supplies of carboplatin will be used for this trial and the drug will not be provided.  
Refer to the prescribing information for additional information. 

 
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8.3.1 
Labeling, Packaging and Supply 
See full prescribing information for carboplatin for complete details. 
8.3.2 
Preparation and Administration of Carboplatin 
See full prescribing information for carboplatin for complete details. 
8.3.3 
Precautions and Risks Associated with Carboplatin 
See full prescribing information for carboplatin for complete details. 
9 
RESPONSE EVALUATIONS AND MEASUREMENTS 
9.1 
Patients with Measurable Disease 
All subjects with measurable disease will be evaluated for response using the RECIST version 
1.1 (Appendix E) (Eisenhauer et al. 2009 ). 
10 STATISTICAL CONSIDERATIONS 
10.1 
Analysis Population 
Sample size considerations are based on PFS and follow-up considerations are based on OS.  The 
median PFS in the control group (carboplatin with pemetrexed plus placebo) is estimated to be 
approximately 5 months.  A PFS target hazard ratio (HR) of 0.60, corresponding to a median 
PFS in the experimental group (carboplatin with pemetrexed plus OGX-427) of 8.3 months is 
hypothesized.  The study will have 85% power to test this hypothesis using a one-sided log-rank 
at the 5% level of significance.  Based on a uniform 15-month accrual period, a minimum of 
approximately 12 months follow-up period for PFS and a loss to follow-up/nonevaluability for 
PFS assessment rate of approximately 10% per year, a total of 155 subjects will be randomized 
in a 1:1 manner to achieve the targeted number of events in the scheduled PFS follow-up time.  
Sample size and power calculations were performed using PASS 2008 software. 
10.2 
Sample Size Considerations 
All statistical analyses will be performed using SAS 9.1 or higher. 
10.2.1 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized using descriptive statistics for 
continuous variables, and frequencies and percentages for categorical variables. 
10.2.2 
Stratification Factors 
Randomization will be stratified by histology and smoking status for the purpose of balance in 
enrollment and exploratory analysis only.  The stratification factors for this study are: 
Histology:  
Large cell carcinoma or adenocarcinoma.  Patients with mixed 
squamous/non-squamous histology are permitted provided the predominant histology 
is non-squamous and are to be stratified as adenocarcinoma.  Patients with NOS 
designation or small-cell elements are not permitted. 

 
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Smoking Status:  Patients will be stratified as smokers or non-smokers.  Patients 
with a lifetime history of <100 cigarettes are stratified as non-smokers.  Patients with  
history of smoking  but have not smoked for >15 years are also considered non-
smokers.  All others will be classified as smokers. 
10.2.3 
Efficacy Analyses 
All efficacy parameters will be analyzed using the intent-to-treat (ITT) population.  Efficacy 
parameters may be additionally analyzed using the Safety population if more than 10% of 
randomized subjects do not receive study treatment. 
The efficacy endpoints are PFS (primary) and the objective response rate (ORR) and OS 
(secondary). 
10.2.4 
Primary Efficacy Endpoint 
Progression-free survival (PFS) is defined as the time (in months) from the date of randomization 
to the date of the first observation of progression based on radiologic assessment (RECIST 
criteria version 1.1) or date of death, whatever the cause, in the absence of progressive disease 
(PD), or censored at the date of last adequate tumor assessment.  
The primary analysis is to conduct a comparison of PFS between the OGX-427 and placebo 
groups in the ITT population using the unstratified log-rank test.  The primary analysis will be 
conducted at the time when at least 117 PFS events have been accumulated for the study.  In 
addition, the hazard ratio (OGX-427: placebo) and corresponding two-sided 95% confidence 
interval (CI) will be estimated based on a Cox proportional hazards model using treatment group 
as the predictive factor.  Each treatment group will be summarized using Kaplan-Meier curves, 
along with the respective median time point and two-sided 95% confidence interval obtained 
from the product-limit estimates. 
10.2.5 
Secondary Efficacy Endpoints 
Objective response rate (ORR) is defined as the proportion of subjects with objective evidence of 
a CR or a PR using RECIST criteria version 1.1.  ORR for each treatment group will be 
presented as the point estimate along with two-sided 95% confidence intervals calculated using 
both asymptotic normal approximation and exact binomial methods.  Comparison of ORR 
between the OGX-427 and placebo treatment groups will be performed using Fisher’s exact test. 
Overall survival (OS) is defined as the time (in months) from the date of randomization to the 
date of death, due to all cause, or censored at the date last known alive.  OS between the OGX-
427 and placebo groups in the ITT population will be compared using the unstratified log-rank 
test.  Each treatment group will be summarized using Kaplan-Meier curves, along with the 
respective median time point and two-sided 95% confidence interval obtained from the product-
limit estimates.  
10.2.6 
Safety Analyses 
All safety parameters will be summarized using the Safety population.  

 
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Safety assessments will consist of monitoring and recording protocol-defined AEs and serious 
adverse events (SAEs); measurement of protocol specified hematology, and clinical chemistry 
variables; measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation.  
The analyses of safety will be based on the frequency of adverse events and their severity.  Worst 
toxicity grades per patient will be tabulated for select adverse events and laboratory 
measurements by using NCI CTCAE criteria v4.0. 
10.3 
Analysis Populations 
The analysis populations for this study are the ITT and Safety populations. 
Intent-to-Treat (ITT) population will consist of all randomized subjects.  
Safety population will consist of all randomized subjects who received at least one dose of study 
treatment.    
10.4 
Planned Interim Analysis 
No interim analyses are planned. 
10.5 
Data Safety Monitor  
Safety monitoring will be performed by an independent Data Safety Monitor (DSM) who will be 
designated for this study since this will be the first evaluation of OGX-427 in combination with 
carboplatin and pemetrexed.  A complete DSM review will occur after the first 12 patients have 
been enrolled (6 patients per treatment arm) and treated for at least one cycle to assess the 
frequency of ≥ Grade 3 adverse events and all serious adverse events.  In addition, a second 
review will occur after the next 12 patients have been enrolled, for a total of 24 patients.  The 
frequency of further safety reviews will be determined by the DSM based on these early safety 
reviews. 
The primary responsibility of the DSM will be overall safety for patients on the protocol.  The 
DSM will monitor the safety of individual patients during the entire adverse event reporting 
period (i.e., from the first administration of Study Drug through 30 days after completion of 
study treatment).  The sponsor will provide the DSM with a copy of any unexpected Study Drug-
related SAE Report Form within 15 business days of receipt by the sponsor.  The sponsor will 
also provide the DSM with copies of all expedited SAE reports submitted to regulatory agencies.  
In addition, the DSM will:   
 Perform periodic reviews of all safety data for individual patients.  These listings 
would be based on the available safety data in the clinical study database and will 
include: demographic characteristics, general medical history (including 
concurrent illnesses), disease history, Study Drug administration, vital signs 
during infusion, clinical laboratory data (serum chemistry, hematology), and 
reported adverse events. 

