Clinical trial NCT02309892
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-Small Cell Lung Cancer Neoplasms Immunoconjugate Tumor microenvironment alkalinization
Sponsor: Helix BioPharma Corporation
Start date: 2015-04-20; Completion date: 2019-09-20
Enrollment: 14 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The primary purpose of this research study is to evaluate how safe, how well tolerated and how effective a range of doses of 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.

Detailed description:
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.

Arms: arm 1: Patients will be recruited into cohorts of L-DOS47 escalating doses, with a minimum of 3 and a maximum of 6 patients per cohort for the first and last two dosing cohorts, and a minimum of 1 and a maximum of 2 patients for the middle three dosing cohorts. The starting dose of L-DOS47 will be 0.59 µg/kg; further planned dose levels to be assessed are 0.78, 1.5, 3.0, 6.0, 9.0 and 12.0 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.
Interventions: intervention 1: L-DOS47
Intervention descriptions: intervention 1: A treatment cycle will be 21 days, with patients receiving L-DOS47 on cycle Days 1, 8, and 15 and pemetrexed/carboplatin on Day 1 of each treatment cycle.

Protocol documents:
Prot_000.pdf: 
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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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Amendment 3 – August 10, 2017 
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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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 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 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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Version 1.1 – April 22, 2014 
 
 
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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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
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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Version 1.1 – April 22, 2014 
 
 
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 
 
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 
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 
 
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 
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 
30 
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 
31 
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 
33 
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 
34 
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 
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) 
Recurrent or Metastatic Non-Squamous Non-Small Cell Lung Cancer 
 
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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 
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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 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 
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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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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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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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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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Version 1.1 – April 22, 2014 
 
 
Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
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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Version 1.1 – April 22, 2014 
 
 
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 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
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 
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 
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 2 – October 18, 2016 
 
 
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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Version 1.1 – April 22, 2014 
 
 
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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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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• 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 


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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. 
 


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LDOS001 (H13-11042) 
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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.  


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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), 
 


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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 


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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 


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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 
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in 
Combination 
With 
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Therapy 
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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. 
 


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L-DOS47 
in 
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With 
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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). 
 


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LDOS001 (H13-11042) 
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L-DOS47 
in 
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With 
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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 


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LDOS001 (H13-11042) 
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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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Amendment 3 – August 10, 2017 
 
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 
 
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 
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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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
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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Amendment 1 – June 2, 2015 
 
 
Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
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 
 
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 
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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Amendment 2 – October 18, 2016 
 
 
Amendment 3 – August 10, 2017 
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 
 
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 
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 
 
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 
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 
 
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 
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 
 
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 
 
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 
 
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 
 
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. 
 
 

SAP_001.pdf: 




 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
2 
Confidential – Entire Page 
Introduction to the Reporting and Analysis Plan 
 
This Reporting and Analysis Plan (RAP) outlines the structure and content of the Clinical 
Study Report (CSR) including the statistical issues associated with the analysis of the 
safety and efficacy findings of this study.  
 
This was a Phase I, open label, multicenter, 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. Initially, cohorts of 3 to 6 patients were to be 
enrolled in ascending dose cohorts until the maximum tolerated dose (MTD) was reached; 
as of Amendment 3, an accelerated dose design was implemented to permit cohorts of 
1 patient up to the L-DOS47 dose level of 6µg/kg, followed by cohorts of 3 to 6 patients for 
the final two L-DOS47 dosing cohorts of 9 and 12 µg/kg. The MTD was defined as the 
highest dose level at which ≤ 1 of 6 patients experienced a dose-limiting toxicity (DLT) 
during the first treatment cycle. Once the MTD was defined, a confirmation cohort of 
approximately 10 patients was planned for enrollment at the MTD to determine the 
recommended Phase II dose for the combination treatment. 
 
The starting dose of L-DOS47 was 0.59 µg/kg administered by intravenous infusion over 
30 minutes. The standard of care doses of pemetrexed [500 mg/m2 administered over 
10 minutes] and carboplatin [AUC6 mg/mL administered over 30 minutes], respectively, 
administered in combination with L-DOS47, remained constant across cohorts. A 
treatment cycle was 21 days with patients receiving L-DOS47 on Days 1, 8, and 15 and 
pemetrexed/ carboplatin on Day 1 of each treatment cycle for up to 4 cycles. Patients who 
tolerated treatment could continue L-DOS47 treatment for additional cycles.  
 
Safety data, including laboratory parameters and adverse events, were collected for all 
patients. Adverse events were classified according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Efficacy was 
assessed after every 2 cycles of treatment using the Response Evaluation Criteria in Solid 
Tumors (RECIST, version 1.1) guidelines. Pharmacokinetic parameters for L-DOS47 were 
determined from plasma samples collected from all patients at protocol-defined time 
points at predose, during the infusion and post infusion during Cycles 1 through 4. 
Patients could continue study treatment in the absence of unacceptable toxicity or until 
disease progression was documented. Continuation of treatment was to be determined 
by the clinical judgment of the Investigator. 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
3 
Confidential – Entire Page 
The following documents were used in the preparation of this RAP: 
Protocol 
Version Date 
Original 
March 5, 2014 
Version 1.1* 
April 22, 2014 
Amendment 1 
June 2, 2015 
Amendment 2 
September 28, 2016 
Amendment 3 
August 10, 2017 
* The first patient was enrolled and treated in accordance with Version 1.1 of the protocol. 
 
CRF 
Version Date 
1068 Annotated Layouts 
February 20, 2018 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
4 
Confidential – Entire Page 
1.0 Title Page 
 
CLINICAL STUDY REPORT 
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 
 
Protocol No. LDOS001 
 
Sponsor: 
Helix BioPharma Corp. 
9120 Leslie Street, Suite 205 
Richmond Hill, ON L4B 3J9 
Canada 
Investigators: 
 
Sarina Piha-Paul, MD 
UT MD Anderson Cancer Center 
Depart of Investigational Cancer Therapeutics 
1515 Holcombe Boulevard, Unit 455 
Houston, TX 77030 
Afshin Dowlati, MD 
Case Western University 
University Hospitals Case Medical 
Center 
11100 Euclid Avenue, LKS 1200 
Cleveland, OH 44106 
 
Chandra Belani, MD 
Penn State Hershey Cancer Institute 
500 University Drive, MC CH72 
Hershey, PA 17033 
 
Medical Monitor: 
Theradex Oncology 
4365 US-1, Suite 101 
Princeton, NJ 08540 
 
Study Initiation Date: 
(First Patient On-Study) 
 
20Apr2015 
Study Completion Date: 
(Last Patient Off-Study) 
 
 
Date of Study Report: 
 
 
This study was performed in compliance with good clinical practice (GCP) including the archiving of 
essential documents. 
This report complies with ICH Guideline E3. 
 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
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Helix BioPharma Corp. 
CLINICAL STUDY REPORT 
Signature Page 
 
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 
 
Protocol No. LDOS001 
 
 
Sponsor 
Representative: 
____________________________________________   
Brenda Lee, M.Sc. 
Clinical Research Consultant to Helix Biopharma 
Corp. 
Helix BioPharma Corp. 
 
 
 
__________________ 
Date 
Medical Monitor: 
____________________________________________   
Richard S. Ungerleider, MD 
Senior Vice President, Clinical Research Affairs 
Theradex Systems, Inc. 
 
 
__________________ 
Date 
Biostatistician: 
____________________________________________  
Dailan Danforth 
Associate Director, Biostatistics  
Theradex Systems, Inc. 
 
 
 
__________________ 
Date 
Medical Writer: 
____________________________________________ 
Janet S. Johnson 
Senior Medical Writer / Regulatory Affairs 
Theradex Systems, Inc.  
__________________ 
Date 
 
 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
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Confidential – Entire Page 
2.0 Synopsis  
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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 [Protocol No. LDOS001] 
 
Investigators and study centers:   
Sarina Piha-Paul, MD    [Site 002] 
UT MD Anderson Cancer Center 
Department of Investigational Cancer 
Therapeutics 
1515 Holcombe Boulevard, Unit 455 
Houston, TX 77030 
 
Afshin Dowlati, MD    [Site 003] 
Case Western University 
University Hospitals Case Medical Center 
11100 Euclid Avenue, LKS 1200 
Cleveland, OH 44106 
 
Chandra Belani, MD    [Site 001]* 
Penn State Hershey Cancer Institute 
500 University Drive, MC CH72 
Hershey, PA 17033 
*Site 001 enrolled and treated 1 patient in 2015, then was closed on 18Aug2017 while the study 
was ongoing. 
 
Publication (reference):   
Not applicable. 
 
Study period (years):  2015 - ____ 
First patient enrolled:  20Apr2015 
Last patient completed:   
 
Clinical 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  


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
7 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
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. 
 
Exploratory Objectives: 
• 
Evaluation of the pharmacokinetics of L-DOS47 in combination treatment with 
pemetrexed/carboplatin 
• 
Evaluation of the immunogenicity of L-DOS47 
 
Methodology:  
This was a Phase I, open label, multicenter, 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 initially utilized a standard “3 + 3” design of dose escalation. 
Patients were recruited into cohorts of L-DOS47 escalating doses, with a minimum of 3 and a 
maximum of 6 patients per cohort. As of Amendment 3, the study implemented an accelerated 
“1 + 2” design up to 6 µg/kg and the standard “3 + 3” design for the final two dosing cohorts.  The 
starting dose of L-DOS47 was 0.59 µg/kg administered by intravenous infusion over 30 minutes. 
The standard of care doses of pemetrexed [500 mg/m2 administered over 10 minutes] and 
carboplatin [AUC6 mg/mL administered over 30 minutes], respectively, administered in 
combination with L-DOS47, remained constant across cohorts. As of Amendment 2, the 
L-DOS47 infusion could be increased from 30 minutes to 60 minutes in the event of a mild 
infusion reaction. 
 
All patients at a given dose level had to complete Cycle 1 before escalation in subsequent 
patients could proceed.  The decision for escalation to the next dose level was made after safety 
data were reviewed by a Safety Review Committee, which consisted of the Investigators, the 
Medical Monitor, and the Sponsor.  Dose escalation was based on dose limiting toxicities (DLTs) 
occurring during the first cycle of treatment.   
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
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8 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
The sequence of administration of the combination therapy on Day 1 of each treatment cycle 
was: 
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 intravenously 
infused over 30 minutes.   
A treatment cycle was 21 days with patients receiving L-DOS47 on Days 1, 8, and 15 and 
pemetrexed/ carboplatin on Day 1 of each treatment cycle.  
 
Patients 
were 
to 
receive 
4 
cycles 
of 
combination 
treatment 
with 
L-DOS47 
+ 
pemetrexed/carboplatin. Patients who did not progress following the 4 cycles of combination 
treatment and who did not experience unacceptable toxicity had the opportunity to continue to 
receive additional cycles of L-DOS47 treatment for as long as there was clinical benefit and it 
was well-tolerated, in the opinion of the Investigator, until disease progression. Patients who 
were unable to complete 4 cycles of L-DOS47 + pemetrexed/carboplatin combination treatment 
due to pemetrexed/carboplatin toxicity had the opportunity to continue receiving L-DOS47 
treatment following discontinuation of pemetrexed/carboplatin, for as long as there was clinical 
benefit and it was well-tolerated, in the opinion of the Investigator, until disease progression. 
 
Patient safety was monitored throughout the study and for a minimum of 30 days after last 
dose of study drug. Long-term follow-up for disease progression was conducted by radiologic 
assessments every 6 weeks (±7 days) until disease progression, the patient initiated non-study 
cancer treatment, the patient withdrew consent or became lost-to-follow-up. Survival data was 
captured by telephone call every 30 days (±7 days) and patients were followed until death. 
Severity of adverse events and laboratory abnormalities were reported according to NCI CTCAE 
version 4.0. Response to treatment was assessed after every 2 cycles using RECIST version 1.1.  
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
9 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
The following table shows the planned dose levels for L-DOS47 treatment: 
 
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 resulted in 
DLT, patients were to be treated at 
the -1 dose level. 
 
Enrollment in each dose cohort proceeded in the standard “3+3” schema where 3 patients were 
initially enrolled per cohort (see note above regarding implementation of accelerated dosing as 
of Amendment 3). The decision to escalate to the next dose level was based on the observation 
of DLT during Cycle 1. If 0 of 3 patients had DLT, escalation could proceed to the next cohort. If, 
however, DLT was observed in 1 of the 3 patients, an additional 3 patients were to be enrolled at 
that dose.  In a cohort of 6, if one patient had DLT, then dose escalation could proceed; if 2 or 
more patients had DLT, then that dose would be declared the maximally administered dose and 
dose escalation would cease. Three additional patients were to be entered at the next lowest 
dose level if only 3 patients had been treated previously at that dose. The MTD/RD was defined 
as the highest dose level at which ≤ 1 of 6 patients experienced a DLT during the first treatment 
cycle. 
MTD Confirmation Cohort: 
Once the MTD was defined, a confirmation cohort of approximately 10 patients was planned for 
enrollment at the MTD to determine the recommended Phase II dose for the combination 
treatment. 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
10 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
Dose-limiting toxicity (DLT): 
DLT was defined as the occurrence of any of the following events (according to NCI CTCAE 
version 4.0) that occurred within 21 days after commencing study drug treatment and was 
considered to be possibly, probably, or definitely related to study drug treatment by the 
Investigator: 
• 
Hematologic adverse events  ≥ grade 4  
• 
Non-hematologic adverse events ≥ grade 3 
• 
One instance each of two unique grade 2 adverse events (accelerated dose cohorts only) 
 
For the purpose of cohort evaluation, if a patient did not receive all of his/her scheduled 
L-DOS47 doses in Cycle 1 due to toxicity, this was considered a DLT. Patients experiencing a DLT 
during the first treatment cycle were to be withdrawn from the study.  
 
Number of patients:   
Enrollment in the study was planned for up to 37 patients (estimation based on 3 patients per 
cohort for 5 dose escalation cohorts, 6 patients per cohort for 2 dose escalation cohorts and 10 
patients in the MTD expansion cohort). 
 
Diagnosis and main criteria for inclusion:   
Inclusion Criteria:  
Patients had to fulfill all of the following criteria to be eligible for the study: 
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 had to be assessed according to TNM, 7th edition and 
based on computed tomography (CT) scan; 
3. EGFR-mutation positive patients had to 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 was 7 days; 
4. Patients whose tumors harbored an anaplastic lymphoma kinase (ALK) translocation had to 
have progressed on or had intolerance to an ALK inhibitor.  The washout period for patients 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
11 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
treated with an ALK inhibitor was 7 days; 
5. No prior adjuvant chemotherapy within 6 months of the first treatment day if there was 
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 were due 
to underlying malignancy; 
11. Male or female patients of child-producing potential had to 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 had to have a negative serum pregnancy test; 
13. Females had to 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 had to be off steroids and not 
taking antiepileptics for brain metastases. 
  
Exclusion Criteria:  
Patients would 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 (prior to Amendment 2, ≥ 12 
months); 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
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12 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
6. 
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 were 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 was permissible; 
9. 
Significant cardiac disease including heart failure that met 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. 
 
Test product, dose and mode of administration, batch number:   
L-DOS47 drug product was provided by Helix BioPharma Corp. 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 was stored at 2-8°C. The lot 
numbers used in the study were OBP-801-001 and OBP-801-003. 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
13 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
L-DOS47 Administration: 
L-DOS47 was administered at a starting dose of 0.59 µg/kg by intravenous infusion over 30 
minutes. As of Amendment 2, the L-DOS47 infusion time could be increased to 60 minutes in 
the event of a mild infusion reaction.    
 
Doublet Chemotherapy: 
Carboplatin was prepared per the drug package insert and  administered by intravenous 
infusion at a dose of AUC6 mg/mL over 30 minutes. 
 
Pemetrexed was prepared per the prescribing information sheet and administered by 
intravenous infusion at a dose of 500 mg/m2 over 10 minutes.   
Pemetrexed pre-medication: 
• 
Vitamin Supplementation: patients were instructed to initiate folic acid 400 µg to 1000 
µg orally once daily beginning 7 days before the first dose of pemetrexed and continue 
during the full course of therapy and for 21 days after the last dose of pemetrexed. 
Vitamin B12 1 mg was administered intramuscularly 1 week prior to the first dose of 
pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 injections could be 
given the same day as treatment with pemetrexed. 
• 
Corticosteroids: Dexamethasone 4 mg orally was administered twice daily the day 
before, the day of, and the day after pemetrexed administration. 
 
Duration of treatment:   
Patients 
were 
to 
receive 
4 
cycles 
of 
combination 
treatment 
with 
L-DOS47 
+ 
pemetrexed/carboplatin. After 4 cycles, patients could continue to receive additional cycles of 
L-DOS47 alone until disease progression as long as there was clinical benefit and it was well-
tolerated. Patients who were unable to complete 4 cycles of combination treatment due to 
pemetrexed/carboplatin toxicity could receive additional cycles of L-DOS47 alone until disease 
progression as long as there was clinical benefit and it was well-tolerated.  
 
Reference therapy, dose and mode of administration, batch number:   
Not applicable. 
 
Criteria for evaluation:   
Safety: Safety data including vital signs, laboratory parameters, and adverse events, etc. were 
collected for all patients. All patients who received any amount of L-DOS47 were included in the 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
14 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
safety analysis. Safety parameters evaluated include adverse events, vital signs, and clinical 
laboratory results, etc. Adverse events were classified according to the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.  
 
Efficacy: Although response was not the primary endpoint of this study, patients with 
measurable disease were assessed using RECIST version 1.1. Objective response assessment 
was performed at baseline, after every 2 cycles, and at off-study using the same method of 
radiologic imaging at each assessment.  For patients with less than 2 cycles of study therapy, 
there had to be clear evidence of clinical progression to be considered eligible for the efficacy 
evaluation. 
 
Exploratory:  
Pharmacokinetic parameters for L-DOS47 were determined from plasma samples collected 
from all patients at protocol-defined time points at predose, during the infusion and post 
infusion during Cycles 1 through 4.  
 
Tumor antigen (CEACAM6) assessment: blood samples were to be drawn from patients twice 
during the study at protocol-defined time points for assessment of tumor antigen. 
 
Immunogenicity of L-DOS47 was assessed from serum samples collected from patients at 
protocol-defined time points prior to L-DOS47, during the study, at the end of treatment, and at 
the follow-up visit 30 days after last study dose.  
 
Statistical methods:   
The primary endpoint of this study was to assess the toxicity of L-DOS47 by determining the 
dose level at which DLTs were observed. The MTD and RP2D were to be determined during the 
course of the study and not during the statistical analysis phase. Safety data were tabulated for 
all patients, include laboratory parameters, vital signs, and AEs. AEs were tabulated by body 
system, preferred term, severity, and relationship to treatment. AEs were arranged by 
decreasing frequency of AEs. Laboratory data was graded according to NCI CTCAE (Version 4.0) 
and tabulated based on maximum grade. AEs were coded using the Medical Dictionary for Drug 
Regulatory Activities (MedDRA®) Version 17.1. 
 
Secondary endpoints of this study were to examine the efficacy and pharmacokinetics of L-
DOS47. For efficacy analysis, best overall response was assessed using RECIST version 1.1. The 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
15 
Confidential – Entire Page 
Name of sponsor:   
Helix BioPharma Corp. 
Individual study table 
referring to part of the 
dossier 
 
Volume: 
 
Page: 
(For national authority 
use only) 
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. 
 
objective antitumor response rate [complete response (CR) or partial response (PR)] and 95% 
confidence interval were calculated based on the proportion of patients with responsive disease 
(CR + PR). The clinical benefit rate (CR+PR+SD) and 95% CI were calculated. Duration of response 
(CR or PR) was evaluated using Kaplan-Meier methodology and the 95% confidence interval for 
the median progression-free time was provided. Pharmacokinetic analysis was performed to 
establish Cmax, Tmax, half-life, AUC, CL, and Vd. 
 
Summary - Conclusions:   
Demographics Summary: 
[Insert demographics summary here] 
 
Safety Summary:   
[Insert safety summary here] 
 
Efficacy Summary: 
[Insert efficacy summary here] 
 
Pharmacokinetics Summary: 
[Insert PK summary here, or “The PK results is presented in a separate report.”] 
 
