A Phase I, Open Label, Dose Escalation Study of Immunoconjugate L-DOS47 in Combination With Pemetrexed/Carboplatin in Patients With Stage IV (TNM M1a and M1b) Recurrent or Metastatic NSCL Lung Cancer
Phase: PHASE1
Conditions: Non-Small Cell Lung Cancer
Sponsor: Helix BioPharma Corporation

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PROTOCOL 
 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate L-DOS47 in 
Combination with Standard Doublet Therapy of Pemetrexed/Carboplatin in Patients with 
Stage IV (TNM M1a and M1b) Recurrent or Metastatic Non-Squamous Non-Small Cell 
Lung Cancer 
 
Helix Protocol No.: 
LDOS001 
Theradex Protocol No.: 
H13-11042  
IND No.: 
105544 
Investigators: 
Sarina Piha-Paul, MD 
UT MD Anderson  
Cancer Center 
Department of Investigational 
Cancer Therapeutics 
1515 Holcombe Blvd, Unit 455 
Houston, TX 77030 
 
 
Afshin Dowlati, MD 
University Hospitals  
Case Medical Center 
11100 Euclid Ave, LKS 1200 
Cleveland, OH 44106 
Sponsor: 
Helix BioPharma Corp 
21 St. Clair Avenue East 
Suite 1100 
Toronto, ON M4T 1L9 
Canada 
Tel: +1 416 925 3232 
 
 
Medical Monitor: 
Theradex 
4365 Route 1 South 
Suite 101 
Princeton, New Jersey  08540 
(609) 799-7580 
 
 
Date: 
August 10, 2017  
 
CONFIDENTIAL 
This document contains strictly confidential information and cannot be disclosed or used, unless 
authorized in writing by Theradex and Helix BioPharma Corp. 

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TABLE OF CONTENTS 
 
        Page No. 
 
INVESTIGATOR’S STATEMENT ..................................................................................... 2 
TABLE OF CONTENTS ....................................................................................................... 3 
CLINICAL STUDY SYNOPSIS ........................................................................................... 6 
LIST OF ABBREVIATIONS .............................................................................................. 18 
1.0 
GENERAL INFORMATION................................................................................ 21 
1.1 Protocol Number and Title of the Study ................................................................. 21 
1.2 Sponsor .................................................................................................................. 21 
1.3 Monitor .................................................................................................................. 21 
1.4 Signature Authorization.......................................................................................... 21 
1.5 Investigators and Institutions .................................................................................. 21 
2.0 
BACKGROUND INFORMATION ...................................................................... 22 
2.1 Introduction ............................................................................................................ 22 
2.2 The Investigational Product .................................................................................... 23 
2.3 Preclinical Studies .................................................................................................. 23 
2.4 Previous Clinical Studies ........................................................................................ 26 
2.5 Potential Risks and Benefits ................................................................................... 27 
2.6 Characteristics of a Well-Conducted Trial.............................................................. 28 
2.7 Patient Population .................................................................................................. 29 
3.0 
TRIAL OBJECTIVES AND PURPOSE .............................................................. 29 
4.0 
TRIAL DESIGN ..................................................................................................... 30 
4.1 Overview of Trial Design ....................................................................................... 31 
4.2 End of Study ........................................................................................................... 31 
4.3 Minimizing Bias ..................................................................................................... 31 
4.4 Drug Product .......................................................................................................... 31 
4.5 Duration of Therapy ............................................................................................... 31 
4.6 Trial Discontinuation .............................................................................................. 32 
4.7 Drug Accountability/Disposition of Clinical Trial Supplies ................................... 32 
4.8 Maintenance of Randomization Codes & Emergency Code Break Procedures ...... 32 
4.9 Registration ............................................................................................................ 32 
5.0 
SELECTION AND WITHDRAWAL OF SUBJECTS........................................ 33 
5.1 Inclusion Criteria .................................................................................................... 33 
5.2 Exclusion Criteria ................................................................................................... 34 
5.3 Inclusion of Women, Minorities and Children ....................................................... 35 
5.4 Withdrawal Criteria ................................................................................................ 35 
5.4.1 Withdrawn Subjects ................................................................................... 35 
5.5 Noncompliance ...................................................................................................... 35 

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6.0 
TREATMENT OF SUBJECTS ............................................................................. 36 
6.1 Drug Preparation and Administration ..................................................................... 36 
6.1.1 Doublet Chemotherapy Preparation and Administration ............................ 36 
6.1.1.1 Carboplatin .......................................................................................... 36 
6.1.1.2 Pemetrexed .......................................................................................... 36 
6.1.2 L-DOS47 Preparation and Administration ................................................. 36 
6.1.3 L-DOS47 Dose Escalation Scheme ............................................................ 38 
6.1.4 Dose Escalation Rules ................................................................................ 38 
6.1.5 Dose-limiting Toxicity ............................................................................... 40 
6.1.6 Maximum Tolerated Dose .......................................................................... 40 
6.2 Dose Reductions/Modifications .............................................................................. 41 
6.3 Concomitant Treatment .......................................................................................... 45 
6.3.1 Disallowed Medications ............................................................................. 46 
6.3.2 Allowed Medications ................................................................................. 46 
6.4 Monitoring Subject Compliance ............................................................................. 46 
7.0 
STUDY EVALUATIONS ...................................................................................... 46 
7.1 Schedule of Study Evaluations ............................................................................... 46 
7.2 Pre-treatment .......................................................................................................... 53 
7.3 During Treatment ................................................................................................... 53 
7.4 Off-Study ............................................................................................................... 56 
7.5 Long-Term Follow-up ............................................................................................ 57 
8.0 
STUDY ASSESSMENTS ....................................................................................... 57 
8.1 Safety Assessments ................................................................................................ 57 
8.1.1 Safety Analysis .......................................................................................... 57 
8.1.2 Reporting of Adverse Events ...................................................................... 58 
8.1.2.1 Adverse Events .................................................................................... 58 
8.1.2.2 Attribution Definitions ......................................................................... 59 
8.1.2.3 Definition of an Unexpected Adverse Event ........................................ 59 
8.1.2.4 Serious Adverse Event (SAE) .............................................................. 59 
8.1.2.5 Pregnancy ............................................................................................ 60 
8.1.2.6 Reporting of Serious Adverse Events .................................................. 60 
8.2 Efficacy Assessments ............................................................................................. 61 
8.2.1 Definitions .................................................................................................. 61 
8.2.1.1 Measurable Disease ............................................................................. 61 
8.2.1.2 Non-measurable Disease ...................................................................... 62 
8.2.1.3 Target Lesions ..................................................................................... 63 
8.2.1.4 Lymph Node Assessment .................................................................... 63 
8.2.1.5 Non-target Lesions ............................................................................... 63 
8.2.2 Guidelines for Evaluation of Measurable Disease ...................................... 63 
8.2.3 Response Criteria ....................................................................................... 65 
8.2.3.1 Evaluation of Target Lesions ............................................................... 65 
8.2.3.1.1 
Assessment of Target Lymph Nodes ............................................... 65 

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8.2.3.1.2 
Target Lesions that Become “too small to measure” ....................... 65 
8.2.3.1.3 
Lesions that Split or Coalesce on Treatment ................................... 66 
8.2.3.2 Evaluation of Non-target Lesions ........................................................ 66 
8.2.3.3 New Lesions ........................................................................................ 66 
8.2.3.4 Evaluation of Best Overall Response ................................................... 66 
8.2.4 Confirmatory Measurement/Duration of Response .................................... 68 
8.2.4.1 Confirmation ........................................................................................ 68 
8.2.4.2 Duration of Overall Response .............................................................. 68 
8.2.4.3 Duration of Stable Disease ................................................................... 69 
8.2.5 Clinical Benefit .......................................................................................... 69 
8.3 Pharmacokinetics ................................................................................................... 69 
8.4 Immunogenicity ..................................................................................................... 71 
9.0 
STATISTICS .......................................................................................................... 71 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ........ 72 
10.1 Monitoring of the Study and Regulatory Compliance ............................................ 72 
10.2 Curricula Vitae and Financial Disclosure of Investigators ...................................... 72 
10.3 Protocol Modifications ........................................................................................... 72 
10.4 Publication Policy .................................................................................................. 72 
11.0 
ETHICAL CONSIDERATIONS .......................................................................... 73 
11.1 Informed Consent ................................................................................................... 73 
11.2 Institutional Review Board/Independent Ethics Committee ................................... 73 
11.3 Patient Privacy ....................................................................................................... 73 
12.0 
DATA HANDLING AND RECORD KEEPING ................................................. 74 
12.1 Data to be Recorded Directly in the Electronic Case Report Form ......................... 74 
12.2 Recording of Data .................................................................................................. 74 
12.3 Study Records ........................................................................................................ 74 
13.0 
REFERENCES ....................................................................................................... 76 
APPENDIX I  -  ECOG PERFORMANCE STATUS ....................................................... 78 
 

 
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CLINICAL STUDY SYNOPSIS 
 
Name of Sponsor: 
Helix BioPharma Corp 
21 St. Clair Avenue East 
Suite 1100 
Toronto, ON M4T 1L9 
Canada 
(416) 925 3232 (phone) 
Name of Monitor: 
Theradex® 
4365 Route 1 South 
Suite 101 
Princeton, NJ 08540 
(609) 799-7580 (phone) 
(609) 799-4148 (fax) 
 
 
Name of finished product:  L-DOS47 
 
Name of active ingredient: L-DOS47 is an immunoconjugate drug composed of single chain 
antibody molecules specific for carcinoembryonic antigen-related cell adhesion molecule 6 
(CEACAM6), cross-linked with a purified urease derived from the Jack-Bean plant. 
 
Title of the study:   
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate L-DOS47 in Combination with 
Standard Doublet Therapy of Pemetrexed/Carboplatin in Patients with Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
Investigators and study centers:   
Sarina Piha-Paul, MD: UT MD Anderson Cancer Center, Department of Investigational Cancer 
Therapeutics, 1515 Holcombe Blvd, Unit 455, Houston, TX 77030 
Afshin Dowlati, MD: University Hospitals Case Medical Center, 11100 Euclid Ave, LKS 1200 
Cleveland, OH 44106 
 
Publication (reference):   
Not applicable 
 
Clinical phase:  Phase I 
 
Objectives:   
Primary Objectives:  
• 
Safety and tolerability of L-DOS47 in combination treatment with pemetrexed/carboplatin 
• 
Determination of dose limiting toxicity of L-DOS47 in combination treatment with 
pemetrexed/carboplatin 
• 
Determination of maximum tolerated dose (MTD) and recommended Phase II dose of  
L-DOS47 in combination treatment with pemetrexed/carboplatin 
 
Secondary Objectives: 
• 
Objective response rate of the combination treatment according to RECIST 1.1 
• 
Evaluation of clinical benefit, defined as the percentage of patients who have achieved 
complete response, partial response, and stable disease following combination treatment with 
L-DOS47 + pemetrexed/carboplatin. For patients to be evaluable for stable disease, the 
duration of stable disease must be at least 42 days from the first dose of study treatment. 

 
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Exploratory Objectives: 
• 
Evaluation of the pharmacokinetics of L-DOS47 in combination treatment with 
pemetrexed/carboplatin 
• 
Evaluation of the immunogenicity of L-DOS47 
 
Methodology:   
This is a Phase I open label, dose-escalation study to evaluate the safety and tolerability of ascending 
doses of L-DOS47 in combination with standard doublet chemotherapy of pemetrexed/carboplatin in 
patients with Stage IV (TNM M1a and M1b) non-squamous non-small cell lung cancer.  The study 
will utilize an accelerated “1 + 2” design up to 6µg/kg and standard “3 + 3” design for the final 
two dosing cohorts.  Patients will be recruited into cohorts of L-DOS47 escalating doses. The 
starting dose of L-DOS47 will be 0.59 µg/kg. The standard of care doses of pemetrexed [500 mg/m2] 
and carboplatin [AUC6], respectively, to be administered in combination with L-DOS47, will remain 
constant across cohorts. 
 
All patients at a given dose level must complete Cycle 1 before escalation in subsequent patients can 
proceed.  The decision for dose escalation to the next dose level will be made after the safety data 
have been reviewed by a Safety Review Committee, consisting of the Investigators, the Medical 
Monitor, and the Sponsor.   
 
Dose escalation will be based on dose limiting toxicities (DLTs).   
 
The starting dose of L-DOS47 will be 0.59 µg/kg, administered by intravenous infusion over 30 
minutes.  Patients will receive L-DOS47 in combination with standard chemotherapy of 
pemetrexed/carboplatin [pemetrexed 500 mg/m2 over 10 min and carboplatin AUC6 mg/mL over 30 
min every 3 weeks].  The sequence of administration of the combination therapy on Day 1 of each 
treatment cycle is as follows: 1) pemetrexed intravenous infusion over 10 minutes; 2) approximately 
30 minutes after the end of the pemetrexed infusion, carboplatin intravenously infused over 30 
minutes; 3) approximately 30 minutes after the end of the carboplatin infusion, L-DOS47 will be 
intravenously infused over 30 minutes.  L-DOS47 infusion may be increased to 60 minutes in the 
event of a mild infusion reaction.  The infusion bag for L-DOS47 must be used within 3 hours of 
preparation.  A treatment cycle will be 21 days, with patients receiving L-DOS47 on Days 1, 8, and 
15 and pemetrexed/carboplatin on Day 1 of each treatment cycle.  
 
It is planned that patients will receive 4 cycles of combination treatment with L-DOS47 + 
pemetrexed/carboplatin. Patients who have not progressed following the 4 cycles of combination 
treatment and who have not experienced unacceptable toxicity will have the opportunity to continue 
to receive additional cycles of L-DOS47 treatment for as long as there is clinical benefit and it is well-
tolerated, in the opinion of the Investigator, until disease progression. Patients who are unable to 
complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination treatment due to 
pemetrexed/carboplatin toxicity will have the opportunity to continue receiving L-DOS47 treatment 
following discontinuation of pemetrexed/carboplatin, for as long as there is clinical benefit and it is 
well-tolerated, in the opinion of the Investigator, until disease progression. 
 
 
Number of patients:  It is anticipated that up to 37 patients will be enrolled in this study (estimation 
based on 3 patients per cohort for 5 dose escalations, 6 patients per cohort for 2 dose escalation 
cohorts and 10 patients in the MTD expansion cohort). 

 
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Diagnosis and main criteria for inclusion:   
Patients may be entered in the study only if they meet all of the following criteria: 
1. Male or female patient ≥ 18 years of age; 
2. Histologically or cytologically confirmed non-squamous NSCLC, classified as: 
• 
Chemotherapy-naive Stage IV (TNM M1a or M1b) non-squamous NSCLC for 
whom pemetrexed/carboplatin would be appropriate therapy 
• 
Stage IV (TNM M1a or M1b) non-squamous NSCLC recurrent following prior 
surgery, radiation and/or adjuvant chemotherapy, for whom pemetrexed/carboplatin 
would be appropriate therapy  
• 
Staging of non-squamous NSCLC must be assessed according to TNM, 7th edition 
and based on computed tomography (CT) scan; 
3. EGFR-mutation positive patients must have progressed on or had intolerance to an EGFR 
small molecule tyrosine kinase inhibitor. The washout period for patients treated with an 
EGFR tyrosine kinase inhibitor is 7 days10; 
4. Patients whose tumors harbor an anaplastic lymphoma kinase (ALK) translocation must have 
progressed on or had intolerance to an ALK inhibitor.  The washout period for patients 
treated with an ALK inhibitor is 7 days11; 
5. No prior adjuvant chemotherapy within 6 months of the first treatment day if there is 
recurrent disease; 
6. At least 1 site of measurable disease per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1; 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and minimum 
life expectancy of ≥ 3 months; 
8. Adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1.5 x 109/L, 
hemoglobin ≥ 9 g/dL, and platelet count ≥100 x 109/L; 
9. Adequate renal function defined as creatinine ≤1.5 x institutional upper limit of normal 
(ULN); 
10. Adequate liver function defined as: total bilirubin ≤1.5 x institutional ULN and not 
increasing more than 25% within the last 4 weeks, alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) ≤ 2.5 x institutional ULN, or < 5 x ULN if liver 
abnormalities are due to underlying malignancy; 
11. Male or female patients of child-producing potential must agree to use an effective method 
of contraception during the study and for 90 days after the last day of treatment; 
12. Females of childbearing potential must have a negative serum pregnancy test; 
13. Females must not be breastfeeding; 
14. Ability to understand study procedures and provision of signed and dated written informed 
consent prior to any study specific procedures; 
15. Patients with treated and stable brain metastases as documented by repeat MRI showing 
stabilization one month after definitive response 
• 
Patients must be off steroids and not taking antiepileptics for brain metastases. 
 