 
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 Perform continued monitoring of Grade 3 and higher adverse events and SAEs on 
an ongoing basis for all patients.   
 Perform toxicity reviews of the first 6 patients enrolled in Group 1 (OGX-427) for 
dose-limiting toxicities (DLTs) and the need for one dose-level reduction for 
weekly OGX-427 for the remainder of the study as defined in Section 10.5.1.  
 
10.5.1 Dose-Limiting Toxicity 
If in the opinion of the Data Safety Monitor, DLTs that are likely to have resulted from exposure 
to OGX-427, the DSM may modify the OGX-427 dose in Group 1.  If the first six (6) patients 
enrolled in the OGX-427 group have 2 or more DLTs during Cycle 1, the weekly dose of 600 mg 
of OGX-427 should be reduced for the remainder of the study to 500 mg for all patients.  There 
will be one dose reduction allowed for patients starting OGX-427 treatment at the weekly dose 
of 500 mg (Table 4).  The loading dose will remain at 600 mg. 
Dose-limiting toxicities will be defined as follows: 
 
Grade 4 neutropenia or thrombocytopenia lasting >7 days;  Grade ≥3 febrile 
neutropenia; and Grade ≥3 thrombocytopenia with Grade >2 hemorrhage; 
 
Grade ≥ 3 non-hematologic toxicity with the exception of:   
o 
Fatigue, malaise, lethargy, anorexia  
o 
Grade ≥3 diarrhea or nausea that resolves to ≤ Grade 2 within 48 hours   
o 
Grade ≥3 ALT/AST elevation that resolves to ≤ Grade 2 within 7 days  
o 
Grade 3 pulmonary embolus 
o 
Grade 3 hyperglycemia in patients with known diabetes mellitus 
 
Treatment delay of ≥21 days due to unresolved toxicity  
 
11 SAFETY REPORTING AND ANALYSES 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB. 
11.1 
Adverse Events  
The PI is responsible for recognizing and reporting AEs (see Section 11).  It is SCRI 
Innovation’s responsibility to report relevant SAEs to the applicable local, national, or 
international regulatory bodies.  Oncogenex will be responsible for reporting to international 
regulatory bodies. 
11.1.1 
Definitions of Adverse Events 
An AE is the development of an undesirable medical condition, or the deterioration of a pre-
existing medical condition following or during exposure to a medicinal product, whether or not 
considered causally related to the product.   

 
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An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver), or the abnormal results of an investigation (e.g., laboratory 
findings). 
11.1.2 
Recording and Reporting of Adverse Events 
All AEs of any subject during the course of the study will be recorded in the CRF, and the 
investigator will give his or her opinion as to the relationship of the AE to the study drug 
treatment (i.e., whether the event is related or unrelated to study drug administration).   
All AEs should be documented.  A description of the event, including its date of onset and 
resolution, whether it constitutes an SAE or not, any action taken (e.g., changes to study 
treatment), and outcome, should be provided, along with the investigator’s assessment of 
causality (i.e., the relationship to the study treatment[s]).  For an AE to be a suspected treatment-
related event there should be at least a reasonable possibility of a causal relationship between the 
protocol treatment and the AE.  Adverse events will be graded according to the NCI CTCAE 4.0.    
If the AE is serious, it should be reported immediately to SCRI Innovations Safety Department.  
Other untoward events occurring in the framework of a clinical study are also to be recorded as 
AEs (i.e., AEs that occur prior to assignment of study treatment that are related to a study-
mandated intervention, including invasive procedures such as biopsies, medication washout, or 
no treatment run-in). 
Any clinically significant signs and symptoms; abnormal test findings; changes in physical 
examination; hypersensitivity; and other measurements that occur will be reported as an AE, and 
collected on the relevant CRF. 
Test findings will be reported as an AE if the test result requires an adjustment in the study 
drug(s) or discontinuation of treatment; and/ or test findings require additional testing or surgical 
intervention; a test result or finding is associated with accompanying symptoms; or a test result is 
considered to be an AE by the investigator. 
All AEs regardless of seriousness or relationship to study treatment, spanning from the start of 
study treatment, until 30 calendar days after discontinuation or completion of study treatment as 
defined by the clinical study for that subject, are to be recorded in the CRF.   
11.1.3 
Handling of Adverse Events 
All AEs resulting in discontinuation from the trial should be followed until resolution or 
stabilization.  Subjects must be followed for AEs for 30 calendar days after discontinuation or 
completion of clinical trial-specific treatment (e.g., chemotherapy, radiation, oral medications, 
targeted therapy, and surgery).  All new AEs occurring during this period must be reported and 
followed until resolution unless, in the opinion of the investigator, the AE or laboratory 
abnormality/ies are not likely to improve because of the underlying disease.  In this case, the 
investigators must record his or her reasoning for this decision in the subject’s medical record 
and as a comment on the CRF.  After 30 days of completion of study-specific treatment or 
discontinuation, only AEs, SAEs, or deaths assessed by the investigator as treatment related are 
to be reported. 

 
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11.2 
Serious Adverse Events  
11.2.1 
Definitions of Serious Adverse Events  
The definitions of SAEs are given below.  The Principal Investigator is responsible for ensuring 
that all staff involved in the trial are familiar with the content of this section. 
An SAE or reaction is defined as any untoward medical occurrence that: results in death, is 
immediately life-threatening, requires at least a 24-hour inpatient hospitalization or prolongation 
of existing hospitalization, results in persistent or significant disability/incapacity, or results in a 
congenital anomaly/birth defect. 
The definition of SAE also includes any important medical event.  Medical and scientific 
judgment 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 subject or may require intervention to 
prevent one of the other outcomes listed in the previous definition.  These should also usually be 
considered serious.  Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or development of drug dependency or drug abuse.  Progression of malignancy 
(including fatal outcomes), if documented by use of appropriate method (for example, as per 
RECIST criteria for solid tumors), should not be reported as an SAE.  
Treatment within or admission to the following facilities is not considered to meet the criteria of 
“inpatient hospitalization” (although if any other SAE criteria are met, the event must still be 
treated as an SAE and immediately reported): 
 Emergency Department or Emergency Room 
 Outpatient or same-day surgery units 
 Observation or short-stay unit 
 Rehabilitation facility 
 Hospice or skilled nursing facility 
 Nursing homes, Custodial care or Respite care facility 
Hospitalization during the trial for a pre-planned surgical or medical procedure (one which was 
planned prior to entry in the trial), does not require reporting as an SAE to the SCRI Innovation 
Safety Department.  Deaths that are attributed by the Investigator solely to the progression of 
disease do not require reporting as an SAE to the SCRI Innovations Safety Department. 
11.2.2 
Serious Adverse Event Reporting by Investigators 
It is important to distinguish between “serious” and “severe” adverse events, as the terms are not 
synonymous.  Severity is a measure of intensity; however, an AE of severe intensity need not 
necessarily be considered serious.  For example, nausea which persists for several hours may be 
considered severe nausea, but may not be considered an SAE.  On the other hand, a stroke which 
results in only a limited degree of disability may be considered only a mild stroke, but would be 