Conclusions: 
[Insert overall discussion and conclusions here] 
 
 


 
 
 
LDOS001 
Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
All rights reserved 
16 
Confidential – Entire Page 
3.0 Table of Contents 
Page No. 
1.0 
Title Page .............................................................................................................................. 4 
2.0 
Synopsis ................................................................................................................................ 6 
3.0 
Table of Contents .............................................................................................................. 16 
3.1 
In-Text Tables ................................................................................................................... 20 
3.2 
In-Text Figures .................................................................................................................. 20 
4.0 
Ethical Conduct of the Study ........................................................................................... 23 
5.0 
Investigators and Study Administration ........................................................................ 23 
5.1 
Investigators ..................................................................................................................... 23 
5.2 
Study Administration ...................................................................................................... 24 
6.0 
Introduction ....................................................................................................................... 24 
7.0 
Study Objectives ................................................................................................................ 25 
8.0 
Investigational Plan ........................................................................................................... 26 
8.1 
Overall Study Design and Plan ....................................................................................... 26 
8.1.1 
Dose Escalation Phase ............................................................................................. 27 
8.1.2 
Dose Limiting Toxicity .............................................................................................. 28 
8.1.3 
Maximum Tolerated Dose ...................................................................................... 28 
8.1.4 
Dose Modifications .................................................................................................. 29 
8.2 
Discussion of Study Design ............................................................................................ 32 
8.3 
Selection of Study Population ........................................................................................ 32 
8.3.1 
Inclusion Criteria ...................................................................................................... 32 
8.3.2 
Exclusion Criteria...................................................................................................... 33 
8.3.3 
Removal of Patients from Treatment or Assessment ........................................ 34 
8.3.4 
Protocol Deviations .................................................................................................. 35 
8.4 
Treatments ....................................................................................................................... 35 
8.4.1 
Treatment Administered ......................................................................................... 35 
8.4.2 
Identity of Investigational Product(s) .................................................................... 35 
8.4.3 
Method of Assigning Patients to Treatment Groups .......................................... 36 
8.4.4 
Selection of Doses in the Study ............................................................................. 36 
8.4.5 
Selection and Timing of Dose for Each Patient .................................................... 36 


 
 
 
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8.4.6 
Blinding ...................................................................................................................... 37 
8.4.7 
Prior and Concomitant Treatment ........................................................................ 37 
8.4.8 
Treatment Compliance ............................................................................................ 38 
8.4.9 
Dose Delay and Modification ................................................................................. 38 
8.4.10 Duration of Therapy ................................................................................................ 38 
8.5 
Efficacy and Safety Variables.......................................................................................... 38 
8.5.1 
Efficacy and Safety Measurements ....................................................................... 38 
8.5.2 
Appropriateness of Measurements ...................................................................... 45 
8.5.3 
Efficacy and Safety Variables .................................................................................. 46 
8.5.4 
Drug Concentration Measurements and Other Assessments .......................... 50 
8.6 
Data Quality Assurance................................................................................................... 51 
8.7 
Statistical Methods Planned in the Protocol and Determination of Sample Size .. 52 
8.7.1 
Determination of Sample Size ................................................................................ 52 
8.7.2 
Analysis of Data ........................................................................................................ 52 
8.7.3 
Study Endpoints ....................................................................................................... 52 
8.7.4 
Statistical Analysis Populations .............................................................................. 53 
8.7.5 
Statistical Methods ................................................................................................... 53 
8.7.6 
Programming Considerations ................................................................................ 59 
8.8 
Changes in the Conduct of the Study or Planned Analyses ...................................... 61 
9.0 
Study Patients .................................................................................................................... 62 
9.1 
Disposition of Patients .................................................................................................... 63 
9.2 
Protocol Deviations ......................................................................................................... 64 
10.0 
Efficacy and Pharmacokinetic Evaluations .................................................................... 64 
10.1 Data Sets Analyzed .......................................................................................................... 64 
10.2 Patient Demographic and Other Baseline Characteristics ........................................ 65 
10.2.1 Demographics and Baseline Characteristics ....................................................... 65 
10.2.2 Baseline Disease Characteristics ........................................................................... 67 
10.2.3 Prior Cancer Therapy ............................................................................................... 68 
10.2.4 Concomitant Measures ........................................................................................... 68 
10.3 Measurements of Treatment Compliance ................................................................... 69 
10.4 Efficacy Results and Tabulation of Individual Patient Data ....................................... 69 
10.4.1 Best Overall Response ............................................................................................. 70 


 
 
 
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10.4.2 Duration of Response .............................................................................................. 73 
10.4.3 Analysis of Efficacy ................................................................................................... 77 
10.4.4 Statistical/Analytical Issues ..................................................................................... 77 
10.4.5 Tabulation of Individual Response Data ............................................................... 78 
10.4.6 Drug Dose, Drug Concentration and Relationships to Response ..................... 78 
10.4.7 Drug-Drug and Drug-Disease Interactions ........................................................... 78 
10.4.8 By-Patient Displays .................................................................................................. 78 
10.4.9 Efficacy Conclusions ................................................................................................ 78 
10.5 Pharmacokinetic Results ................................................................................................ 78 
11.0 
Safety Evaluation ............................................................................................................... 78 
11.1 Extent of Exposure, Compliance and Dose .................................................................. 78 
11.1.1 Cycle 1 ........................................................................................................................ 79 
11.1.2 All Treatment Cycles ................................................................................................ 81 
11.2 Adverse Events ................................................................................................................. 85 
11.2.1 Brief Summary of Adverse Events ......................................................................... 85 
11.2.2 Display of Adverse Events ....................................................................................... 86 
11.2.3 Analysis of Adverse Events ..................................................................................... 92 
11.2.4 Listing of Adverse Events by Patient ..................................................................... 93 
11.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events ..... 93 
11.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ......................................................................................................... 93 
11.3.2 Patient Narratives .................................................................................................... 96 
11.4 Clinical Laboratory Evaluations ..................................................................................... 96 
11.5 Performance Status, Vital Signs, Physical Findings, ECG Findings and Other 
Observations Related to Safety ..................................................................................... 97 
11.6 Safety Conclusions ........................................................................................................... 97 
12.0 
Discussion and Overall Conclusions ............................................................................... 98 
13.0 
Tables, Figures and Graphs Referred to but not Included in the Text ...................... 99 
14.0 
Reference List .................................................................................................................. 101 
15.0 
Appendices ....................................................................................................................... 102 
RAP-Specific Sections Presenting Sample Tables and Listings.............................................. 104 
Tables for Section 14: Referred to But Not Presented In-Text .............................................. 104 


 
 
 
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Listings for Section 16 ................................................................................................................. 138 
List of CSR Appendices ................................................................................................................ 182 
 


 
 
 
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3.1 In-Text Tables  
Page No. 
Table 1: Study Populations ........................................................................................................... 63 
Table 2: Patient Disposition .......................................................................................................... 64 
Table 3: Demographic Characteristics ........................................................................................ 66 
Table 4: Baseline Disease Characteristics .................................................................................. 67 
Table 5: Prior Cancer Therapy...................................................................................................... 68 
Table 6: Summary of Concomitant Measures Received by at Least XX%  of  Patients ........ 69 
Table 7: Best Overall Response Summary Efficacy Evaluable ................................................. 71 
Table 8: Best Overall Response Summary Intent-to-Treat ...................................................... 72 
Table 9: Life Table Summary of Duration of Response ............................................................ 74 
Table 10: Life Table Summary of Duration of Clinical Benefit................................................. 76 
Table 11: Summary of L-DOS47 Administration and Compliance During Cycle 1 ............... 80 
Table 12: Summary of L-DOS47 Administration and Compliance for All Treatment 
Cycles ............................................................................................................................. 82 
Table 13: Summary of Patients with L-DOS47 Dose 
Reductions/Delay/Interruptions/Discontinuations ................................................. 84 
Table 14: Overall Summary of Treatment-Emergent Adverse Events ................................... 86 
Table 15: Summary of Treatment-Emergent Adverse Events by System Organ Class ........ 87 
Table 16: Summary of Treatment-Emergent Adverse Events Occurring in at Least “XX”% 
of Patients by System Organ Class and Preferred Term ........................................ 88 
Table 17: Summary of Drug-Related, Treatment-Emergent Adverse Events Occurring in 
at Least “XX”% of Patients by System Organ Class and Preferred Term ............. 89 
Table 18: Summary of Grade 3 or Greater, Treatment-Emergent Adverse Events 
Occurring in at Least “XX”% of Patients by System Organ Class and Preferred 
Term ............................................................................................................................... 90 
Table 19: Summary of Grade 3 or Greater, Drug-Related, Treatment-Emergent Adverse 
Events by System Organ Class and Preferred Term .............................................. 91 
Table 20: Patient Listing of Dose Limiting Toxicities ................................................................. 92 
Table 21: Patient Listing of Treatment-Emergent Adverse Events Leading to Death .......... 94 
Table 22: Patient Listing of Deaths On-Study or Within the 30 Day Follow-up Period ........ 94 
Table 23: Patient Listing of Serious Adverse Events ................................................................. 95 
Table 24: Patient Listing of Treatment-Emergent Adverse Events Leading to Treatment 
Discontinuation ............................................................................................................ 96 
Table 25: Patient Listing of Grade 3 and 4 Laboratory Values During Treatment Period ... 97 
 
3.2 In-Text Figures 
Figure 1: Best Change in Lesion Size from Baseline Overtime (Waterfall Plot) .................... 73 
Figure 2: Duration of Response ................................................................................................... 75 
Figure 3: Duration of Clinical Benefit .......................................................................................... 77 


 
 
 
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List of Acronyms, Abbreviations and Definitions of Terms 
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 
CR 
Complete response 
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 
hCG 
Human chorionic gonadotropin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
i.v. 
Intravenous 
ICH 
International Conference on Harmonization 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 


 
 
 
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MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
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 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria in Solid Tumour 
RP2D 
Recommended phase 2 dose 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SD 
Stable disease 
t½ 
Terminal elimination half-life 
Tmax 
Time of maximum observed plasma drug concentration after dosing 
TNM 
Tumor, Node, Metastasis tumor staging classification 
ULN 
Upper limit of normal 
Vss 
Volume of distribution at steady state 
Vz 
Volume of distribution 
WBC 
White blood cell 


 
 
 
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4.0 
Ethical Conduct of the Study 
The study protocol, amendments, and informed consent form were reviewed and 
approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC) at 
each participating site.   
 
The study was conducted in accordance with International Conference on Harmonization 
Good Clinical Practice (ICH/GCP), the protocol, all applicable regulatory requirements, and 
the guiding principles of the Declaration of Helsinki.   
 
Written informed consent to participate in the study was obtained from each patient 
before study enrollment and the performance of any study-specific procedures. 
 
 
5.0 Investigators and Study Administration 
5.1 Investigators 
Site No. 
Investigator / Institution 
002 
Sarina Piha-Paul, MD 
UT MD Anderson Cancer Center 
Department of Investigational Cancer Therapeutics 
1515 Holcombe Boulevard, Unit 455 
Houston, TX 77030 
 
003 
Afshin Dowlati, MD 
Case Western University 
University Hospitals Case Medical Center 
11100 Euclid Avenue, LKS 1200 
Cleveland, OH 44106 
 
001* 
Chandra Belani, MD  
Penn State Hershey Cancer Institute 
500 University Drive, MC CH72 
Hershey, PA 17033 
*Site 001 enrolled and treated 1 patient in 2015, then was closed on 
18Aug2017 while the study was ongoing. 
 
 


 
 
 
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5.2 Study Administration 
The study was sponsored by Helix BioPharma Corp., 9120 Leslie Street, Suite 205, 
Richmond Hill, ON L4B 3J9, Canada. 
 
The study was monitored by Theradex Oncology, a Contract Research Organization (CRO), 
located at 4365 US-1, Suite 101, Princeton, NJ 08540 USA. Data management, statistical 
analysis and clinical report writing services were also provided by Theradex Oncology. 
 
Compliance with GCP was assured in the clinical trial in a number of ways including, but 
not limited to: site initiation visits, routine monitoring visits at the sites, and the site close-
out visits conducted by Theradex Oncology; periodic teleconferences were conducted 
during the course of the study between Theradex Oncology, the Sponsor and the study 
sites regarding safety data and study status. 
 
The Theradex Oncology study medical monitor was responsible for safety monitoring of 
the study which included a review of all serious adverse events (SAEs) as they were 
reported by the study sites. The study medical monitor was in contact with site monitors 
and site coordinators to evaluate adverse events and was available to discuss issues 
concerning safety with site staff. 
 
Prior to site initiation, the Theradex Oncology site monitor reviewed the case report form 
(CRF) and other pertinent study materials with the Investigator’s research staff to assure 
protocol compliance and the valid recording of study data. At routine monitoring visits the 
Theradex Oncology site monitor examined and verified CRFs using source documents in 
the individual subject’s medical records, and assured that the study was conducted 
according to the approved protocol and in agreement with pertinent regulatory 
requirements. The review of medical records was done in a manner to assure that patient 
confidentiality was maintained. 
 
 
6.0 Introduction  
Helix BioPharma Corp. developed an immunoconjugate cancer therapeutic to exploit the 
acidic tumor extracellular environment produced by human solid tumors. 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 


 
 
 
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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. 
 
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 were to determine the safety and tolerability of L-DOS47, 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). 
 
Prior to this study, a first-in-human 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) had been initiated in Poland and was ongoing. The primary objective 
of the Phase I portion of that trial was 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 was to make a preliminary assessment of the efficacy of L-DOS47 in 
patients with non-squamous NSCLC. The secondary objectives of both phases of that 
study were to evaluate the pharmacokinetics of L-DOS47, the immunogenicity, and the 
safety and tolerability of L-DOS47 in patients. 
 
 
7.0 Study 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 


 
 
 
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stable disease, 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 
 
 
8.0 Investigational Plan 
8.1 Overall Study Design and Plan 
This was a Phase I, open label, multicenter, 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 initially utilized a standard “3 + 3” 
design of dose escalation. Patients were recruited into cohorts of L-DOS47 escalating 
doses, with a minimum of 3 and a maximum of 6 patients per cohort. As of Amendment 
3, the study implemented an accelerated “1 + 2” design up to 6 µg/kg and the standard “3 
+ 3” design for the final two dosing cohorts.  The starting dose of L-DOS47 was 0.59 µg/kg 
administered by intravenous infusion over 30 minutes. The standard of care doses of 
pemetrexed [500 mg/m2 administered over 10 minutes] and carboplatin [AUC6 mg/mL 
administered over 30 minutes], respectively, administered in combination with L-DOS47, 
remained constant across cohorts. As of Amendment 2, the L-DOS47 infusion could be 
increased from 30 minutes to 60 minutes in the event of a mild infusion reaction. 
 
All patients at a given dose level had to complete Cycle 1 before escalation in subsequent 
patients could proceed.  The decision for escalation to the next dose level was made after 
safety data were reviewed by a Safety Review Committee, which consisted of the 
Investigators, the Medical Monitor, and the Sponsor. Dose escalation was based on dose 
limiting toxicities (DLTs) occurring during the first cycle of treatment.   
 
The sequence of administration of the combination therapy on Day 1 of each treatment 
cycle was: 
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 
intravenously infused over 30 minutes.   
A treatment cycle was 21 days with patients receiving L-DOS47 on Days 1, 8, and 15 and 
pemetrexed/carboplatin on Day 1 of each treatment cycle.  


 
 
 
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Patients were to receive 4 cycles of combination treatment with L-DOS47 + pemetrexed/ 
carboplatin. Patients who did not progress following the 4 cycles of combination 
treatment and who did not experience unacceptable toxicity had the opportunity to 
continue to receive additional cycles of L-DOS47 treatment for as long as there was 
clinical benefit and it was well-tolerated, in the opinion of the Investigator, until disease 
progression. Patients who were unable to complete 4 cycles of L-DOS47 + 
pemetrexed/carboplatin combination treatment due to pemetrexed/carboplatin toxicity 
had the opportunity to continue receiving L-DOS47 treatment following discontinuation of 
pemetrexed/carboplatin, for as long as there was clinical benefit and it was well-tolerated, 
in the opinion of the Investigator, until disease progression. 
 
Patient safety was monitored throughout the study and for a minimum of 30 days after 
last dose of study drug. Long-term follow-up for disease progression was conducted by 
radiologic assessments every 6 weeks (±7 days) until disease progression, the patient 
initiated non-study cancer treatment, the patient withdrew consent or became lost-to-
follow-up. Survival data was captured by telephone call every 30 days (±7 days) and 
patients were followed until death. Severity of adverse events and laboratory 
abnormalities were reported according to NCI CTCAE version 4.0. Response to treatment 
was assessed after every 2 cycles using RECIST version 1.1.  
 
8.1.1 Dose Escalation Phase 
The following table shows the planned dose levels for L-DOS47 treatment: 
 
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 resulted 
in DLT, patients were to be treated 
at the -1 dose level. 
 


 
 
 
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Enrollment in each dose cohort proceeded in the standard “3+3” schema where 3 patients 
were initially enrolled per cohort. As of Amendment 3, the study implemented an 
accelerated “1 + 2” design up to 6 µg/kg and the standard “3 + 3” design for the final two 
dosing cohorts. The decision to escalate to the next dose level was based on the 
observation of DLT during Cycle 1. If 0 of 3 patients had DLT, escalation could proceed to 
the next cohort. If, however, DLT was observed in 1 of the 3 patients, an additional 
3 patients were to be enrolled at that dose.  In a cohort of 6, if one patient had DLT, then 
dose escalation could proceed; if 2 or more patients had DLT, then that dose would be 
declared the maximally administered dose and dose escalation would cease. Three 
additional patients were to be entered at the next lowest dose level if only 3 patients had 
been treated previously at that dose. The MTD/RD was defined as the highest dose level 
at which ≤ 1 of 6 patients experienced a DLT during the first treatment cycle. 
 
MTD Confirmation Cohort: 
Once the MTD was defined, a confirmation cohort of approximately 10 patients was 
planned for enrollment at the MTD to determine the recommended Phase II dose for the 
combination treatment.   
 
8.1.2 Dose Limiting Toxicity 
DLT was defined as the occurrence of any of the following events (according to NCI CTCAE 
version 4.0) that occurred within 21 days after commencing study drug treatment and 
was considered to be possibly, probably, or definitely related to study drug treatment by 
the Investigator: 
• 
Hematologic adverse events  ≥ grade 4  
• 
Non-hematologic adverse events ≥ grade 3 
• 
One instance each of two unique grade 2 adverse events (accelerated dose cohorts 
only) 
 
For the purpose of cohort evaluation, if a patient did not receive all of his/her scheduled 
L-DOS47 doses in Cycle 1 due to toxicity, this was considered a DLT. Patients experiencing 
a DLT during the first treatment cycle were to be withdrawn from the study. 
 
8.1.3 Maximum Tolerated Dose 
The maximum tolerated dose (MTD)/recommended dose (RD) was defined as the highest 
dose level at which ≤ 1 of 6 patients experienced a dose limiting toxicity during the first 
treatment cycle. 
 
If the MTD/RD was not confirmed following the evaluation of the final dosing cohort 
defined in the protocol, consideration was to be given to test further cohorts. The same 
dosing schema was to be used in determining these cohorts. 


 
 
 
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Once the MTD was defined, a confirmation cohort of approximately 10 patients was to be 
enrolled at the MTD to determine the recommended Phase II doses for the combination 
treatment. 
 
8.1.4 Dose Modifications 
8.1.4.1 Dose reductions/modifications for L-DOS47 
If a patient experienced an AE meeting the definition of DLT (see Section 9.1.2), then the 
patient was to be withdrawn from the study and not receive further doses of L-DOS47. 
Any AE occurring after the defined DLT criteria window was not considered a DLT. 
 
If a patient’s dose of L-DOS47 was to be reduced, it was to be given at the subsequent 
lower dose level of L-DOS47. Only 1 dose level reduction was allowed. 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 did not meet the retreatment criteria, the dose will to be held and the 
patient reassessed weekly (or sooner if deemed clinically appropriate) for possibility of 
retreatment.  If treatment was delayed for more than 14 days, the patient was to be 
withdrawn from the study, unless discussed and agreed with the Medical Monitor. 
 
Dose modification for subsequent cycles was required when any of the following dose 
delay conditions were met: 
 
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 the study was discussed with the 
Medical Monitor. A decision to not withdraw a patient had to be 
agreed upon by the Sponsor and Medical Monitor, clinically 
supported and documented. 
 