Main Exclusion Criteria: 
Patients will not be entered in the study for any of the following reasons: 
1. Histologic evidence of predominantly squamous cell NSCLC; 
2. Patients with brain metastasis unless asymptomatic, not requiring steroids or antiseizure 
medications, and treated and stable for at least 4 weeks prior to start of study treatment; 
3. Peripheral neuropathy > CTCAE grade 1; 
4. Possibility of a curative local treatment (surgery and/or radiotherapy); 
5. Previous chemotherapy except adjuvant treatment with progression of disease 
documented ≥ 6 months after end of adjuvant treatment; 

 
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6. Having received treatment in another clinical study within the 30 days prior to 
commencing study treatment or having side effects of a prior study drug that are not 
recovered to grade ≤ 1 or baseline, except for alopecia; 
7. Concurrent chronic systemic immunotherapy, chemotherapy or hormone therapy; 
8. Chronic treatment with systemic steroids (other than inhalers or topical steroids) or other 
medications to suppress the immune system; acute steroid use is permissible; 
9. Significant cardiac disease including heart failure that meets New York Heart Association 
(NYHA) class III and IV definitions, history of myocardial infarction within six months 
of study entry, uncontrolled dysrhythmias or poorly controlled angina; 
10. Sustained QTc (the QT interval corrected for heart rate) with Fridericia’s correction > 470 
ms at screening or a history of additional risk factors for Torsades de Pointes (e.g., heart 
failure, hypokalemia, family history of long QT syndrome); 
11. Known positive human immunodeficiency virus (HIV), known hepatitis B surface 
antigen positivity, or hepatitis C antibody positivity; 
12. Previous malignancy within the last 5 years (except history of basal cell carcinoma of 
skin or pre-invasive carcinoma of the cervix with adequate treatment); 
13. Serious uncontrolled medical condition, other life-threatening illness, significant organ 
dysfunction, or clinically significant laboratory abnormality, which in the opinion of the 
Investigator, would either compromise the patient’s safety or interfere with evaluation of 
the safety of the study treatment;  
14. History of severe psychiatric illness; 
15. Dementia or significantly altered mental status that would prohibit the understanding or 
rendering of informed consent or compliance with the requirements of the protocol; 
16. Life expectancy of < 3 months; 
17. Known hypersensitivity reaction to any of the components of the study treatment;  
18. Pregnancy (absence to be confirmed by ß-hCG test) or breastfeeding; 
19. History of hepatic encephalopathy; 
20. Presence of interstitial pneumonitis. 
 

 
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Test product, dose and mode of administration, batch no.:  
Test Product L-DOS47 
L-DOS47 drug product is provided as a lyophilized cake in 3 mL stoppered and crimped Type I glass 
vials intended for reconstitution for i.v. infusion in normal saline (0.9% NaCl) solution with 0.02% 
polysorbate 80. L-DOS47 should be stored at 2-8°C.  
 
L-DOS47 will be administered at a starting dose of 0.59 µg/kg by intravenous infusion over 30 
minutes. 
 
Doublet Chemotherapy 
Carboplatin: 
Carboplatin will be prepared as described in the drug package insert.  It will be administered by 
intravenous infusion at a dose of AUC6 mg/mL over 30 minutes. 
 
Pemetrexed: 
Pemetrexed will be prepared as described in the prescribing information sheet.  It will be administered 
by intravenous infusion at a dose of 500 mg/m2 over 10 minutes.   
 
Pemetrexed Pre-medication: 
Vitamin Supplementation  
Instruct patients to initiate folic acid 400 µg to 1000 µg orally once daily beginning 7 days before the 
first dose of pemetrexed.  Continue folic acid during the full course of therapy and for 21 days after 
the last dose of pemetrexed.  
 
Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of pemetrexed and every 
3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with 
pemetrexed. 
  
Corticosteroids  
Administer dexamethasone 4 mg orally twice daily the day before, the day of, and the day after 
pemetrexed administration.  
Dose Escalation Scheme: 
The dose escalation scheme is described in the table below: 
 
Cohort 
L-DOS47 Dose in µg/kg 
-1* 
0.46 
1 
0.59 
2 
0.78 
3 
1.5 
4 
3.0 
5 
6.0 
6 
9.0 
7 
12.0 
*If the starting dose level results in 
DLT, patients will be treated at 
the -1 dose level. 
Dose limiting Toxicity (DLT): 
 
In the accelerated dose escalation phase of the study, dose limiting toxicity (DLT) is defined as 
the occurrence of any of the following events (according to NCI CTCAE version 4.0) that are 
considered to be related to L-DOS47: 
• 
Hematologic adverse events  ≥ grade 4  
• 
Non-hematologic adverse events ≥ grade 3 

 
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• 
One instance each of two unique grade 2 adverse events 
that occur within 21 days after commencing study drug treatment considered to be possibly, 
probably, or definitely related to L-DOS47 by the Investigator. 
 
In the standard dose escalation phase, a DLT is defined as the occurrence of any of the following 
events (according to NCI CTCAE version 4.0): 
• 
Hematologic adverse events  ≥ grade 4  
• 
Non-hematologic adverse events ≥ grade 3 
that occur within 21 days after commencing study drug treatment considered to be possibly, probably, 
or definitely related to study drug treatment by the Investigator. 
 
For the purpose of cohort evaluation, if a patient does not receive all of his/her scheduled L-DOS47 
doses in Cycle 1 due to toxicity, this will be considered a DLT. 
 
Patients experiencing a DLT during the first treatment cycle will be withdrawn from the study.  
 
Dose escalation and determination of maximum tolerated dose (MTD) and recommended dose 
(RD) for Phase II: 
Dose escalation will proceed according to the following scheme based on DLTs occurring during the 
first cycle of treatment.   
During the accelerated design phase (Cohorts 1 – 5)  
No. of Patients 
with DLT at a 
Given Dose Level 
 
 
Escalation Decision Rule 
0 out of 1 
Enter patient(s) at the next dose level. 
 
1 out of 1 
Enter at least 2 more patients at this dose level. 
• 
If 0 of these 2 patients experiences DLT, proceed to the next dose 
level. 
• 
If 1 or more of this group suffer DLT, then dose escalation is 
stopped and this dose is declared the maximally administered 
dose. A total of 6 patients will be dosed at the next lowest dose 
level.  
1 out of 1 
Enter an additional 3 patients at this dose level, if the patient suffers a 
DLT as a result of one instance each of two unique grade 2 adverse 
events. Escalation decision will be based on standard design rules for 
these additional patients.   
≤ 1 out of 6 at 
highest dose level 
below the 
maximally 
administered dose 
This will be the Recommended Phase II Dose. At least 6 patients will be 
entered at this dose. 
 
During the standard design phase (Cohorts 6 and 7) 

 
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No. of Patients 
with DLT at a 
Given Dose Level 
 
 
Escalation Decision Rule 
0 out of 3 
Enter patient(s) at the next dose level. 
 
≥ 2 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose (highest dose administered). Three additional 
patients will be entered at the next lowest dose level if only 3 patients were 
treated previously at that dose level.  
1 out of 3 
Enter at least 3 more patients at this dose level. 
• 
If 0 of these 3 patients experiences DLT, proceed to the next dose 
level. 
• 
If 1 or more of this group suffer DLT, then dose escalation is stopped 
and this dose is declared the maximally administered dose. Three 
additional patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose.  
≤ 1 out of 6 at 
highest dose level 
below the 
maximally 
administered dose 
This will be the Recommended Phase II Dose. At least 6 patients will be 
entered at this dose. 
The MTD/RD is defined as the highest dose level at which ≤ 1 of 6 patients experience a dose limiting 
toxicity during the first treatment cycle.  
 
MTD Confirmation Cohort: 
Once the MTD is defined, a confirmation cohort of approximately 10 patients will be enrolled at the 
MTD to determine the recommended Phase II dose for the combination treatment. 
Criteria for retreatment: 
Criteria for retreatment on Day 1: 
The following criteria must be met in order for the patient to initiate therapy on Day 1 of any cycle: 
ANC ≥ 1.5 x 109/L  
Platelet count ≥ 100 x 109/L  
 
Criteria for retreatment on Days 8 and 15: 
Toxicity considered by the Investigator to be related to therapy with L-DOS47 (except alopecia or 
anemia) must have resolved to ≤ Grade 2, or to a level considered acceptable by the Investigator, or to 
the patient’s baseline values. 
Dose modifications: 
Dose reductions/modifications for L-DOS47 
If a patient experiences an AE meeting the definition of DLT (see Section 6.1.5), the patient will be 
withdrawn from the study and will not receive further doses of L-DOS47.  Any AE occurring after the 
defined DLT criteria window will not be considered a DLT. 
The table below provides a list of L-DOS47 doses and dose reductions for each cohort.  Criteria for 
dose reductions are described in Section 6.2. 

 
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Dosing schedule for each treatment cycle (including dose reductions) 
 
Cohort 
Dose (µg/kg) 
Dose Reduction (µg/kg) 
1 
0.59 
0.46 (-1 Dose) 
2 
0.78 
0.59 
3 
1.5 
0.78 
4 
3.0 
1.5 
5 
6.0 
3.0 
6 
9.0 
6.0 
7 
12.0 
9.0 
To meet the criteria for retreatment, all toxicities considered by the Investigator to be related to 
therapy with L-DOS47 (except alopecia or anemia) must have resolved to ≤ Grade 2, or to a level 
considered acceptable by the Investigator, or to the patient’s baseline values. 
If the patient does not meet the retreatment criteria, the dose will be held and the patient should be 
reassessed weekly (or sooner if deemed clinically appropriate) for possibility of retreatment.  If 
treatment is delayed for more than 14 days, the patient should be withdrawn from the study, unless 
discussed and agreed with the Medical Monitor.  
Dose delay/modifications 
Dose modification for subsequent cycles is required when any of the dose delay conditions in the 
table below or L-DOS47 toxicity criteria are met.  Only one dose level reduction is allowed as 
outlined in the table above. 
In making the decision for dose modification, the worst case scenario should be used. 
Dose delay definitions 
Dose delay 
Occurrence 
Action for L-DOS47 
Up to 7 days 
1st 
None 
Up to 7 days 
2nd 
Dose Reduction 
Up to 7 days 
3rd 
Withdrawn1 
8 to 14 days 
1st 
Dose Reduction 
8 to 14 days 
2nd 
Withdrawn1 
1 The withdrawal of patients from study will be discussed with the Medical Monitor.  A 
decision to not withdraw a patient must be agreed upon by the Sponsor and Medical 
Monitor, clinically supported and documented. 
 
Toxicity criteria for L-DOS47 dose modification 
Toxicity 
Grade 
Occurrence 
Relationship 
Action for 
L-DOS47 
Hematological 
Neutropenia 
 
 
 
 

 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
3 or 4 
Any 
Possible, probable, definite 
None 
 
3 or 4 
Any, prior delay of dosing 
Possible, probable, definite 
Dose Reduction 
 
3 or 4 
2nd, prior dose reduction 
Possible, probable, definite 
Withdrawn1 
Thrombocytopenia2  
 
 
 
 
 
3 or 4 
Any 
Possible, probable, definite 
None 
 
3 or 4 
Any, prior delay of dosing 
Possible, probable, definite 
Dose Reduction 
 
3 or 4 
2nd, prior dose reduction 
Possible, probable, definite 
Withdrawn1 
Bleeding 
 
 
 
 
 
1 or 2 
1st 
Possible, probable, definite 
Dose Reduction 
 
1 or 2 
Any, prior dose reduction 
Possible, probable, definite 
Withdrawn1 
 
3 or 4 
1st 
Possible, probable, definite 
Withdrawn1 
Non-Hematological 
 
3 
1st 
Possible, probable, definite 
Dose Reduction 
 
3 
2nd, prior dose reduction 
Possible, probable, definite 
Withdrawn1 
 
4 
1st 
Possible, probable, definite 
Withdrawn1 
1 The withdrawal of patients from study will be discussed with the Medical Monitor. A decision to not withdraw a patient must 
be agreed upon by the Sponsor and Medical Monitor, clinically supported and documented. 
2. Without bleeding or platelet transfusion. 
 
Dose reductions/modifications for pemetrexed and carboplatin: 
 
Doses will be reduced for hematological and other adverse events. Dose adjustments are to be made 
according to the system showing the greatest degree of toxicity, graded using the Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE).  
 
Any patient who requires a dose reduction will continue to receive a reduced dose for the remainder 
of the study. Any patient with 2 prior dose reductions who experiences a toxicity that would cause a 
third dose reduction must discontinue from pemetrexed and carboplatin therapy.  
 
Hematologic Toxicity 
 
Dose adjustments at the start of a subsequent cycle of therapy will be based on platelet and neutrophil 
nadir (lowest value) counts from the preceding cycle of therapy. ANC must be ≥ 1.5 x 109/L and 
platelets ≥ 100 x 109/L prior to the start of any cycle. Treatment should be delayed to allow sufficient 
time for recovery. Upon recovery, if treatment is resumed, it should be according to the guidelines in 
the table below. 
 
 
Dose adjustments for pemetrexed and carboplatin based on nadir hematologic values 
for preceding cycle 
Abbreviation: ANC = absolute neutrophil count. 

 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
Non-hematologic toxicity 
 
In the event of diarrhea requiring hospitalization (or of at least Grade 3), treatment should be delayed 
until diarrhea has resolved before proceeding.  Treatment with pemetrexed should be resumed at 75% 
of the previous dose level. The carboplatin should remain the same. 
 
For other non-hematologic effects greater than or equal to Grade 3, with the exception of alopecia and 
mucositis, treatment must be delayed until resolution to less than or equal to the patient’s baseline 
CTCAE grade before proceeding. Treatment should resume at 75% of the previous dose level if 
deemed appropriate by the treating physician. For Grade 3 or 4 transaminase elevations, the drug dose 
level should not be reduced. 
 
Dose modifications for pemetrexed and carboplatin for mucositis 
 
 
Dose for Next Cycle 
CTCAE Grade 
Pemetrexed 
Carboplatin (AUC) 
Grade 0-2 
100% of previous dose 
100% of previous dose 
Grade 3-4 
50% of previous dose 
100% of previous dose 
Recurrence of Grade 3 or 4 after 
treatment at 2 dose reductions 
Discontinue pemetrexed 
Discontinue carboplatin 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events 
 
 
 Dose modifications for 
pemetrexed and carboplatin in 
case of neurosensory toxicity 
Dose for Next Cycle 
CTCAE Grade 
Pemetrexed 
Carboplatin (AUC) 
Grade 0-1 
100% of previous dose 
100% of previous dose 
Grade 2 
100% of previous dose 
  50% of previous dose 
Grade 3-4 (or recurrence of Grade 2 
after treatment at dose reduction for 
Carboplatin) 
Discontinue pemetrexed 
Discontinue carboplatin 
Abbreviations: AUC = area under the curve; CTCAE = Common Terminology Criteria for Adverse Events          
Platelets (x 109/L) Nadir   
 
ANC (x 109/L) Nadir 
Percent of Previous Dose 
> 50 
and 
>0.5 
100% 
> 50 
and 
< 0.5 
75% 
< 50 
and 
any 
75% 
< 50 + bleeding 
and 
any 
50% 
any 
and 
< 1.0 + fever of ≥  38.5°C 
75% 
Recurrence of Grade 3 or 4 
thrombocytopenia after 2 dose 
reductions 
 
 
Recurrence of Grade 3 or 4 
neutropenia after 2 dose 
reductions 
Discontinue pemetrexed and 
carboplatin 
 
Duration of treatment:   
It is planned that patients will receive up to 4 cycles of combination treatment with L-DOS47 + 
pemetrexed/carboplatin. Patients who have not progressed following the 4 cycles of combination 
treatment and who have not experienced unacceptable toxicity will have the opportunity to continue 
to receive additional cycles of L-DOS47 treatment for as long as there is clinical benefit and it is well-

 
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tolerated, in the opinion of the Investigator, until disease progression. Patients who are unable to 
complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination treatment due to 
pemetrexed/carboplatin toxicity will have the opportunity to continue to receive additional cycles of 
L-DOS47 treatment following discontinuation of pemetrexed/carboplatin, for as long as there is 
clinical benefit and it is well-tolerated, in the opinion of the Investigator, until disease progression. 
 
Reference therapy, dose and mode of administration, batch no.:   
Not applicable. 
 
Criteria for evaluation:   
 
Safety:   
Safety data will be reported for all patients who received any amount of L-DOS47.  These data will 
include vital signs, laboratory parameters, and adverse events.  The severity of adverse events and 
laboratory abnormalities will be reported according to NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0.   
 
DLTs, SAEs, AEs leading to treatment discontinuation, and the MTD of L-DOS47 in combination 
with pemetrexed/carboplatin doublet chemotherapy will be determined. Once the MTD is defined, a 
confirmation cohort of approximately 10 patients will be enrolled at the MTD to determine the 
recommended Phase II doses for the combination treatment. 
 
Efficacy:   
Objective response assessment will be performed at baseline, after every 2 cycles, and at off-study 
using the same method of radiologic imaging at each assessment.  Objective tumor response will be 
assessed according to RECIST version 1.1 in patients who have completed at least 2 cycles of study 
treatment and who have at least 1 post-treatment disease assessment.  For patients with fewer than 2 
cycles of study treatment, there must be clear evidence of clinical progression to be considered 
evaluable for efficacy.   
 
Exploratory: 
Pharmacokinetic parameters for L-DOS47 will be determined from plasma samples collected from all 
patients at the following timepoints:  
Cycle 1, Days 1 and 8: predose and serially postdose (time relative to the start of infusion) at 15 
(during infusion), 30 (prior to end of infusion)*, 45 minutes* and 1*, 1.5, 2, 3, 4, 24, and 48 hours 
postdose; Cycles 2 and 4, Day 8: predose and serially postdose (time relative to the start of infusion) 
at 15 (during infusion), 30 (prior to end of infusion)*, 45 minutes* and 1*, 1.5, 2, 3, 4, and 24 hours 
postdose; Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: predose and 30 minutes* postdose 
(time relative to the start of infusion, to be collected just prior to end of infusion).  
* If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a mild 
infusion reaction, there will be no change in the PK sampling timepoints, which are all relative to the 
start of L-DOS47 infusion.  PK samples collected at 30 minutes and 45 minutes will be considered 
during infusion samples and PK sample collected at 60 minutes (1 hour) will be a prior to end of 
infusion sample. All other timepoints remain the same. 
 
Tumor antigen (CEACAM6) assessment: blood samples will be drawn (predose [0 hours]) on Day 1 
(predose [0 hours]) of Cycle 2 and on Day 8 of Cycle 4 or the End of Treatment Visit (whichever 

 
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occurs first). 
 