 
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considered an SAE.  Severity and seriousness should be independently assessed when recording 
AEs on the CRF and SAEs on the SAE Report Form. 
Adverse events classified by the treating investigator as serious require expeditious handling and 
reporting to SCRI Innovations Safety Department in order to comply with regulatory 
requirements.  Serious adverse events may occur at any time from the start of study treatment 
through the 30-day follow-up period after the last study treatment.  SCRI Innovations Safety 
Department must be notified of all SAEs, regardless of causality, within one business day of the 
first knowledge of the event by the treating physician or research personnel.   
To report an SAE, the SAE Report Form should be completed with the necessary information.  
All SAEs occurring from the start of study treatment, until 30 calendar days of last study 
treatment must be reported to the SCRI Innovations Safety Department as SAEs on the SAE 
Report Form and followed until resolution (with autopsy report if applicable). 
Deaths and other SAEs occurring >30 calendar days after last study treatment that are deemed 
‘possibly’ or ‘probably’ related to study drug must be reported as SAEs on the SAE Report Form 
within 1 day of first knowledge of the event by the treating physician or research personnel (with 
an autopsy report if available). 
Deaths occurring >30 calendar days after last study treatment and not attributed to study 
treatment (e.g., disease progression) need not be reported as SAEs, but simply captured on the 
appropriate CRF. 
To report an SAE, the SAE Report Form should be completed with the necessary information. 
The SAE report Form should be sent to SCRI Innovations Safety Department via fax or e-mail 
using the following contact information (during both business and non-business hours):   
SCRI Innovations Safety Department  
Safety Dept. Phone #:  615-329-7358 
Safety Dept. Fax #:      866-807-4325 
Safety Dept. Email:     CANN.SAE@scresearch.net 
 
 
Transmission of the SAE report Form should be confirmed by the site personnel submitting the 
report. 
Follow-up information for SAEs and information on non-serious AEs that become serious should 
also be reported to SCRI Innovations Safety Department as soon as it is available; these reports 
should be submitted using the SCRI Innovations SAE Report Form.  The detailed SAE reporting 
process will be provided to the sites in the SAE reporting guidelines contained in the trial 
reference manual. 
Investigators must report SAEs and follow-up information to their responsible Institutional 
Review Board (IRB) according to the policies of the responsible IRB. 

 
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11.2.3 
Sponsor Serious Adverse Event Reporting Requirements  
This section applies solely to SCRI Development Innovations  
The Sponsor is responsible for reporting relevant SAEs to the competent authority, other 
applicable regulatory authorities, and participating investigators, in accordance with International 
Conference on Harmonization (ICH) guidelines, FDA regulations, and/or local regulatory 
requirements. 
The Sponsor will fax within one business day copies of the SCRI Innovations SAE Reporting 
Form for all SAEs that occur during the trial to the pharmaceutical company(ies) (i.e., 
OncoGenex Technologies, Inc) that are supporting the trial.  Follow-up reports and information 
for non-serious AEs that become serious will also be faxed to the pharmaceutical company(ies).  
If applicable, copies of investigational new drug (IND) Safety Reports and Medwatch 3500A 
form(s) submitted to the FDA will be faxed to the pharmaceutical companies as applicable.  
Reporting information and requirements specific to the pharmaceutical company(ies) who are 
supporting this trial are listed below.  
Safety reporting will be communicated to OncoGenex Technologies, Inc. using the contact 
information below: 
OncoGenex Technologies, Inc 
Phone:    
425-686-1500 
Fax:  
425-686-1600 
The Sponsor is responsible for reporting unexpected fatal or life-threatening events associated 
with the use of the study drugs to the regulatory agencies and competent authorities via 
telephone or fax within 7 calendar days after being notified of the event.  The Sponsor will report 
all related but unexpected SAEs including non-death/non-life-threatening SAEs associated with 
the use of the trial medications to the appropriate competent authorities (according to local 
guidelines), investigators, and central IRBs/Ethics Committees (except in the United States 
where investigators are responsible for reporting to their IRBs per local requirements) by a 
written safety report within 15 calendar days of notification. 
11.2.4 
Sponsor Reporting for Trials under an Investigational New Drug Assignment 
All written IND Safety Reports submitted to the FDA by the Sponsor must also be faxed to 
pharmaceutical company(ies) that are supporting the trial:  
OncoGenex Technologies, Inc. 
Phone:    
425-686-1500 
Fax:  
425-686-1600 
 

 
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11.3 
Recording of Adverse Events and Serious Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs or SAEs on 
the SAE Report Form and AE CRF.  Avoid colloquialisms and abbreviations. 
All AEs, including those that meet SAE reporting criteria, should be recorded on the AE CRF; 
AEs that meet the definition of an SAE should additionally be reported following the procedures 
noted in Section 11.2.  
11.3.1 
Diagnosis vs. Signs and Symptoms 
All AEs should be recorded individually in the subject’s own words (verbatim) unless, in the 
opinion of the Investigator or designated physician, the AEs constitute components of a 
recognized condition, disease, or syndrome.  In the latter case, the condition, disease, or 
syndrome should be named rather than each individual sign or symptom.  If a constellation of 
signs and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at 
the time of reporting, each individual event should be recorded as an AE or SAE as appropriate 
on the relevant form(s) (SAE Report Form and/or AE CRF).  If a diagnosis is subsequently 
established, it should be reported as follow-up information is available.  If a diagnosis is 
determined subsequent to the reporting of the constellation of symptoms, the signs/symptoms 
should be updated to reflect the diagnosis. 
11.3.2 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between subject evaluation 
timepoints.  Such events should only be recorded once on the SAE Report Form and/or the 
AE CRF.  If a persistent AE becomes more severe or lessens in severity, it should be recorded on 
a separate SAE Report Form and/or AE CRF.   
A recurrent AE is one that occurs and resolves between subject evaluation timepoints, and 
subsequently recurs.  All recurrent AEs should be recorded on an SAE Report Form and/or 
AE CRF. 
11.3.3 
Abnormal Laboratory Values 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as an AE or SAE, and the associated laboratory value or 
vital sign should be considered additional information that must be collected on the relevant 
CRF.  If the laboratory abnormality is a sign of a disease or syndrome, only the diagnosis needs 
to be recorded on the SAE Report Form or AE CRF. 
Abnormal laboratory values will be reported as an AE if the laboratory result requires an 
adjustment in the study drug(s) or discontinuation of treatment; and/ or laboratory findings 
require additional testing or surgical intervention; a laboratory result or finding is associated with 
accompanying symptoms; or a laboratory result is considered to be an AE by the investigator. 
11.3.4 
Deaths 
Deaths that occur during the study-specified AE reporting period that are attributed by the 
Investigator solely to progression of disease will be recorded on the “Trial Discontinuation” 