 
 
 
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Dose modification for subsequent cycles was required when any of the following L-DOS47 
toxicity criteria conditions were met: 
 
 
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 the study was discussed with the Medical Monitor. A decision to not 
withdraw a patient had to be agreed upon by the Sponsor and Medical Monitor, clinically supported 
and documented. 
2 Without bleeding or platelet transfusion. 
 
 
8.1.4.2 Dose reductions/modifications for pemetrexed and carboplatin 
Doses were to be reduced for hematological and other adverse events. Dose adjustments 
were 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 required a dose reduction was to continue to receive a reduced dose for 
the remainder of the study. Any patient with 2 prior dose reductions who experienced a 
toxicity that would cause a third dose reduction was to discontinue pemetrexed and 
carboplatin therapy.   
 


 
 
 
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Hematologic Toxicity: 
Dose adjustments at the start of a subsequent cycle of therapy were based on 
platelet and neutrophils nadir (lowest value) counts from the preceding cycle of therapy. 
ANC had to be ≥ 1.5 x 10 9/L and platelets ≥ 100 x 109/L prior to the start of any cycle. 
Treatment was to be delayed to allow sufficient time for recovery. Upon recovery, if 
treatment resumed, it was according to the guidelines below: 
 
Dose adjustments for pemetrexed and carboplatin based on nadir hematologic values from 
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  
Pemetrexed and 
carboplatin 
discontinued 
ANC = absolute neutrophil count 
 
Non-hematologic toxicity: 
In the event of diarrhea requiring hospitalization (or of at least Grade 3), treatment 
was to be delayed until diarrhea resolved before proceeding. Treatment with 
pemetrexed was to be resumed at 75% of the previous dose level. The carboplatin 
remained the same. 
 
For other non-hematologic effects ≥ Grade 3, with the exception of alopecia and 
mucositis, treatment had to be delayed until resolution to less than or equal to the 
patient’s baseline CTCAE grade before proceeding. Treatment was to 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 was not to 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 
pemetrexed discontinued 
carboplatin discontinued 
CTCAE = Common Terminology Criteria for Adverse Events 
 
 


 
 
 
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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) 
pemetrexed discontinued 
carboplatin discontinued 
AUC = area under the curve; CTCAE = Common Terminology Criteria for Adverse Events 
 
 
8.2 Discussion of Study Design 
This was a Phase I, open label, multicenter, dose-escalation study of L-DOS47 in 
combination 
with 
standard 
doublet 
chemotherapy 
of 
pemetrexed/carboplatin 
administered to patients with Stage IV (TNM M1a and M1b) non-squamous NSCLC. Safety 
and tolerability were evaluated in cohorts of 1 to 6 patients enrolled in escalating dose 
levels of L-DOS47 until determination of the MTD. Pharmacokinetic parameters for 
L-DOS47 were evaluated from plasma samples collected from patients. The starting dose 
of L-DOS47 was 0.59 µg/kg administered by intravenous infusion over 30 minutes (after 
Amendment 2, over 60 minutes in the event of a mild infusion reaction). The doses of 
pemetrexed (500 mg/m2 administered over 10 minutes) and carboplatin (AUC6 mg/mL 
administered over 30 minutes) were the standard of care, administered in combination 
with L-DOS47, and remained constant across cohorts.  
 
8.3 
Selection of Study Population 
8.3.1 Inclusion Criteria 
Patients had to fulfill all of the following criteria to be eligible for the study: 
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 had to be assessed according to TNM, 7th edition 
and based on computed tomography (CT) scan; 
3. EGFR-mutation positive patients had to 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 was 7 days; 


 
 
 
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4. Patients whose tumors harbored an anaplastic lymphoma kinase (ALK) translocation 
had to have progressed on or had intolerance to an ALK inhibitor.  The washout 
period for patients treated with an ALK inhibitor was 7 days; 
5. No prior adjuvant chemotherapy within 6 months of the first treatment day if there 
was 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 were due to underlying malignancy; 
11. Male or female patients of child-producing potential had to 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 had to have a negative serum pregnancy test; 
13. Females had to 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 had to be off 
steroids and not taking antiepileptics for brain metastases. 
 
8.3.2 Exclusion Criteria 
Patients would 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 (prior to Amendment 2, ≥ 12 
months); 


 
 
 
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6. 
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 were 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 was 
permissible; 
9. 
Significant cardiac disease including heart failure that met 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. 
 
8.3.3 Removal of Patients from Treatment or Assessment 
Protocol therapy was to be discontinued at any time if any of the following situations 
occurred: 
 
1.  Progressive disease.  
2. The development of toxicity which, in the Investigator’s judgment, precluded further 
therapy.  
3. Patient refusal. 
4. Lost to follow-up/noncompliance. 
5. Intercurrent illness. 


 
 
 
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6. At the discretion of the Investigator. 
7. Pregnancy. 
8. Study termination. 
 
Note: When a patient was removed from the study, the Investigator was to document the 
reason in the medical record and complete the appropriate case report form (CRF) page 
describing the reason for discontinuation. In addition, every effort was to be made to 
complete the appropriate study assessments. 
 
8.3.4 Protocol Deviations 
Protocol deviations were not collected in the CRFs and therefore are not part of the 
clinical database. Instances of noncompliance and resulting protocol deviations were 
collected in Monitor Express, the Theradex Oncology proprietary Clinical Trial 
Management System.    
 
8.4 Treatments 
8.4.1 Treatment Administered 
Patients received L-DOS47 on Days 1, 8, and 15 and pemetrexed/carboplatin on Day 1 of 
each 21-day treatment cycle. The sequence of administration on Day 1 of each cycle was: 
1) pemetrexed was prepared per the prescribing information sheet and administered by 
intravenous infusion at a dose of 500 mg/m2 over 10 minutes (see Section 9.4.7.1 for 
pemetrexed pre-medications);  
2) approximately 30 minutes after the end of the pemetrexed infusion, carboplatin, 
prepared per the drug package insert, was intravenously infused over 30 minutes at a 
dose of AUC6 mg/mL;  
3) approximately 30 minutes after the end of the carboplatin infusion, L-DOS47 was 
intravenously infused over 30 minutes*.   
 
*As of Amendment 2, the L-DOS47 infusion time could be increased to 60 minutes in the 
event of a mild infusion reaction.    
 
8.4.2 Identity of Investigational Product(s) 
L-DOS47 drug product was provided by Helix BioPharma Corp. 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 was stored at 2-
8°C. The lot numbers used in the study were OBP-801-001 and OBP-801-003. 
 


 
 
 
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8.4.3 Method of Assigning Patients to Treatment Groups 
Patients were assigned to treatment groups in the order that they were enrolled in the 
study. 
 
8.4.4 Selection of Doses in the Study 
Results of pivotal GLP repeat-dose toxicology studies in rats and monkeys showed 
premature deaths occurring at higher doses of i.v. L-DOS47 that were not predicted by 
any premonitory signs at lower doses. Therefore, careful monitoring of plasma Cmax levels 
in patients was planned in the clinic. Prior to the current study, a first-in-human Phase I/II, 
open label, non-randomized, dose escalation study of L-DOS47 monotherapy in patients 
with non-squamous NSCLC was being conducted in Poland. In that study, patients had 
been treated at L-DOS47 doses ranging from 0.12 µg/kg to 13.55 µg/kg. The adverse 
events reported in that study were expected for the population under study; the safety 
profile was consistent with that of animals treated with L-DOS47. For the present study, 
considering preclinical toxicology studies, a very conservative starting dose was chosen 
which was relatively consistent when calculated by the three standard approaches to 
starting dose. A maximum safety factor of 10 and a human equivalent dose (HED) scaling 
from animal to human dose (body surface area) were also utilized. The L-DOS47 starting 
dose chosen for this trial was 0.59 µg/kg, with planned escalation following a modified 
Fibonacci schema.  
 
8.4.5 Selection and Timing of Dose for Each Patient 
L-DOS47 was administered by intravenous infusion on Days 1, 8, and 15 of each 21-day 
combination treatment cycle in Cycles 1 through 4. Patients who had not progressed 
following the 4 cycles of combination treatment and had not experienced unacceptable 
toxicity had the opportunity to receive additional cycles of L-DOS47 treatment for as long 
as there was clinical benefit and it was well-tolerated, in the opinion of the Investigator, 
until disease progression. Patients who were unable to complete 4 cycles of L-DOS47 + 
pemetrexed/carboplatin combination treatment due to pemetrexed/carboplatin toxicity 
had the opportunity to continue to receive additional cycles of L-DOS47 treatment 
following discontinuation of pemetrexed/ carboplatin, for as long as there was clinical 
benefit and it was well-tolerated, in the opinion of the Investigator, until disease 
progression. 
 
Simultaneous dosing of patients within a dosing cohort was prohibited. Patient dosing 
was to be separated by at least 24 hours which allowed for the assessment of possible 
infusion reactions and/or allergic reactions and enabled communication between study 
centers. 
 


 
 
 
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The L-DOS47 dose of each cycle was calculated based on the patient’s weight on Day 1 of 
that cycle. The dose was not adjusted for body weight on Day 8 or 15 of the treatment 
cycles. Full weight-based doses were to be used to treat obese patients.  
 
If a patient exhibited signs and symptoms of anaphylaxis, he or she should was to be 
managed per local institutional guidelines. For mild infusion reactions (transient flushing, 
rash or low grade fever < 38ºC or < 100.4ºF), anti-histamine, corticosteroids, and other 
medical intervention could be used as needed.  If symptoms resolved within 30 minutes, 
the infusion could be resumed at a minimum 50% reduction in rate.  If symptoms 
recurred or worsened despite antihistamine and corticosteroids, the patient was to be 
removed from the study.  If a patient exhibited signs and symptoms of moderate to 
severe (anaphylaxis) infusion reactions such as bronchospasm with or without urticaria, 
edema/angioedema, hypotension, then the L-DOS47 infusion was to be stopped 
immediately and the patient managed per local institutional guidelines. 
 
Patients who experienced mild infusion reactions manageable with anti-histamine and 
corticosteroids could be pre-medicated for subsequent doses. 
 
Patients were to remain in the out-patient observation area for 2 hours after completion 
of the L-DOS47 infusion for observation prior to discharge.  
 
8.4.6 Blinding 
This was an open-label safety and tolerability study. The treatments were not blinded. 
 
8.4.7 Prior and Concomitant Treatment 
Chronic use of systemic steroids was prohibited. Acute use of systemic steroids was 
permitted.  Use of steroid inhalers and topical steroids was permitted. 
 
Any medication the patient took other than the study treatment was considered a 
concomitant medication. All concomitant medications were to be recorded on the eCRF. 
At the Screening Visit, patients were asked what medications they had taken during the 
last 30 days. At each subsequent study visit, patients were asked what concomitant 
medications they were currently taking. 
 
Other than the study treatments planned in this protocol, patients were not to receive the 
following medications during the study: hormonal agents, other investigational drugs, 
systemic corticosteroids, and immunotherapy.  
 
Radiotherapy could be given concomitantly for the control of bone pain; irradiated lesions 
were not evaluable for response. Any medication which was considered necessary for the 


 
 
 
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patient’s welfare and which would not interfere with administration of the study 
treatments, could be given at the discretion of the Investigator. 
 
8.4.7.1 Pemetrexed pre-medication 
• 
Vitamin Supplementation: patients were instructed to initiate folic acid 400 µg to 1000 
µg orally once daily beginning 7 days before the first dose of pemetrexed and 
continue during the full course of therapy and for 21 days after the last dose of 
pemetrexed. Vitamin B12 1 mg was administered intramuscularly 1 week prior to the 
first dose of pemetrexed and every 3 cycles thereafter. Subsequent vitamin B12 
injections could be given the same day as treatment with pemetrexed. 
• 
Corticosteroids: Dexamethasone 4 mg orally was administered twice daily the day 
before, the day of, and the day after pemetrexed administration. 
 
8.4.8 Treatment Compliance 
L-DOS47 (and pemetrexed/carboplatin) was administered intravenously by clinical trial 
personnel in a clinic setting, thus ensuring that patients received the appropriate dose of 
study drug on schedule as per protocol. Any instances of noncompliance and resulting 
protocol deviations were recorded in Monitor Express. 
 
8.4.9 Dose Delay and Modification 
Study dose administration could be delayed and/or modified as described in 
Section 9.1.4. 
 
8.4.10 Duration of Therapy 
Patients were to receive 4 cycles of combination treatment with L-DOS47 + pemetrexed/ 
carboplatin. After 4 cycles, patients could continue to receive additional cycles of L-DOS47 
alone until disease progression as long as there was clinical benefit and it was well-
tolerated. Patients who were unable to complete 4 cycles of combination treatment due 
to pemetrexed/ carboplatin toxicity could receive additional cycles of L-DOS47 alone until 
disease progression as long as there was clinical benefit and it was well-tolerated. 
 
8.5 Efficacy and Safety Variables 
8.5.1 Efficacy and Safety Measurements 
The schedule of study evaluations is presented in Section 9.5.1.1.  Assessments prior to 
Day 1 of each cycle were used to determine whether a patient could start the cycle. 
Radiologic examination and tumor measurements were made after every 2 cycles (i.e., 6 
weeks). Concomitant medications, physical examination, laboratory parameters, vital 
signs, ECOG performance status, and ECG were assessed at baseline, during the 
treatment period, and at off-study. Adverse events were monitored throughout the 


 
 
 
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treatment period and at off-study. Long-term follow-up was conducted until disease 
progression and survival data was captured until death (Section 9.5.1.3). 
 


 
 
 
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8.5.1.1 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 
 
 
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 
X 
predose 
Cycle 4 
 
 
X 
(only if not 
done on 
X 
(only if not 
done on 
 
 
 


 
 
 
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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) 
only 
only 
C4D8) 
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)  
 
 
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 
 
 
 
 
 
 
 
 


 
 
 
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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) 
Plasma PK sampling14,20 
 
X 
X 
 
 
 
 
 
 
 
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 was obtained before any experimental procedure or test was performed. 
2 Patients were administered up to 4 cycles of L-DOS47 during the study treatment period. Treatment cycles would be repeated for patients who 
tolerated the previous treatment cycle of L-DOS47 and showed no clinical signs of progression of disease.  
3 The End-of-Treatment Visit was performed one time for all patients who discontinued the study at or before the end of Cycle 4. For patients who 
continued to receive additional cycles of L-DOS47 (i.e., Cycle 5 and beyond), this visit was performed twice: (i) after the completion of 4 cycles, and (ii) 
at the time of discontinuation from the study. Note: All patients who withdrawn from the study were to complete the End-of-Treatment Visit 
immediately at the time of withdrawal. 


 
 
 
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4 The corresponding procedures were 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 were performed during screening, unless results from appropriate scans performed within 28 days prior to the first dose of 
study drug were available and every other treatment cycle (i.e., every 6 weeks) until disease progression; an MRI could be conducted only in 
exceptional cases. Radiologic examination was to be repeated at the End of Treatment Visit if > 6 weeks had passed since the last evaluation.  
7 Tumor antigen (CEACAM6) assessment: blood samples were 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 occurred first). 
8 Vital signs (temperature, heart rate, blood pressure, respiratory rate and oxygen saturation [pulse oximetry]) were assessed prior to 
pemetrexed/carboplatin administration on Day 1 of the cycle; on treatment days in which L-DOS47 was administered (Days 1, 8, and 15), vital signs 
were also 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 were recorded on Days 1 and 8 of each cycle at predose and at 1 and 1.5 hours postdose. 
10 For additional cycles, all ECG recordings were optional.   
11 In women of childbearing potential, serum ß-HCG tests were conducted at Screening and at the End-of-Treatment/Early Termination Visit. Urine ß-
HCG tests were conducted on Day 1 of each treatment cycle. 
12 L-DOS47 was administered on Days 1, 8, and 15 of each treatment cycle. Treatment with L-DOS47 could continue beyond four cycles for as long as 
the patient was receiving sustained clinical benefit and it was well tolerated, in the opinion of the Investigator, until disease progression. 
13 Pemetrexed/carboplatin were 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 were 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 was increased from 30 minutes to 60 minutes in the event 
of a mild infusion reaction, there was no change in the PK sampling timepoints, which were all relative to the start of L-DOS47 infusion.  PK samples 
collected at 30 minutes and 45 minutes were considered during infusion samples and PK sample collected at 60 minutes (1 hour) was a prior to end 
of infusion sample. All other timepoints remained the same. 


 
 
 
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15 Serum samples were 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 were recorded predose on Days 1 and 8 of each cycle.  
17 Adverse events (AE) were 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 was monitored by telephone contact. Adverse event monitoring on Day 21 occurred only if the patient was coming off study and the next 
cycle was not being initiated. 
18 Patients were followed to collect data pertaining to progression and survival. *Survival data was captured by telephone call every 30 days (± 7 days) 
until death. **Follow-up for progression was conducted by radiologic assessments (CT scans of chest, abdomen and pelvis, or as appropriate per the 
Investigator) every 6 weeks (± 7 days) until disease progression, patient initiated non-study cancer treatment, patient withdrew consent, or patient 
was lost-to-follow-up. 
19 Cycle 5, Day 1 assessments did not need to be repeated if the end of Cycle 4 evaluations were performed within 7 days prior to Day 1 of Cycle 5.  
20 ECG/Vital signs/PK time window table presented below defines an acceptable lapse in assessment/sample collection. 
  
ECG/Vital signs/PK time window a 
 
ECG 
Vital signs 
PK 
During infusion 
± 5 min 
± 3 min 
±2 min 
Post infusion 
± 5 min 
± 5 min 
± 5 min b,c  
a. 
All timepoints were relative to the start of L-DOS47 infusion. 
b. 
If the L-DOS47 infusion time was increased from 30 minutes to 60 minutes in 
the event of a mild infusion reaction, there was no change in the PK sampling 
timepoints. The PK sample collected at 60 minutes (1 hour) was the end of 
infusion sample. All other timepoints remained the same.  
c. 
For PK samples collected at 24 and 48 hours timepoints, the window will be  
± 30 min.  
 
 


 
 
 
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8.5.1.2 Off-Study Assessments 
For the initial 4 cycles, The End-of-Treatment Visit was conducted Day 21 of Cycle 4 
(patients who complete all 4 treatment cycles) or was the Early Termination visit (for 
patients withdrawn from the study), whichever occurred first. All patients were required 
to complete the End-of-Treatment Visit. Patients who completed the initial 4 cycles and 
continued treatment, completed the End-of-Treatment Visit on Day 21 of Cycle 4 and their 
next visit was Cycle 5, Day 1. Patients continuing beyond Cycle 4 completed the 
End-of-Treatment Visit again at the time of withdrawal from the study. All patients who 
were withdrawn from the study completed the End-of-Treatment Visit immediately at the 
time of withdrawal.  
 
The following assessments were performed and measurements recorded: 
• 
Physical examination 
• 
ECOG performance status  
• 
Radiologic examination (if > 6 weeks had passed since the last evaluation) 
• 
Tumor antigen assessment: performed 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 
 
8.5.1.3 Long-Term Follow-Up 
Follow-up assessments were conducted after the End-of-Treatment Visit. Long-term 
follow-up for disease progression was conducted by radiologic assessments every 
6 weeks (± 7 days) until disease progression, patient initiated non-study cancer treatment, 
patient withdrew consent or became lost-to-follow-up. Survival data was captured by 
telephone call every 30 days (± 7 days) and patients were followed until death.  
 
8.5.2 Appropriateness of Measurements 
Safety and efficacy assessments were standard, as indicated by the use of CTCAE Version 
4.0 and RECIST 1.1, respectively. 
 


 
 
 
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8.5.3 Efficacy and Safety Variables 
8.5.3.1 
Safety Assessments 
• 
AEs, vital signs, and laboratory parameters were assessed. 
• 
All AEs and laboratory abnormalities were assessed according to CTCAE version 4.0. 
• 
DLTs, SAEs and AEs leading to treatment discontinuation were determined. 
 
Adverse Events (AEs): An 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 AE 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 AE reporting period commenced after the initial dosing of pemetrexed 
premedication. If an AE occurred before the first dose of study drug it was considered a 
non-treatment emergent AE. At each evaluation patients were interviewed in a non-
directed manner to elicit potential adverse reactions from the patient. The occurrence of 
an adverse event was based on changes in the patient’s physical examination, laboratory 
results, and/or signs and symptoms. 
 