The immunogenicity of L-DOS47 will be evaluated from serum samples collected on Cycle 1, Day 1 
(predose; baseline) and Day 8 (predose), Cycles 2 through 4 (Day 1, predose), all additional cycles 
(i.e., Cycle 5 and beyond, Day 1 (predose), at the end of treatment or early termination visit, and at 
the follow-up visit (30 days after the last dose). 
 
Statistical methods:   
Demographic data will be displayed and descriptive summary statistics will be used to describe the 
study population (e.g., ranges, mean and medians of age, and weight; numbers of males and females; 
description of baseline performance status characteristics; tabulation of tumor types and histology). 
 
Safety data will be tabulated for all patients who receive any amount of study treatment.  These data 
will include laboratory parameters, adverse events, and cardiographic values.  The tabulation of 
laboratory parameters will indicate the normal ranges for each parameter.  Each value will be 
classified as falling above, below, or within the normal range.   
 
Adverse events will be tabulated by body system, severity and relation to treatment.  For the purposes 
of presentation, groups will be arranged by decreasing frequency of adverse events. 
 
Efficacy data will be tabulated.  The best overall response rate, defined using RECIST 1.1, will be 
summarized for efficacy-evaluable patients.  The percentage of patients in each of the best overall 
response categories will be presented.  The overall response rate will be calculated as the proportion 
of patients with responsive disease (CR and PR). Clinical benefit will be calculated as the percentage 
of patients achieving complete response, partial response, and stable disease.  For patients to be 
evaluable for stable disease, the duration of stable disease must be at least 42 days from the first dose 
of study treatment. Clinical benefit data from all cohorts will be displayed in a waterfall plot. 
 
Pharmacokinetic parameters will be determined from L-DOS47 concentrations using non-
compartmental methods (WinNonLin®).  L-DOS47 PK parameters to be calculated (if adequate data 
are available for estimation) will include maximum concentration (Cmax), time of Cmax (Tmax), 
applicable area under the curve (AUC) parameters, terminal half-life (t½), systemic clearance (CL), 
volumes of distribution (Vz) and volume of distribution at steady state (Vss) and urinary excretion 
parameters.  The concentrations and PK parameters will be summarized using descriptive statistics (n, 
mean, standard deviation, percent coefficient of variation, geometric mean, median, minimum and 
maximum). 
 
Immunogenicity data will be tabulated.  The concentration of anti-L-DOS47 antibodies will be 
evaluated using descriptive statistics. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
LIST OF ABBREVIATIONS  
AE 
Adverse event 
AFAIKL2 
Recombinant camelid single domain antibody 
ALT 
Alanine aminotransferase  
ANC 
Absolute neutrophil count 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase  
AUC 
Area under the concentration-time curve 
BP 
Blood pressure 
CEACAM6 
Carcinoembryonic antigen-related cell adhesion molecule 6 
CL 
Systemic clearance 
Cmax 
Maximum observed plasma concentration after dosing 
CNS 
Central nervous system 
CR 
Complete response 
CrCl 
Creatinine Clearance 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte colony-stimulating factor 
GLP 
Good Laboratory Practice 
GM-CSF 
Granulocyte macrophage colony-stimulating factor 
hCG 
Human chorionic gonadotropin 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
i.v. 
Intravenous 
ICH 
International Conference on Harmonization 
IFN 
Interferon (e.g, IFN-γ) 
Ig 
Immunoglobulin (e.g., IgG) 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
IL 
Interleukin (e.g., IL-2) 
IP 
Interferon gamma-induced protein (e.g., IP-10) 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MABEL 
Minimum Anticipated Biological Effect Level 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
No observed adverse effect level 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
PD 
Progressive disease 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PFS 
Progression-Free Survival 
PR 
Partial response 
PT 
Prothrombin time 
QT 
A measure of the time between the start of the Q wave and the end of the T 
wave 
QTc 
The QT interval corrected for heart rate 
RBC 
Red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumour 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
t½ 
Terminal elimination half-life 
TK 
Toxicokinetic 
Tmax 
Time of maximum observed plasma drug concentration after dosing 
TNF 
Tumor necrosis factor (e.g., TNF-α) 
TNM 
Tumor, Node, Metastasis tumor staging classification 
TTP 
Time to disease progression 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
ULN 
Upper limit of normal 
Vss 
Volume of distribution at steady state 
Vz 
Volume of distribution 
WBC 
White blood cell 
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
1.0 GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Study 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate L-DOS47 in Combination 
with Standard Doublet Therapy of Pemetrexed/Carboplatin in Patients with Stage IV (TNM M1a 
or M1b) Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer. 
Helix Protocol No. LDOS001; Theradex Protocol No. H13-11042. 
 
1.2 
Sponsor 
Helix BioPharma Corp 
21 St. Clair Avenue East 
Suite 1100 
Toronto, ON M4T 1L9 
Canada 
(416) 925 3232 
 
1.3 
Monitor 
Theradex 
4365 Route 1 South 
Suite 101 
Princeton, New Jersey 08540 
(609) 799-7580 
 
1.4 
Signature Authorization 
Theradex® will act as the Sponsor Representative.  
 
1.5 
Investigators and Institutions 
Sarina Piha-Paul, MD 
UT MD Anderson Cancer Center 
Department of Investigational Cancer 
Therapeutics 
1515 Holcombe Blvd, Unit 455 
Houston, TX 77030 
 
Afshin Dowlati, MD 
University Hospitals Case Medical Center 
11100 Euclid Ave, LKS 1200 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Cleveland, OH 44106 
 
2.0 BACKGROUND INFORMATION 
2.1 
Introduction 
Advanced lung cancer is a serious and life-threatening illness with a poor prognosis. Due to the 
difficulty in destroying solid tumors a fairly toxic treatment is generally required to kill the 
cancer cells. Research has explored the tumor microenvironment in order to exploit it in 
developing anticancer therapy. It has been observed that human solid tumors produce an acidic 
local microenvironment. This phenomenon can impact the efficacy of certain chemotherapeutics 
by altering their partitioning coefficient between extracellular and intracellular compartments 
due to charge alternations.1, 2, 3, 4, 5  This metabolic condition can also induce metastasis and 
confer a growth advantage to certain cancers.  
 
Helix BioPharma Corp. has developed an immunoconjugate cancer therapeutic to exploit the 
acidic tumor extracellular environment. The molecule, L-DOS47, is a protein conjugate 
consisting of jack bean urease conjugated to a llama monoclonal antibody (AFAIKL2) that is 
targeted to the carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) 
antigenic tumor marker. The urease and the AFAIKL2 antibody are chemically conjugated by a 
hetero-bifunctional cross linker yielding a final product with an antibody-to-enzyme ratio of 8-
10:1. CEACAM6 is a glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecule that 
is overexpressed in many cancers that is associated with adhesion and invasion. The AFAIKL2 
antibody serves as a targeting agent to deliver the enzyme to the affected sites while the urease 
enzyme converts urea, an abundant metabolite, into ammonia and generates a local pH increase. 
The combined effect of ammonia toxicity and pH increase is cytotoxic to cancer cells in culture 
and in xenograft models.6  
 
When targeted to lung tumors by the AFAIKL2 mAb at an appropriate i.v. dose, L-DOS47 can 
potentially kill the tumor cells through alkalinization of the local milieu and production of 
ammonia. 
 
However, as with many cancer treatments, at higher doses L-DOS47 has the potential to induce 
undesirable toxic effects. The primary goals of this Phase I study are to determine the safety and 
tolerability, and to establish maximum tolerated dose (MTD) and recommended Phase II dose of 
L-DOS47 in combination with standard doublet chemotherapy of pemetrexed/carboplatin  in 
patients with Stage IV (TNM M1a and M1b) recurrent or metastatic non-squamous non-small 
cell lung cancer (NSCLC). 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
2.2 
The Investigational Product 
L-DOS47 drug substance is an immunoconjugate of approximately 680 kDa comprising a single 
urease hexamer covalently linked to multiple molecules of AFAIKL2, a recombinant camelid 
single domain antibody directed against CEACAM6. AFAIKL2 is a recombinant protein 
expressed in E. coli; urease is sourced from jack beans. 
 
The AFAIKL2 portion of L-DOS47 active substance functions as a targeting molecule, 
delivering the enzyme to the tumor, where it acts to raise the pH of the cellular 
microenvironment through conversion of urea to ammonia and carbon dioxide. The resulting 
high local concentration of ammonia leads to cell death. The increased pH may also facilitate 
tumor cell cytotoxicity by co-administered chemotherapeutic agents. 
 
L-DOS47 drug product is provided to the clinic in 3 mL stoppered and crimped Type I glass 
vials, intended for reconstitution for i.v. infusion with normal saline (0.9% NaCl) solution with 
0.02% polysorbate 80. The product is a white to practically white solid before reconstitution. 
After reconstitution, the product is a clear and colorless to slightly yellow liquid which may 
contain some translucent particles. The composition (before reconstitution) of L-DOS47 is as 
follows: 
 
Table 1. Composition of L-DOS47 
Ingredient 
Amount/Concentration 
Function 
Quality Standard 
L-DOS47 
1.7 mg/mL 
Active ingredient 
Internal standard 
L-histidine 
10 mM 
Buffering agent 
USP 
Disodium EDTA 
02 mM 
Chelating agent 
USP 
Sucrose 
1% 
Stabilizer 
NF 
 
 
Stability studies indicate that the drug product remains within specification for 12 months when 
stored between 2-8°C. Stability studies are ongoing and therefore the shelf-life may be adjusted as 
warranted. 
 
L-DOS47 should be stored at 2-8°C. Detailed instructions for reconstitution of L-DOS47 are 
provided in the Pharmacy Manual.  
 
2.3 
Preclinical Studies 
In vitro, ex vivo, and in vivo studies have been conducted to provide proof of concept data to 
support ongoing development of L-DOS47 and establish a safety/tolerability profile to support 
clinical development. The specificity of L-DOS47 for lung cancer cells expressing CEACAM6 
on the cell surface was assessed through in vitro binding studies, demonstrating that L-DOS47 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
binds with high affinity to the human CEACAM6 antigen. This result was confirmed in an ex 
vivo binding assessment of L-DOS47 to human malignant tumor sections, where the antibody 
component of L-DOS47 bound robustly and significantly to human lung carcinoma tissue 
sections. Inhibition of CEACAM6 expression by gene knockdown technology prevented 
L-DOS47 binding, further highlighting the specificity of the immunoconjugate targeting moiety 
for CEACAM6. The specific, targeted function of the L-DOS47 antibody for human tumors has 
been confirmed in vivo in biodistribution studies conducted in nude mice human tumor 
xenografts; L-DOS47 is observed at the tumor site 12 hours post injection and accumulation 
continues for up to 48 hours post-dosing. Additional in vitro studies indicated that an enzyme to 
antibody conjugation ratio of greater than 8:1 was optimal for L-DOS47 binding to CEACAM6. 
 
The mechanism of action of L-DOS47 was investigated through in vitro and in vivo 
pharmacodynamic (PD) studies. Urease is the active component of L-DOS47, and studies 
demonstrated that urease is cytotoxic to human tumor cells in vitro, and intratumoral 
administration of urease to A549 (lung adenocarcinoma) and MCF 7 (breast cancer) tumors in 
nude mice xenograft models inhibits tumor growth. L-DOS47 was observed to bind with high 
affinity to two human tumor cell lines, BxPC-3 (pancreatic) and A549 (lung), with binding 
affinity/avidity shown as BxPC-3>A549. The cytotoxic effect of L-DOS47 in these cell lines 
corresponded to the binding affinity. In vivo studies confirmed this cytotoxic effect, with 
intravenous (i.v.) administration of L-DOS47 to nude mouse tumor xenograft models of 
pancreatic adenocarcinoma (BxPC-3) and lung adenocarcinoma (A549) inhibiting tumor growth.   
 
Six toxicology studies have been conducted to establish the safety and tolerability of L-DOS47. 
Single-dose i.v. toxicity has established the maximum tolerated dose (MTD) of L-DOS47 as 
520 μg/kg in Sprague-Dawley rats and 70 μg/kg in cynomolgus monkeys.  
 
Pharmacology was assessed by repeat-dosing of L-DOS47 in Sprague-Dawley rats and 
cynomolgus monkeys. In rats, pre-terminal deaths were recorded when dosing with 
170-255 μg/kg L-DOS47, where clinical observations associated with toxicity included 
decreased activity, laboured breathing, production of vomitus or uncharacteristic liquid material, 
and tremors or sustained convulsions. Histopathologic analysis identified some liver pathology 
when L-DOS47 is administered at dose levels ≥ 210 μg/kg. The no observed adverse effect level 
(NOAEL) in rats is considered to be 85 μg/kg/dose.  
 
Repeat i.v. dosing of L-DOS47 in cynomolgus monkeys established the NOAEL to be 26 μg/kg 
L-DOS47, where one death was recorded following the first dosing of 35 μg/kg. The 4-week 
repeated administration of 60 μg/kg was tolerated in a non-Good Laboratory Practice (GLP) 
compliant study; however, this dose was associated with clinical signs of toxicity that were 
consistent with those observed in the rat model. Clinical signs of toxicity are consistently 
observed within 1-2 hours of dose administration. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
In the repeat-dose toxicity study in monkeys, cardiovascular parameters were assessed through 
electrocardiograms (ECGs), monitoring of blood pressure and heart rate, both pre-treatment and 
at Week 4. Respiratory rate was also examined in all animals once prior to commencement of 
treatment and at Week 4. The results of these tests demonstrated that there was no 
L-DOS47-related effect on heart rate, blood pressure, respiratory rate, and ECG measurements in 
the monkeys over the course of the study. 
 
Administration of L-DOS47 did not elicit dose-dependent changes in cytokine release in vitro in 
all species assayed. Similarly, changes in the production of cytokines in rats following 4-weekly 
injections of L-DOS47 were not attributable to dosing with the test article. Changes in the 
concentrations of Interleukin-2 (IL-2) and granulocyte macrophage colony-stimulating factor 
(GM-CSF) in monkeys following repeat dosing of L-DOS47 were inconsistent with those 
observed in control groups however, and therefore these effects may be treatment-related. No 
change in the concentrations of other cytokines was observed in monkeys following L-DOS47 
dosing, and no consistent dose-dependent changes in cytokine release were apparent.  
 
The administration of L-DOS47 elicited production of anti-LDOS47 immunoglobulin G (IgG) 
and IgM antibodies in rats at all dose levels, and appeared to be dose-dependent in males. The 
magnitude of the immunogenic response was greater in females, where the antibody titre was 
consistently higher across all treatment groups. The generation of anti-drug antibodies by Day 15 
following repeat dose administration of L-DOS47 was consistent with toxicokinetic (TK) data, 
which highlighted a high degree of inter-animal variability in plasma L-DOS47 concentrations 
following dosing on Day 22. The half-life of L-DOS47 ranged from 6.35 to 13.5 hours in rats. 
Toxicokinetic analysis demonstrated no accumulation of L-DOS47 over 4-weekly injections, and 
an approximately proportional dose-dependent increase in exposure on Day 1 was noted.  
 
Immunogenicity analysis of serum samples following repeat dosing of monkeys with L-DOS47 
indicated the presence of anti-drug antibodies by Day 14, and these were correlated with 
decreased exposure as determined by TK analysis. The half-life of L-DOS47 generally ranged 
from 7 to 13 hours in monkeys. Similar to that observed following repeat dosing of rats, no 
L-DOS47 accumulation was apparent over the duration of dosing.  
 
Whilst the reproductive toxicity of L-DOS47 has not been directly assessed, histopathology of 
reproductive organs identified no signs of toxicity following repeat dosing of both rats and 
monkeys. Assessment of the local tolerance following administration of the test article similarly 
indicated that L-DOS47 is well tolerated across all dose levels in both rats and monkeys.  
 
The nonclinical development of L-DOS47 has established the efficacy and safety profile of 
L-DOS47. Clinical development of L-DOS47 is being undertaken, with the view of providing 
critical data such as an evaluation of immunogenicity of L-DOS47 in tumor-bearing patients 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
over potentially multiple cycles of therapy, the stability of the L-DOS47 immunoconjugate prior 
to targeting, as well as the pharmacokinetics (PK) of L-DOS47. 
 
2.4 
Previous Clinical Studies 
A first-in-human clinical trial with L-DOS47 has been initiated in Poland (LDOS002).  It is a 
Phase I/II, open label, non-randomized, dose escalation study of L-DOS47 monotherapy in 
patients with non-squamous non-small cell lung cancer (NSCLC).   
 
The primary objective of the Phase I portion of the trial is to define the MTD of multiple doses 
of L-DOS47 administered i.v. to patients with non-squamous NSCLC.  The primary objective of 
the Phase II portion is to make a preliminary assessment of the efficacy of L-DOS47 in patients 
with non-squamous NSCLC. 
 
The secondary objectives of both phases of the study are to evaluate the pharmacokinetics of 
L-DOS47, the immunogenicity, and the safety and tolerability of L-DOS47 in these patients. 
 
A total of 55 patients received doses of L-DOS47 ranging from 0.12 μg/kg to 13.55 μg/kg in 
the phase I component of study LDOS002. The most common adverse events (AEs) were 
dyspnoea, fatigue, anaemia, nausea, insomnia and decreased appetite. During the 
treatment period, serial blood samples (serum) were collected for the measurement of 
cytokines. Brief increases in cytokines IL-6, IL-8, IL-12, IP-10 and TNFα were observed. 
These were not observed in all patients or all dose levels studied. There were no trends 
observed in the data that would suggest a significant shift in cytokines analyzed in Phase I 
patients. To date, there is no evidence that L-DOS47 elicits a dose-dependent release of 
cytokines in treated patients. 
 