 
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CRF.  All other on-trial deaths, regardless of attribution, will be recorded on an SAE Report 
Form and expeditiously reported to the SCRI Innovations Safety Department. 
When recording an SAE with an outcome of death, the event or condition that caused or 
contributed to the fatal outcome should be recorded as the single medical concept on the SAE 
Report Form and Adverse Event page of the CRF.  If the cause of death is unknown and cannot 
be ascertained at the time of reporting, record “Death NOS” on the CRF Adverse Event page.  
During post-trial survival follow-up, deaths attributed to progression of disease will be recorded 
only on the “After Progressive Disease Follow-Up” CRF. 
11.3.5 
Hospitalization, Prolonged Hospitalization, or Surgery 
Any AE that results in hospitalization of >24 hours or prolongation of preexisting hospitalization 
should be documented and reported as an SAE unless specifically instructed otherwise in this 
protocol.  There are some hospitalizations that do not require reporting as an SAE (refer to 
Section 11.2). 
11.3.6 
Pre-Existing Medical Condition 
A pre-existing medical condition is one that is present at the start of the trial.  Such conditions 
should be recorded on the General Medical History CRF.  A pre-existing medical condition 
should be recorded as an AE or SAE only if the frequency, severity, or character of the condition 
worsens during the trial.  When recording such events on an SAE Report Form and/or AE CRF, 
it is important to convey the concept that the pre-existing condition has changed by including 
applicable descriptors. 
11.3.7 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies 
Pregnancy, abortion, birth defects, and congenital anomalies are events of special interest.  
Please refer to Section 11.4 for specific instructions. 
11.3.8 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria (See Section 11.2).  New primary cancers are those that are not 
the primary reason for the administration of the study treatment and have developed after the 
inclusion of the subject into the trial.  They do not include metastases of the original cancer.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
11.4 
Protocol-Defined Events of Special Interest 
The following are events of special interest, and will need to be reported expeditiously (see 
Section 11.2): 
Pregnancy, Abortion, Birth Defects/Congenital Anomalies: 
If a subject becomes pregnant while enrolled in the trial, a Pregnancy Form (a paper report form) 
should be completed and faxed to SCRI Innovations Safety Department.  If a pregnancy is 
confirmed, the subject must not receive any study drug(s), and must be discontinued from the 

 
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trial.  SCRI Innovations Safety Department should be notified expeditiously, irrespective of 
whether or not it meets the criteria for expedited reporting.  Abortions (spontaneous, accidental, 
or therapeutic) must also be reported to SCRI Innovations Safety Department. 
Congenital anomalies/birth defects always meet SAE criteria, and should therefore be 
expeditiously reported as an SAE, using the previously described process for SAE reporting.  A 
Pregnancy Form should also have been previously completed, and will need to be updated to 
reflect the outcome of the pregnancy. 
Pemetrexed, Carboplatin or OGX-427 Overdose 
Symptomatic and non-symptomatic overdose must be reported in the CRF.  Any accidental or 
intentional overdose with the study treatment that is symptomatic, even if not fulfilling a 
seriousness criterion, is to be reported to SCRI Innovations Safety Department within 
one working day using the corresponding screens in the  CRF, and following the same process 
described for SAE reporting (see Section 11.2) if the overdose is symptomatic.  
For information on how to manage an overdose of OGX-427, see the Investigator Brochure. 
For information on how to manage an overdose of pemetrexed, see the Package Insert. 
For information on how to manage an overdose of carboplatin, see the Package Insert. 
12 ETHICAL, FINANCIAL, AND REGULATORY CONSIDERATIONS 
This trial will be conducted according to the standards of Good Clinical Practice outlined in the 
ICH E6 Tripartite Guideline and CFR Title 21 part 312, applicable government regulations, 
institutional research policies and procedures and any other local applicable regulatory 
requirement(s).  
12.1 
Institutional Review Board Approval 
The trial protocol, ICF, IB, available safety information, subject documents (e.g., trial diary), 
subject recruitment procedures (e.g., advertisements), information about payments (i.e., PI 
payments) and compensation available to the subjects and documentation evidencing the PI’s 
qualifications should be submitted to the IRB for ethical review and approval if required by local 
regulations, prior to the trial start. 
The PI/Study Chair/Sponsor/CRO and/or designee will follow all necessary regulations to ensure 
appropriate, initial, and ongoing, IRB trial review.  The PI/Study Chair/Sponsor (as appropriate) 
must submit and, where necessary, obtain approval from the IRB for all subsequent protocol 
amendments and changes to the informed consent document.  Investigators will be advised by 
the Sponsor or designee whether an amendment is considered substantial or non-substantial and 
whether it requires submission for approval or notification only to an IRB. 
Safety updates provided by OncoGenex for OGX-427, will be prepared by the Sponsor or its 
representative as required, for submission to the relevant IRB. 
12.2 
Regulatory Approval 
As required by local regulations, the Sponsor will ensure all legal aspects are covered, and 
approval of the appropriate regulatory bodies obtained, prior to trial initiation.  If required, the 