All AEs (except grade 1 and 2 laboratory abnormalities that did not require an 
intervention), regardless of causal relationship, were to be recorded in the case report 
form and source documentation.  The Investigator determined the intensity of any 
adverse events according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.0 and their causal relationship. Those AEs not covered by these criteria 
were graded as outlined in the protocol. 
 
AEs were followed until resolution or stabilization while the patient remained on-study. 
Once the patient was removed from study, events thought to be related to the study 
medication were followed until resolution or stabilization, unless, in the Investigator’s 
opinion the event was unlikely to resolve due to the patient’s underlying disease, or until 
the patient started a new treatment regimen or the patient was lost to follow-up. 
 
Serious Adverse Events (SAEs): A SAE was defined as any untoward medical occurrence 
that at any dose: 
• 
Resulted in death. 
• 
Was Life threatening (i.e., the patient was at risk of death at the time of the event. It 
did not refer to an event that hypothetically might have caused death if it was more 
severe). 


 
 
 
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• 
Required 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. 
• 
Resulted in persistent or significant disability/incapacity. 
• 
Was a congenital anomaly/birth defect. 
• 
Other medically important condition. 
 
Important medical events that might not result in death, Life threatening, or required 
hospitalization could be considered SAEs when, based on appropriate medical judgment, 
they might jeopardize the patient and required medical or surgical intervention to prevent 
1 of the outcomes listed above.  
 
8.5.3.2 
Efficacy Assessments 
Although response was not the primary endpoint of this study, patients with measurable 
disease were assessed by standard criteria.  For the purposes of this study, patients were 
to be evaluated every 6 weeks. In addition to a baseline scan, confirmatory scans were 
also to be obtained 4 weeks following initial documentation of an objective response. 
Changes in only the largest diameter (unidimensional measurement) of the tumor lesions 
are used in RECIST 1.1. Note: Lesions are either measurable or non-measurable using the 
criteria provided below.  
 
8.5.3.2.1 Definitions Based on RECIST version 1.1 
Response and progression were evaluated using the international criteria (version 1.1) 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee.  
 
Lesions were either measurable or non-measurable using the following criteria: 
 
Measurable Disease 
Measurable lesions were defined as those that could 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 could not be accurately 
measured with calipers were to be recorded as non-measurable) 
• 
mm by chest x-ray 
 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node had to be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice 
thickness no greater than 5 mm). 
 


 
 
 
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Non-measurable Disease 
All other lesions (or sites of disease), including small lesion (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) were considered non-
measurable disease.  
All measurements were recorded in metric notation, using a ruler or calipers. All baseline 
evaluations were performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
 
8.5.3.2.2 Evaluation of Target and Non-Target Lesions 
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. 
 
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. 
 


 
 
 
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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. 
 
 
8.5.3.2.2.1 Evaluation of Best Overall Response 
Overall response determination as outlined in RECIST (version 1.1) took into account the 
assessments of both target and non-target lesions. Best overall response was 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 depended on 
findings of both target and non-target disease and the appearance of new lesions. 
Furthermore, depending on the nature of the study, it might also require confirmatory 
measurement.  
 
A summary of the overall response status calculation at each time point for patients who 
had measurable disease at baseline is presented below. 
 
Time Point 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 
 


 
 
 
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Complete or partial responses might be claimed only if the criteria for each were 
confirmed by a repeated assessment at least 4 weeks later. In this circumstance, the best 
overall response could be interpreted as described below. 
 
Best Overall Response when Confirmation of CR and PR Required: 
Overall response
First time point 
Overall response 
Subsequent time 
point 
 
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 was truly met at first time point, then any disease seen at a subsequent time point, 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 time point. Under these circumstances, the 
original CR should be changed to PR and the best response is PR. 
 
 
8.5.4 Drug Concentration Measurements and Other Assessments 
8.5.4.1 Pharmacokinetic Assessments 
Plasma sampling for pharmacokinetic (PK) measurements of L-DOS47 concentrations 
were conducted during Cycles 1 through 4 as follows:  


 
 
 
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• 
Cycle 1, Days 1 and 8: predose, during the infusion, and serially postdose per protocol-
defined timepoints up to 48 hours. 
• 
Cycles 2 and 4, Day 8: predose, during the infusion, and serially postdose per protocol-
defined timepoints up to 24 hours. 
• 
Cycle 2, Day 1; Cycle 3, Days 1 and 8; Cycle 4, Day 1: predose and postdose (collected 
just prior to end of infusion). 
 
8.5.4.2 Tumor Antigen Assessment 
Blood samples for tumor antigen (CEACAM6) assessment were drawn Cycles 2 and 4 (or 
at the off treatment visit). 
 
8.5.4.3 Immunogenicity 
Immunogenicity of L-DOS47 was evaluated from serum samples collected each cycle, at 
the end of treatment or the early termination visit, and at the follow-up visit (30 days after 
the last dose). 
 
8.6 
Data Quality Assurance 
Compliance with GCP was assured in the clinical trial in a number of ways including, but 
not limited to the site initiation visit, routine monitoring visits at the site, and the site 
close-out visit conducted by Theradex Oncology; periodic teleconferences conducted 
during the course of the study between Theradex Oncology, the Sponsor and the study 
site regarding safety data and study status. 
 
The Theradex Oncology study medical monitor was responsible for safety monitoring of 
the study, which included a review of all serious adverse events (SAEs) as they were 
reported by the study site. The study medical monitor was in contact with site monitors 
and site coordinators to evaluate adverse events and was available to discuss issues 
concerning safety with site staff. 
 
Prior to site initiation, the Theradex Oncology site monitor reviewed the case report form 
(CRF) and other pertinent study materials with the Investigator’s research staff to assure 
protocol compliance and the valid recording of study data. At routine monitoring visits the 
Theradex Oncology site monitor examined and verified CRFs using source documents in 
the individual subject’s medical records, and assured that the study was conducted 
according to the approved protocol and in agreement with pertinent regulatory 
requirements. The review of medical records was done in a manner to assure that patient 
confidentiality was maintained. 
 
CRFs were monitored and collected, data entered, data edit checks performed, data 
discrepancies resolved, and the database locked according to Theradex Oncology SOPs. 


 
 
 
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After database lock, the data was retrieved from the Oracle® relational database and 
processed using SAS®. All statistical analyses were performed using SAS® statistical 
software (Version 9.4). Tables and listings were generated by validated SAS® programs. 
 
8.7 Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
All data summaries are descriptive and provided separately for each dose cohort. Data 
summaries include frequency counts and percent for categorical measures and the mean, 
median, standard deviation, minimum and maximum for continuous variables. 
 
8.7.1 Determination of Sample Size 
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). 
 
8.7.2 Analysis of Data 
Evaluation of the data for the study will consist primarily of data listings and summary 
displays. Demographic and other baseline characteristic information are summarized. 
Adverse events are tabulated by body system, preferred term, severity, and relation to 
treatment. Similar presentations are provided for serious adverse events, adverse events 
leading to discontinuation from study, and adverse events leading to death. The listing of 
laboratory parameters will indicate the normal range for each parameter. Each value is 
classified as falling above, below, or within the normal range.  
 
RECIST 1.1[1] is used for tumor response evaluation. Tumor-related endpoints including 
best overall response, objective response rate, duration of response (CR or PR), clinical 
benefit (CR+PR+SD) will be summarized for patients with baseline measurable disease. 
Tumor response for patients with baseline non-measurable disease will be provided in a 
listing.  
 
8.7.3 Study Endpoints 
The primary endpoints are the number of patients with DLTs, toxicity, MTD and the 
recommended Phase II dose (RD) of L-DOS47 in combination with pemetrexed/ 
carboplatin.  
 
The secondary endpoints are best overall response, objective response rate (CR or PR), 
clinical benefit rate (CR+PR+SD) and duration of response following combined treatment. 
 


 
 
 
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The exploratory endpoints are PK parameters for L-DOS47 in combination with 
pemetrexed/ carboplatin, antibody concentration and other immunogenicity data of L-
DOS47.  
 
8.7.4 Statistical Analysis Populations 
Intent-to-Treat Population: Includes all patients enrolled in the study whether or not they 
met the eligibility criteria or received study drug. This population will be summarized for 
demographics and other baseline characteristics, and serve as the secondary analysis 
population for efficacy. 
 
Safety Evaluable Population: Includes all patients who received any amount of L-DOS47 or 
pemetrexed premedication. This population will be summarized for all safety parameters. 
 
Efficacy-Evaluable Population: Includes all patients who met the eligibility criteria with 
baseline measurable disease, completed 2 cycles of study treatment, and had at least one 
post-baseline tumor 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. The efficacy-evaluable population will be the primary analysis population for 
efficacy.  
 
8.7.5 Statistical Methods 
8.7.5.1 Safety and Tolerability Analyses 
All patients who received any amount of L-DOS47, or pemetrexed premedication will be 
evaluated for safety. Safety data includes adverse events, vital signs, laboratory 
parameters, and cardiographic values, etc. Descriptive statistics (e.g., mean, SD, median, 
minimum, and maximum values, and number and percent of patients within specified 
categories) will be used to summarize the safety parameters. Safety data will be 
summarized for each cohort. 
 
8.7.5.1.1 Adverse Events 
Treatment-Emergent Adverse Events (TEAEs) will be defined as all AEs that occurred from 
the date of first dose to 30 days after the last dose of study drug. TEAEs will be 
summarized and tabulated by MedDRA Version 17.1 system organ class and preferred 
term, by maximum CTCAE (Version 4.0) grade as well as by relationship to treatment 
(unrelated, unlikely, possible, probable, and definite). Drug-related TEAEs will include 
those considered to have a possible, probable or definite relationship to study drug. 
Patients with multiple TEAEs will only be counted once within a summary category: 
system organ class, preferred term, maximum grade (using the most severe grade), or 
relationship to treatment. Patients with events in more than one category will be counted 
once within each category. TEAEs classified as serious (SAEs), TEAEs leading to study 


 
 
 
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discontinuation, and TEAEs with the outcome of death will be summarized and patient 
narratives will be provided regarding these events. Dose limiting toxicities will be listed. 
 
8.7.5.1.2 Laboratory Data 
Hematology, blood chemistry, and coagulation data will be converted to common 
reporting units and graded according to CTCAE (Version 4.0) prior to summarization.  
 
Laboratory data of hematology, blood chemistry, coagulation and urinalysis were 
collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-
DOS47+Pemetrexed/ Carboplatin at Day 1, 8 of Cycle 1 to 4 and End of Treatment (last 
non-missing value recorded off-study but within 30 days after last dose), or immediately 
after early termination; for L-DOS47 only at Day 1, 8, 15 of additional Cycle x.  For 
summary purposes, the Last Value will be defined as the last non-missing value after 
receiving study medication up to 30 days post last dose. 
 
The absolute change from baseline will be summarized at each of the laboratory time 
points, using descriptive statistics (mean, median, SD, minimum, maximum) for 
hematology, blood chemistry and coagulation as specified below.  
 
The changes from baseline to maximum CTCAE grade during the treatment period will be 
summarized using shift tables for every gradable hematology, blood chemistry and 
coagulation test. Maximum CTCAE Grade will be defined as the highest CTCAE version 4.0 
Grade reported for a patient after first dose and up to 30 days post last dose.  
 
A listing of patients with abnormal laboratory values defined as Grade 3 or 4 during the 
treatment period will be provided.  
 
Laboratory tests include: 
Hematology: hemoglobin, hematocrit, WBC, platelets, neutrophils, lymphocytes, 
monocytes, eosinophils, basophils, bands, combined other cells, sum of the differentials.  
 
Blood 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, phosphorus, potassium, sodium, 
magnesium, total bilirubin, total protein. 
 
Coagulation: INR, PT, aPTT. 
 
Urinalysis: glucose, total protein, ketones, bilirubin, occult blood. 
 


 
 
 
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8.7.5.2 Study Treatment Exposure and Compliance 
The study drug L-DOS47 and the other two combined study treatment pemetrexed, 
carboplatin will be presented respectively. The number of cycles of study drug will be 
summarized using descriptive statistics (N, mean, median, standard deviation, and 
minimum, maximum). Study drug exposure will be summarized for Cycle 1 and for all 
treatment cycles combined. Duration of Exposure will be defined as the duration between 
the first and last dose of study drug (last date of study drug administration - first date of 
study drug administration + 1). Total Dose will be defined as the sum of all study drug 
administered. Total Intended Dose will be defined as the sum of the intended doses 
during the Duration of Exposure. Total intended dose is based on no modifications to 
dose or schedule. Total Prescribed Dose will be defined as the sum of all study drug 
prescribed during the Duration of Exposure. Total prescribed dose is based on any 
modifications to dose or schedule. The Percent Intended Dose will be defined as the total 
dose divided by the total intended dose multiplied by 100% for each patient. The percent 
compliance will be defined as the cumulative dose of study drug actually administered 
divided by the total prescribed dose multiplied by 100% for each patient. The frequency 
and percentage of patient receiving <100%, 100%, and >100% of their intended and 
prescribed dose will be summarized.  
 
The number of patients with dose reduction, delay, interruption, and the reasons will 
each be summarized using frequency counts and percentages. The number of dose 
reduction, delay, interruption and their duration will also be summarized using 
descriptive statistics.  
 
8.7.5.3 Concomitant Measures 
Concomitant measures will be coded using the World Health Organization Drug 
Dictionary (WHO-DD version June 2014), tabulated by drug class and term, and 
summarized by frequency counts and percentages. Patients will be counted only once in 
each summary category (e.g., drug class or term). All medications that were ongoing at 
study start (Day 1) or started on Day 1 or thereafter up to and including 30 days after the 
last dose are concomitant. 
 
8.7.5.4 ECOG Performance Status 
ECOG status was collected at Baseline (last pre-treatment value from Day -28 to Day 1);  
for L-DOS47+Pemetrexed/Carboplatin at Day 1 of Cycle 1 to 4, and End of Treatment (last 
non-missing value recorded off-study but within 30 days after last dose), or immediately 
after early termination; for L-DOS47 only at Day 1 of additional Cycle x. The change from 
baseline score to maximum score over the treatment period will be summarized using a 
shift table. 
 


 
 
 
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8.7.5.5 Vital Signs 
Vital signs were collected at Baseline (last pre-treatment value from Day -28 to Day 1); for 
L-DOS47+Pemetrexed/Carboplatin at Day 1, 8, 15 of Cycle 1 to 4, and End of Treatment 
(last non-missing value recorded off-study but within 30 days after last dose), or 
immediately after early termination; for L-DOS47 only at Day 1, 8, 15 of additional Cycle x. 
Vital signs including (temperature, pulse rate, blood pressure, respiratory rate, pulse 
oximetry will be summarized using descriptive statistics and provided in a listing for all 
time points. Height, weight and BSA will be summarized at baseline only. 
 
8.7.5.6 Physical Exams  
Physical exams were performed at Baseline (last pre-treatment value from Day -28 to 
Day 1), for L-DOS47+Pemetrexed/Carboplatin at Day 1, 8 of Cycle 1 to 4, and End of 
Treatment (last non-missing value recorded off-study but within 30 days after last dose), 
or immediately after early termination; for L-DOS47 only at Day 1, 8, 15 of additional Cycle 
x.  Physical exam dates and indications of significant findings will be provided in a listing. 
 
8.7.5.7 Cardiac Evaluations 
ECG data was collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-
DOS47+Pemetrexed/Carboplatin at Day 1, 8 of Cycle 1 to 4; and End of Treatment (last 
non-missing value recorded off-study but within 30 days after last dose), or immediately 
after early termination; for L-DOS47 only at Day 1, 8 of additional Cycle x. 
 
ECG parameters include heart rate (HR), PR, QT, QTc and QRS. For each parameter, the 
values and change from baseline will be summarized using descriptive statistics (n, mean, 
median, standard deviation, minimum and maximum) at each scheduled assessment. In 
addition, the maximum change from baseline over the course of the study will also be 
summarized using descriptive statistics (n, mean, median, standard deviation, minimum 
and maximum). Prior to analysis, the triplicate values will be averaged for each patient. 
 
For QT and QTc, the interval categories: ≤ 450 msec, > 450 msec, > 480  msec, and > 500 
msec, will be summarized using descriptive statistics (frequency and percentage) at each 
scheduled assessment. The change from baseline categories: ≤ 30 msec increase, > 30 
msec increase, and > 60 msec increase will also be summarized using descriptive statistics 
(frequency and percentage) at each scheduled assessment. In addition, the maximum 
interval and maximum increase from baseline over the course of the study will also be 
summarized using descriptive statistics (frequency and percentage). Prior to analysis, the 
triplicate values will be averaged for each patient. 
 


 
 
 
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8.7.5.8 Pharmacokinetics 
Plasma samples for L-DOS47 PK were collected at allowable time windows (e.g., ± 5 min) 
from Cycle 1 through 4 at Day 1 and 8. PK parameters 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), volume of distribution at 
steady state (Vss) and urinary excretion parameters. 
 
The determination of PK parameters and summaries of descriptive statistics for plasma 
concentration time-point data and PK parameters are outside the scope of this RAP. The 
results of the evaluation will be compiled in a separate report. 
 
8.7.5.9 Efficacy Analysis 
Tumor assessments were to be performed at 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. Measurable 
lesions are defined as those that can be accurately measured in at least one dimension 
[longest diameter (LD)] with a minimum size of 10 mm by CT scan, 10 mm caliper 
measurement by clinical exam, or 20 mm by chest x-ray.  
 
Best overall response will be assessed using RECIST version 1.1[1]. Frequency counts and 
percentages will be presented for the tumor response categories defined by RECIST 1.1. 
The objective overall antitumor response rate (CR or PR) will be defined as the proportion 
of patients with confirmed responses. The overall response rate and its 95% confidence 
interval will be calculated. For duration of response, life table estimates will be calculated 
using Kaplan-Meier methodology and the 95% confidence interval will be calculated for 
the median time. For duration of response, a patient alive with no disease progression 
will be censored at the date of the last evaluable tumor assessment. 
 
8.7.5.9.1 Best Overall Response and Objective Response Rate  
Best Overall Response: 
Best Overall Response is defined as the best response assessment of target, non-target 
lesion and the appearance of new lesions from the start of study treatment until disease 
progression/recurrence, including unscheduled assessments. Valid response assessments 
ranked from best to worst are as follows: CR, PR, SD, and PD. CR and PR must be 
confirmed at least 4 weeks later. Symptomatic deterioration will not be considered PD 
when determining Best Overall Response. Best Overall Response for a patient without any 
evaluable assessments will be reported as Not Evaluable (NE).   
 
The minimum duration of treatment for a valid assessment of Stable Disease is 42 days. 
Response data reported as Stable Disease (SD) that occurs before Study Day 42 will be 


 
 
 
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excluded from the determination of Best Overall Response. No minimum duration of 
treatment is required for assessments of complete response (CR) or partial response (PR). 
 
A confirmatory scan for CR and PR is required and must be at least 4 weeks following 
initial documentation of the CR or PR; if this is not satisfied, that response will be 
considered unconfirmed. All unconfirmed assessments of CR and PR will be considered 
Stable Disease (SD) for the determination of Best Overall Response. A confirmed 
complete response is a CR which is followed by another CR without any intervening 
assessment of PD. A confirmed partial response is a PR preceded or followed by a CR or 
another PR, allowing for one interim assessment of SD. 
 
Scheduled assessments having no data (i.e., incomplete assessment, not assessed, or 
missing) will be ignored and the best overall response will be based on the known 
assessments. However, if the first 2 (or more) scheduled assessments are not evaluable 
and followed by PD or death, Best Overall Response will be NE. 
 
The percentage of patients in each of the best overall response categories (CR, PR, SD, PD, 
NE) will be calculated. Patients will be counted once in each of the response categories 
based on their best response assessment.  
 
Best Overall Response and response date are captured on the Off-Study eCRF. 
 
Objective Response Rate: 
The objective response rate (ORR) is based on best overall response and is defined as the 
percentage of patients with a best overall response of CR or PR. 
 
The two-sided 95% Clopper-Pearson confidence interval will be calculated for the 
objective response rate using the following SAS® code: 
 
LowerCL = 1-betainv(1-alpha/2,N-x+1,x) 
 
UpperCL = betainv(1-alpha/2,x+1,N-x) 
where: N=sample size, X=number of responders, alpha=0.05 for a 95% confidence 
interval.[2] 
 
Clinical Benefit Rate: 
Clinical benefit will be calculated as the percentage of patients achieving complete 
response, partial response and stable disease, 95% CI is provided by the same method as 
above. 
 