An assessment of L-DOS47 maximum observed plasma concentration after dosing (Cmax) 
associated with morbidity and mortality in the nonclinical pivotal repeat-dose toxicology 
studies determined that plasma Cmax concentrations of ≤ 899 ng/mL L-DOS47 did not 
result in any pre-terminal animal death. In determining a safe clinical dose for this study, 
the Sponsor selected a plasma Cmax level of ≤ 500 ng/mL, approximately 1.6-fold below the 
dose considered safe in the repeat dose toxicology studies. The largest individual Cmax 
reported following a review of pharmacokinetic (PK) data was 261.68 ng/mL, observed 50 
minutes following the start of administration of the 13.55µg/kg dose at Cycle 1 Day 1. 
 
Time of maximum observed plasma concentration after dosing (Tmax) was consistent 
across dose levels and treatment cycles and occurred within the first hour following the 
start L-DOS47 infusion. A decrease in the area under the concentration-time curve from 
dosing to time of last measureable concentration (AUC0-t) was observed in most patients 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
following the Cycle 2 Day 8 dosing for all dose levels where PK data are available. This is 
consistent with production of anti-L-DOS47 antibodies.  
 
The mean terminal elimination half-life (t½) of L-DOS47 for data analysed to-date 
administered to date range from 2.38 to 10.9 hours. This is consistent with what was 
observed in the nonclinical pivotal repeat-dose TK studies. There is no trend between the 
plasma half-life and the increase in the dose of L-DOS47. These data support a more 
frequent dosing of L-DOS47 than the weekly dosing schedule followed in the LDOS002 
protocol. 
 
The majority of patients in study LDOS002 developed anti-L-DOS47 antibodies during the 
protocol-defined treatment period. Anti-L-DOS47 antibodies are detectable as early as 
8 days after the start of L-DOS47 administration. After reviewing both the PK parameters 
calculated for the first 12 dosing cohorts for study LDOS002 and anti-L-DOS47 antibodies 
measured for these patients, it is highly probable that the production of these antibodies 
are having an impact on L-DOS47 PK.  
 
In this study, a total of 9 patients received doses of L-DOS47 ranging from 0.59μg/kg to 
0.78μg/kg. The most common AEs reported were constipation, rash, dyspnea, decreased 
neutrophil and white blood cell counts. AEs reported to-date were low grade and patients 
recovered without sequelae. No DLTs were reported. 
 
2.5 
Potential Risks and Benefits 
The Investigator Brochure may be updated during the course of this study with additional risks 
and benefits. Please see the current Investigator Brochure for further details about the potential 
risks and benefits associated with this study. 
 
Toxic effects of L-DOS47 as seen in toxicology studies in Sprague-Dawley rats and cynomolgus 
monkeys appear to relate mainly to effects on the lung and CNS. Some of these toxic effects are 
most likely associated with increased blood levels of ammonia. Increased blood levels of 
ammonia have been associated with toxicity in the lung, including bronchiolar and alveolar 
edema and airway destruction resulting in respiratory distress or failure.7,8,9 Increased blood 
levels of ammonia have also been associated with convulsions.9 At high doses of L-DOS47 the 
CNS effects are likely to be the result of increased blood ammonia concentration. The facts that 
the results of the pivotal GLP repeat-dose toxicology studies with L-DOS47 in rat and monkey 
resemble those for the toxicology study with DOS47 (urease) in mice suggest that the toxicities 
associated with administration of high doses of L-DOS47 are due to the urease component of the 
conjugate.  
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
It is anticipated that the major potential risks for this trial will be related to allergic infusion 
reactions and to systemic effects on untested organ systems and cells, given that the drug is 
administered intravenously.  
 
Human exposure to L-DOS47 is limited to data generated from the Polish Phase I/II study 
(LDOS002) and the ongoing U.S. Phase I study (LDOS001). A total of 85 patients received 
doses of L-DOS47 ranging from 0.12μg/kg to 13.55μg/kg. Repeat administrations of 
L-DOS47 for doses up to 13.55µg/kg were safe and well tolerated. Only 1 AE (spinal pain) 
met the definition of a dose-limiting toxicity (DLT) at the dose of 5.76μg/kg in study 
LDOS002. Most of the events were mild to moderate in intensity and transient in duration; 
they subsided spontaneously during continued administration of L-DOS47. Many of the 
events reported were expected for the population under study. The most common adverse 
events (AEs) were dyspnoea, fatigue, anaemia, nausea, insomnia and decreased appetite. 
 
In order to maximize the number of patients receiving a potentially active dose of 
L-DOS47, an accelerated dose design up to 6µg/kg will be implemented in this study 
followed by a standard 3+3 design for the final two dosing cohorts, 9 and 12 µg/kg 
respectively.  Adverse events reported from all completed and ongoing studies support an 
accelerated dose design of L-DOS47 in combination with standard of care 
pemetrexed/carboplatin up to 6 µg/kg.  
 
Dose escalation will be conducted with the specified increments as follows: initially, patients 
will receive increasing doses of L-DOS47 from 0.46 to 0.78 µg/kg (cohorts 1 to 2) using a 
modified Fibonacci schema.  Subsequent increments then followed a modified schedule of 100% 
(cohorts 3, 4 and 5), 50% (cohort 6), and 33% increments (cohort 7).  Cohort transition will be 
monitored by a Safety Review Committee consisting of the Investigators, the medical Monitor, 
and the Sponsor.  
 
2.6 Characteristics of a Well-Conducted Trial 
The following characteristics of an adequate and well-conducted trial will be implemented: 
 
1. 
The Investigators will be well qualified by scientific training and experience. 
 
2. 
Detailed electronic Case Report Forms (eCRFs) will be completed for every patient. 
 
3. 
Requirements for institutional ethics review as set forth by the appropriate Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of Federal 
Regulations (CFR) Part 56, the European Union Directive 2001/20/EC and its associated 
Detailed Guidances, European Union GCP Directive 2005/28/EC, the ICH Guideline for 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Good Clinical Practice, Sections 3 and 4, and the terms of the Declaration of Helsinki 
(2013), will be followed. 
 
4. 
Requirements for informed consent in accordance with institutional guidelines, FDA 
requirements as specified in Title 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidances, European Union GCP Directive 
2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 4.8, and the terms of 
the Declaration of Helsinki (2013), will be followed. 
 
5. 
Safety data will be recorded and evaluated. 
 
6. 
Routine monitoring visits will be conducted by the Sponsor’s representative (Theradex) 
to ensure data accuracy. 
 
7. 
Drug accountability will be strictly maintained. 
 
8. 
This trial will be conducted according to Good Clinical Practice (GCP), the protocol and 
applicable regulatory requirements. 
 
2.7 
Patient Population 
Patients with Stage IV (TNM M1a and M1b) recurrent or metastatic non-squamous non-small 
cell lung cancer. It is anticipated that up to 37 patients will be enrolled in this study (estimation 
based on 3 patients per cohort for 5 dose escalations, 6 patients per cohort for 2 dose 
escalation cohorts and 10 patients in the MTD expansion cohort). 
 
3.0 TRIAL OBJECTIVES AND PURPOSE 
Primary Objectives:  
• Safety 
and 
tolerability 
of 
L-DOS47 
in 
combination 
treatment 
with 
pemetrexed/carboplatin 
• Determination of dose limiting toxicity of L-DOS47 in combination treatment with 
pemetrexed/carboplatin 
• Determination of maximum tolerated dose (MTD) and recommended Phase II dose of 
L-DOS47 in combination treatment with pemetrexed/carboplatin 
 
Secondary Objectives: 
• Objective response rate of the combination treatment according to RECIST 1.1 
• Evaluation of clinical benefit, defined as the percentage of patients who have achieved 
complete response, partial response, and stable disease following combination treatment 
with L-DOS47 + pemetrexed/carboplatin. For patients to be evaluable for stable disease, 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Original – March 5, 2014 
Confidential - Entire Page 
 
Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
the duration of stable disease must be at least 42 days from the first dose of study 
treatment. 
 
Exploratory Objectives: 
• Evaluation of the pharmacokinetics of L-DOS47 in combination treatment with 
pemetrexed/carboplatin 
• Evaluation of the immunogenicity of L-DOS47 
 
4.0 TRIAL DESIGN 
This is a Phase I open label, dose-escalation study to evaluate the safety and tolerability of 
ascending doses of L-DOS47 in combination with standard doublet chemotherapy of 
pemetrexed/carboplatin in patients with Stage IV (TNM M1a and M1b) non-squamous non-
small cell lung cancer.  The study will utilize an accelerated “1 + 2” design up to 6µg/kg and 
standard “3 + 3” design for the final two dosing cohorts. Patients will be recruited into cohorts 
of L-DOS47 starting at a dose of 0.59 µg/kg. The standard of care doses of pemetrexed 
[500 mg/m2] and carboplatin, [AUC6] respectively, to be administered in combination with 
L-DOS47, will remain constant across cohorts. 
 
All patients at a given dose level must complete Cycle 1 before escalation in subsequent patients 
can proceed.  Simultaneous dosing of patients within a dosing cohort is prohibited. Patient 
dosing will be separated by at least 24 hours. This will allow for the assessment of possible 
infusion reactions and/or allergic reactions and enable communication between study centers. 
The decision for dose escalation to the next dose level will be made after the safety data have 
been reviewed by a Safety Review Committee consisting of the Investigators, the Medical 
Monitor, and the Sponsor.   
 
Dose escalation will be based on dose limiting toxicities (DLTs).   
 
The starting dose of L-DOS47 will be 0.59 µg/kg, administered by intravenous infusion over 30 
minutes.  Patients will receive L-DOS47 in combination with standard doublet chemotherapy of 
pemetrexed/carboplatin [pemetrexed 500 mg/m2 over 10 minutes and carboplatin AUC6 mg/mL 
over 30 min every 3 weeks]. The sequence of administration of the combination therapy on Day 
1 of each treatment cycle is as follows: 1) pemetrexed intravenous infusion over 10 minutes; 2) 
approximately 30 minutes after the end of the pemetrexed infusion, carboplatin intravenously 
infused over 30 minutes; 3) approximately 30 minutes after the end of the carboplatin infusion, 
L-DOS47 will be intravenously infused over 30 minutes.   L-DOS47 infusion may be increased 
to 60 minutes in the event of a mild infusion reaction.  The infusion bag for L-DOS47 must be 
used within 3 hours of preparation.  A treatment cycle will be 21 days, with patients receiving 
L-DOS47 on Days 1, 8, and 15 and pemetrexed/carboplatin on Day 1 of each treatment cycle.  
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Original – March 5, 2014 
Confidential - Entire Page 
 
Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
4.1 
Overview of Trial Design 
It is planned that patients will receive 4 cycles of combination treatment with L-DOS47 + 
pemetrexed/carboplatin. Patients who have not progressed following the 4 cycles of combination 
treatment and who have not experienced unacceptable toxicity will have the opportunity to 
continue to receive L-DOS47 treatment for as long as there is clinical benefit and it is well-
tolerated, in the opinion of the Investigator, until disease progression. Patients who are unable to 
complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination treatment due to 
pemetrexed/carboplatin toxicity will have the opportunity to continue receiving L-DOS47 
treatment following discontinuation of pemetrexed/carboplatin, for as long as there is clinical 
benefit and it is well-tolerated, in the opinion of the Investigator, until disease progression. 
 
4.2 
End of Study 
The end of the study is defined as the date of the last visit of the last patient undergoing the trial. 
 
4.3 
Minimizing Bias 
This is an open-label study, and randomization will not be used. 
 
4.4 
Drug Product  
L-DOS47 drug product is provided as a lyophilized cake in 3 mL stoppered and crimped Type I 
glass vials intended for reconstitution for i.v. infusion in normal saline (0.9% NaCl) solution 
with 0.02% polysorbate 80. L-DOS47 should be stored at 2-8°C.  
 
Detailed instructions for reconstitution of L-DOS47 are provided in the Pharmacy Manual. 
 
L-DOS47 will be administered at a starting dose of 0.59 µg/kg by intravenous infusion over 30 
minutes.   
 
4.5 
Duration of Therapy 
It is planned that patients will receive up to 4 cycles of combination treatment with L-DOS47 + 
pemetrexed/carboplatin. Patients who have not progressed following the 4 cycles of combination 
treatment and who have not experienced unacceptable toxicity will have the opportunity to 
continue to receive additional cycles of L-DOS47 treatment for as long as there is clinical benefit 
and it is well-tolerated, in the opinion of the Investigator, until disease progression.  Patients who 
are unable to complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination treatment 
due to pemetrexed/carboplatin toxicity will have the opportunity to continue receiving L-DOS47 
treatment following discontinuation of pemetrexed/carboplatin, for as long as there is clinical 
benefit and it is well-tolerated, in the opinion of the Investigator, until disease progression. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
32 
Original – March 5, 2014 
Confidential - Entire Page 
 
Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
4.6 
Trial Discontinuation  
For reasonable cause, either the Investigator or the Sponsor may terminate this study 
prematurely. Written notification of the termination is required.  Conditions that may warrant 
termination include, but are not limited to: 
 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study 
• Failure of the Investigator to enter patients at an acceptable rate 
• Insufficient adherence to protocol requirements (non-compliance) 
• Lack of evaluable and/or complete data 
• Decision to modify the developmental plan of the drug 
• A decision on the part of the Sponsor to suspend or discontinue development of the drug 
 
 
4.7 
Drug Accountability/Disposition of Clinical Trial Supplies 
Drug accountability records will be maintained for all clinical trial supplies. 
 
The Investigator is responsible for maintaining accurate study treatment accountability records 
throughout the study.  The Investigator will confirm the date of receipt and contents of each 
consignment of study drug received. 
 
Each use of study treatment will be documented on the eCRF. 
 
All unused, used or partially used study treatment supplies must be returned or destroyed as per 
written directives from the Sponsor or designee (i.e., may be returned to a third party for 
destruction or may be destroyed on site, provided that the Investigator retains sufficient records 
of study treatments that were destroyed). 
 
4.8 
Maintenance of Randomization Codes & Emergency Code Break Procedures 
Not applicable, as this is an open label study. 
 
4.9 
Registration 
Prior to registration and any study-specific evaluations being performed, all patients must have 
given written informed consent for the study and must have completed the pre-study evaluations 
(see Section 7.2).  Patients must meet all of the eligibility requirements listed in Section 5.0.  

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Original – March 5, 2014 
Confidential - Entire Page 
 
Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Patients will be registered on the study by contacting Theradex (see the Study Operations 
Manual for specific instructions). 
 
5.0 SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1 
Inclusion Criteria 
Patients may be entered in the study only if they meet all of the following criteria: 
1. Male or female patient ≥ 18 years of age; 
2. Histologically or cytologically confirmed non-squamous NSCLC, classified as: 
• Chemotherapy-naive Stage IV (TNM M1a or M1b) non-squamous NSCLC 
for whom pemetrexed/carboplatin would be appropriate therapy 
• Stage IV (TNM M1a or M1b) non-squamous NSCLC recurrent following 
prior surgery, radiation and/or adjuvant chemotherapy, for whom 
pemetrexed/carboplatin would be appropriate therapy  
• Staging of non-squamous NSCLC must be assessed according to TNM, 7th 
edition and based on computed tomography (CT) scan; 
3. EGFR-mutation positive patients must have progressed on or had intolerance to an 
EGFR small molecule tyrosine kinase inhibitor. The washout period for patients 
treated with an EGFR tyrosine kinase inhibitor is 7 days10; 
4. Patients whose tumors harbor an anaplastic lymphoma kinase (ALK) translocation 
must have progressed on or had intolerance to an ALK inhibitor. The washout period 
for patients treated with an ALK inhibitor is 7 days11; 
5. No prior adjuvant chemotherapy within 6 months of the first treatment day if there is 
recurrent disease; 
6. At least 1 site of measurable disease per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1; 
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and 
minimum life expectancy of ≥ 3 months; 
8. Adequate bone marrow function defined as: absolute neutrophil count (ANC) ≥ 1.5 x 
109/L, hemoglobin ≥ 9 g/dL, and platelet count ≥100 x 109/L; 
9. Adequate renal function defined as creatinine ≤1.5 x institutional upper limit of normal 
(ULN); 
10. Adequate liver function defined as: total bilirubin ≤1.5 x institutional ULN and not 
increasing more than 25% within the last 4 weeks, alanine aminotransferase (ALT) 
and aspartate aminotransferase (AST) ≤ 2.5 x institutional ULN, or < 5 x ULN if liver 
abnormalities are due to underlying malignancy; 
11. Male or female patients of child-producing potential must agree to use an effective 
method of contraception during the study and for 90 days after the last day of 
treatment; 
12. Females of childbearing potential must have a negative serum pregnancy test; 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Original – March 5, 2014 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
13. Females must not be breastfeeding; 
14. Ability to understand study procedures and provision of signed and dated written 
informed consent prior to any study specific procedures; 
15. Patients with treated and stable brain metastases as documented by repeat MRI 
showing stabilization one month after definitive response. 
• Patients must be off steroids and not taking antiepileptics for brain metastases. 
 