 
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Sponsor will also ensure that the implementation of substantial amendment to the protocol and 
other relevant study documents happen only after approval by the relevant regulatory authorities. 
Safety updates provided by OncoGenex for OGX-427 will be prepared by the Sponsor or its 
representative as required, for submission to the relevant regulatory authority. 
12.3 
Insurance and Indemnity 
Details of insurance and/or indemnity will be contained within the written agreement between 
the PI or site and the Sponsor. 
12.4 
Informed Consent 
Informed consent is a process by which a subject voluntarily confirms his or her willingness to 
participate in a particular trial, after having been informed of all aspects of the trial that are 
relevant to the subject's decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form. 
The informed consent form will be submitted for approval to the IRB that is responsible for 
review and approval of the trial.  Each consent form must include all of the relevant elements 
currently required by the FDA, as well as local county authority or state regulations and national 
requirements. 
Before recruitment and enrollment into the trial, each prospective candidate will be given a full 
explanation of the trial.  Once the essential information has been provided to the prospective 
candidate, and the investigator is sure that the individual candidate understands the implications 
of participating in this trial, the candidate will be asked to give consent to participate in the trial 
by signing an informed consent form.  A notation that written informed consent has been 
obtained will be made in the subject’s medical record.  A copy of the informed consent form, to 
include the subject’s signature, will be provided by the investigator to the subject. 
If an amendment to the protocol substantially alters the trial design or the potential risks to the 
subjects, the subject’s consent to continue participation in the trial should be obtained. 
12.4.1 
Confidentiality 
12.4.2 
Subject Confidentiality 
Confidentiality of subject’s personal data will be protected in accordance with the Health 
Insurance Portability and Accountability Act of 1996 (HIPAA) and national data protection laws, 
as applicable.  HIPAA regulations require that, in order to participate in the trial, a subject must 
sign an authorization from the trial that he or she has been informed of following:  
 What protected health information (PHI) will be collected from subjects in this trial; 
 Who will have access to that information and why; 
 Who will use or disclose that information;  
 That health information may be further disclosed by the recipients of the information, and 
that if the information is disclosed the information may no longer be protected by federal 
or state privacy laws;  

 
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 The information collected about the research trial will be kept separate from the subject’s 
medical records, but the subject will be able to obtain the research records after the 
conclusion of the trial; 
 Whether the authorization contains an expiration date; and 
 The rights of a research subject to revoke his or her authorization.  
 
In the event that a subject revokes authorization to collect or use his or her PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e., that the subject is alive) 
at the end of their scheduled trial period. 
In compliance with ICH GCP guidelines and applicable parts of 21 CFR it is a requirement that 
the investigator and institution permit authorized representatives of the Sponsor, the regulatory 
authorities and the IRB direct access to review the subject’s original medical records at the site 
for verification of trial-related procedures and data.  
Measures to protect confidentiality include: only a unique trial number and initials will identify 
subjects on the CRF or other documents submitted to the Sponsor.  This information, together 
with the subject’s date of birth, will be used in the database for subject identification. Subject 
names or addresses will not be entered in the CRF or database.  No material bearing a subject’s 
name will be kept on file by Sponsor.  Subjects will be informed of their rights within the ICF. 
12.4.3 
Investigator and Staff Information 
Personal data of the investigators and sub-investigators may be included in the SCRI Innovations 
database, and shall be treated in compliance with all applicable laws and regulations.  When 
archiving or processing personal data pertaining to the investigator or sub-investigator, SCRI 
Innovations shall take all appropriate measures to safeguard and prevent access to this data by 
any unauthorized party. 
12.5 
Financial Information 
SCRI Innovations is sponsoring this trial.  OncoGenex Technologies, Inc. will provide funding to 
SCRI Innovations for this trial.  OncoGenex Technologies, Inc. will provide the study drug 
OGX-427 for study participants.  The physicians participating in this study will receive 
compensation from SCRI Innovations. 
 
13 RECORD RETENTION AND DOCUMENTATION OF THE TRIAL 
13.1 
Amendments to the Protocol 
Amendments to the protocol shall be planned, documented and signature authorized prior to 
implementation.   
If an amendment to the protocol is required, the amendment will be originated and documented 
by the Sponsor.  All amendments require review and approval of OncoGenex Technologies and 

 
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the Study Chair supporting the trial.  The written amendment must be reviewed and approved by 
the Sponsor, and submitted to the IRB at the Investigator’s facility for the board’s approval. 
Amendments specifically involving change to trial design, risk to subject, increase to dosing or 
exposure, subject number increase, addition or removal of new tests or procedures, shall be 
reviewed and approved by the IRB at the Investigator’s facility. 
The amendment will be submitted formally to the FDA or other regulatory authorities by 
SCRI Innovations as applicable, after IRB approval and specifically when an increase to dosing 
or subject exposure and/or subject number has been proposed; or, when the addition or removal 
of an Investigator is necessitated. 
Items requiring a protocol amendment with IRB and/or FDA approval include, but are not 
limited to, the following: 
 Change to trial design  
 Risk to subjects 
 Increase in dose or subject exposure to drug  
 Subject number increase  
 Addition or removal of tests and/or procedures  
 Addition/removal of an Investigator  
 
It should be further noted that, if an amendment to the protocol substantially alters the study 
design or the potential risks to the subjects, their consent to continue participation in the study 
should be obtained. 
13.2 
Documentation Required to Initiate Study 
Before the study may begin, certain documentation required by FDA regulations must be 
provided by the Investigator.   
Documents at a minimum required to begin a trial in the US include, but are not limited to, the 
following: 
 A signature-authorized contract; 
 A copy of the official IRB approval of the trial and the IRB members list; 
 Current Curricula Vita for the Principal Investigator and any associate investigator(s) 
who will be involved in the trial; 
 Indication of appropriate accreditation for any laboratories to be used in the trial and a 
copy of the normal ranges for tests to be performed by that laboratory; 
 Original Form FDA 1572 (Statement of Investigator), appropriately completed and 
signed; 
 A copy of the IRB-approved consent form containing permission for audit by 
representatives of SCRI Innovations, the IRB, and the FDA;  
 Financial disclosure forms for all investigators listed on Form FDA 1572; 

 
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 Site qualification reports, where applicable; 
 Verification of Principal Investigator acceptability from local and/or national debarment 
list(s) (to be performed and documented by SCRI Innovations). 
 
13.3 
Trial Documentation and Storage 
The PI must maintain a list of appropriately qualified persons to whom he/she has delegated trial 
duties and should ensure that all persons assisting in the conduct of the trial are informed of their 
obligations.  All persons authorized to make entries and/or corrections on the CRFs are to be 
included on this document.  All entries in the subject’s CRF are to be supported by source 
documentation where appropriate. 
Source documents are the original documents, data, records, and certified copies of original 
records of clinical findings, observations, and activities from which the subject’s CRF data are 
obtained.  These can include, but are not limited to, hospital records, clinical and office charts, 
laboratory, medico-technical department and pharmacy records, diaries, microfiches, ECG 
traces, copies or transcriptions certified after verification as being accurate and complete, 
photographic negatives, microfilm or magnetic media, X-rays, and correspondence. 
The PI and trial staffs are responsible for maintaining a comprehensive and centralized filing 
system (Site Trial File/SSF or ISF) of all trial-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable regulatory 
authorities.  The ISF/SSF must consist of those documents that individually or collectively 
permit evaluation of the conduct of the trial and the quality of the data produced.  The ISF/SSF 
should contain as a minimum all relevant documents and correspondence as outlined in ICH 
GCP Section 8 and 21 CFR Part 312.57, including key documents such as the IB and any 
amendments, protocol and any amendments, signed ICFs, copies of completed CRFs, IRB 
approval documents, Financial Disclosure forms, subject identification lists, enrollment logs, 
delegation of authority log, staff qualification documents, laboratory normal ranges, records 
relating to the study drug including accountability records.  Drug accountability records should, 
at a minimum, contain information regarding receipt, shipment, and disposition.  Each form of 
drug accountability record, at a minimum, should contain PI name, date drug shipped/received, 
date, quantity and batch/code, or lot number for identity of each shipment.  In addition, all 
original source documents supporting entries in the CRF must be maintained and be readily 
available. 
The Sponsor shall maintain adequate investigational product records and financial interest 
records as per 21CFR Part 54.6 and Part 312.57 for no less than 2 years after the last marketing 
application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
The IRB shall maintain adequate documentation / records of IRB activities as per 21CFR 
Part 56.115 for at least 3 years after completion of the research. 
The Investigator shall maintain adequate records of drug disposition, case histories and any other 
trial-related records as per 21 CFR Part 312.62 for no less than 2 years after the last marketing 