Summaries for Best Overall Response, ORR and clinical benefit will be presented for the 
Efficacy Evaluable, and Intent-to-Treat populations.  
 


 
 
 
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8.7.5.9.2 Duration of Response (CR or PR) 
Duration of response is calculated from date of first response (first occurrence of CR or 
PR) to the first date of recurrence or objectively documented PD (not including 
symptomatic deterioration) or death due to any cause, whichever occurs first. For a 
patient without evidence of disease recurrence or objective disease progression or death, 
duration of response will be censored at the date of the last evaluable tumor assessment. 
Only patients with a confirmed PR or CR are included in the analysis. 
 
If two or more consecutive tumor assessments have no data (incomplete assessment, not 
assessed, or missing) followed by a PD, the duration of response will be calculated at the 
time of the last prior assessment with valid data, and not at the time of PD. If a single 
assessment has no data, this assessment will be ignored and any prior and subsequent 
assessments will be used to determine the duration of response. 
 
Life Table estimates are calculated using the Kaplan-Meier methodology. The 95% 
confidence interval for the median progression-free time will be presented and is 
calculated using the method by Brookmeyer and Crowley[3]. The 95% confidence 
intervals will be presented for point estimates of the survival distribution [1 months (30 
days), 2 months (60 days), 3 months (90 days), 6 months (180 days), and 9 months (270 
days) if applicable] using the method described by Kalbfleisch and Prentice[4]. The 
Kaplan-Meier curve for the duration of response will also be presented. These summaries 
will be presented for the Efficacy Evaluable populations. 
 
The derived data used in the summarization of the duration of response will also be 
provided. These listings will include the patient number, treatment information, response, 
date of response (CR or PR), date of progression or censoring, and the duration of 
response in days. 
 
8.7.6 Programming Considerations 
All tables, data listings, figures (TLFs), and statistical analyses are generated using SAS® 
Version 9.4.  
 
8.7.6.1 TLF Outputs 
Unless otherwise noted, the estimated mean and median for a set of values are printed 
out to one more significant digit than the original values, and standard deviations are 
printed out to 2 more significant digits than the original values. The minimum and 
maximum report the same significant digits as the original values. For example, for age: 
 
N 
XX 
Mean 
XX.X 


 
 
 
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Standard Deviation 
X.XX 
Median 
XX.X 
Minimum 
XX 
Maximum                     XX 
 
Percentage values are printed with one digit to the right of the decimal point in 
parentheses 1 space after the count (e.g., 7 (12.8%), 13 (5.4%)).  
 
For patient listings and variables with numeric fields, trailing zeroes to the right of the 
decimal point are not displayed. 
 
Missing data in patient listings is represented as “NA” or “ND”, with the footnote “NA = not 
applicable” or “ND = not done”. Missing descriptive statistics due to non-estimability are 
reported as “-”. 
 
8.7.6.2 Data Conventions and Rules 
This section provides rules for calculations and definitions for naming conventions that 
are common to all applicable tables. 
 
The baseline value of a variable is defined as the last value obtained on or before the 
administration date and time of the first study drug dose.  
 
For any variable where percent change from baseline is evaluated at Visit X: Percent 
Change from Baseline value = [(Visit X value - Baseline value)/Baseline value] x100 
 
For any variable where absolute change from Baseline is evaluated at Visit X: Absolute 
Change from Baseline value = Visit X value - Baseline value 
 
Concomitant medications missing both start and stop dates, or having a start date prior 
to the last dose of study drug and missing the stop date, or having a stop date after the 
start of study drug and missing the start date, are counted as concomitant.  
 
Relative Study Day: The first day of treatment is Day 1. A minus (-) sign indicates days 
prior to the start of treatment (e.g., Day -3 represents 3 days before start of therapy; there 
is no Day 0). The relative study day for a specific visit (day of study relative to start of 
treatment) is calculated as: Visit Date - Date of First Dose +1 (for post-treatment visits) and 
Visit Date - Date of First Dose (for pre-treatment visits). 
 
Relative Cycle Day: Cycle X Day 1 is the first day of dosing within the cycle. The relative 
cycle day for a specific visit (relative to first dosing day within the cycle) is calculated as: 
Visit Date - Date of First Dose Within Cycle + 1. 


 
 
 
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8.8 Changes in the Conduct of the Study or Planned Analyses 
Conduct of the Study 
 
The protocol and amendments are presented in Appendix 16.1. The original protocol was 
dated March 5, 2014. Version 1.1 of the  protocol, dated April 22, 2014, was the first 
version used to enroll and treat patients. The protocol was subsequently updated three 
times. 
 
In Amendment 1, dated June 2, 2015: 
• 
The protocol mandated washout period was minimized to 7 days for patients treated 
with an EGFR tyrosine kinase inhibitor and/or for patients treated with an ALK 
inhibitor.  
• 
Patients had to have no prior adjuvant chemotherapy within 6 months (shortened 
from 12 months) of the first treatment day if there was recurrent disease. 
• 
Patients with treated and stable brain metastases could enroll if they were off steroids 
and not taking antiepileptics for brain metastases; patients with brain metastases that 
were active, symptomatic, or required treatment with steroids or antiepileptics were 
excluded. 
• 
The instructions for L-DOS47 preparation were updated to include the guidance that 
full weight-based doses would be used to treat obese patients. 
• 
The option to delayed treatment with pemetrexed and carboplatin for up to 42 days 
to allow recovery from drug-related pemetrexed and/or carboplatin toxicity was 
removed. 
• 
The start of the adverse event/serious adverse event reporting period was defined as 
commencing after the initial dosing of pemetrexed premedication. 
• 
Minor clarifications were made to timing and conduct of study evaluations. 
 
In Amendment 2, dated September 28, 2016: 
• 
The allowed interval for progression of disease documented after end of adjuvant 
treatment prior to enrollment was shortened from “≥ 12 months” to “≥ 6 months”. 
• 
The L-DOS47 infusion time could be increased from 30 minutes to 60 minutes in the 
event of mild infusion reaction; it was specified that the L-DOS47 infusion bag had to 
be used within 3 hours of preparation. 
• 
The dose escalation scheme was modified: planned dose levels changed from “0.46, 
0.59, 0.78, 1.04, 1.38, and 1.84 µg/kg” to “0.46, 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, and 
12.0 µg/kg”; planned dose reductions were modified accordingly. 
• 
Clarification was added to the PK sampling times in the event the L-DOS47 infusion 
time was increased from 30 minutes to 60 minutes in the event of a mild infusion 
reaction. 


 
 
 
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• 
Allowable time windows (e.g., ± 5 min) were added to ECGs, vital signs monitoring, and 
collection of PK samples; selected timepoints for ECGs, vital signs monitoring and PK 
sample collections were removed. 
• 
Cycle 5, Day 1 assessments did not need to be repeated if the end of Cycle 4 
evaluations were performed within 7 days prior to Day 1 of Cycle 5. 
• 
Due to the addition of cohorts 6 and 7 to the dose escalation scheme, the anticipated 
total number of patients to be enrolled in the study increased from 40 to 52 patients. 
 
In Amendment 3, dated August 10, 2017: 
• 
An accelerated “1+2” dose design, up to the L-DOS47 dose level of 6µg/kg, was 
implemented and to be followed by the standard “3+3” design for the final two 
L-DOS47 dosing cohorts of 9 and 12 µg/kg. 
• 
The anticipated total number of patients to be enrolled in the study decreased from 
52 to 37 patients. 
• 
In the accelerated dose escalation phase of the study, the definition of dose limiting 
toxicity (DLT) was updated to also include “One instance each of two unique grade 2 
adverse events” that occurred within 21 days after commencing study drug treatment 
and considered to be possibly, probably, or definitely related to L-DOS47 by the 
Investigator. 
• 
Chandra Belani, MD (Penn State Hershey) was removed from the list of Investigators 
and the Sponsor’s address and phone number were updated. 
 
Planned Analysis 
 
There were no changes to the planned analysis. 
 
9.0 Study Patients 
A total of nnn patients were enrolled as shown in Table 1. The first patient was enrolled 
on xx Month year and treated beginning on xx Month year. The final patient was removed 
from the study on xx Month year. The study populations are summarized in Table 1. 
               


 
 
 
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Table 1: Study Populations 
All Enrolled 
(N=n)  
 LDOS001 Phase I Study 
 
 
 
 
                     L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Study Populations 
 
 
Dose 1 
Repeat 
Overall  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
All Enrolled [1] 
 
 
nnn (100.0%) 
nnn (100.0%) 
nnn (100.0%) 
 
Met All Eligibility Criteria 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
    Did Not Meet Eligibility Criteria 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Inclusion 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Exclusion 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Waiver Granted 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluable [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Efficacy Evaluable [3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Patients who consented to participate in the study. Number of All Enrolled patients used as denominator to calculate 
percentages. 
[2] Patients treated with any amount of  L-DOS47 or Pemetrexed premedication. 
[3] Patients who met the eligibility criteria with baseline measurable disease, completed 2 cycles of study therapy, and had 
at least one post- baseline tumor assessment, or, patients with less than 2 cycles of study therapy must have clear evidence 
of clinical progression to be  considered evaluable for efficacy. 
Note: waivers no longer granted after eCRF update post-March 2018 Helix audit.  
 
Cross-References: Appendix Listings 16.2.1.1, 16.2.1.2.   
PROGRAMMER’S NOTES:   
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
 
 
9.1 Disposition of Patients 
Of the nnn patients treated in the study, [insert description of reasons patient went off 
study here]. Patient disposition is summarized in Table 2. 
 
 


 
 
 
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Table 2: Patient Disposition 
All Enrolled  
 (N=n)   
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Patient Disposition 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of  Treated Patients 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Patients Off-Study [1] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Reasons for Off-Study [2] 
 
 
 
 
 
 
Off-Study Reason  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Off-Study Reason 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Treated Patients used as denominator to calculate percentages. 
[2] Patients Off-Study used as denominator to calculate percentages. 
  
Cross-References: Appendix Listing 16.2.1.2. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 
subject is in each of the 3 dose levels. 
Only present Off-Study reason categories that are used in the database from the “Off-Study” CRF.  
Sort “Reasons for Off-Study” in descending order of  “Overall” frequency. 
 
 
9.2 Protocol Deviations 
Instances of noncompliance and resulting protocol deviations were collected in Monitor 
Express. Protocol deviations are  [insert the deviations if data is available, otherwise there 
were no important deviations noted during the study].  
 
10.0 Efficacy and Pharmacokinetic Evaluations 
10.1 Data Sets Analyzed 
The patient populations analyzed in this report are as follows: 
 
Intent-to-Treat Population (N=nnn): All patients registered in the study whether or not 
they met the eligibility criteria or received study treatment. This population will be 
summarized for demographics and other baseline characteristics, and serve as the 
secondary analysis population for efficacy.  
 


 
 
 
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Safety Evaluable Population (N=nnn): All patients who received any amount of 
L-DOS47, or Pemetrexed premedication. This population will be summarized for all safety 
parameters. 
 
Efficacy Evaluable Population (N=nnn): All patients who met the eligibility criteria with 
baseline measurable disease, completed 2 cycles of study therapy, and had at least one 
post-baseline tumor 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. The efficacy-evaluable population will be the primary analysis population for 
efficacy.  
[Insert description of patient exclusions here, if applicable.] 
 
10.2 Patient Demographic and Other Baseline Characteristics 
10.2.1 Demographics and Baseline Characteristics 
Demographic characteristics are summarized in Table 3. Of the nnn patients treated in 
the study, nnn patients (xx.x%) were male and nnn female (xx.x%). The median age was 
xx.x years (range: xx to xx). xx patients (xx.x%) were [insert Ethnic Origin discussion here]. 
At baseline, nnn patients (xx.x%) had ECOG performance status of 0, nnn patients (xx.x%) 
had ECOG status of 1.   


 
 
 
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Table 3: Demographic Characteristics 
Intent-to-Treat 
 (N=n)   
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Demographic Characteristics 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Age (years)  
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
18 to 64 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
65 + 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Unknown 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Gender 
 
 
 
 
 
 
Female 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Male 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
BSA (m2) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
Asian 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
White 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Black or African American 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Native Hawaiian or Pacific Islander 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
American Indian or Alaska Native 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Not Reported 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Other 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
Hispanic or Latino 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Not Hispanic or Latino 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
 
 
 
 
 
0 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
1 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
 
Cross-References:  Appendix Listings 16.2.4.1 and 16.2.9.3. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 


 
 
 
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The exact age was calculated in years without decimal places as follows: 
Age (years) = (Year of On-Study – Year of Birth) – Correction 
Where: Correction = 1, if Birth Month > On-Study Month or Birth Month = On-Study Month and Birth Day > On-Study Day 
Else: Correction = 0 
Sort Age categories as shown in table. 
Sort Gender categories in descending order of  “Overall” frequency. 
Sort Race categories in descending order of  “Overall” frequency. 
Sort Ethnicity categories in descending order of  “Overall” frequency. 
Sort ECOG Performance Status categories as shown in table. 
 
10.2.2 Baseline Disease Characteristics 
Baseline disease characteristics are summarized in Table 4. Histopathology was [insert 
histopathology discussion here]. The median duration of disease for all patients, 
calculated from the Date of Initial Diagnosis to the Date of Inform Consent Form, was 
xxxx.x (Months) (range: xxxx to xxxx Months).  
 
Table 4: Baseline Disease Characteristics 
 Intent-to-Treat 
 (N=n)   
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Disease Characteristics 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Histopathology [1] 
 
 
 
 
 
 
Histopathology Reported 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Histopathology Reported 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Duration of Disease (Months)  
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 [1] Number of Patients used as denominator to calculate percentages. 
 
Cross-References: Appendix Listing 16.2.4.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Duration is calculated in Months: (Date of Informed Content - Date of Initial Diagnosis)/(365.25/12). 
Sort categories in descending order of  “Overall” frequency. 
 
 


 
 
 
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10.2.3 Prior Cancer Therapy 
Prior cancer therapies are summarized in Table 5; patients may have been treated with 
more than one category of prior therapy. [Insert prior therapy discussion here for each 
category.]  
 
 
Table 5: Prior Cancer Therapy 
 Intent-to-Treat 
 (N=n)   
LDOS001 Phase I Study 
 
 
 
 
  L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Prior Therapy [1] 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [2] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients With: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Chemotherapy 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Prior Immunotherapy 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Prior Hormonal Therapy 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Other Prior Therapy 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Prior Cancer Radiation 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Prior Cancer Surgeries 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Patients may be counted in more than one prior therapy category. 
[2] Number of Patients used as denominator to calculate percentages. 
  
Cross-References: Appendix Listings 16.2.4.2, 16.2.4.3, 16.2.4.4. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Prior Therapies include Chemotherapy, Hormonal Therapy, Immunotherapy, Other therapy, Prior Radiation Therapy and 
Prior Cancer Surgeries. 
Patient counts presented.  
Patient may be in more than one prior  therapy category.  
 
10.2.4 Concomitant Measures 
All medications that were ongoing at study start (Day 1) or taken on Day 1 or thereafter 
up to 30 days post last dose are summarized in Attachment Table 14.1.2.  Table 6 
presents all medications that were ongoing at study start (Day 1) or taken on Day 1 or 
thereafter up to 30 days post last dose in at least XX% of safety patients (> nnn patients). 
[Insert concomitant measures discussion here.] 
 


 
 
 
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Table 6: Summary of Concomitant Measures Received by at Least XX%  of  Patients 
Safety Evaluable 
 (N=n)   
LDOS001 Phase I Study 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
 
WHO-DD ATC Class Category Level II [1][2] 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
 
 
Number of Patients [3]                                                      nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
 
 
Number of Patients Taking Concomitant Measures 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
WHO-DD ATC Class Category Level II 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
[1] Patients may be counted in more than one therapeutic class; patients are only counted once within a therapeutic class.  
[2] Summarizes medications that were ongoing at study start (Day 1) or started on Day 1 or  thereafter  up to 30 days post 
last dose. 
[3] Number of Patients used as denominator to calculate percentages. 
  
Cross-References: Attachment Table 14.1.2 and Appendix Listing 16.2.10.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Present all “Therapeutic Class” categories found in the database. 
Only present concomitant measures that occur in XX% or more of patients. 
Sort “Therapeutic Class” column in descending order based on column frequency count. 
 
10.3 Measurements of Treatment Compliance 
Patients received L-DOS47 intravenously for 30 to 60 minutes on Days 1, 8 and 15 of each 
cycle for the first 4 cycles or until the evidence of disease progression, intolerable adverse 
events, or withdrawal of patient consent. Pemetrexed and carboplatin were infused on 
Day 1 of the first 4 cycles.   
The drug administration data are presented in Appendix 16.2.5.1 and are summarized in 
Table 10 through Table 12 in Section 12.1.  
 
10.4 Efficacy Results and Tabulation of Individual Patient Data 
Patients were assessed for tumor response and evidence of disease progression after 
every 6 weeks. Tumor response was evaluated using RECIST version 1.1. Of the nnn 
Intent-to-Treat patients in the study, nnn were evaluable for response. The efficacy 


 
 
 
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evaluable population served as the primary analysis population; the intent-to-treat served 
as the secondary analysis population. 
 
10.4.1 Best Overall Response 
Of the nnn patients in the efficacy evaluable population, nnn patients (xx.x%) had CR, nnn 
patients (xx.x%) had PR, nnn patients (xx.x%) had SD as their best response to therapy, 
nnn patients (xx.x%) had PD and nnn patients (xx.x%) were NE. The Objective Response 
Rate is xx.x% (95% CI: xx.x%, xx.x%). The Clinical Benefit Rate is xx.x% (95% CI: xx.x%, 
xx.x%). Best Overall Response, Objective Response and Clinical Benefit are summarized in 
Table 7.  


 
 
 
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Table 7: Best Overall Response Summary 
Efficacy Evaluable  
(N=n)   
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Best Overall Response 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Complete Response (CR)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Partial Response (PR) 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Stable Disease (SD)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Progressive Disease (PD)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Not Evaluable   
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Objective Response Rate (CR+PR) [2][4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Lower 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
Upper 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
 
 
 
 
 
 
 
Clinical Benefit (CR+PR+SD) [3][4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Lower 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
Upper 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Objective Response Rate is based on patients with either a Complete Response (CR) or Partial Response (PR). 
[3] Clinical Benefit is based on patients with either a CR or PR or SD (stable disease). 
[4] Clopper-Pearson method used for the calculation of the 95% confidence interval. 
 
  
Cross-References: Appendix Listings 16.2.6.1 - 16.2.6.3. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Assumptions: Assessments of SD before Study Day 42 were treated as missing. Confirmatory scans for CR and PR must 
have been at least 4 weeks (28 days) following initial documentation of a valid objective response or that response was 
considered unconfirmed. If scheduled assessments had no data (incomplete assessment, not assessed, or missing), the 
best overall response was based upon the known assessments.  
The two-sided 95% Clopper-Pearson confidence interval was calculated for the response rates using the following SAS® 
code: 
 
LowerCL = 1-betainv(1-alpha/2,N-x+1,x) 
 
UpperCL = betainv(1-alpha/2,x+1,N-x) 
where: N=sample size, X=number of responders, alpha=0.05 for a 95% confidence interval [2]. 
 
Of the nnn patients in the Intent-to-Treat population, nnn patients (xx.x%) had CR, nnn 
patients (xx.x%) had PR, nnn patients (xx.x%) had SD as their best response to therapy, 
nnn patients (xx.x%) had PD and nnn patients (xx.x%) were NE. The Objective Response 
Rate is xx.x% (95% CI: xx.x%, xx.x%). The Clinical Benefit Rate is xx.x% (95% CI: xx.x%, 
xx.x%). Best Overall Response, Objective Response and Clinical Benefit are summarized in 
Table 8. Figure 1 is a Waterfall Plot to show best change in lesion size from baseline 
overtime. 
 