 
5.2 
Exclusion Criteria 
Patients will not be entered in the study for any of the following reasons: 
1. Histologic evidence of predominantly squamous cell NSCLC; 
2. Patients with brain metastasis unless asymptomatic, not requiring steroids or 
antiseizure medications, and treated and stable for at least 4 weeks prior to start of 
study treatment; 
3. Peripheral neuropathy > CTCAE grade 1; 
4. Possibility of a curative local treatment (surgery and/or radiotherapy); 
5. Previous chemotherapy except adjuvant treatment with progression of disease 
documented ≥ 6 months after end of adjuvant treatment; 
6. Having received treatment in another clinical study within the 30 days prior to 
commencing study treatment or having side effects of a prior study drug that are not 
recovered to grade ≤ 1 or baseline, except for alopecia; 
7. Concurrent chronic systemic immunotherapy, chemotherapy or hormone therapy; 
8. Chronic treatment with systemic steroids (other than inhalers or topical steroids) or 
other medications to suppress the immune system; acute steroid use is permissible; 
9. Significant cardiac disease including heart failure that meets New York Heart 
Association (NYHA) class III and IV definitions, history of myocardial infarction 
within six months of study entry, uncontrolled dysrhythmias or poorly controlled 
angina; 
10. Sustained QTc (the QT interval corrected for heart rate) with Fridericia’s correction > 
470 ms at screening or a history of additional risk factors for Torsades de Pointes (e.g., 
heart failure, hypokalemia, family history of long QT syndrome); 
11. Known positive human immunodeficiency virus (HIV), known hepatitis B surface 
antigen positivity, or hepatitis C antibody positivity; 
12. Previous malignancy within the last 5 years (except history of basal cell carcinoma of 
skin or pre-invasive carcinoma of the cervix with adequate treatment); 
13. Serious uncontrolled medical condition, other life-threatening illness, significant organ 
dysfunction, or clinically significant laboratory abnormality, which in the opinion of 
the Investigator, would either compromise the patient’s safety or interfere with 
evaluation of the safety of the study treatment;  
14. History of severe psychiatric illness; 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
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Doublet 
Therapy 
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Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
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15. Dementia or significantly altered mental status that would prohibit the understanding 
or rendering of informed consent or compliance with the requirements of the protocol; 
16. Life expectancy of < 3 months; 
17. Known hypersensitivity reaction to any of the components of the study treatment;  
18. Pregnancy (absence to be confirmed by ß-hCG test) or breastfeeding; 
19. History of hepatic encephalopathy; 
20. Presence of interstitial pneumonitis. 
 
5.3 
Inclusion of Women, Minorities and Children 
Both men and women and members of all races and ethnic groups are eligible for this study. 
Children are not eligible for this study because the safety and tolerability of the proposed dosing 
schedule has not been determined in adults. 
 
5.4 
Withdrawal Criteria 
Protocol therapy will be discontinued at any time if any of the following situations occur: 
 
1.  Progressive disease.  
2. The development of toxicity which, in the Investigator’s judgment, precludes further therapy.  
3. Patient refusal. 
4. Lost to follow-up/noncompliance. 
5. Intercurrent illness. 
6. At the discretion of the Investigator. 
7. Pregnancy. 
8. Study termination. 
 
5.4.1 Withdrawn Subjects  
When a patient is removed from the study, the Investigator will clearly document the reason in 
the medical record and complete the appropriate case report form page describing the reason for 
discontinuation.  In addition, every effort should be made to complete the appropriate 
assessments listed in Section 7.4.   
 
5.5 
Noncompliance 
All instances of noncompliance and all resulting protocol deviations will be recorded on the case 
report forms.  
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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6.0 TREATMENT OF SUBJECTS 
6.1 
Drug Preparation and Administration 
6.1.1 Doublet Chemotherapy Preparation and Administration 
Doublet chemotherapy of pemetrexed and carboplatin will be administered on Day 1 of each 
21-day combination treatment cycle in Cycles 1 through 4 prior to L-DOS47 infusion.   
 
6.1.1.1 Carboplatin 
Carboplatin will be prepared as described in the drug package insert.  It will be administered by 
intravenous infusion at a dose of AUC6 mg/mL over 30 minutes. 
 
6.1.1.2 Pemetrexed 
Pemetrexed will be prepared as described in the drug package insert.  It will be administered by 
intravenous infusion at a dose of 500 mg/m2 over 10 minutes.   
 
Pemetrexed Pre-medication:12 
Vitamin Supplementation  
Instruct patients to initiate folic acid 400 µg to 1000 µg orally once daily beginning 7 days 
before the first dose of pemetrexed.  Continue folic acid during the full course of therapy and for 
21 days after the last dose of pemetrexed.  
 
Administer vitamin B12 1 mg intramuscularly 1 week prior to the first dose of pemetrexed and 
every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as 
treatment with pemetrexed. 
  
Corticosteroids  
Administer dexamethasone 4 mg orally twice daily the day before, the day of, and the day after 
pemetrexed administration. 
 
6.1.2 L-DOS47 Preparation and Administration 
L-DOS47 will be administered by intravenous infusion on Days 1, 8, and 15 of each 21-day 
combination treatment cycle in Cycles 1 through 4.  Patients who have not progressed following 
the 4 cycles of combination treatment and who have not experienced unacceptable toxicity will 
have the opportunity to continue to receive additional cycles of L-DOS47 treatment for as long 
as there is clinical benefit and it is well-tolerated, in the opinion of the Investigator, until disease 
progression. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Patients who are unable to complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination 
treatment due to pemetrexed/carboplatin toxicity will have the opportunity to continue to receive 
additional cycles of L-DOS47 treatment following discontinuation of pemetrexed/carboplatin, 
for as long as there is clinical benefit and it is well-tolerated, in the opinion of the Investigator, 
until disease progression. 
 
Simultaneous dosing of patients within a dosing cohort is prohibited. Patient dosing will be 
separated by at least 24 hours. This will allow for the assessment of possible infusion reactions 
and/or allergic reactions and enable communication between study centers. 
 
L-DOS47 drug product is provided as a lyophilized cake in 3 mL stoppered and crimped Type I 
glass vials intended for reconstitution for i.v. infusion in normal saline (0.9% NaCl) solution 
with polysorbate 80. L-DOS47 should be stored at 2 - 8°C.  
 
Complete instructions for L-DOS47 reconstitution and i.v. solution preparation can be found in 
the Pharmacy Manual.  The starting dose of L-DOS47 in this trial is 0.59 µg/kg. 
 
The L-DOS47 dose of each cycle will be calculated based on the patient’s weight on Day 1 of 
that cycle.  The dose will not be adjusted for body weight on Day 8 or 15 of the treatment cycles. 
Full weight-based doses will be used to treat obese patients.  
 
L-DOS47 will be administered over a 30-minute period using an i.v. infusion pump.  The start 
and end time of the infusion (actual clock time in 24 hour format) will be recorded on the eCRF.  
The rate of infusion may be decreased based on assessment of tolerability, and this will be 
reported as an adverse event (AE).  Under no circumstances will the dose be administered in less 
than a 30-minute period.  L-DOS47 infusion may be increased to 60 minutes in the event of a 
mild infusion reaction.  The infusion bag for L-DOS47 must be used within 3 hours of 
preparation.  If a patient exhibits signs and symptoms of anaphylaxis, he or she should be 
managed per local institutional guidelines.  A central venous catheter is not required for infusion 
of L-DOS47; however, if the patient has a central venous catheter in place, it is recommended 
that it be used for the infusion. 
 
For mild infusion reactions (transient flushing, rash or low grade fever < 38ºC or < 100.4ºF), 
anti-histamine, corticosteroids, and other medical intervention may be used as needed.  If 
symptoms resolve within 30 minutes, the infusion may be resumed at a minimum 50% reduction 
in rate.  If symptoms recur or worsen despite antihistamine and corticosteroids, the patient should 
be removed from the study.  If a patient exhibits signs and symptoms of moderate to severe 
(anaphylaxis) infusion reactions such as bronchospasm with or without urticaria, 
edema/angioedema, hypotension, L-DOS47 infusion must be stopped immediately and they 
should be managed per local institutional guidelines. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Patients who experience mild infusion reactions manageable with anti-histamine and 
corticosteroids can be pre-medicated in the subsequent doses. 
 
Patients must remain in the out-patient observation area for 2 hours after completion of the 
L-DOS47 infusion for observation prior to discharge.  
 
6.1.3 L-DOS47 Dose Escalation Scheme 
Dose escalation (Table 2) will be conducted with the specified increments as follows: initially, 
patients will receive increasing doses of L-DOS47 from 0.46 to 0.78 µg/kg (cohorts 1 to 2) using 
a modified Fibonacci schema13.  Subsequent increments then followed a modified schedule of 
100% (cohorts 3, 4 and 5), 50% (cohort 6), and 33% increments (cohort 7). 
 
Table 2. L-DOS47 dose escalation scheme 
Cohort 
L-DOS47 Dose in µg/kg 
-1* 
0.46 
1 
0.59 
2 
0.78 
3 
1.5 
4 
3.0 
5 
6.0 
6 
9.0 
7 
12.0 
 
 
 
 
*If the starting dose level results in DLT,  
 
 
 
 
patients will be treated at the -1 dose level. 
 
 
6.1.4 Dose Escalation Rules 
Dose escalation will proceed according to the following scheme based on DLTs occurring during 
the first cycle of treatment.   
 
Table 3. Dose escalation rules 
During the accelerated design phase (Cohorts 1 – 5)  
No. of Patients 
with DLT at a 
Given Dose Level 
 
 
Escalation Decision Rule 
0 out of 1 
Enter patient(s) at the next dose level. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
1 out of 1 
Enter at least 2 more patients at this dose level. 
• 
If 0 of these 2 patients experiences DLT, proceed to the 
next dose level. 
• 
If 1 or more of this group suffer DLT, then dose 
escalation is stopped and this dose is declared the 
maximally administered dose. A total of 6 patients will be 
dosed at the next lowest dose level.  
1 out of 1 
Enter an additional 3 patients at this dose level, if the patient 
suffers a DLT as a result of one instance each of two unique 
grade 2 adverse events. Escalation decision will be based on 
standard design rules for these additional patients.   
≤ 1 out of 6 at highest 
dose level below the 
maximally administered 
dose 
This will be the Recommended Phase II Dose. At least 6 patients 
will be entered at this dose. 
 
During the standard design phase (Cohorts 6 and 7) 
No. of Patients 
with DLT at a 
Given Dose Level 
 
 
Escalation Decision Rule 
0 out of 3 
Enter patient(s) at the next dose level. 
 
≥ 2 
Dose escalation will be stopped. This dose level will be declared the 
maximally administered dose (highest dose administered). Three 
additional patients will be entered at the next lowest dose level if 
only 3 patients were treated previously at that dose level.  
1 out of 3 
Enter at least 3 more patients at this dose level. 
• 
If 0 of these 3 patients experiences DLT, proceed to the 
next dose level. 
• 
If 1 or more of this group suffer DLT, then dose escalation 
is stopped and this dose is declared the maximally 
administered dose. Three additional patients will be entered 
at the next lowest dose level if only 3 patients were treated 
previously at that dose.  
≤ 1 out of 6 at highest dose 
level below the maximally 
administered dose 
This will be the Recommended Phase II Dose. At least 6 patients 
will be entered at this dose. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
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6.1.5 Dose-limiting Toxicity 
In the accelerated dose escalation phase of the study, Dose limiting toxicity (DLT) is 
defined as the occurrence of any of the following events (according to NCI CTCAE version 
4.0) that are considered to be related to L-DOS47: 
• Hematologic adverse events  ≥ grade 4  
• Non-hematologic adverse events ≥ grade 3 
• One instance each of any two unique grade 2 adverse events 
that occur within 21 days after commencing study drug treatment considered to be 
possibly, probably, or definitely related to L-DOS47 by the Investigator. 
 
In the standard dose escalation phase, a DLT is defined as the occurrence of any of the 
following events (according to NCI CTCAE version 4.0): 
• Hematologic adverse events  ≥ grade 4  
• Non-hematologic adverse events ≥ grade 3 
that occur within 21 days after commencing study drug treatment considered to be possibly, 
probably, or definitely related to study drug treatment by the Investigator. 
 
For the purpose of cohort evaluation, if a patient does not receive all of his/her scheduled 
L-DOS47 doses in Cycle 1 due to toxicity, this will be considered a DLT. 
 
Patients experiencing a DLT during the first treatment cycle will be withdrawn from the study.  
 
6.1.6 Maximum Tolerated Dose 
The maximum tolerated dose (MTD)/recommended dose (RD) is defined as the highest dose 
level at which ≤ 1 of 6 patients experiences a dose limiting toxicity during the first treatment 
cycle. 
 
If the MTD/RD is not confirmed following the evaluation of the final dosing cohort defined in 
the protocol, consideration will be given to test further cohorts. The same dosing schema will be 
used in determining these cohorts. 
 
Once the MTD is defined, a confirmation cohort of approximately 10 patients will be enrolled at 
the MTD to determine the recommended Phase II doses for the combination treatment. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
6.2 
Dose Reductions/Modifications 
Dose reductions/modifications for L-DOS47 
If a patient experiences an AE meeting the definition of DLT (see Section 6.1.5), the patient will 
be withdrawn from the study and will not receive further doses of L-DOS47.  Any AE occurring 
after the defined DLT criteria window will not be considered a DLT. 
 
Table 4 below provides a list of L-DOS47 doses and dose reductions for each cohort.  Criteria 
for dose reductions are described in Table 6. 
 
Table 4. Dosing schedule for each treatment cycle (including dose reductions) 
 
Cohort 
Dose (µg/kg) 
Dose Reduction (µg/kg) 
1 
0.59 
0.46 (-1 dose) 
2 
0.78 
0.59 
3 
1.5 
0.78 
4 
3.0 
1.5 
5 
6.0 
3.0 
6 
9.0 
6.0 
7 
12.0 
9.0 
 
To meet the criteria for retreatment, all toxicities considered by the Investigator to be related to 
therapy with L-DOS47 (except alopecia or anemia) must have resolved to ≤ Grade 2, or to a 
level considered acceptable by the Investigator, or to the patient’s baseline values. 
 
If the patient does not meet the retreatment criteria, the dose will be held and the patient should 
be reassessed weekly (or sooner if deemed clinically appropriate) for possibility of retreatment.  
If treatment is delayed for more than 14 days, the patient should be withdrawn from the study, 
unless discussed and agreed with the Medical Monitor.  
 
Dose delay/modifications 
Dose modification for subsequent cycles is required when any of the dose delay conditions in 
Table 5 or L-DOS47 toxicity criteria in Table 6 are met.  Only one dose level reduction is 
allowed as outlined in Table 4. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
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In making the decision for dose modification, the worst case scenario should be used. 
 
Table 5. Dose delay definitions 
 
Dose delay 
Occurrence 
Action for L-DOS47 
Up to 7 days 
1st 
None 
Up to 7 days 
2nd 
Dose Reduction 
Up to 7 days 
3rd 
Withdrawn1 
8 to 14 days 
1st 
Dose Reduction 
8 to 14 days 
2nd 
Withdrawn1 
1 The withdrawal of patients from study will be discussed with the Medical 
Monitor. A decision to not withdraw a patient must be agreed upon by the Sponsor 
and Medical Monitor, clinically supported and documented. 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
Table 6. Toxicity criteria for L-DOS47 dose modification 
Toxicity 
Grade 
Occurrence 
Relationship 
Action for 
L-DOS47 
Hematological 
Neutropenia 
 
 
 
 
 
3 or 4 
Any 
Possible, probable, 
definite 
None 
 
3 or 4 
Any, prior delay of 
dosing 
Possible, probable, 
definite 
Dose 
Reduction 
 
3 or 4 
2nd, prior dose reduction 
Possible, probable, 
definite 
Withdrawn1 
Thrombocytopenia2  
 
 
 
 
 
3 or 4 
Any 
Possible, probable, 
definite 
None 
 
3 or 4 
Any, prior delay of 
dosing 
Possible, probable, 
definite 
Dose 
Reduction 
 
3 or 4 
2nd, prior dose reduction 
Possible, probable, 
definite 
Withdrawn1 
Bleeding 
 
 
 
 
 
1 or 2 
1st 
Possible, probable, 
definite 
Dose 
Reduction 
 
1 or 2 
Any, prior dose reduction 
Possible, probable, 
definite 
Withdrawn1 
 
3 or 4 
1st 
Possible, probable, 
definite 
Withdrawn1 
Non-Hematological 
 
3 
1st 
Possible, probable, 
definite 
Dose 
Reduction 
 
3 
2nd, prior dose reduction 
Possible, probable, 
definite 
Withdrawn1 
 
4 
1st 
Possible, probable, 
definite 
Withdrawn1 
1 The withdrawal of patients from study will be discussed with the Medical Monitor. A decision to not withdraw 
a patient must be agreed upon by the Sponsor and Medical Monitor, clinically supported and documented. 
2. Without bleeding or platelet transfusion. 
 
Dose reductions/modifications for pemetrexed and carboplatin:14 
Doses will be reduced for hematological and other adverse events. Dose adjustments are to be 
made according to the system showing the greatest degree of toxicity, graded using the 
Common 
Terminology 
Criteria 
for 
Adverse 
Events 
version 
4.0 
(CTCAE)  
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf). 
 
Any patient who requires a dose reduction will continue to receive a reduced dose for the 
remainder of the study. Any patient with 2 prior dose reductions who experiences a toxicity that 
would cause a third dose reduction must discontinue pemetrexed and carboplatin therapy.  
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
Hematologic Toxicity 
 
Dose adjustments at the start of a subsequent cycle of therapy will be based on platelet 
and neutrophils nadir (lowest value) counts from the preceding cycle of therapy. ANC must be 
≥ 1.5 x 109/L and platelets ≥ 100 x 109/L prior to the start of any cycle. Treatment should 
be delayed to allow sufficient time for recovery. Upon recovery, if treatment is resumed, it 
should be according to the guidelines in Table 7 below. 
 