 
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application has been approved by FDA; or, in the event that the marketing application has not 
been approved by FDA, for no less than 2 years after the last shipment / delivery of the drug for 
investigational use is discontinued and FDA has been notified of the discontinuation. 
To enable evaluations and/or audits from regulatory authorities or from the Sponsor or its 
representative, the Investigator additionally agrees to keep records, including the identity of all 
participating subjects (sufficient information to link records e.g., CRFs and medical records), all 
original, signed informed consent forms, and copies of all CRFs, SAE Reporting forms, source 
documents, detailed records of treatment disposition, and related essential regulatory documents.  
The documents listed above must be retained by the Investigator for as long as needed to comply 
with national and international regulations (generally 2 years after discontinuing clinical 
development or after the last marketing approval).  SCRI Innovations will notify the 
investigator(s)/institutions(s) when the trial-related records are no longer required.   
If the Investigator relocates, retires, or for any reason withdraws from the trial, both SCRI 
Innovations should be prospectively notified.  The trial records must be transferred to an 
acceptable designee, such as another investigator, another institution, or to the Sponsor.  The 
Investigator must obtain the Sponsor’s written permission before disposing of any records, even 
if retention requirements have been met.    
13.4 
Data Collection 
The trial CRF is the primary data collection instrument for the trial.  CRFs will be completed 
using the English language and should be kept current to enable the sponsor to review the 
subjects’ status throughout the course of the trial. 
In order to maintain confidentiality, only trial number, subject number, initials and date of birth 
will identify the subject in the CRF.  If the subject’s name appears on any other document 
(e.g., laboratory report), it must be obliterated on the copy of the document to be supplied to 
SCRI Innovations and replaced instead with the subject number and subject’s initials.  The 
investigator will maintain a personal subject identification list (subject numbers with 
corresponding subject identifiers) to enable records to be identified and verified as authentic.  
Subject data/information will be kept confidential, and will be managed according to applicable 
local, state, and federal regulations. 
All data requested on the CRF must be supported by and be consistent with the subject’s source 
documentation.  All missing data must be explained.  When a required laboratory test, 
assessment, or evaluation has not been done or an “Unknown” box is not an option on the CRF, a 
note should be created verifying that the field was “Not done” or “Unknown”.  For any entry 
errors made, the error(s) must be corrected, and a note explaining the reason for change should 
be provided. 
The investigator will electronically sign and date the subject CRF casebook indicating that the 
data in the CRF has been assessed.  Each completed CRF will be signed and dated by the PI, 
once all data for that subject is final. 
13.5 
Trial Monitoring, Auditing, and Inspecting 
Participation as an Investigator in this trial implies the acceptance of potential inspection by 
government regulatory authorities, the Sponsor, or its representative(s). 

 
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At the Sponsor’s discretion Source Document Verification (SDV) may be performed on all data 
items or a percentage thereof. 
13.6 
Quality Assurance and Quality Control 
Each trial site shall be required to have Standard Operating Procedures (SOP’s) to define and 
ensure quality assurance/control processes for trial conduct, data generation and collection, 
recording of data/documentation and reporting according to the protocol, GCP and any 
applicable local, national or international regulations. 
13.7 
Disclosure and Publication Policy 
All information provided regarding the trial, as well as all information collected/documented 
during the course of the trial, will be regarded as confidential.  SCRI Innovations reserves the 
right to release literature publications based on the results of the trial.  Results from the trial will 
be published/presented as per the SCRI Innovations publication strategy.  Oncogenex will review 
any materials for publication prior to submission. 
SCRI Innovations will register the trial on www.clinicaltrials.gov.  In addition, SCRI Innovations 
will publish the results of the trial.  

 
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14 REFERENCES 
Ciuleanu et al. 2008 
Ciuleanu TE, Brodowicz T, Belani CP, Kim J, Zielinski CC, et al. Maintenance pemetrexted 
plus best supportive care (BSC) versus placebo plus BSC: a phase III study [abstract]. In: Proc 
Am Soc Clin Onc 44th annual meeting program: 2008 May 30 to June 3; Chicago. J Clin 
Oncol 26. Abstract 8011. 
 
Eisenhauer et al. 2009 
Eishenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009:45:228-247. 
 
Gronberg et al. 2009 
Gronberg BH, et al. Phase III study of Norwegian lung cancer study group : pemetrexed plus 
carboplatin compared with gemcitabine as first-line chemotherapy in advanced non-small cell 
lung cancer. J Clin Oncol 27:3271-24, 2009. 
 
Pazdur et al 2004 
Pazdur R, Coia LR, Hoskins WJ, Wagman LD, eds. Cancer Management: a Multidisciplinary 
Approach. 8th ed. Manhasset, NY: CMP Healtchcare Media. 2004. 
 
Scagliotti et al. 2008 
Scagliotti GV, Parihk P, von Pawel J, et al. Phase III study comparing cisplatin plus 
gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-
stage non-small-cell lung cancer. J Clin Oncol 2008:26:3542-51. 
 
Vogelzang et al. 2003 
Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III Study of Pemetrexed in 
Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural 
Mesothelioma. J Clin Oncol. 2003:21:2636-44. 
 
Wu et al. 2007 
Wu R. Kausar H, Johnson P, Montoya-Durango DE, and et al. Hsp27 regulates Akt activation 
and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex J Biol 
Chem 2007: 282:21598-21608 
Zheng et al. 2006 
Zheng C, Lin Z, Zhao ZJ, Yang Y, Niu H, Shen X: MAPK-activated protein kinase-2 (MK2)-
mediated formation and phosphorylation-regulated dissociation of the signal complex 
consisting of p38, MK2, Akt, and Hsp27. J Biol Chem 2006: 281:37215-37226. 