 
 
 
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Table 8: Best Overall Response Summary 
Intent-to-Treat  
(N=n)   
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Best Overall Response 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Complete Response (CR)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Partial Response (PR) 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Stable Disease (SD)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Progressive Disease (PD)  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Not Evaluable  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Objective Response Rate (CR+PR) [2][4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Lower 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
Upper 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
 
 
 
 
 
 
 
Clinical Benefit (CR+PR+SD) [3][4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Lower 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
Upper 95% Confidence Limit 
 
 
          xx.x% 
          xx.x% 
          xx.x% 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Objective Response Rate is based on patients with either a Complete Response (CR) or Partial Response (PR). 
[3] Clinical Benefit is based on patients with either a CR or PR or SD (stable disease). 
[4] Clopper-Pearson method used for the calculation of the 95% confidence interval. 
  
Cross-References: Appendix Listings 16.2.6.1 - 16.2.6.3. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Assumptions: Assessments of SD before Study Day 42 were treated as missing. Confirmatory scans for CR and PR must 
have been at least 4 weeks (28 days) following initial documentation of a valid objective response or that response was 
considered unconfirmed. If scheduled assessments had no data (incomplete assessment, not assessed, or missing), the 
best overall response was based upon the known assessments.  
The two-sided 95% Clopper-Pearson confidence interval was calculated for the response rates using the following SAS® 
code: 
 
LowerCL = 1-betainv(1-alpha/2,N-x+1,x) 
 
UpperCL = betainv(1-alpha/2,x+1,N-x) 
where: N=sample size, X=number of responders, alpha=0.05 for a 95% confidence interval [2]. 
 


 
 
 
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Figure 1: Best Change in Lesion Size from Baseline Overtime (Waterfall Plot) 
Efficacy Evaluable 
(N=n)   
LDOS001 Phase I Study 
 
 
 
PROGRAMMER’S NOTE: Use Efficacy Evaluable population. Present patient ID on X-axis; percentage of best change in lesion 
from baseline for target lesions on Y-axis. 
Cross-References: Appendix Listing 16.2.6.1- 16.2.6.3 
 
10.4.2 Duration of Response 
Duration of response is calculated from date of first response (first occurrence of CR or 
PR) to the first date of recurrence or objectively documented PD (not including 
symptomatic deterioration) or death due to any cause. For a patient without evidence of 
objective disease progression or death, duration of response will be censored at the date 
of the last evaluable tumor assessment. Only patients with a confirmed PR or CR are 
included in the analysis. Duration of response is summarized in Table 9 for the efficacy 
evaluable population. Of the [nnn] patients who had a CR or PR, the median duration of 
response was xxx days (95% CI: xxx days, xxx days). The progression-free rate at 1 month 
(30 days) was xx.x%, at 2 months (60 days) was xx.x%, xx.x%, at 3 months (90 days), xx.x% 
at 6 months (180 days), and xx.x% at 9 months (270 days), if applicable. 
 
Duration of clinical benefit is calculated from date of first occurrence CR or PR or SD to 
the first date of recurrence or objectively documented PD (not including symptomatic 
deterioration) or death due to any cause, is also summarized in Table 10. Only patients 
with a SD or confirmed CR or PR are included in the analysis. Of the [nnn] patients who 


 
 
 
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had clinical benefit, the median duration of clinical benefit was xxx days (95% CI: xxx days, 
xxx days). 
 
 
Table 9: Life Table Summary of Duration of Response 
Efficacy Evaluable 
(N=n)   
LDOS001 Phase I Study 
 
Duration of Response 
Overall 
 
 
Number of Patients 
nnn 
Number of Events 
xx ( xx.x%) 
Number Censored 
xx ( xx.x%) 
 
 
Duration of Response[1][2] 
 
75% Duration 
xxx days 
Median 
xxx days 
Lower 95% Confidence Limit 
xx.x% 
Upper 95% Confidence Limit 
xx.x% 
25% Duration 
xxx days 
 
 
Progression-Free Rate  
 
1 Month (30 days) 
xx.x% 
2 Month (60 days) 
xx.x% 
3 Months (90 days) 
xx.x% 
6 Months (180 days) 
xx.x% 
9 Months (270 days) 
xx.x% 
 
 
[1] Duration of Response is calculated from date of first response (first occurrence of CR or PR) to first date 
of recurrence or objectively documented PD (not including symptomatic deterioration) or death due to 
any cause. For a patient without evidence of objective disease progression or death, duration of 
response will be censored at the date of the last evaluable tumor assessment. Only patients with a 
confirmed PR or CR are included in the analysis. 
[2] Life Table estimates are calculated using Kaplan-Meier methodology.  Confidence interval for the 
median duration time is calculated using the method by Brookmeyer and Crowley. 
 
Cross-References: Attachments Table 14.2.1.1, Figure 2, and Appendix Listing 16.2.6.1-16.2.6.3  
PROGRAMMER’S NOTES: 
Only include if CR or PR responses are found in the database.   
Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for the median 
survival time is calculated using the method by Brookmeyer and Crowley. 
 
The Kaplan-Meier curve for the duration of response for the efficacy evaluable population 
is presented in Figure 2. The point where the Kaplan-Meier curve crosses the horizontal 
reference line represents the median duration of response.  
 


 
 
 
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Figure 2: Duration of Response 
Efficacy Evaluable 
(N=n)   
LDOS001 Phase I Study 
 
 
 
 
 
 
Duration of Response is calculated from date of first response (first occurrence of CR or PR) to first date of recurrence or 
objectively documented PD (not including symptomatic deterioration) or death due to any cause. For a patient without 
evidence of objective disease progression or death, duration of response will be censored at the date of the last evaluable 
tumor assessment. Only patients with a confirmed PR or CR are included in the analysis. 
 
Cross-References: Attachments Tables 9, Table 14.2.1.1, and Appendix Listing 16.2.6.1-16.2.6.3. 
PROGRAMMER’S NOTES: 
Only include if CR or PR responses are found in the database. 
Kaplan-Meier curve generated using SAS. Draw horizontal reference line representing 50% level (median). 
Present Progression Free Survival Probability on y-axis. 
 
 
 


 
 
 
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Table 10: Life Table Summary of Duration of Clinical Benefit 
Efficacy Evaluable 
(N=n)   
LDOS001 Phase I Study 
 
Duration of Response 
Overall 
 
 
Number of Patients 
nnn 
Number of Events 
xx ( xx.x%) 
Number Censored 
xx ( xx.x%) 
 
 
Duration of Clinical Benefit [1][2] 
 
75% Duration 
xxx days 
Median 
xxx days 
Lower 95% Confidence Limit 
xx.x% 
Upper 95% Confidence Limit 
xx.x% 
25% Duration 
xxx days 
 
 
Progression-Free Rate  
 
1 Month (30 days) 
xx.x% 
2 Month (60 days) 
xx.x% 
3 Months (90 days) 
xx.x% 
6 Months (180 days) 
xx.x% 
9 Months (270 days) 
xx.x% 
 
 
[1] Duration of Clinical Benefit is calculated from date of first (CR or PR or SD) to first date of recurrence or 
objectively documented PD (not including symptomatic deterioration) or death due to any cause. For a 
patient without evidence of objective disease progression or death, duration of clinical benefit will be 
censored at the date of the last evaluable tumor assessment. Only patients with a SD or confirmed CR 
or PR are included in the analysis. 
[2] Life Table estimates are calculated using Kaplan-Meier methodology.  Confidence interval for the 
median duration time is calculated using the method by Brookmeyer and Crowley. 
 
 
Cross-References: Attachments Table 14.2.1.1, Figure 3, and Appendix Listing 16.2.6.1-16.2.6.3  
PROGRAMMER’S NOTES: 
Only include if CR or PR responses are found in the database.   
Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for the median 
survival time is calculated using the method by Brookmeyer and Crowley. 
 
The Kaplan-Meier curve for the duration of clinical benefit for the efficacy evaluable 
population is presented in Figure 3. The point where the Kaplan-Meier curve crosses the 
horizontal reference line represents the median duration of clinical benefit. 


 
 
 
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Figure 3: Duration of Clinical Benefit 
Efficacy Evaluable 
(N=n)   
LDOS001 Phase I Study 
 
 
 
 
 
 
Duration of Clinical  Benefit is calculated from date of first (CR or PR or SD) to first date of recurrence or objectively 
documented PD (not including symptomatic deterioration) or death due to any cause. For a patient without evidence of 
objective disease progression or death, duration of clinical benefit will be censored at the date of the last evaluable tumor 
assessment. Only patients with a confirmed SD or CR or PR are included in the analysis. 
 
Cross-References: Attachments Tables 10, Table 14.2.1.1,  and Appendix Listing 16.2.6.1-16.2.6.3. 
PROGRAMMER’S NOTES: 
Only include if CR or PR responses are found in the database. 
Kaplan-Meier curve generated using SAS. Draw horizontal reference line representing 50% level (median). 
Present Progression Free Survival Probability on y-axis. 
 
 
10.4.3 Analysis of Efficacy 
There were no statistical comparisons planned among the dose cohorts. All data 
summaries were descriptive. Statistical methods are presented in Appendix 16.1.9. 
 
10.4.4 Statistical/Analytical Issues 
There are no specific hypothesis related to the analysis. The 95% Clopper-Pearson 
confidence intervals were calculated for objective response rates.[2] 
 


 
 
 
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10.4.5 Tabulation of Individual Response Data 
Patient listing of target and non-target lesion evaluations are provided in Appendix Listing 
16.2.6.1. The individual patient response at each tumor assessment is provided in 
Appendix Listing 16.2.6.2. 
 
10.4.6 Drug Dose, Drug Concentration and Relationships to Response 
[Insert discussion on drug concentration and dose-response, if data is available.] 
 
10.4.7 Drug-Drug and Drug-Disease Interactions 
[Insert relationship between response and concomitant therapy and between response 
and past and/or concurrent illness, if data is available.] 
 
10.4.8 By-Patient Displays 
Not applicable. 
 
10.4.9 Efficacy Conclusions 
A total of nnn patients were evaluated for efficacy in the efficacy-evaluable population. 
The Objective Response Rate was xx.x% (95% CI: xx.x%, xx.x%).  The clinical benefit rate 
was xx.x% (95% CI: xx.x%, xx.x%). [Insert additional efficacy summary described here.] 
 
10.5 Pharmacokinetic Results 
[Insert PK summary here, or “The PK results will be presented in a separate report.”] 
 
11.0 Safety Evaluation 
Protocol specified time windows in Protocol Table 10 Schedule of study evaluation were 
used for applicable safety table assessments. 
 
11.1 Extent of Exposure, Compliance and Dose  
A total of nnn patients (xx.x%) received study therapy and were therefore evaluable for 
safety.   
 
Patients received L-DOS47 intravenously on Days 1, 8 and 15 of each cycle for the first 4 
cycles or until the evidence of disease progression, intolerable adverse events, or 
withdrawal of patient consent. Drug administration and compliance during Cycle 1, and 
for all treatment cycles are summarized in the following sections. The other study 
treatment Pemetrexed and Carboplatin will also be summarized separately. 
 


 
 
 
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11.1.1 Cycle 1  
Study drug L-DOS47 administration, intended dose and compliance are summarized in 
Table 11 for Cycle 1 only. The median duration of exposure was xxx.x days (range: xxx to 
xxx days). Percent Compliance was calculated by dividing the cumulative dose of study 
drug actually administered during Cycle 1 by the prescribed cumulative dose during Cycle 
1. Median compliance was xxx.xx% (range: xxx.x% to xxx.x%) with nnn patients receiving 
100% of their prescribed dose, nnn patients receiving < 100% and nnn patients receiving 
> 100%. Percent Intended Dose was calculated as the cumulative dose of study drug 
actually administered during Cycle 1 divided by the intended cumulative dose during 
Cycle 1. Median intended dose was xxx.xx% (range: xxx.x% to xxx.x%) with nnn patients 
receiving 100% of their intended dose, nnn patients receiving < 100% and nnn patients 
receiving > 100%.  
[Insert dose relationship discussion here]. 
 


 
 
 
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Table 11: Summary of L-DOS47 Administration and Compliance During Cycle 1 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin 
 
L-DOS47 Administration  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Duration of Exposure (days) [1] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Dose (mg) [2] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Intended Dose (mg) [3] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Prescribed Dose (mg) [4] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Percent Intended Dose (%) [5] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Percent Compliance (%) [6] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 


 
 
 
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Table 11: Summary of L-DOS47 Administration and Compliance During Cycle 1 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin 
 
L-DOS47 Administration  
 
 
Dose 1 
Repeat 
Overall 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Percent Intended Dose Category [7] 
 
 
 
 
 
 
>100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
<100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Percent Compliance Category [7] 
 
 
 
 
 
 
>100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
<100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Duration of Exposure was defined as the duration between the first and last dose of L-DOS47 for Cycle 1. 
[2] Total Dose was defined as the sum of all L-DOS47 administered.  
[3] Total Intended Dose was defined as the sum of the intended doses, ie, total intended dose based on no modifications to 
dose or schedule. 
[4] Total Prescribed Dose was defined as the sum of the prescribed doses, ie, total prescribed dose based on any 
modifications to dose or schedule. 
[5] The Percent Intended Dose was defined as the cumulative dose of study drug actually administered divided by the total 
intended dose multiplied by 100% for each patient. 
[6] The Percent Compliance was defined as the cumulative dose of study drug actually administered divided by the 
prescribed dose multiplied by 100% for each patient. 
[7] Number of Patients used as denominator to calculate percentages. 
 
Cross-References: Appendix Listing 16.2.5.1.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Summarize for Cycle 1 only. 
Compliance categories may need to be modified based on the data. 
 
 
11.1.2 All Treatment Cycles 
Study drug L-DOS47 administration, intended dose and compliance are summarized in 
Table 12 for all treatment cycles combined. The median number of treatment cycles 
received was xxx.x cycles (range: xxx to xxx cycles) and the median duration of exposure 
was xxx.x days (range: xxx to xxx days). Percent Compliance was calculated by dividing 
the cumulative dose of study drug actually administered by the prescribed cumulative 
dose. Median compliance was xxx.xx% (range: xxx.x% to xxx.x%) with nnn patients 
receiving 100% of their prescribed dose, patients receiving < 100% and nnn patients 
receiving > 100%. Percent Intended Dose was calculated as the cumulative dose of study 
drug actually administered for all cycles only divided by the intended cumulative dose for 
all cycles. Median intended dose was xxx.xx% (range: xxx.x% to xxx.x%) with nnn patients 


 
 
 
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receiving 100% of their intended dose, nnn patients receiving < 100% and nnn patients 
receiving > 100%. [Insert dose relationship discussion here.] 
 
 
Table 12: Summary of L-DOS47 Administration and Compliance for All Treatment Cycles 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin 
 
L-DOS47 Administration  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Cycles 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Duration of Exposure (days) [1] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Dose (mg) [2] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Intended Dose (mg) [3] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Total Prescribed Dose (mg) [4] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 


 
 
 
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Table 12: Summary of L-DOS47 Administration and Compliance for All Treatment Cycles 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin 
 
L-DOS47 Administration  
 
 
Dose 1 
Repeat 
Overall 
 
Percent Intended Dose (%) [5] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Percent Compliance (%) [6] 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Percent Intended Dose Category [7] 
 
 
 
 
 
 
>100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
<100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Percent Compliance Category [7] 
 
 
 
 
 
 
>100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
<100% 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Duration of Exposure was defined as the duration between the first and last dose of study drug for all cycles. 
[2] Total Dose was defined as the sum of all study drug administered.  
[3] Total Intended Dose was defined as the sum of the intended doses, ie, total intended dose based on no modifications to 
dose or schedule. 
[4] Total Prescribed Dose was defined as the sum of the prescribed doses, ie, total prescribed dose based on any 
modifications to dose or schedule. 
[5] The Percent Intended Dose was defined as the cumulative dose of study drug actually administered divided by the total 
intended dose multiplied by 100% for each patient. 
[6] The Percent Compliance was defined as the cumulative dose of study drug actually administered divided by the 
prescribed dose multiplied by 100% for each patient. 
[7] Number of Patients used as denominator to calculate percentages. 
 
Cross-References: Appendix Listing 16.2.5.1.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Summarize for all treatment cycles. 
Compliance categories may need to be modified based on the data. 
 
 


 
 
 
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The number of patients with dose reductions, dose delay, dose interruptions, and dose 
discontinuations are summarized in Table 13. [Add text] 
 
Table 13: Summary of Patients with L-DOS47 Dose Reductions/Delay/Interruptions/Discontinuations 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
L-DOS47 Administration 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients[1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Patients with No Dose Reduction  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Reduction Due to AE  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Reduction Due to Non-
compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Reduction Due to Other 
Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with No Dose Delay 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Delay Due to AE  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Delay Due to Non-compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Delay Due to Other Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with No Dose Interruption  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Interruption Due to AE 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Interruption Due to Non-
compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Dose Interruption Due to Other 
Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Patients with Any Dose Interruption (at least one) 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
  One Interruption 
  Two Interruptions 
  Etc for 3,4… 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with Dose Reduction and Interruption  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to AE 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Non-compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Other Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with Dose Delay and Reduction 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to AE 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Non-compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Other Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with Dose Delay and Interruption  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to AE 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Non-compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Other Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with Dose Delay, Reduction and 
Interruption  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to AE 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Due to Non-compliance  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 


 
 
 
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Due to Other Reasons 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
Patients with Dose Discontinuation Due to AE [1]
 
 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
 
Cross-References: Appendix Listing  16.2.5.1.1, 16.2.7.2.1 - 16.2.7.2.8 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
 
 
11.2 Adverse Events 
All reported adverse events were converted to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA Version 17.1) translation dictionary . Adverse 
events were categorized by system organ class and preferred term. Treatment-Emergent 
Adverse Events (TEAEs) were defined as all AEs that occurred after the first dose of study 
medication up to 30 days post last dose. AEs were graded according to NCI CTCAE 
(Version 4.0). Patients with multiple TEAEs were only counted once within a summary 
category: system organ class, preferred term, maximum grade, or relationship to 
treatment. Patients with events in more than one category were counted once within 
each category. 
 
11.2.1 Brief Summary of Adverse Events 
Table 14 presents the overall summary of the TEAEs that were reported during the study. 
Sections 12.2.2 through 12.2.2.4 present the summary of TEAEs by system organ classes, 
preferred terms, the events reported most frequently, the events considered to be 
related to study therapy, the most severe events, and the events considered to be both 
related to study therapy and severe. Dose limiting toxicities (DLTs) are presented in 
Section 12.2.2.5 and the determination of MTD and the recommended Phase II dose are 
discussed in the discussion of safety results and conclusions. 
 
Of the nnn patients treated in the study, nnn (xx.x%) experienced at least one TEAE. 
[Insert discussion of any exceptions or patients without TEAEs here.] 
 
 


 
 
 
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Table 14: Overall Summary of Treatment-Emergent Adverse Events 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
 
 
 
LDOS47DoseCohort(µg/kg)+Pemetrexed/Carboplatin 
 
Treatment-Emergent Adverse Events  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients: 
 
 
 
 
 
 
With Any Treatment-Emergent Adverse Events (TEAEs) 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Drug-Related TEAEs[2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Severity Grade 3, 4 or 5 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Severity Grade 3, 4 or 5 Drug-Related TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Any Serious TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Any Serious, Drug-Related TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Discontinued Drug Due to TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Discontinued Drug Due to Drug-Related TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Died Due to TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Died Due to Drug-Related TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Considered to have a Possible, Probable or Definite relationship to study drug. 
  
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 
for excluded events. 
 
 
11.2.2 Display of Adverse Events 
All TEAEs are summarized by system organ class in Table 15 for all patients. TEAEs were 
reported for ≥ XX% of patients in the following system organ classes, in descending order: 
[List most common TEAEs here.] TEAEs in other system organ classes were reported for 
< XX% of patients. 
 


 
 
 
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Table 15: Summary of Treatment-Emergent Adverse Events by System Organ Class 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
MedDRA System Organ Class  
 
 
All TEAEs 
Related [3] Any 
Grade [4] 
Any Relationship 
≥Grade 3 [4] 
Related [3] 
≥Grade 3 [4] 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
Number of Patients with Any 
TEAEs [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Blood and lymphatic system 
disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Cardiac disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Ear and labyrinth disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Eye disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Gastrointestinal disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
General disorders and 
administration site conditions 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Infections and infestations 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Investigations 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Metabolism and nutrition 
disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Musculoskeletal and connective 
tissue disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Nervous system disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Psychiatric disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Renal and urinary disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Reproductive system and breast 
disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Respiratory, thoracic and 
mediastinal disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Skin and subcutaneous tissue 
disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
Vascular disorders 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: 
system organ class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than 
one category were counted once within each category. TEAEs were defined as all AEs that occurred after the first dose of 
study medication up to 30 days post last dose. 
[3] Considered to have a Possible, Probable or Definite relationship to study drug.  
[4] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=fatal. 
 