Table 7. Dose adjustments for pemetrexed and carboplatin based on nadir hematologic 
values for preceding cycle 
 
Platelets (× 109/L) Nadir 
ANC (× 109/L) Nadir 
Percent of Previous 
Dose 
> 50 
and 
≥ 0.5 
100% 
> 50 
and 
< 0.5 
75% 
< 50 
and 
any 
75% 
< 50 + bleeding 
and 
any 
50% 
any 
and 
< 1.0 + fever of ≥ 38.5°C 
75% 
Recurrence of Grade 3 or 
4 thrombocytopenia after 
2 dose reductions 
Recurrence of Grade 3 
or 4 neutropenia after 
2 dose reductions              
Discontinue 
pemetrexed and 
carboplatin 
Abbreviation: ANC = absolute neutrophil count. 
 
 
Non-hematologic toxicity 
 
In the event of diarrhea requiring hospitalization (or of at least Grade 3), treatment 
should be delayed until diarrhea has resolved before proceeding.  Treatment with pemetrexed 
should be resumed at 75% of the previous dose level. The carboplatin should remain the same. 
 
For other non-hematologic effects greater than or equal to Grade 3, with the exception of 
alopecia and mucositis, treatment must be delayed until resolution to less than or equal to 
the patient’s baseline CTCAE grade before proceeding. Treatment should resume at 75% of 
the previous dose level if deemed appropriate by the treating physician. For Grade 3 or 4 
transaminase elevations, the drug dose level should not be reduced. 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Table 8. Dose modifications for pemetrexed and carboplatin for mucositis 
 
 
Dose for Next Cycle 
CTCAE Grade 
Pemetrexed 
Carboplatin (AUC) 
Grade 0-2 
100% of previous dose 
100% of previous dose 
Grade 3-4 
  50% of previous dose 
100% of previous dose 
Recurrence of Grade 3 or 4 after 
treatment at 2 dose reductions 
Discontinue 
pemetrexed 
Discontinue carboplatin 
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events 
 
 
Table 9. Dose modifications for pemetrexed and carboplatin in case of neurosensory 
toxicity 
 
 
Dose for Next Cycle 
CTCAE Grade 
Pemetrexed 
Carboplatin (AUC) 
Grade 0-1 
100% of previous dose 
100% of previous dose 
Grade 2 
100% of previous dose 
  50% of previous dose 
Grade 3-4 (or recurrence of Grade 2 after 
treatment at dose reduction for 
Carboplatin) 
Discontinue 
pemetrexed 
Discontinue carboplatin 
Abbreviations: AUC = area under the curve; CTCAE = Common Terminology Criteria for Adverse Events 
                                 
 
 
 
6.3 
Concomitant Treatment  
Chronic use of systemic steroids is prohibited.  Acute use of systemic steroids is permitted.  Use 
of steroid inhalers and topical steroids is permitted. 
 
Any medication the patient takes other than the study treatment is considered a concomitant 
medication.  All concomitant medications must be recorded on the eCRF. The following 
information must be recorded on the eCRF for each concomitant medication: generic name, route 
of administration, start date, stop date, dosage and indication.  Any changes in the dosage or 
regimen of a concomitant medication must be recorded on the eCRF. 
 
At the Screening Visit, patients will be asked what medications they have taken during the last 
30 days. At each subsequent study visit, patients will be asked what concomitant medications 
they are currently taking. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
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6.3.1 Disallowed Medications 
Other than the study treatments planned in this protocol, patients must not receive the following 
medications during the study: hormonal agents, other investigational drugs, systemic 
corticosteroids, and immunotherapy.  
 
6.3.2 Allowed Medications 
Radiotherapy may be given concomitantly for the control of bone pain; irradiated lesions will not 
be evaluable for response. Any medication which is considered necessary for the patient’s 
welfare and which will not interfere with administration of the study treatments, may be given at 
the discretion of the Investigator. 
 
6.4 
Monitoring Subject Compliance 
Study-related drugs will be administered only under the direction of the Investigator.  Patients 
should attend scheduled clinic visits and comply with the protocol instructions. The Investigator 
will assess the patient for compliance with study procedures and visits and provide further advice 
to patients as necessary.   
 
 
7.0 STUDY EVALUATIONS 
7.1 
Schedule of Study Evaluations 
Study evaluations are summarized in the Table 10 and described in Sections 7.2 through 7.5. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
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Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Table 10. Schedule of study evaluations  
 
Pre-
treatment 
Screening 
 
During Treatment 
L-DOS47 + 
Pemetrexed/Carboplatin2 
 
Cycles 1 through 4 
Cycle Days (D) 
 
End-of-Treatment Visit3 
 
Additional 
Treatment 
Cycles3 
 
Follow-up Visits 
 
Procedures 
 
Days -28 to 0 
D1 
D8 
D15 
D21 
Cycle 4 
Day 21  
7 ( ± 5) days 
post last dose 
Early  
Termination 
(immediately) 
 
 
L-DOS47 only19 
30 Days 
post 
last dose 
Thereafter, 
every 30 days* 
(± 7 days) 
or 
every 6 weeks** 
(± 7 days) 
Informed Consent1 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
predose 
 
 
 
 
 
X 
D1  
predose 
 
 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
predose 
X 
predose 
 
 
X 
X 
X 
D1, 8, 15  
predose 
 
 
Performance status 
(ECOG) 
X 
X 
 
 
 
X  
 
X  
 
X 
D1 
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 3 – August 10, 2017 
 
Pre-
treatment 
Screening 
 
During Treatment 
L-DOS47 + 
Pemetrexed/Carboplatin2 
 
Cycles 1 through 4 
Cycle Days (D) 
 
End-of-Treatment Visit3 
 
Additional 
Treatment 
Cycles3 
 
Follow-up Visits 
 
Procedures 
 
Days -28 to 0 
D1 
D8 
D15 
D21 
Cycle 4 
Day 21  
7 ( ± 5) days 
post last dose 
Early  
Termination 
(immediately) 
 
 
L-DOS47 only19 
30 Days 
post 
last dose 
Thereafter, 
every 30 days* 
(± 7 days) 
or 
every 6 weeks** 
(± 7 days) 
Radiologic 
examination6 
and tumor assessment 
X 
X 
 
 
 
X 
(if > 6 wks 
post last scan) 
X 
(if > 6 wks post 
last scan) 
X 
D1 every other 
cycle 
X 
X 
Historic biopsy sample  
(if available) 
X 
 
 
 
 
 
 
 
 
 
Tumor antigen 
assessment 
(CEACAM6)7 
 
X 
predose 
Cycle 2 
only 
X 
predose 
Cycle 4 
only 
 
 
X 
(only if not 
done on C4D8) 
X 
(only if not 
done on C4D8) 
 
 
 
Vital Signs 
(temp/HR/BP/RR/pulse 
oximetry)8,20 
X 
X 
pre- & 
post- 
dose 
X 
pre- & 
post- 
dose 
X 
 
 
X 
X 
X 
D1, 8, 15 
 
 
Electrocardiogram9, 20 
X 
X 
pre- & 
post- 
dose 
X 
pre- & 
post- 
dose 
 
 
X 
X 
X 
D1 and 8 Predose  
& postdose 
(optional 10)  
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 3 – August 10, 2017 
 
Pre-
treatment 
Screening 
 
During Treatment 
L-DOS47 + 
Pemetrexed/Carboplatin2 
 
Cycles 1 through 4 
Cycle Days (D) 
 
End-of-Treatment Visit3 
 
Additional 
Treatment 
Cycles3 
 
Follow-up Visits 
 
Procedures 
 
Days -28 to 0 
D1 
D8 
D15 
D21 
Cycle 4 
Day 21  
7 ( ± 5) days 
post last dose 
Early  
Termination 
(immediately) 
 
 
L-DOS47 only19 
30 Days 
post 
last dose 
Thereafter, 
every 30 days* 
(± 7 days) 
or 
every 6 weeks** 
(± 7 days) 
Clinical lab tests4 
Hematology 
Chemistry 
Coagulation 
X 
X 
predose 
X 
predose 
 
 
X 
X 
X 
D1, 8, 15 
predose 
 
 
Urinalysis5 
X 
X 
predose 
X 
predose 
 
 
X 
X 
X 
D 1, 8, 15 
 predose 
 
 
Pregnancy test11 
X 
X 
predose 
 
 
 
X 
X 
X 
D1 
predose 
 
 
L-DOS47 
administration12 
 
X 
X 
X 
 
 
 
X 
D1, 8, 15 
 
 
Pemetrexed/Carboplatin 
administration13 
 
X 
 
 
 
 
 
 
 
 
Plasma PK sampling14,20 
 
X 
X 
 
 
 
 
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 3 – August 10, 2017 
 
Pre-
treatment 
Screening 
 
During Treatment 
L-DOS47 + 
Pemetrexed/Carboplatin2 
 
Cycles 1 through 4 
Cycle Days (D) 
 
End-of-Treatment Visit3 
 
Additional 
Treatment 
Cycles3 
 
Follow-up Visits 
 
Procedures 
 
Days -28 to 0 
D1 
D8 
D15 
D21 
Cycle 4 
Day 21  
7 ( ± 5) days 
post last dose 
Early  
Termination 
(immediately) 
 
 
L-DOS47 only19 
30 Days 
post 
last dose 
Thereafter, 
every 30 days* 
(± 7 days) 
or 
every 6 weeks** 
(± 7 days) 
Serum collection for 
anti-L-DOS47 antibody 
testing15 
 
X 
predose 
 
X 
predose 
C1 only 
 
 
X 
X 
X 
Day 1 
 predose 
X 
 
Concomitant 
medications 
X 
X16 
predose 
X16 
predose 
 
 
X 
X 
X 
D1, 8, 15  
predose 
X 
 
Adverse Events 
 
X17 
X17 
X17 
X17 
X 
X 
X 
D1, 8, 15 
predose and 
postdose 
X 
 
Disease progression and 
Survival18 
 
 
 
 
 
 
 
 
 
X 
ECOG: Eastern Cooperative Oncology Group; Temp: Temperature; HR; Heart rate; BP: Blood pressure; RR: Respiratory rate; PK: Pharmacokinetic; ECG: 
Electrocardiogram; CT: Computed tomography; MRI: Magnetic resonance imaging  
 
1 
Informed consent will be obtained before any experimental procedure or test is performed. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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2 All patients will be administered up to four cycles of L-DOS47 during the study treatment period. Treatment cycles will be repeated for patients who tolerate the previous 
treatment cycle of L-DOS47 and show no clinical signs of progression of disease.  
3 The End-of-Treatment Visit will be performed one time for all patients who discontinue the study at or before the end of Cycle 4. For patients who continue to receive 
additional cycles of L-DOS47 (i.e., Cycle 5 and beyond), this visit will be performed twice: (i) after the completion of 4 cycles; (ii) at the time of discontinuation from 
the study. Note: All patients who are withdrawn from the study will complete the End-of-Treatment Visit immediately at the time of withdrawal. 
4 The corresponding procedures will be performed on the day specified for each L-DOS47 cycle: 
 Hematology: CBC with differential and platelet count;  
Serum chemistry: albumin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), urea, calcium, 
bicarbonate, chloride, creatinine (by Cockcroft-Gault formula), globulin (serum globulin: total protein minus serum albumin), glucose, phosphate, potassium, sodium, 
magnesium, total bilirubin, total protein. 
Coagulation: prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT). 
5 Urinalysis: bilirubin, glucose, ketones, occult blood, protein. 
6 Radiologic examinations will be performed during screening, unless results from appropriate scans performed within 28 days prior to the first dose of study drug are 
available and every other treatment cycle (i.e., every 6 weeks) until disease progression; an MRI may be conducted only in exceptional cases. Radiologic examination is 
to be repeated at the End of Treatment Visit if > 6 weeks have passed since the last evaluation.  
7 Tumor antigen (CEACAM6) assessment: blood samples will be drawn (predose [0 hours]) on Day 1 (predose [0 hours]) of Cycle 2 and on Day 8 of Cycle 4 or the End of 
Treatment Visit (whichever occurs first). 
8 Vital signs (temperature, heart rate, blood pressure, respiratory rate and oxygen saturation [pulse oximetry]) will be assessed prior to pemetrexed/carboplatin 
administration on Day 1 of the cycle; on treatment days in which L-DOS47 will be administered (Days 1, 8, and 15), vital signs will also be serially recorded relative to 
start of L-DOS47 infusion as follows: Cycle 1, Days 1 and 8: predose and 10 and 20 minutes (during infusion), and 30 minutes (prior to end of infusion) and 1, 2, and 4 
hours postdose; Cycle 2, Days 1 and 8: predose and 15 minutes (during infusion), and 30 minutes (prior to end of infusion).  Cycle 2, Day 1 at 1 and 2 hours postdose; 
Cycle 2, Day 8 at 1, 2, and 4 hours postdose; Cycles 3 and 4, Days 1 and 8: predose and 30 minutes (prior to end of infusion). All cycles, Day 15: 15 minutes (during 
infusion), and 30 minutes (prior to end of infusion). 
9 Serial 12-lead ECG measurements will be recorded on Days 1 and 8 of each cycle as follows: predose and at 1 and 1.5 hours postdose. 
10 For additional cycles, all ECG recordings are optional.   
11 In women of childbearing potential, serum ß-HCG tests will be conducted at Screening and at the End-of-Treatment/Early Termination Visit. Urine ß-HCG tests will be 
conducted on Day 1 of each treatment cycle. 
12 L-DOS47 will be administered on Days 1, 8, and 15 of each treatment cycle. Treatment with L-DOS47 may continue beyond four cycles for as long as the patient is 
receiving sustained clinical benefit and it is well tolerated, in the opinion of the Investigator, until disease progression. 
13 Pemetrexed/carboplatin will be administered according to standard prescribing information on the first day of treatment cycles 1 through 4, prior to L-DOS47 
administration. 
14 Serial blood samples (plasma) for L-DOS47 PK will be collected from all patients as follows: Cycle 1, Days 1 and 8: predose and serially postdose (time relative to the 
start of infusion) at 15 (during infusion), 30 (prior to end of infusion)*, 45 minutes* and 1*, 1.5, 2, 3, 4, 24, and 48 hours postdose; Cycles 2 and 4, Day 8: predose and 
serially postdose (time relative to the start of infusion) at 15 (during infusion), 30 (prior to end of infusion)*, 45 minutes* and 1*, 1.5, 2, 3, 4, and 24 hours postdose; 
Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: predose and 30 minutes* postdose (time relative to the start of infusion, to be collected just prior to end of 
infusion). * If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a mild infusion reaction, there will be no change in the PK sampling 
timepoints, which are all relative to the start of L-DOS47 infusion.  PK samples collected at 30 minutes and 45 minutes will be considered during infusion samples and 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
PK sample collected at 60 minutes (1 hour) will be a prior to end of infusion sample. All other timepoints remain the same. Also refer to Section 8.3 and Table 14 for PK 
timepoints. 
15 Serum samples will be collected (2 mL/ in SST tubes) for anti-L-DOS47 antibody testing on Cycle 1 (Day 1 [predose; baseline] and Day 8 [predose]), Cycles 2 through 4 
(Day 1 [predose]), all additional cycles (i.e., Cycle 5 and beyond, Day 1 [predose], at the End-of-Treatment Visit or Early Termination Visit, and 30 days after the last 
dose. 
16 Concomitant medications will be recorded predose on Days 1 and 8 of each cycle  
17 Adverse events (AE) will be recorded predose and postdose on Days 1, 8, and 15 of each cycle, and the Cycle 4 End-of-Treatment Visit. On non-visit days, AE will be 
monitored by telephone contact.  Adverse event monitoring on Day 21 need only occur under the circumstance that the patient is coming off study and the next cycle is 
not being initiated. 
18 Patients will be followed to collect data pertaining to progression and survival. Survival data* will be captured by telephone call every 30 days (± 7 days) until death. 
Follow-up for progression** will be conducted by radiologic assessments (CT scans of chest, abdomen and pelvis, or as appropriate per the Investigator) every 6 weeks 
(± 7 days) until one of the following occurs: disease progression, patient initiates non-study cancer treatment, patient withdraws consent, or patient is lost-to-follow-up. 
19 Cycle 5, Day 1 assessments may not need to be repeated if the end of Cycle 4 evaluations are performed within 7 days prior to Day 1 of Cycle 5.  
20 ECG/Vital signs/PK time window table presented below define an acceptable lapse in assessment/sample collection. 
  