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

 
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Appendix B: Guidelines for Women of Child-Bearing Potential 
 
Women of Child-Bearing Potential are Defined as Follows: 
 Any female who has experienced menarche and does not meet the criteria for 
“Women Not of Childbearing Potential”. 
  
Women Not of Childbearing Potential are Defined as Follows: 
 
Women who are permanently sterilized (e.g., tubal occlusion, hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) 
 
Women who are >45 years of age, not using hormone replacement therapy 
and who have experienced total cessation of menses for at least 1 year OR 
who have a follicle stimulating hormone (FSH) value >40 mIU/mL and an 
estradiol value <40 pg/mL (140 pmol/L) 
 
Women who are >45 years of age, using hormone replacement therapy and 
who have experienced total cessation of menses for at least 1 year OR who 
have had documented evidence of menopause based on FSH >40 mIU/mL 
and estradiol <40 pg/mL prior to initiation of hormone replacement therapy 
   
Acceptable Contraception Methods: 
Male subjects with female partners of child-bearing potential and women subjects of 
childbearing potential are required to use two forms of acceptable contraception, including one 
barrier method, during their participation in the trial and for 6 months (women) or 6 months 
(men) following discontinuation of study treatment.  Male subjects must also refrain from 
donating sperm for 6 months following discontinuation of study treatment. 
The following are acceptable forms of barrier contraception:  
 
Latex condom, diaphragm or cervical/vault cap when used with spermicidal 
foam/gel/film/cream/suppository 
 
The following are acceptable forms of secondary contraception, when used with a barrier 
method and spermicide:  
 
True abstinence.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception 

 
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Appendix B: 
Guidelines Regarding Women of Childbearing Potential (continued) 
 
 
 
Male sterilisation (with the appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate)  
 
Placement of an intrauterine device (IUD) or intrauterine system (IUS), with 
the exception of IUD progesterone T 
 
The following are unacceptable forms of contraception for women of childbearing potential:  
 
IUD progesterone T  
 
Female condom  
 
Natural family planning (rhythm method) or breastfeeding  
 
Fertility awareness  
 
Withdrawal  
 
Cervical shield

 
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Appendix C: New York Heart Association (NYHA) Classification of Cardiac Disease 
The following table presents the NYHA classification of cardiac disease. 
Class 
Functional Capacity 
Objective 
Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective 
evidence of 
cardiovascular 
disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence 
of minimal 
cardiovascular 
disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence 
of moderately severe 
cardiovascular 
disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased. 
Objective evidence 
of severe 
cardiovascular 
disease. 
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels.  9th Ed. Boston, MA:  Little, 
Brown & Co; 1994:253-256. 

 
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Appendix D: LUN 229 Schedule of Assessments 
 
Assessments 
Pre-
Treatment 
 
Loading 
Dose 
Study Treatment Phase 
(Cycle = 21 days) 
Maintenance Phasej 
Off-
Treatment 
Follow-Up 
Cycle 1 
Cycle 2-4 
Restage 
End of 
Cycles 
2 and 4 
(±7d) 
 
Restage 
Every 2 
Cycles 
(±7d) 
End of 
Study 
Treatmentk 
Off 
Treatment 
Prior to 
Progressionl 
After 
Disease 
Progression
m 
Baselinea 
Days 
-9 to 0 
Days 
Days 
Days   
1 
8/15 
1 
8/15 
1 
8/15 
TESTS AND OBSERVATIONS 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam and weightb  
X 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Vital signsc  
X 
X 
X 
X  
X 
X 
 
X 
X 
 
X 
X 
 
ECOG PS  
X  
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
ECGe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation  
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
Concomitant medication review 
X 
X 
X 
  
X 
  
 
X 
X 
 
X 
X 
 
Survival status  
 
 
 
 
 
 
 
 
 
 
 
 
X 
LABORATORY EVALUATIONS 
 
CBC, 3-part differential, platelets  
X 
 
X 
X  
X 
X 
 
X 
X 
 
X 
 
 
CMPd 
X 
 
X 
X   
X 
  
 
X 
 
 
X 
 
 
Serum or urine pregnancy testf  
X 
 
  
  
  
 
 
  
 
 
  
 
 
Correlative serum testingg 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
Archive tissue collectiong 
X 
 
 
 
 
 
 
 
 
 
 
 
 
STAGING 
 
CT Scan of Chest w/adrenalsi 
X 
 
Xh 
 
Xh 
X 
X 
 
CT Scan of Abdomen/Pelvisi 
X 
 
 
 
Xh 
 
 
Xh 
X 
X 
 
PET Scan or Bone Scan  
X 
 
 
 
  
 
 
  
 
 
 
MRI Brain or Head CT Scan  
X 
 
 
 
 
 
 
 
 
 
 

 
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Appendix D: LUN 229 Schedule of Assessments (continuation) 
a 
The physical examination, medical history, concomitant medications recorded ≤30 days prior to trial entry, ECOG PS, CBC, CMP, and 12-lead ECG should be done ≤7 days prior to 
initiation of treatment.  However, if these initial examinations are obtained within 72 hours prior to the initiation of treatment they do not have to be repeated.  Scans to document evaluable 
disease (i.e., tumor measurement) should be performed ≤4 weeks prior to initiation of treatment.  The smoking history should be recorded at the baseline visit.    
b 
Physical examination will include measurements of height  and weight  at the baseline visit.  Physical examinations (PE) done at all other times during the trial will include only 
measurements of weight.        
c 
Vital signs (resting heart rate, blood pressure, oral temperature) will be collected at baseline and prior to each dose of OGX-427, and at anytime there are signs or symptoms of an infusion 
reaction. 
d  
CMP will include measurements of glucose, BUN, creatinine, sodium, potassium, chloride, calcium, CO2, ALP, AST (SGOT), ALT (SGPT), total bilirubin, total protein, and  albumin.      
e  
ECG at baseline.  Repeat if clinically indicated.   
f  
Pregnancy tests will only be performed in women of childbearing potential ≤72 hours prior to first dose of study treatment. 
g  
Correlative testing will include the collection of archival tumor tissues and blood samples.  Blood samples will be collected from all patients and assessed for serum levels of Hsp27.   At 
these time points, approximately 7 mL of blood will be collected (red topped tube).  In addition, a paraffin-embedded tumor tissue block (from the primary tumor or metastasis) obtained at 
diagnosis may be used for correlative testing.  In the absence of paraffin-embedded tissue, 15 unstained paraffin-embedded tumor slides are acceptable. 
h  
Patients will be restaged after every 2 cycles (every 6 weeks, ±7days)  during Study Treatment Phase and Maintenance Phase.  Patients with progressive disease or unacceptable toxicity 
should be discontinued from the study; patients with stable disease or response to therapy will continue treatment. 
i  
If adrenal glands are not captured in the CT scan of the chest, then a CT scan of the abdomen and pelvis will be required.     
j  
Patients without evidence of undue toxicity may continue treatment with study drug (OGX-427 or placebo) and pemetrexed until disease progression occurs as long as they are achieving 
clinical benefit and desire to continue therapy.     
k  
After patients complete therapy or are discontinued from the study they will visit the study center ≤30 days after finishing treatment for end-of-treatment assessments.  All patients will be 
followed during the off -treatment period until all treatment related toxicity resolves, and for at least 30 days post-study drug discontinuation.   
l  
Patients who discontinue study treatment prior to the occurrence of disease progression will be followed every 6 weeks from the date of last dose of trial drug until disease progression or for 
up to 2 years whichever comes first.   
m 
Patients with documented disease progression will be followed every 2 months for survival status (e.g., date and cause of death) for up to 2 years or death whichever comes first. Patients 
may be contacted during outpatient visits or by telephone. 