Cross-References: Attachments Table 14.3.1.2, 14.3.1.3, 14.3.1.4, 14.3.1.5, 14.3.1.6 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
Sort System Organ Class in descending order using “All Adverse Events” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 
for excluded events.   
 
 


 
 
 
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11.2.2.1 Frequently Reported Adverse Events 
Table 16 presents the TEAEs reported for ≥ “XX”% of patients overall, regardless of 
severity or drug relationship. The most frequently reported TEAEs, regardless of severity 
or drug relationship, were MedDRA Preferred Term (nnn patients, xx.x%), [insert 
additional details here].  All TEAEs are summarized by system organ class and frequency 
in Attachment Table 14.3.1.2. 
 
Table 16: Summary of Treatment-Emergent Adverse Events Occurring in at Least “XX”% of Patients by 
System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
MedDRA Preferred Term  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any TEAEs [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: 
system organ class, preferred term. Patients with events in more than one category were counted once within each 
category. TEAEs were defined as all AEs that occurred after the first dose of study medication up to 30 days post last 
dose. 
  
Cross-References: Attachment Table 14.3.1.2 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Only present adverse events that occur “XX”% or more Overall. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 
for excluded events 
 


 
 
 
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11.2.2.2 Drug-Related Adverse Events 
Table 17 presents the TEAEs reported for ≥ “XX”% of patients overall that were considered 
to be drug-related (considered to have a Possible, Probable or Definite relationship to 
study therapy), regardless of severity. The most frequently reported drug-related TEAEs 
were MedDRA Preferred Term (nnn patients, xx.x%), [insert additional details here]. All 
drug-related TEAEs are summarized by system organ class and frequency in Attachment 
Table 14.3.1.3. 
  
Table 17: Summary of Drug-Related, Treatment-Emergent Adverse Events Occurring in at Least “XX”% of Patients by 
System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose Cohort (µg/kg)+ Pemetrexed/Carboplatin 
 
MedDRA Preferred Term 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any Drug-Related, TEAEs 
[2][3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: 
system organ class, preferred term or relationship to treatment. Patients with events in more than one category were 
counted once within each category. TEAEs were defined as all AEs that occurred after the first dose of study medication  
up to 30 days post last dose. 
[3] Considered to have a Possible, Probable or Definite relationship to study drug. 
  
Cross-References: Attachment Table 14.3.1.3 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Only present drug-related adverse events that occur in “XX”% or more Overall. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 


 
 
 
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for excluded events. 
 
11.2.2.3 Severe Adverse Events 
Table 18 presents the TEAEs reported for ≥ “XX”% of patients overall that were considered 
to be severe (≥ Grade 3 in severity), regardless of drug relationship. The most frequently 
reported severe TEAEs were MedDRA Preferred Term (nnn patients, xx.x%), [insert 
additional details here]. All severe TEAEs are summarized by system organ class and 
frequency in Attachment Table 14.3.1.5. 
 
 
Table 18: Summary of Grade 3 or Greater, Treatment-Emergent Adverse Events Occurring in at Least “XX”% of Patients by 
System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose Cohort (µg/kg)+Pemetrexed/Carboplatin 
 
MedDRA Preferred Term  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any Grade 3 or Greater, 
TEAEs [2][3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: 
system organ class, preferred term or maximum grade to treatment. Patients with events in more than one category 
were counted once within each category. TEAEs were defined as all AEs that occurred after the first dose of study 
medication up to 30 days post last dose. 
[3] Grade: 3=Severe, 4=Life threatening, 5=Fatal. 
  
Cross-References: Attachment Table 14.3.1.5 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Only present grade 3 or greater adverse events that occur in “XX”% or more Overall. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 
for excluded events.  


 
 
 
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11.2.2.4 Severe and Drug-Related Adverse Events  
Table 19 presents a summary of all severe and drug-related TEAEs reported. TEAEs that 
were both considered to be drug-related and ≥ Grade 3 in severity were reported by nnn 
patients (xx.x%). The reported severe and drug-related TEAEs were MedDRA Preferred 
Term (nnn patients, xx.x%), [insert additional details here]. All severe and drug-related 
TEAEs are summarized by system organ class and frequency in Attachment Table 14.3.1.6. 
 
 
Table 19: Summary of Grade 3 or Greater, Drug-Related, Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose Cohort(µg/kg)+Pemetrexed/Carboplatin 
 
MedDRA Preferred Term  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any Grade 3 or Greater, 
Drug-Related, TEAEs [2][3][4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: 
system organ class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one 
category were counted once within each category. TEAEs were defined as all AEs that occurred after the first dose of 
study medication up to 30 days post last dose. 
[3] Grade: 3=Severe, 4=Life threatening, 5= fatal. 
[4] Considered to have a Possible, Probable or Definite relationship to study drug. 
  
Cross-References: Attachment Table 14.3.1.6 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 


 
 
 
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L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in 
each of the 3 dose levels. 
Only present grade 3 or greater drug-related adverse events. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 
for excluded events.  
 
 
11.2.2.5 Dose-Limiting Toxicities 
Dose limiting toxicities (DLTs) were not reported for nnn patients (xx.x%) but were 
reported for nnn patients (xx.x%). The patients with DLTs are summarized below and in 
Table 20; patient narratives are presented in Section 11.3.2. 
 
[Insert DLT discussions by patient here.] 
 
Table 20: Patient Listing of Dose Limiting Toxicities 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
MedDRA Preferred Term  
Grade 
[1] 
Onset 
/Day [2] 
Duration 
(Days) [3] 
Relation 
To Therapy 
 Outcome 
[4] 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
x 
xx/ xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/ xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
MedDRA Preferred Term  
x 
xx/ xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/ xx 
xx 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/ xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5= Fatal. 
[2] On-Study day relative to first dose. 
[3] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[4] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with 
sequelae, 5=Fatal, 6=Unknown. 
  
Cross-References: Attachment Table 14.3.2.1 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
DLT defined by flag in Adverse Event dataset. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
 
11.2.3 Analysis of Adverse Events 
Safety results were tabulated and summarized by dose cohort for all patients who 
received L-DOS47.  


 
 
 
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Of the xx patients who received L-DOS47 (N=xx), xx reported adverse events. xx patients 
(xx.x%) reported a drug-related event, xx patients (xx.x%) reported a grade 3 or greater 
event, and xx patients (xx.x%) reported an event that was both drug-related and grade 3 
or greater in severity.  
 
Frequently reported TEAEs were as follows: xxxxxx (xx.x%), xxxxxx (xx.x%), xxxxxx (xx.x%), 
xxxxxx (xx.x%) and xxxxxx (xx.x%). The most frequently reported L-DOS47-related events 
were in the xxxxxx system organ class [additional analysis as appropriate]. 
 
Frequently reported drug-related TEAEs that were grade 3 or greater in severity were 
[insert additional details here]. 
 
11.2.4 Listing of Adverse Events by Patient 
The adverse events listings by patient are provided in Appendix Listing 16.2.7.1. 
 
11.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse 
Events 
11.3.1 Listing of Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
11.3.1.1 Deaths 
On-study deaths or deaths within the 30 day follow-up period post last dose were 
reported for nnn patients ([insert patient numbers here]), nnn patients [insert additional 
details here]. Table 21 presents the summary of the TEAEs leading to death; patient 
narratives are presented in Section 12.3.2. 
 
 


 
 
 
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Table 21: Patient Listing of Treatment-Emergent Adverse Events Leading to Death 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
MedDRA Preferred Term 
Grade 
[1] 
Onset 
/Day[2] 
Duration 
(Days)[3] 
Relation 
To Therapy 
 Outcome 
[4] 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
[1] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5= Fatal. 
[2] On-Study day relative to first dose. 
[3] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[4] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with 
sequelae, 5=Fatal, 6=Unknown . 
  
Cross-References: Attachment Table 14.3.2.6 and Table 14.3.2.7 and Appendix Listing 16.2.7.1 and Listing 16.2.7.4 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
Table 22 presents the summary of patients who died during the study or within the 30-
day follow-up period post last dose; patient narratives are presented in Section 12.3.2.  
 
Table 22: Patient Listing of Deaths On-Study or Within the 30 Day Follow-up Period 
Safety Evaluable 
(N=n) 
LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
Last Dose Date 
Date Off Study 
Date of Death 
Days [1] 
Primary Cause of Death 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
x/x 
Reported Cause of Death  
 
 
 
 
 
 
 
[1] Off-Study to Death calculated in days.  
  
Cross-References: Attachment Table 14.3.2.8 and Appendix Listing 16.2.7.4. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
 
11.3.1.2 Other Serious Adverse Events 
Treatment-emergent serious adverse events (SAE) were reported for nnn of the nnn 
patients treated in the study. Of these, nnn patients ([insert patient numbers here]) had 
SAEs that were considered to be related to study therapy which included [insert details 
here]. SAEs are presented by patient in Table 23 and also in the patient narratives in 
Section 12.3.2. 


 
 
 
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Table 23: Patient Listing of Serious Adverse Events 
Safety Evaluable 
(N=n) 
 LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
MedDRA Preferred Term  
Grade 
[1] 
Onset 
/Day[2] 
Duration 
(Days)[3] 
Relation 
To Therapy 
 
Outcome 
 [4] 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
MedDRA Preferred Term  
x 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
A serious adverse event is defined as any untoward medical occurrence at any dose that results in death, life threatening, 
hospitalization, significant disability or congenital anomaly or birth defect. 
[1] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
[2] On-Study day relative to first dose. 
[3] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[4] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with 
sequelae, 5=Fatal, 6=Unknown. 
  
Cross-References: Attachment Table 14.3.2.2 and Table 14.3.2.3 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
 
11.3.1.3 Other Significant Adverse Events 
The nnn patients ([insert patient numbers here]) who discontinued study medication due 
to TEAEs are summarized in Table 24; patient narratives are presented in Section 11.3.2. 
The drug-related TEAEs resulting in treatment discontinuation are [insert description and 
patient numbers here]. 
 
 
 
 


 
 
 
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Table 24: Patient Listing of Treatment-Emergent Adverse Events Leading to Treatment Discontinuation 
Safety Evaluable  
(N=n) 
LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
MedDRA Preferred Term 
Grade 
[1] 
Onset 
/Day[2] 
Duration 
(Days)[3] 
Relation 
To Therapy 
 Outcome 
 [4] 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
xx 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
MedDRA Preferred Term  
x 
xx/xx 
x 
Relationship 
x 
 
 
MedDRA Preferred Term  
xx 
xx/xx 
xx 
Relationship 
x 
 
 
MedDRA Preferred Term  
xx 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
MedDRA Preferred Term  
xx 
xx/xx 
xx 
Relationship 
x 
 
 
MedDRA Preferred Term  
xx 
xx/xx 
xx 
Relationship 
x 
 
 
 
 
 
 
 
 
[1] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
[2] On-Study day relative to first dose. 
[3] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[4] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with 
sequelae, 5=Fatal, 6=Unknown. 
 
Cross-References: Cross-References: Attachment Table 14.3.2.4 and Table 14.3.2.5 and Appendix Listing 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
 
11.3.2 Patient Narratives  
Patient narratives are presented for patients who had an SAE, were removed from the 
study due to toxicity, had DLT, or died within 30 days of receiving study drugs. 
 
Patient ccc-ppp (SAEs: [Insert Grade and event description here])  
This xx-year-old [insert narrative discussion here].  
 
 
11.4 Clinical Laboratory Evaluations 
Table 25 presents a summary of patients with Grade 3 and 4 laboratory values during the 
treatment period including the 30 day follow-up period post last dose. 
 
 
 
 


 
 
 
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Table 25: Patient Listing of Grade 3 and 4 Laboratory Values During Treatment Period 
Safety Evaluable  
(N=n) 
LDOS001 Phase I Study 
 
Patient 
Age/Sex 
L-DOS47 
Dose Level 
(µg/kg) 
Abnormal Laboratory  
 Test  
Baseline Grade 
[1] 
Post Grade 
[1] 
Onset/Day 
[2] 
Result 
Unit 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
xxx 
Laboratory Test Name  
x 
x 
 
 
 
x/xx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
[1] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
[2] On-Study day relative to first dose within cycle. 
  
Cross-References: Attachment Tables 14.3.4.1-14.3.4.4 and Appendix Listings 16.2.7.1, 16.2.8.1-16.2.8.5 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
Summaries of the shift from baseline to maximum severity grade for hematology and 
blood chemistry parameters are provided in Tables 14.3.4.1 and 14.3.4.2. Summaries of 
quantitative changes from baseline for hematology, blood chemistry and coagulation 
parameters are provided in Tables 14.3.4.3 and 14.3.4.4. 
 
Individual patient laboratory data are provided in Appendix Listings 16.2.8.1-16.2.8.8 for 
hematology, blood chemistry, coagulation, urinalysis and other significant laboratory 
tests. 
 
[Insert discussion of clinically significant laboratory findings]. 
 
11.5 Performance Status, Vital Signs, Physical Findings, ECG Findings and 
Other Observations Related to Safety 
[Insert discussion of changes in performance status, physical examination findings and 
vital signs and ECG parameter findings.] 
 
11.6 Safety Conclusions 
[Insert Safety conclusions.] 


 
 
 
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12.0 Discussion and Overall Conclusions 
[Insert discussion and conclusions.]  


 
 
 
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13.0 Tables, Figures and Graphs Referred to but not Included in the Text 
List of Tables and Figures  
Table 14.1.1 Vital Signs at Baseline Including Height and Weight ........................................ 105 
Table 14.1.2 Summary of Concomitant Measures .................................................................. 108 
Table 14.2.1.1 Life Table Analysis of Duration of Response (CR or PR): Confidence 
Intervals for Point Estimates Efficacy Evaluable ......................................................... 109 
Table 14.2.1.2 Life Table Analysis of Duration of Response (CR or PR): Confidence 
Intervals for Point Estimates Intent-to-Treat ............................................................... 110 
Table 14.2.2 Patient Listing for Duration of Response (CR or PR) Intent-to-Treat ............. 111 
Table 14.3.1.1 Summary of Treatment-Emergent Adverse Events During Cycle 1 ............ 112 
Table 14.3.1.2 Summary of Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term .............................................................................................. 113 
Table 14.3.1.3 Summary of Drug-Related Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term .................................................................... 114 
Table 14.3.1.4 Summary of Treatment-Emergent Adverse Events by Highest Drug 
Relationship, System Organ Class and Preferred Term ............................................ 115 
Table 14.3.1.5 Summary of Treatment-Emergent Adverse Events by Maximum 
Severity Grade, System Organ Class and Preferred Term ........................................ 116 
Table 14.3.1.6 Summary of Drug-Related, Treatment-Emergent Adverse Events by 
Maximum Severity Grade, System Organ Class and Preferred Term ..................... 117 
Table 14.3.2.1 Patient Listing of Dose Limiting Toxicities ...................................................... 118 
Table 14.3.2.2 Summary of Serious Adverse Events by System Organ Class and 
Preferred Term ................................................................................................................ 119 
Table 14.3.2.3 Patient Listing of Serious Adverse Events ...................................................... 120 
Table 14.3.2.4 Summary of Treatment-Emergent Adverse Events Leading to 
Treatment Discontinuation by System Organ Class and Preferred Term .............. 121 
Table 14.3.2.5 Patient Listing of Treatment-Emergent Adverse Events Leading to 
Treatment Discontinuation ............................................................................................ 122 
Table 14.3.2.6 Summary of Treatment-Emergent Adverse Events Leading to Death 
by System Organ Class and Preferred Term ............................................................... 123 
Table 14.3.2.7 Patient Listing of Treatment-Emergent Adverse Events Leading to 
Death ................................................................................................................................. 124 
Table 14.3.2.8 Patient Listing of Deaths On-Study or Within the 30 Days Follow-up 


 
 
 
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Period ................................................................................................................................ 125 
Table 14.3.4.1 Summary of Shift from Baseline to Maximum CTCAE Grade During 
Treatment Period for Hematology Tests ..................................................................... 126 
Table 14.3.4.2 Summary of Shift from Baseline to Maximum CTCAE Grade During 
Treatment Period for Blood Chemistry Tests ............................................................. 127 
Table 14.3.4.3 Summary of Absolute Change from Baseline During Treatment 
Period for Hematology Tests ......................................................................................... 128 
Table 14.3.4.4 Summary of Absolute Change from Baseline During Treatment 
Period for Blood Chemistry Tests ................................................................................. 129 
Table 14.3.4.5 Summary of Change from Baseline for ‘ECG Parameter (units)’ ................. 130 
Table 14.3.4.6 Categorical Summary of ‘QT/QTc Parameter’ Interval .................................. 132 
Table 14.3.4.7 Categorical Summary of ‘QT/QTc Parameter’ Interval Change from 
Baseline............................................................................................................................. 133 
Table 14.3.5.1 Summary of Shift from Baseline to Maximum ECOG Performance 
Status Score...................................................................................................................... 134 
Table 14.3.6.1  Summary of Anti-L-DOS47 Antibodies ........................................................... 135 
Table 14.3.6.2 Summary of Titer Values of Anti-L-DOS47 Antibodies.................................. 136 
Table 14.3.6.3 Change from Baseline of Tumour Antigen CEACAM6 .................................. 137 
 
 


 
 
 
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14.0 Reference List 
 
[1]  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. (2009) 
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). 
Eur J Cancer 45: 228-247. 
 
[2] Clopper CJ, Pearson ES. (1934) The Use of Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika; 26(4)404-413. 
 
[3] Brookmeyer, R. and Crowley, J. (1982), A Confidence Interval for the Median Survival 
Time, Biometrics, 38, 29-41. 
 
[4] Kalbfleisch, J.D. and Prentise, R.L. (1980) The Statistical Analysis of Failure Time Data. 
New York: John Wiley & Sons, Inc. 
 