ECG/Vital signs/PK time window a 
 
ECG 
Vital signs 
PK 
During infusion 
± 5 min 
± 5 min 
± 5 min 
Post infusion 
± 5 min 
± 5 min 
± 5 min b,c  
a. 
All timepoints are relative to the start of L-DOS47 infusion 
b. 
If the L-DOS47 infusion time is increased from 30 minutes 
to 60 minutes in the event of a mild infusion reaction, there 
will be no change in the PK sampling timepoints. The PK 
sample collected at 60 minutes (1 hour) will be the end of 
infusion sample. All other timepoints remain the same.  
c. 
For PK samples collected at 24 and 48 hours timepoints, the 
window will be  ± 30 min.  
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
7.2 
Pre-treatment 
To be conducted within 28 days prior to first dose of study treatment (Days -28 to 0). 
The following assessments will be performed and measurements recorded after the patient has 
read and signed the informed consent: 
• Verify conformance with entry criteria 
• Demographics 
• Weight 
• Record medical history 
• Physical examination 
• ECOG performance status 
• Radiologic examination, unless results from appropriate scans performed within 28 days 
of the first dose of study drug are available  
• Historic biopsy sample (if available) 
• Vital signs (temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
[pulse oximetry]) 
• 12-lead Electrocardiogram (ECG) 
• Hematology, blood chemistry and coagulation 
• Urinalysis 
• Serum pregnancy test, for women of childbearing potential 
• Concomitant medication 
 
7.3 
During Treatment 
Cycles 1 through 4 
Prior to L-DOS47 Dosing 
Days 1 and 8 
The following assessments will be performed for each treatment cycle on Days 1 and 8 (unless 
specified otherwise) and measurements recorded before dosing: 
• Verify conformance with entry criteria (Cycle 1, Day 1 only) 
• Weight (Day 1 of each cycle) 
• Physical examination 
• ECOG performance status (Day 1 of each cycle) 
• Radiologic examination after the completion of Cycle 2 and every 6 weeks thereafter 
• Tumor antigen assessment: blood draws on Day 1 (predose [0 hours]) of Cycle 2 and 
Day 8 of Cycle 4 (or performed at the End-of-Treatment/Early Termination Visit- 
depending on which occurs first). 
• Vital signs (temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
[pulse oximetry]) 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
• 12-lead ECG 
• Hematology, blood chemistry and coagulation 
• Urinalysis 
• Urine pregnancy test (Day 1 of each cycle) 
• Plasma PK sampling  
• Serum collection for anti-L-DOS47 antibody testing (Cycle 1, Day 1 (baseline) and 
Day 8; Cycles 2 through 4, Day 1 only) 
• Concomitant medications 
• Adverse event monitoring 
 
Dosing 
• Administration of pemetrexed/carboplatin (Day 1 of Cycles 1 through 4) 
• Administration of L-DOS47 (Days 1, 8, and 15 of Cycles 1 through 4) 
 
During L-DOS47 Dosing  
The following assessments will be performed and measurements recorded during dosing: 
PK/Vital signs/ECG timepoint assessments will be obtained in the following order: 
1. Vital signs 
2. 12-lead ECG 
3. PK blood sample 
4. Any other scheduled or unscheduled measurements at that timepoint 
Serial recordings and sampling will be timed relative to the start of infusion: 
• Vital signs (temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
[pulse oximetry]) as follows (relative to start of infusion):  
o Cycle 1, Days 1 and 8: 10 and 20 minutes (during infusion) and 30 minutes (prior 
to end of infusion) 
o Cycle 2, Days 1 and 8: 15 minutes (during infusion) and 30 minutes (prior to end 
of infusion) 
o Cycles 3 and 4, Days 1 and 8: 30 minutes (prior to end of infusion). 
o All cycles, Day 15: 15 minutes (during infusion) and 30 minutes (prior to end of 
infusion) 
• Plasma PK sampling as follows (time relative to start of infusion) (also refer to Section 
8.3 for PK timepoints):  
o Cycle 1, Days 1 and 8: 15 (during infusion) and 30 minutes* (prior to end of 
infusion)  
o Cycles 2 and 4, Day 8: 15 (during infusion) and 30 minutes * (prior to end of 
infusion)  
o Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: 30 minutes * (prior to end 
of infusion)  
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
* If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a 
mild infusion reaction, there will be no change in the PK sampling timepoints, which are all 
relative to the start of L-DOS47 infusion.  PK samples collected at 30 minutes and 45 
minutes will be considered during infusion samples and PK sample collected at 60 minutes (1 
hour) will be a prior to end of infusion sample. All other timepoints remain the same. 
 
Post L-DOS47 Dosing  
The following assessments will be performed and measurements recorded after dosing: 
• Vital signs (temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
[pulse oximetry]) as follows (relative to start of infusion):  
o Cycle 1 Days 1 and 8: 1, 2, and 4 hours postdose 
o Cycle 2 Day 1: 1 and 2 hours postdose 
o Cycle 2 Day 8: 1, 2, and 4 hours postdose 
• 12-lead ECG: 1 and 1.5 hours postdose (Days 1 and 8 of each cycle) 
• Plasma PK sampling as follows (time relative to start of infusion) (also refer to Section 
8.3 for PK timepoints):  
o Cycle 1, Days 1 and 8: 45  minutes* and 1*, 1.5 , 2, 3, 4, 24 and 48 hours postdose  
o Cycles 2 and 4, Day 8: 45 minutes* and 1*, 1.5, 2, 3 , 4  and 24 hours postdose  
 
* If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a 
mild infusion reaction, there will be no change in the PK sampling timepoints, which are all 
relative to the start of L-DOS47 infusion. PK samples collected at 30 minutes and 45 minutes 
will be considered during infusion samples and PK sample collected at 60 minutes (1 hour) 
will be a prior to end of infusion sample. All other timepoints remain the same. 
• Adverse event monitoring (Days 1, 8, 15 and 21 of each cycle), on non-visit days AEs 
will be monitored by telephone contact 
 
Day 15  
Prior to L-DOS47 Dosing 
• Adverse event monitoring 
• Vital signs 
 
Dosing  
• Administration of L-DOS47 
• Vital signs 
 
Post L-DOS47 Dosing 
• Adverse event monitoring 
• Vital signs 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Day 21 
• Adverse event monitoring by telephone contact – to be done only if the patient is coming 
off study and the next cycle is not being initiated 
 
Additional Treatment Cycles 
After completion of four cycles of L-DOS47, patients may continue to receive L-DOS47 for as 
long as there is sustained clinical benefit and it is well tolerated, in the opinion of the 
Investigator, until disease progression.  
 
Cycle 5, Day 1 assessments may not need to be repeated if the end of Cycle 4 evaluations are 
performed within 7 days prior to Day 1 of Cycle 5.  
 
For those patients who continue to receive additional cycles of L-DOS47, the following 
assessments will be performed on Days 1, 8, and 15 predose during each treatment cycle (unless 
specified otherwise) and measurements recorded:  
 
 
• Weight (Day 1 of each cycle) 
• Physical examination (Days 1, 8, and 15 of each cycle) 
• ECOG performance status (Day 1 of each cycle) 
• Radiological exam (Day 1 of every other cycle, i.e., every 6 weeks) 
• Vital signs [temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
(pulse oximetry)] (Days 1, 8, and 15 of each cycle)  
• Optional 12-lead ECG (predose and postdose): Days 1 and 8 of each cycle 
• Hematology, blood chemistry and coagulation (Days 1, 8, and 15 of each cycle) 
• Serum collection for anti-L-DOS47 antibody testing (Day 1 only) 
• Urinalysis (Days 1, 8, and 15 of each cycle) 
• Urine pregnancy test, for women of childbearing potential (Day 1 of each cycle) 
• Concomitant medications (Days 1, 8, and 15 of each cycle) 
• Adverse event monitoring (Days 1, 8 and 15 pre- and post-dose) 
 
7.4 
Off-Study 
For the initial four cycles, The End-of-Treatment Visit will be Day 21 of Cycle 4 (patients who 
complete all four treatment cycles) or will be the Early Termination visit (for patients withdrawn 
from the study), whichever occurs first. All patients will be required to complete the 
End-of-Treatment Visit.  
 
Patients who are continuing beyond the initial four cycles, (i.e., completed the initial four 
cycles), will complete the End-of-Treatment Visit on Day 21 of Cycle 4 and the next visit will be 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
1042P17AUG.001 
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Confidential - Entire Page 
 
Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
Cycle 5, Day 1. Patients continuing beyond Cycle 4 will complete the End-of-Treatment Visit 
again at the time of withdrawal from the study.  
 
All patients who are withdrawn from the study will complete the End-of-Treatment Visit 
immediately at the time of withdrawal.  
The following assessments will be performed and measurements recorded: 
• Physical examination 
• ECOG performance status  
• Radiologic examination (if > 6 weeks have passed since the last evaluation) 
• Tumor antigen assessment: perform only if not done on Day 8 of Cycle 4  
• Vital signs (temperature, heart rate, blood pressure, respiratory rate, oxygen requirement 
[pulse oximetry]) 
• 12-lead ECG 
• Hematology, blood chemistry and coagulation 
• Urinalysis 
• Serum collection for anti-L-DOS47 antibody testing  
• Serum pregnancy test, for women of childbearing potential 
• Concomitant medications 
• Adverse event monitoring 
 
7.5 
Long-Term Follow-up 
Follow-up assessments will be conducted after the End-of-Treatment Visit. Long-term follow-up 
for disease progression will be conducted by radiologic assessments every 6 weeks (± 7 days) 
until one of the following occurs: disease progression, patient initiates non-study cancer 
treatment, patient withdraws consent or becomes lost-to-follow-up. Survival data will be 
captured by telephone call every 30 days (± 7 days) and patients will be followed until death.  
 
 
8.0 STUDY ASSESSMENTS 
8.1 
Safety Assessments 
8.1.1 Safety Analysis 
Safety data will be tabulated for all patients and include vital signs, laboratory parameters, and 
adverse events. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
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8.1.2 Reporting of Adverse Events 
8.1.2.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with the treatment.  An adverse event can be any unfavorable and unintended sign 
(including a laboratory finding), symptom or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.  
 
The adverse event reporting period will commence after the initial dosing of pemetrexed 
premedication.   If an AE occurs before the first dose of study drug it will be considered a non-
treatment emergent AE.  At each evaluation patients should be interviewed in a non-directed 
manner to elicit potential adverse reactions from the patient.  The occurrence of an adverse event 
will be based on changes in the patient’s physical examination, laboratory results, and/or signs 
and symptoms. 
 
All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an 
intervention), regardless of causal relationship, are to be recorded in the case report form and 
source documentation.  The Investigator must determine the intensity of any adverse events 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
(see http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf) 
and their causal relationship. Those AEs not covered by these criteria will be graded as follows:  
 
1. 
Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug 
not ordinarily needed for relief of symptom but may be given because of personality of 
patient. 
 
2. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is able 
to continue in study; treatment for symptom may be needed. 
 
3. 
Severe: Incapacitating, severe discomfort with inability to work or to perform normal 
daily activity. Severity may cause cessation of treatment with test drug; treatment for 
symptom may be given and/or patient hospitalized. 
 
4. 
Life-Threatening: Symptom(s) place the patient at immediate risk of death from the 
reaction as it occurred; it does not include a reaction that had it occurred in a more 
serious from, might have caused death. 
 
5.  
Fatal: Event caused the death of the patient.  

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Adverse events will be followed until resolution or stabilization while the patient remains on-
study.  Once the patient is removed from study, events thought to be related to the study 
medication will be followed until resolution or stabilization, unless, in the Investigator’s opinion 
the event is unlikely   to resolve due to the patient’s underlying disease, or until the patient starts 
a new treatment regimen or the patient is lost to follow-up. 
 
8.1.2.2 Attribution Definitions 
An adverse event is considered to be associated with the use of the Investigational agent if the 
attribution is determined as possible, probable or definite. Attribution of AEs will be recorded in 
the CRF as: 
 
• Unrelated: The AE is clearly NOT related to the study treatment. 
• Unlikely: The AE is doubtfully related to the study treatment. 
• Possible: The AE may be related to the study treatment. 
• Probable: The AE is likely related to the study treatment. 
• Definite: The AE is clearly related to the study treatment. 
 
8.1.2.3 Definition of an Unexpected Adverse Event 
An unexpected adverse event is defined as any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator Brochure; or, if an Investigator 
Brochure is not required or available, the specificity or severity of which is not consistent with 
the risk information described in this protocol or in the regulatory agency study authorization 
application.   
 
Unexpected, as used in this definition, refers to an adverse drug experience that has not been 
previously observed (e.g., included in the Investigator Brochure) rather than from the perspective 
of such experience not being anticipated from the pharmacological properties of the 
pharmaceutical product. 
 
8.1.2.4 Serious Adverse Event (SAE) 
A serious adverse event is defined as any untoward medical occurrence that at any dose: 
 
1. 
Results in death, 
 
2. 
Is life-threatening (i.e., the patient was at risk of death at the time of the event. It does not 
refer to an event which hypothetically might have caused death if it was more severe), 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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3. 
Requires in-patient hospitalization or prolongation of existing hospitalization excluding 
that for pain management, disease staging/re-staging procedures, or catheter placement 
unless associated with other serious events,  
 
4. 
Results in persistent or significant disability/incapacity, or 
 
5. 
Is a congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based on appropriate 
medical judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
8.1.2.5 Pregnancy 
Any pregnancy diagnosed during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator. Pregnancy, in and of itself, is not 
regarded as an adverse event, unless there is suspicion that study medication may have interfered 
with the effectiveness of a contraceptive medication. If the patient becomes pregnant while on-
study, the study drug should be immediately discontinued. Pregnancy information about a female 
patient or a female partner of a male patient should be reported immediately from the time the 
Investigator first becomes aware of a pregnancy or its outcome. This will be performed by the 
Investigator completing a Pregnancy Form and faxing it [in the US] to Theradex® at (609) 799-
1567; contact the Theradex® Safety Desk (see Section 8.1.2.6) for the Pregnancy Form.   
 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for 
medical reasons, outcome of stillbirth, congenital anomaly/birth defect, or serious adverse event 
in the mother will be recorded as an SAE and will be reported as described in Section 8.1.2.6.  
 
8.1.2.6 Reporting of Serious Adverse Events 
Adverse events classified as serious require expeditious handling and reporting to Theradex to  
comply with regulatory requirements. 
 
The serious adverse event reporting period will commence after the initial dose of pemetrexed 
premedication.  
 
For any serious adverse event (SAE) that occurs while a patient is on-study; within 30 days of 
the last study drug administration, regardless of any opinion as to the relationship of the SAE to 
the study drug; or if any SAE that the Investigator feels is related to the study drug occurs later 
than 30 days after the last study drug administration, the Theradex Safety Desk must be notified 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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immediately (within 24 hours of becoming aware of the event) by fax, email or telephone. 
Notification by email is preferred. The fax and telephone numbers and the email address listed 
below may be used during both business and non-business hours. During non-business hours a 
recorded message will provide the caller with the contact information for the on-call monitor. 
 
All SAEs require that a Serious Adverse Event Report Form be completed and forwarded either 
via facsimile or as a PDF via email to Theradex at the fax number or email listed below within 
24 hours of becoming aware of the event.  
 
 
In the USA, SAEs will be reported to: 
Theradex Safety Desk 
 
 
 
 
 
 
Telephone:  (609) 799-7580 
 
 
 
 
 
 
Fax:  (609) 799-1567 
 
 
 
 
 
 
Email: SafetyDeskUS@Theradex.com 
 
8.2 
Efficacy Assessments 
Although response is not the primary endpoint of this study, patients with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, patients should be evaluated 
every 6 weeks.  In addition to a baseline scan, confirmatory scans will also be obtained 4 weeks 
following initial documentation of an objective response. 
 
8.2.1 Definitions 
Response and progression will be evaluated in this study using the international criteria (version 
1.1) proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [Eur J 
Cancer. 45 (2009) 228-247].15 Changes in only the largest diameter (unidimensional 
measurement) of the tumor lesions are used in the RECIST 1.1 criteria. Note: Lesions are either 
measurable or non-measurable using the criteria provided below. The term “evaluable” in 
reference to measurability will not be used because it does not provide additional meaning or 
accuracy. 
 
8.2.1.1 Measurable Disease 
Measurable disease is defined by the presence of at least one measurable lesion. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension [longest 
diameter (LD) in the plane of measurement 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 which cannot be accurately measured 
with calipers should be recorded as non-measurable) 
• 20 mm by chest x-ray 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness no 
greater than 5 mm). 
 
8.2.1.2 Non-measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) are considered non-measurable 
disease. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, 
abdominal masses/abdominal organomegaly identified by physical exam and not followed by CT 
or MRI. 
 
Bone lesions, cystic lesions and lesions previously treated with local therapy must be considered 
as follows: 
 
Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions.  However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques (i.e., CT or MRI) can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
• Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered measurable lesions, 
if they meet the definition of measurability described above.  However, if non-cystic lesions 
are present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with prior local treatment: 
• Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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8.2.1.3 Target Lesions 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). 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. 
The baseline sum diameters will be used as reference by which to characterize the objective 
tumor response. 
 
8.2.1.4 Lymph Node Assessment 
For lymph nodes, measurements should be made of the short axis, which is defined as 
perpendicular to the LD of node assessed in the plane of measurement: 
• Target lesion if short axis ≥ 15 mm 
• Non-target lesion if short axis is ≥ 10 but < 15 mm 
• Normal if short axis < 10 mm 
For baseline, add the actual short axis measurement to the sum of LD of non-nodal lesions. 
 
8.2.1.5 Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of these lesions are not 
required and these lesions should be followed as “present,” “absent,” or in rare cases 
“unequivocal progression.”  In addition, it is possible to record multiple non-target lesions 
involving the same organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic 
lymph nodes’ or ‘multiple liver metastases’). 
 
8.2.2 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 and 
never more than 4 weeks before the beginning of the treatment. 
 
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 
antitumor effect of a treatment. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
and  ≥ 10 mm diameter as assessed using calipers (e.g., skin nodules). In the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. When lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may be reviewed at the end of the 
study. 
 
Chest x-ray. Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint. Lesions on chest x-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.   
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice 
thickness > 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is acceptable in certain situations (e.g., for body scans). 
 
Ultrasound (US). US should not be used to measure tumor lesions. US examinations cannot be 
reproduced in their entirety for independent review at a later date because they are operator 
dependent.  If new lesions are identified by US, confirmation by CT or MRI is advised.  If there 
is concern about radiation exposure at CT, MRI may be used instead of CT. 
 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques can be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
 
Tumor markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Because tumor markers are disease specific (e.g., PSA 
response in recurrent prostate cancer and CA-125 in recurrent ovarian cancer) instructions for 
their measurement should be incorporated into protocols on a disease specific basis. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types such as 
germ cell tumors, where known residual benign tumors can remain). When effusions are known 
to be a potential adverse effect of treatment (e.g., with certain taxane compounds or 
angiogenesis inhibitors) the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria 
for response or stable disease (SD) in order to differentiate between response (or SD) and 
progressive disease (PD). 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 3 – August 10, 2017 
 
8.2.3 Response Criteria 
8.2.3.1 Evaluation of Target Lesions 
Complete Response (CR): 
 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to 
< 10 mm. 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. The appearance of one or more new 
lesions is also considered progression.  
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study. 
 