 
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Appendix E: Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
Subjects with Measureable Disease 
Lesions are either measurable or non-measurable using the criteria provided below.  The term 
“evaluable” in reference to measurability will not be used, as it does not provide additional 
meaning or accuracy. 
Baseline Eligibility 
Measurable Disease: 
Tumor lesions:  Must be accurately measured in at least one 
dimension (longest diameter in the plane of measurement is to 
be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater 
than 5 mm). 
 10 mm caliper measurement by clinical exam (lesions 
that cannot be accurately measured with calipers should 
be recorded as non-measurable). 
 20 mm by chest X-ray. 
 
Skin lesions:  Documentation by color photography, including 
a ruler to estimate the size of the lesion, is recommended. 
 
Malignant lymph nodes:  To be considered pathologically 
enlarged and measurable, a lymph node must be >15 mm in 
short axis when assessed by CT scan.  At baseline and in 
follow-up, only the short axis will be measured and followed.  
Non-Measurable Disease: 
All other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with >10- to <15-mm 
short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory 
breast disease, lymphangitic involvement of skin or lung, 
abdominal masses, and abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging 
requirements.  

 
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Target Lesions: 
The most reproducible measurable lesions, up to a maximum 
of 2 lesions per organ and 5 lesions in total, representative of 
all involved organs should be identified as target lesions and 
recorded and measured at baseline.   
Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), should be representative of 
all involved organs, and in addition should be those that lend 
themselves to reproducible repeated measurements.  
Pathological nodes which are defined as measurable and that 
may be identified as target lesions must meet the criterion or a 
short axis of >15 mm by CT scan. 
A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then as noted above, only the 
short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective 
tumor response. 
Non-Target Lesions: 
All other lesions should be identified as non-target lesions at 
baseline.  Measurements of these lesions are not required, but 
the presence or absence of each should be noted throughout 
follow-up. 
15.1.1 
Guidelines for Evaluation of Measurable Disease  
All measurements should be taken and recorded in metric notation, using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment, as per study screening requirements. 
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.  Imaging-based evaluation is 
preferred to evaluation by clinical examination when both methods have been used to assess 
the anti-tumor effect of a treatment. 
Clinical Lesions: 
Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes).  
In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the 
lesion, is recommended. 
Chest X-ray: 
Lesions on chest X-ray are acceptable as measurable lesions 
when they are clearly defined and surrounded by aerated lung.  
However, CT is preferable. 

 
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Conventional CT and MRI: CT is the best currently available and reproducible method to 
measure target lesions selected for response assessment.  This 
guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5mm or 
less.  MRI of the chest should only be performed in 
extenuating circumstances.  Even if IV contract cannot be 
administered (for example, in the situation of allergy to 
contract), a non-contrast CT of the chest is still preferred over 
MRI. 
Ultrasound: 
Ultrasound should not be used to measure tumor lesions.    
Ultrasound may be useful to confirm the complete 
disappearance of superficial lesions usually assessed by 
clinical examination. 
Endoscopy and 
Laparoscopy: 
Use of endoscopy and laparoscopy should not be used to 
measure tumor lesions. Such techniques can be useful in 
confirming complete pathological response when biopsies are 
obtained. 
Tumor Markers: 
Tumor markers are not used to assess response in this 
protocol. 
Cytology and Histology: 
Cytology and histology can be used to differentiate between 
PR and CR in rare cases (e.g., after treatment to differentiate 
between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 

 
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15.1.2 
Response Criteria 
Evaluation of Target Lesions 
Complete Response:  
Complete disappearance of all target lesions.  Any 
pathological lymph node (target or non-target) must have a 
reduction in short axis to < 10 mm).   
Partial Response:  
 
A decrease from baseline of ≥30% of the diameter(s) of all 
target lesions. 
Stable Disease:   
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
(nadir) sum of the diameters of target lesions while on study. 
Progressive Disease:   
 
At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest (nadir) sum while on 
study (this includes the baseline sum if that is the smallest on 
study), or the appearance of one or more new lesions.  
Requires not only 20% increase, but absolute increase of a 
minimum of 5 mm over sum. 
 
 
Evaluation of Non-Target Lesions 
Complete Response: 
Disappearance of all non-target lesions.  All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
Stable Disease:    
 
Persistence of one or more non-target lesions. 
Progressive Disease:  
 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  When the subject 
also has measurable disease, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must 
be an overall level of substantial worsening in non-target 
disease such that, even in presence of SD or PR in the target 
disease, the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy. 

 
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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the 
treatment started).  In general, the subject’s best response assignment will depend on the achievement of both 
measurement and confirmation criteria.   
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
NO 
CR 
CR 
SD 
NO 
PR 
CR 
NE 
NO 
PR 
PR 
SD OR NE 
NO 
PR 
SD 
SD OR NE 
NO 
SD 
PD 
ANY 
YES OR NO 
PD 
ANY 
PD 
YES OR NO 
PD 
ANY 
ANY 
YES 
PD 
NE 
SD 
NO 
NE 
CR=complete response; NE=not evaluable; PD = progressive disease; PR=partial response; SD=stable disease. 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  When the evaluation 
of a CR depends upon this determination, it is recommended that the residual lesion be investigated by fine needle 
aspirate or biopsy to confirm the CR status.  
When nodal disease is included in the sum of target lesions, and the nodes decrease to “normal” size (<10 mm), 
they may still have a measurement reported on scans.  This measurement should be recorded even though the 
nodes are normal in order not to overstate progression, should it be based on increase in size of the nodes.  As 
noted earlier, this means that subjects with CR may not have a total sum of “zero” on the Case Report Form (CRF).