8.2.3.1.1 Assessment of Target Lymph Nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline exam), even if the nodes regress 
to below 10 mm on study.  In order to qualify for CR, each node must achieve a short axis < 10 
mm.  For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the 
sum of target lesions. 
 
8.2.3.1.2 Target Lesions that Become “too small to measure” 
All lesions (nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm). If it is the opinion of 
the radiologist that the lesion has disappeared, the measurement should be recorded as 0 mm. If 
the lesion is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned.   
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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8.2.3.1.3 Lesions that Split or Coalesce on Treatment 
When non-nodal lesions fragment, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum.  Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining diameter measurements of each individual 
lesion.  If the lesions have truly coalesced such that they are no longer separable, the vector of 
the longest diameter should be the maximal longest diameter for the ‘coalesced lesion.’ 
 
8.2.3.2 Evaluation of Non-target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(< 10 mm short axis). 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (The 
appearance of one or more new lesions is also considered 
progression.) 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 the presence of 
SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation. 
 
8.2.3.3 New Lesions 
The finding of a new lesion should be unequivocal (i.e., not attributed to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor, such as a ‘new’ healing bone lesion).  A lesion identified on a follow-up study in an 
anatomical location that was not scanned at baseline is considered a new lesion and will indicate 
disease progression.  If a new lesion is equivocal, continued therapy and follow-up evaluation 
will clarify if it represents truly new disease.  If repeat scans confirm this is definitely a new 
lesion, then progression should be declared using the date of the initial scan. 
 
8.2.3.4 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The patient’s best overall response 
assignment will depend on findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study, 
it may also require confirmatory measurement. Specifically, in non-randomized trials where 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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response is the primary endpoint, confirmation of PR or CR is needed to deem either one the 
“best overall response.”   
 
It is assumed that at each protocol-specified timepoint, a response assessment occurs. Table 11 
provides a summary of the overall response status calculation at each timepoint for patients who 
have measurable disease at baseline.  When patients have non-measurable disease, Table 12 
should be used. 
Table 11. Timepoint response: Patients with target (+/- non-target) disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR / non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response, PR=partial response, SD=stable disease 
PD=progressive disease, NE=inevaluable 
 
Table 12. Timepoint response: Patients with non-target disease only 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR / non-PD 
No 
Non-CR / non-PD* 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR=complete response; PD=progressive disease; NE=inevaluable 
* Non-CR/non-PD is preferred over SD for non-target disease 
 
Best response determination for studies where confirmation of CR or PR is required: Complete 
or partial responses may be claimed only if the criteria for each are confirmed by a repeat 
assessment at least 4 weeks later. In this circumstance, the best overall response can be 
interpreted as in Table 13. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Table 13. Best overall response when confirmation of CR and PR required 
Overall response 
First timepoint 
Overall response 
Subsequent timepoint 
 
BEST overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR* 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NE=inevaluable 
* If CR is truly met at first timepoint, then any disease seen at a subsequent timepoint, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in the fact patient had PR, not 
CR, at the first timepoint. Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
 
8.2.4 Confirmatory Measurement/Duration of Response 
8.2.4.1 Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed by 
repeat assessments that should be performed 4 weeks after the criteria for response are first met. 
In the case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum interval of 42 days 
 
8.2.4.2 Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
8.2.4.3 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 
8.2.5 Clinical Benefit 
Clinical benefit will be calculated as the percentage of patients achieving complete response, 
partial response, and stable disease.  For patients to be evaluable for stable disease, the duration 
of stable disease must be at least 42 days from the first dose of study treatment.  
 
8.3 
Pharmacokinetics 
Plasma samples for pharmacokinetics will be collected as follows: 
Cycle 1, Days 1 and 8: predose and serially postdose (time relative to the start of infusion) at 15 
(during infusion), 30 (prior to end of infusion)*, 45 minutes* and 1*, 1.5, 2, 3, 4, 24, and 48 hours 
postdose Cycles 2 and 4, Day 8: predose and serially postdose (time relative to the start of 
infusion) at 15 (during infusion), 30 (prior to end of infusion) *, 45  minutes* and  1*, 1.5, 2, 3, 4, 
and 24 hours postdose; Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: predose and 30 
minutes* postdose (time relative to the start of infusion, to be collected just prior to end of 
infusion)  
 
Cycles 2 and 4, Day 8: predose and serially postdose (time relative to the start of infusion) at 15 
(during infusion), 30 (prior to end of infusion)*, 45  minutes* and  1*, 1.5, 2, 3, 4, 6, and 24 hours 
postdose; Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: predose and  30 minutes * 
postdose (time relative to the start of infusion, to be collected just prior to end of infusion). 
 
* If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a mild 
infusion reaction, there will be no change in the PK sampling timepoints, which are all relative to 
the start of L-DOS47 infusion.  PK samples collected at 30 minutes and 45 minutes will be 
considered during infusion samples and PK sample collected at 60 minutes (1 hour) will be a 
prior to end of infusion sample. All other timepoints remain the same. [see Table 14]. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Table 14. L-DOS47 plasma pharmacokinetic sampling schedule 
Protocol Scheduled Day 
Protocol Scheduled Timepointa 
Cycle 1, Day 1 
and 
Cycle 1, Day 8 
Predose 
During infusion: 
15 minutes 
30  minutes (prior to end of infusion) b 
Post infusion: c 
45 minutes b  
1 hour b  
1.5 hours  
2 hours  
3 hours  
4 hours  
24  hours (Day 2) 
48 hours (Day 3) 
Cycle 2, Day 8 
Cycle 4, Day 8 
Predose 
During infusion: 
15 minutes 
30  minutes ( prior to end of infusion) b 
Post infusion: c 
45 minutes b 
1 hour b 
1.5 hours 
2 hours 
3 hours 
4 hours 
24 hours (Day 9) 
Cycle 2, Day 1 
Cycle 3, Day 1 
Cycle 3, Day 8 
Cycle 4, Day 1 
Predose 
During infusion: 
30 minutes (prior to end of infusion) b 
a. 
Time windows for PK samples collected during infusion and post infusion are ± 5 min, exception include 
PK samples collected at 24 and 48 hours (post infusion) timepoints, the time window for these timepoints 
will be ± 30 min. 
b. If the L-DOS47 infusion time is increased from 30 minutes to 60 minutes in the event of a mild infusion 
reaction, there will be no change in the PK sampling timepoints, which are all relative to the start of L-
DOS47 infusion. PK samples collected at 30 minutes and 45 minutes will be considered during infusion 
samples and PK sample collected at 60 minutes (1 hour) will be a prior to end of infusion sample. All 
other timepoints remain the same.  
c. 
Time relative to start of infusion 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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8.4 
Immunogenicity 
The immunogenicity of L-DOS47 will be evaluated from serum samples collected on Cycle 1, 
Day 1 (predose; baseline) and Day 8 (predose), Cycles 2 through 4 (Day 1, predose), all 
additional cycles (i.e., Cycle 5 and beyond, Day 1 (predose), at the end of treatment or early 
termination visit, and at the follow-up visit (30 days after the last dose). 
 
 
9.0 STATISTICS 
Demographic data will be displayed and descriptive summary statistics will be used to describe 
the study population (e.g., ranges, mean and medians of age, and weight; numbers of males and 
females; description of baseline performance status characteristics; tabulation of tumor types and 
histology). 
 
Safety data will be tabulated for all patients who receive any amount of study treatment.  These 
data will include laboratory parameters, adverse events, and cardiographic values.  The 
tabulation of laboratory parameters will indicate the normal ranges for each parameter.  Each 
value will be classified as falling above, below, or within the normal range.   
 
Adverse events will be tabulated by body system, severity and relation to treatment.  For the 
purposes of presentation, groups will be arranged by decreasing frequency of adverse events. 
 
Efficacy data will be tabulated.  The best overall response rate, defined using RECIST 1.1, will 
be summarized for efficacy-evaluable patients.  The percentage of patients in each of the best 
overall response categories will be presented.  The overall response rate will be calculated as the 
proportion of patients with responsive disease (CR and PR). Clinical benefit will be calculated as 
the percentage of patients achieving complete response, partial response, and stable disease.  For 
patients to be evaluable for stable disease, the duration of stable disease must be at least 42 days 
from the first dose of study treatment. Clinical benefit data from all cohorts will be displayed in a 
waterfall plot. 
 
Pharmacokinetic parameters will be determined from L-DOS47 concentrations using non-
compartmental methods (WinNonLin®).  L-DOS47 PK parameters to be calculated (if adequate 
data are available for estimation) will include maximum concentration (Cmax), time of Cmax 
(Tmax), applicable area under the curve (AUC) parameters, terminal half-life (t½), systemic 
clearance (CL), volumes of distribution (Vz) and volume of distribution at steady state (Vss) and 
urinary excretion parameters.  The concentrations and PK parameters will be summarized using 
descriptive statistics (n, mean, standard deviation, percent coefficient of variation, geometric 
mean, median, minimum and maximum). 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 3 – August 10, 2017 
Immunogenicity data will be tabulated.  The concentration of anti-L-DOS47 antibodies will be 
evaluated using descriptive statistics. 
 
 
10.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
10.1 Monitoring of the Study and Regulatory Compliance 
The project manager, or designee, will make an initiation site visit to each institution to review 
the protocol and its requirements with the Investigator(s), inspect the drug storage area, fully 
inform the Investigator of his/her responsibilities and the procedures for assuring adequate and 
correct documentation.  During the initiation site visit the case report forms (CRFs) will be 
reviewed. Other pertinent study materials will also be reviewed with the Investigator’s research 
staff.  During the course of the study, the monitor will make regular site visits in order to review 
protocol compliance, examine CRFs and individual subject’s medical records and assure that the 
study is being conducted according to pertinent regulatory requirements. All CRF entries will be 
verified with source documentation. The review of medical records will be done in a manner to 
assure that patient confidentiality is maintained.  
 
10.2 Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum 
vitae, a completed FDA Form 1572 (required in the USA) and a financial disclosure statement 
(required in the USA) to Theradex. All Sub-investigators will be required to provide a current 
curriculum vitae and a financial disclosure statement (required in the USA) to Theradex. 
 
10.3 Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor or the Sponsor’s representative (Theradex). Any such changes which may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, must receive 
prior approval by the IRB/IEC. The exception to this is where modifications are necessary to 
eliminate an immediate hazard to trial subjects, or when the change involves only logistical or 
administrative aspects of the trial (e.g., change in monitor, change in telephone number). Other 
administrative revisions which may impact the clinical portion of a study will be duly reported to 
the IRB/IEC by the Principal Investigator. 
 
10.4 Publication Policy 
The Investigator agrees to inform the Sponsor of any publication or presentations on the study.  
All manuscripts, abstracts or presentations (in outline form with copies of slides if available) will 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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be submitted to the Sponsor and Theradex at least 30 days prior to the submission of the data 
for publication in order for the Sponsor to protect proprietary information.  The Sponsor will 
review the submitted material within a reasonable period of time and will not unreasonably 
withhold publication permission. 
 
11.0 ETHICAL CONSIDERATIONS 
11.1 Informed Consent 
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed and dated. The 
informed consent form will contain all the Essential Elements of Informed Consent set forth in 
21 CFR, Part 50, the European Union Directive 2001/20/EC and its associated Detailed 
Guidances, European Union GCP Directive 2005/28/EC, the ICH Guideline for Good Clinical 
Practice, Section 4.8, and the terms of the Declaration of Helsinki (2013). Copies of the signed 
document should be given to the patient and filed in the Investigator’s study file, as well as the 
patient’s medical record if in conformance with the institution’s Standard Operating Procedures.  
 
In cases where minors or incapacitated subjects are to be included, two sets of information sheets 
might be needed according to national regulations. In addition to the information given to the 
patient’s parent or legal representative, the patient should be given information according to 
his/her capacity to understand.  This information should include, where appropriate, a statement 
that the patient’s decision not to participate or to withdraw from a trial will be respected, even if 
consent is given by the parent/legal representative. 
 
11.2 Institutional Review Board/Independent Ethics Committee 
The study will not be initiated without approval of the appropriate Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and compliance with all administrative 
requirements of the governing body of the institution.  This protocol, consent procedures, and 
any amendments must be approved by the IRB/IEC in compliance with current regulations of the 
FDA and the European Union as applicable and in accordance with ICH/GCPs.  A letter of 
approval will be sent to the Sponsor prior to initiation of the study and when any subsequent 
modifications are made.  The IRB/IEC will be kept informed by the Investigator, Theradex or 
the Sponsor, as required by national regulations, as to the progress of the study as well as to any 
serious and unexpected adverse events.  
 
11.3 Patient Privacy  
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned patient 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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numbers; patients should not be identified by name.  In accordance with local, national or federal 
regulations, the Investigator will allow the Sponsor or designee personnel access to all pertinent 
medical records in order to verify the data gathered on the case report forms and to audit the data 
collection process.  Regulatory agencies such as the US Food and Drug Administration (FDA) 
and the UK Medicine and Healthcare Products Regulatory Agency (MHRA) may also request 
access to all study records, including source documentation for inspection.  Clinical information 
will not be released without the written permission of the patient as outlined in the patient 
consent form. 
 
 
12.0 DATA HANDLING AND RECORD KEEPING 
12.1 Data to be Recorded Directly in the Electronic Case Report Form 
Not applicable.  
 
12.2 Recording of Data 
Data collected during the study will be recorded in the patient’s eCRFs by the investigational site 
staff. The staff will keep records of the patient’s visit in the files considered as source documents 
for the site, e.g., hospital chart, research chart. The Investigator will be responsible for the 
recording of all data on the CRF and for submitting the data to the Sponsor or their designee in a 
timely manner. Should any value be significantly different from normal, the Investigator will 
comment in the appropriate sections provided in the CRF.  
 
12.3 Study Records 
U.S. Federal laws require that an Investigator maintain all study records for the indication under 
investigation for two years following the date a Product Licensing Application is approved or, if 
no application is to be filed or if the application is not approved for such indication, until two 
years after the investigation is discontinued and the FDA is notified. 
 
European laws require that the Investigator maintain all study records (excluding the subject’s 
medical files, see below): 
- for at least 15 years after completion or discontinuation of the trial, 
- or for at least two years after the granting of the last marketing authorization in the European 
Community (EC) and where there are no pending or contemplated marketing applications in the 
EC, 
- or for at least two years after the formal discontinuation of clinical development of the 
investigational product. 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
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Amendment 3 – August 10, 2017 
Subject’s medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice. 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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13.0 REFERENCES 
 
1 Tannock IF, and Rotin D. Acid pH in tumors and its potential for therapeutic exploitation. 
Cancer Res. 49: 4373-84, 1989 
 
2 Gerweck LE, et al. Tumor pH controls the in vivo efficacy of weak acid and base 
chemotherapeutics. Mol. Cancer Ther.5: 1275-9, 2006 
 
3 Raghunand N, et al. Enhancement of chemotherapy by manipulation of tumor pH. Br J 
Cancer 80: 1005-11, 1999 
 
4 Raghunand N, et al. Tumor acidity, ion trapping and chemotherapeutics. II. pH-dependent 
partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic 
chemotherapeutic agents. Biochem. Pharmacol.66: 1219-29, 2003 
 
5 Cowan DS, and Tannock IF. Factors that influence the penetration of methotrexate through 
solid tissue. Int J Cancer 91: 120-5, 2001 
 
6 Wong, et al. Urease-induced alkalinization of extracellular pH and its antitumor activity in 
human breast and lung cancers. J. Exp. Ther. Oncol. 5(2):93-9, 2005 
 
7 Clayton, GD and Clayton FE (eds) Patty’s Industrial Hygiene and Toxicology. Volumes 2A, 
2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley & Sons Inc. 1993-1994, 
pg. 758 
 
8 Buckley LA, et al. Respiratory tract lesions induced by sensory irritants at the RD50 
concentration. Toxicol Appl Pharmacol. 74(3):417-429, 1984 
 
9 NIOSH; Criteria Document: Ammonia p. 48 DHEW Pub. NIOSH 74-136, 1974 
 
10 Chaft JE, et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with 
EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib – implications for 
clinical trial design. Clin Cancer Res. 17(19):6298-6303, 2011 
 
11 Pop O, et al. Disease flare after treatment discontinuation in a patient with EML4-ALK lung 
cancer and acquired resistance to crizotinib. J Thoracic Oncol. 7(8):e1-e2, 2012 
 
12 ALIMTA [prescribing information] Indianapolis, IN: Lilly USA, LLC; 2012 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
13 Eisenhauer EA, et al. Phase I clinical trial design in cancer drug development. J Clin Oncol. 
18(3): 684-692, 2000 
 
14 Ardizzoni A, et al. Pemetrexed versus pemetrexed and carboplatin as second-line 
chemotherapy in advanced non-small cell lung cancer (NSCLC): results of GOIRC 02-2006 
randomized phase II study and pooled analysis with NVALT7 trial. J Clin Oncol. 30(36):4501-
4507, 2012.  
 
15 Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).  Eur J Cancer. 45: 
228-247, 2009 
 
 
 

Helix BioPharma Corp. 
LDOS001 (H13-11042) 
A Phase I, Open Label, Dose Escalation Study of Immunoconjugate 
L-DOS47 
in 
Combination 
With 
Standard 
Doublet 
Therapy 
of 
Pemetrexed/Carboplatin  in Patients With Stage IV (TNM M1a and M1b) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
 
APPENDIX I  -  ECOG PERFORMANCE STATUS 
 
 
Grade 
 
 
 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
 
1 
 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work. 
 
 
2 
 
Ambulatory and capable of all self-care but unable to carry out any 
work activities.  Up and about more than 50% of waking hours. 
 
 
3 
 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours. 
 
 
4 
 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
 
5 
 
Dead.