 


 
 
 
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15.0 Appendices  
Appendix 16.2.1.1 Inclusion/Exclusion Criteria ....................................................................... 138 
Appendix 16.2.1.2  Patient Disposition ..................................................................................... 139 
Appendix 16.2.4.1 Demographic and Disease-Related Characteristics ............................... 140 
Appendix 16.2.4.2 Prior Cancer Therapy.................................................................................. 142 
Appendix 16.2.4.3 Prior Cancer Radiation ............................................................................... 143 
Appendix 16.2.4.4 Prior Cancer Surgeries ............................................................................... 144 
Appendix 16.2.4.5 Medical History/Baseline Symptoms ....................................................... 145 
Appendix 16.2.4.6 Pregnancy Test ............................................................................................ 146 
Appendix 16.2.5.1.1  L-DOS47 Administration ........................................................................ 147 
Appendix 16.2.5.1.2  Carboplatin Administration ................................................................... 148 
Appendix 16.2.5.1.3  Pemetrexed Administration .................................................................. 149 
Appendix 16.2.5.2 Pharmacokinetic Sampling: Blood ............................................................ 150 
Appendix 16.2.6.1 Extent of Disease: Target and Non-Target Lesions ................................ 151 
Appendix 16.2.6.2 Cycle Response Assessment ..................................................................... 154 
Appendix 16.2.6.3 Patient Listing for Duration of Clinical Benefit (CR or PR or SD) .......... 155 
Appendix 16.2.7.1 Adverse Events ............................................................................................ 156 
Appendix 16.2.7.2.1 Treatment-Emergent Adverse Events Leading to Dose 
Reduction .......................................................................................................................... 157 
Appendix 16.2.7.2.2 Treatment-Emergent Adverse Events Leading to Dose 
Interruption ...................................................................................................................... 158 
Appendix 16.2.7.2.3 Treatment-Emergent Adverse Events Leading to Dose Delay .......... 159 
Appendix 16.2.7.2.4 Treatment-Emergent Adverse Events Leading to Dose 
Reduction and Interruption ........................................................................................... 160 
Appendix 16.2.7.2.5 Treatment-Emergent Adverse Events Leading to Dose Delay 
and Reduction .................................................................................................................. 161 
Appendix 16.2.7.2.6 Treatment-Emergent Adverse Events Leading to Dose Delay 
and Interruption .............................................................................................................. 162 
Appendix 16.2.7.2.7 Treatment-Emergent Adverse Events Leading to Dose Delay, 
Reduction and Interruption ........................................................................................... 163 
Appendix 16.2.7.2.8 Treatment-Emergent Adverse Events Leading to Dose 
Discontinuation ............................................................................................................... 164 


 
 
 
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Appendix 16.2.7.3 Patients With Incomplete Adverse Event Information Excluded 
From Summary Tables ................................................................................................... 165 
Appendix 16.2.7.4 Death Summary .......................................................................................... 166 
Appendix 16.2.8.1 Clinical Laboratory Tests - Hematolog ..................................................... 168 
Appendix 16.2.8.2 Clinical Laboratory Tests - Blood Chemistry ........................................... 169 
Appendix 16.2.8.3 Clinical Laboratory Tests - Coagulation ................................................... 170 
Appendix 16.2.8.4 Clinical Laboratory Tests – Urinalysis ....................................................... 171 
Appendix 16.2.8.5 Other Clinically Significant Laboratory Results ....................................... 172 
Appendix 16.2.9.1 Physical Examination .................................................................................. 173 
Appendix 16.2.9.2 Vital Signs ..................................................................................................... 174 
Appendix 16.2.9.3 ECOG Performance Status ......................................................................... 176 
Appendix 16.2.9.4 Electrocardiogram ...................................................................................... 177 
Appendix 16.2.9.5 Immunogenicity Data of L-DOS47 ............................................................ 179 
Appendix 16.2.9.6 Immunogenicity Data of Tumour Antigen (CEACAM6) .......................... 180 
Appendix 16.2.10.1 Concomitant Measures ............................................................................ 181 


 
 
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RAP-Specific Sections Presenting Sample Tables and Listings 
Tables for Section 14: Referred to But Not Presented In-Text 
 
 
 


 
 
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Table 14.1.1 
Vital Signs at Baseline Including Height and Weight 
Safety Evaluable 
(N=n) 
 
 
 
L-DOS47 Dose Cohort(µg/kg)+ Pemetrexed/Carboplatin  
 
Vital Signs 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Pulse Rate (beats/min) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Cross-Reference: Appendix Listings 16.2.9.2. 
PROGRAMMER’S NOTES: 
 
 
 


 
 
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Table 14.1.1 
 Vital Signs at Baseline Including Height and Weight 
Safety Evaluable 
(N=n) 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
Vital Signs 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Temperature (unit) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Respiration (breaths/min) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Pulse Oximetry (%) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Height (cm) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 


 
 
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Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
BSA (mA2) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Mean 
 
 
xx.x  
xx.x  
xx.x  
 
Standard Deviation 
 
 
xx.xx 
xx.xx 
xx.xx 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Cross-Reference: Appendix Listings 16.2.9.2. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
 
 
 
 


 
 
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Table 14.1.2 
Summary of Concomitant Measures 
Safety Evaluable 
 (N=n) 
 
WHO-DD ATC Class Category Level II 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 WHO-DD Preferred Term [1][2] 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients[3] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients Receiving Concomitant 
Measures 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
WHO-DD ATC Class Category Level II 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
WHO-DD ATC Class Category Level II 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
WHO-DD Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Patients may be counted in more than one therapeutic class; patients are only counted once within a therapeutic class. 
[2] Summarizes medications that were ongoing at study start (Day 1) or started on Day 1 or thereafter up to 30 days post last dose. 
[3] Number of Patients used as denominator to calculate percentages. 
   
Cross-References: Appendix Listing 16.2.10.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Present all “Therapeutic Class” categories found in the database. 
Sort “Therapeutic Class” column in descending order based on “Overall” column frequency count. 
 
 


 
 
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Table 14.2.1.1 
Life Table Analysis of Duration of Response (CR or PR): Confidence Intervals for Point Estimates 
Efficacy Evaluable 
(N=n)   
 
 
Number at 
Cumulative 
Progression-Free 
95% Confidence Interval 
[2] 
 
Risk 
Events [1] 
Rate 
Lower 
Upper 
 
 
 
 
 
 
Baseline 
nnn 
nnn 
100.0% 
xx.x% 
xx.x% 
1 Month (30 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
2 Month (60 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
3 Months (90 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
6 Months (180 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
9 Months (270 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Duration of Response is calculated from date of first response (first occurrence of CR or PR) to first date of recurrence or 
objectively documented PD (not including symptomatic deterioration) or death due to any cause. For a patient without evidence of 
objective disease progression or death, duration of response will be censored at the date of the last evaluable tumor 
assessment. Only patients with a confirmed PR or CR are included in the analysis. 
[2] Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for a point estimate on the survival 
distribution is calculated using the method by Kalbfleisch and Prentice. 
Cross-References: Appendix Listing 16.2.6.3 
PROGRAMMER’S NOTES: 
Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for a point estimate on the survival 
distribution was calculated using the method by Kalbfleisch and Prentice. 
 
 
 


 
 
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Table 14.2.1.2 
Life Table Analysis of Duration of Response (CR or PR): Confidence Intervals for Point Estimates 
Intent-to-Treat 
(N=n)   
 
 
Number at 
Cumulative 
Progression-Free 
95% Confidence Interval [2] 
 
Risk 
Events [1] 
Rate 
Lower 
Upper 
 
 
 
 
 
 
Baseline 
nnn 
nnn 
100.0% 
xx.x% 
xx.x% 
1 Month (30 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
2 Months (60 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
3 Months (90 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
6 Months (180 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
9 Months (270 days) 
nnn 
nnn 
xx.x% 
xx.x% 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Duration of Response is calculated from date of first response (first occurrence of CR or PR) to first date of recurrence or 
objectively documented PD (not including symptomatic deterioration) or death due to any cause. For a patient without evidence of 
objective disease progression or death, duration of response will be censored at the date of the last evaluable tumor assessment. 
Only patients with a confirmed PR or CR are included in the analysis. 
[2] Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for a point estimate on the survival 
distribution is calculated using the method by Kalbfleisch and Prentice. 
Cross-References: Appendix Listing 16.2.6.3 
PROGRAMMER’S NOTES: 
Life Table estimates are calculated using Kaplan-Meier methodology. Confidence interval for a point estimate on the survival 
distribution is calculated using the method by Kalbfleisch and Prentice. 
 
 
 


 
 
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Table 14.2.2 
Patient Listing for Duration of Response (CR or PR) 
Intent-to-Treat 
(N=n)   
 
 
 
Patient 
Age/Sex 
L-DOS47 
Dose Cohort 
(µg/kg) 
Date of 
First Dose 
Date of 
First CR 
Date of 
First PR 
 
Date of 
PD  
Date of 
Censoring 
Duration 
of 
Response 
[1] 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ddmmmyyyy 
ddmmmyyyy 
 
 
ddmmmyyyy 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ddmmmyyyy 
 
ddmmmyyyy 
 
ddmmmyyyy 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ddmmmyyyy 
ddmmmyyyy 
 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ddmmmyyyy 
ddmmmyyyy 
 
 
ddmmmyyyy 
 
xxx 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ddmmmyyyy 
ddmmmyyyy 
 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
 
 
[1] Duration of Response is calculated from date of first response (first occurrence of CR or PR) to first date of 
recurrence or objectively documented PD (not including symptomatic deterioration) or death due to any cause. For a 
patient without evidence of objective disease progression or death, duration of response will be censored at the date 
of the last evaluable tumor assessment. Only patients with a confirmed PR or CR are included in the analysis. 
Note: CR= complete response, PR= partial response, PD = progressive 
Cross-Reference: Appendix Listing 16.2.6.3 
 
 
PROGRAMMER’S NOTES: 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Data used in the SAS Life Table procedure. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg.  
 
 
 
 


 
 
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Table 14.3.1.1 
Summary of Treatment-Emergent Adverse Events During Cycle 1 
Safety Evaluable 
(N=n) 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
Treatment-Emergent Adverse Events[1] 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [2] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients: 
 
 
 
 
 
 
With Any TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Drug-Related TEAEs [3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Severity Grade 3, 4 or 5 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Severity Grade 3, 4 or 5 Drug-Related TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Any Serious TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
With Any Serious, Drug-Related TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Discontinued Drug Due to TEAEs 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Discontinued Drug Due to Drug-Related TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Died Due to TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Who Died Due to Drug-Related TEAEs  
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted once 
within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post last 
dose. 
[2] Number of Patients used as denominator to calculate percentages. 
[3] Considered to have a Possible, Probable or Definite relationship to study drug.  
Cross-References: Appendix Listing 16.2.7.1   
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
 
 
 
 


 
 
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Table 14.3.1.2 
Summary of Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
MedDRA Preferred Term  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any TEAEs [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post 
last dose. 
Cross-References: Appendix Listing 16.2.7.1   
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
 
 
 


 
 
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Table 14.3.1.3 
Summary of Drug-Related Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
L-DOS47 Dose 
Cohort(µg/kg)+Pemetrexed/Carboplatin  
 
MedDRA Preferred Term  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any Drug-Related TEAEs [2][3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post 
last dose. 
[3] Considered to have a Possible, Probable or Definite relationship to study drug. 
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
 
 
 


 
 
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Table 14.3.1.4 
Summary of Treatment-Emergent Adverse Events by Highest Drug Relationship, System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
MedDRA Preferred Term 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
Highest Drug Relationship  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any TEAEs [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Unrelated 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Unlikely 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Possible 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Probable 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Definite 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Not Related [3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Related [4] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted once 
within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post last 
dose. 
[3] Considered to be Unrelated or have an Unlikely relationship to study drug. 
[4] Considered to have a Possible, Probable or Definite relationship to study drug.  
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 3 
dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 for excluded 
events. 
 
 
 


 
 
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Table 14.3.1.5 
Summary of Treatment-Emergent Adverse Events by Maximum Severity Grade, System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
MedDRA Preferred Term 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
Maximum Severity Grade  
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any TEAEs [2] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
< Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 1 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 2 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 4 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 5 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
>= Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post 
last dose. 
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 for 
excluded events. 
 
 
 


 
 
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Table 14.3.1.6 
Summary of Drug-Related, Treatment-Emergent Adverse Events by Maximum Severity Grade, System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
MedDRA Preferred Term 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin  
 
Maximum Severity Grade 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Number of Patients with Any Drug-Related TEAE [2][3] 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
< Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 1 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 2 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 4 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
Grade 5 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
>= Grade 3 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
MedDRA Preferred Term 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post 
last dose. 
[3] Considered to have a Possible, Probable or Definite relationship to study drug. 
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Excludes events with incomplete information for grade or drug relationship. Add footnote if required: See Listing 16.2.7.3 for 
excluded events. 
 
 
 


 
 
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Table 14.3.2.1 
Patient Listing of Dose Limiting Toxicities 
Safety Evaluable 
(N=n) 
 
Patient 
Age/Sex 
L-DOS47 Dose 
Level (µg/kg) 
Adverse Event 
(MedDRA Preferred Term)  
Onset 
Cycle/Day 
[1] 
Duration 
of AE 
[2] 
Treatment 
Duration 
[3] 
Grade 
[4] 
Serious 
[5] 
Drug  
Relationship 
Outcome 
[6] 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
xx/xx 
x 
x 
x 
x 
Relationship 
x 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ADVERSE EVENT 
xx/xx 
x 
x 
x 
x 
Relationship 
x 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
x 
x 
Relationship 
x 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ADVERSE EVENT 
xx/xx 
x 
x 
x 
x 
Relationship 
x 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[3] Treatment Duration calculated from first dose of study medication to treatment discontinuation. 
[4] Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
[5] Serious: 1=Not serious, 2=Death, 3=Life threatening, 4=Hospitalization, 5=Significant Disability, 6=Congenital Anomaly/Birth  
    Defect, 7=Other Medically Important Event. 
[6] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with sequelae, 5=Fatal, 
    6=Unknown.   
Cross-References: Appendix Listings 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg.  
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
DLT defined by flag in Adverse Event dataset; ‘Dose Limiting Toxicity’ tic box checked on AE CRF. 
 
 
 


 
 
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Table 14.3.2.2 
Summary of Serious Adverse Events by System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin  
 
MedDRA Preferred Term  
 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
 
Number of Patients with Any Serious Adverse Events [2] 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] A serious adverse event is defined as any untoward medical occurrence at any dose that results in death, life threatening, 
hospitalization, significant disability or congenital anomaly or birth defect. 
Cross-References: Appendix Listing 16.2.7.1 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Use Serious Code > 1. Serious: 1=Not Serious, 2=Results in Death, 3=Life threatening, 4=Hospitalization, 5=Significant 
Disability,6=Congenital Anomaly or Birth Defect, 7=Other Medically Important Event. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Medical writer may take away this table if it is too short. 
 
 
 


 
 
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Table 14.3.2.3 
Patient Listing of Serious Adverse Events 
Safety Evaluable 
(N=n) 
 
Patient 
Age/Sex 
L-DOS47  
Dose Level 
(µg/kg) 
Adverse Event 
(MedDRA Preferred Term) 
Onset 
Cycle/Day[1] 
Last Dose 
to AE 
Onset[2] 
Duration of 
AE[3] 
 Outcome 
[4] 
Action 
[5] 
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
x/xx 
xx 
xx 
x 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ADVERSE EVENT 
x/xx 
xx 
xx 
x 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
x/xx 
xx 
xx 
x 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
x/xx 
xx 
xx 
x 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A serious adverse event is defined as any untoward medical occurrence at any dose that results in death, life threatening, 
hospitalization, significant disability or congenital anomaly or birth defect. 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Duration calculated in days from Onset Date to the Resolution Date. 
[4] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with sequelae, 5=Fatal, 
6=Unknown.      
[5] Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 6 = Dose 
Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued. 
Cross-References: Appendix Listings 16.2.7.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Use Serious Code > 1. Serious: 1=Not serious, 2=Death, 3=Life threatening, 4=Hospitalization, 5=Significant Disability, 6=Congenital 
Anomaly/Birth Defect, 6=Other Medically Important Event. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Medical writer may take away this table if there is no SAE. 
 
 
 


 
 
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Table 14.3.2.4 
Summary of Treatment-Emergent Adverse Events Leading to Treatment Discontinuation by System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
 
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
MedDRA Preferred Term  
 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
 
Number of Patients [1] 
 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
 
Number of Patients with Any Treatment-Emergent Adverse 
Events Leading to Treatment Discontinuation [2] 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
MedDRA Preferred Term 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
MedDRA System Organ Class 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
REPEAT AS NEEDED 
 
 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days 
after the last dose. 
Cross-References: Appendix Listing 16.2.7.1, 16.2.7.2.8 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Use Action Code =9. Action Taken: Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced 
and Interrupted, 6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose 
Discontinued. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
 
 
 


 
 
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Table 14.3.2.5 
Patient Listing of Treatment-Emergent Adverse Events Leading to Treatment Discontinuation 
Safety Evaluable 
(N=n) 
 
Patient 
Age/Sex 
L-DOS47  
Dose 
Level 
(µg/kg) 
Adverse Event 
(MedDRA Preferred Term) 
Onset 
Cycle/Day[1] 
Last Dose 
to 
Onset[2] 
Treatment 
Duration[3] 
Duration 
of AE[4] 
Serious[5]  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
x 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose of study medication to treatment discontinuation. 
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
[5] Serious: 1=Not serious, 2=Death, 3=Life threatening, 4=Hospitalization, 5=Significant Disability, 6=Congenital Anomaly or Birth 
    Defect, 7=Other Medically Important Event.  
Cross-References: Appendix Listings 16.2.7.1, 16.2.7.2.8 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Use Action Code = 9. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and 
Interrupted, 6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose 
Discontinued.  
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
 
 
 


 
 
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Table 14.3.2.6 
Summary of Treatment-Emergent Adverse Events Leading to Death by System Organ Class and Preferred Term 
Safety Evaluable 
(N=n) 
 
MedDRA System Organ Class 
 
  
L-DOS47 Dose Cohort (µg/kg) + 
Pemetrexed/Carboplatin  
 
MedDRA Preferred Term  
   Dose 1 
Repeat 
Overall 
 
 
    
 
 
 
Number of Patients [1] 
   nnn 
nnn 
nnn 
 
 
    
 
 
 
Number of Patients with Any Treatment-Emergent Adverse Events Leading to Death[2]    nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
 
    
 
 
 
MedDRA System Organ Class 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
MedDRA Preferred Term 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
 
    
 
 
 
MedDRA System Organ Class 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
REPEAT AS NEEDED 
   nnn ( xx.x%) nnn ( xx.x%) nnn ( xx.x%)  
 
    
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
[2] Patients with multiple Treatment-Emergent Adverse Events (TEAEs) were only counted once within a summary category: system organ 
class, preferred term, maximum grade, or relationship to treatment. Patients with events in more than one category were counted 
once within each category. TEAEs were defined as all AEs occurring on or after the first study medication date up to 30 days post 
last dose. 
Cross-References: Appendices Listings 16.2.7.1 and 16.2.7.4 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Sort System Organ Class and then Preferred term in descending order using “Overall” frequency column. 
Medical writer may take away this table if it is too short. 
 
 
 


 
 
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Table 14.3.2.7 
Patient Listing of Treatment-Emergent Adverse Events Leading to Death 
Safety Evaluable 
(N=n) 
 
Patient 
Age/Sex 
L-DOS47 Dose 
Level (µg/kg) 
Adverse Event 
(MedDRA Preferred Term) 
 
 
Onset 
Cycle/Day[1] 
Last Dose 
to Death[2] 
Off-Study  
to Death[3] 
Drug Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
 
 
xx/xx 
xx 
xx 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
ADVERSE EVENT 
 
 
xx/xx 
xx 
xx 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
 
 
xx/xx 
xx 
xx 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
ADVERSE EVENT 
 
 
xx/xx 
xx 
xx 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Death calculated in days. 
[3] Off-Study to Death calculated in days. 
Cross-References: Appendices Listings 16.2.7.1 and 16.2.7.4 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Medical writer may take away this table if there is no death. 
 
 
 


 
 
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Table 14.3.2.8 
Patient Listing of Deaths On-Study or Within the 30 Days Follow-up Period 
Safety Evaluable 
(N=n) 
 
Patient 
Age/Sex 
L-DOS47  
Dose Level 
(µg/kg) 
Cause of Death 
Date of 
Death[1] 
Date of 
Last Dose 
Last Dose 
to Death[2] 
Off-Study 
Date 
Off-Study to 
Death[3] 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
Reported Primary Cause of 
Death 
ddmmmyyyy 
ddmmmyyyy xx 
ddmmmyyyy 
xx 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Female 
xxx 
Reported Primary Cause of 
Death 
ddmmmyyyy 
ddmmmyyyy xx 
ddmmmyyyy 
xx 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
Reported Primary Cause of 
Death 
ddmmmyyyy 
ddmmmyyyy xx 
ddmmmyyyy 
xx 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
XX/Male 
xxx 
Reported Primary Cause of 
Death 
ddmmmyyyy 
ddmmmyyyy xx 
ddmmmyyyy 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Includes deaths within 30 days after the Off-Study Date. 
[2] Last Dose to Death calculated in days. 
[3] Off-Study to Death calculated in days.  
Cross-Reference: Appendix Listing 16.2.7.4. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Medical writer may take away this listing if there is no death. 
 
 
 


 
 
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Table 14.3.4.1 
Summary of Shift from Baseline to Maximum CTCAE Grade During Treatment Period for Hematology Tests 
Safety Evaluable 
(N=n)   
 
Hematology Test 
 
Baseline Severity Grade  
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Maximum CTCAE Grade [1][2] 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Overall 
Lab Parameter1 (unit) 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
Grade 0 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 1 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 2 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 3 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 4 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 5 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Overall 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
 
 
 
 
 
 
 
Repeat   
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
Grade 0 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 1 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 2 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 3 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 4 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 5 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Overall 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
 
 
 
 
 
 
 
Lab Parameter2 (unit) 
 
 
 
 
 
 
Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Number of patients with both a baseline evaluation and an on-study evaluation used as denominator to calculate percentages. 
[2] Maximum CTCAE Grade was defined as the highest CTCAE Grade reported for a patient after first dose. 
Cross-References: Appendices Listing 16.2.8.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Grand total used as denominator to calculate percentages within each dose level. 
Hematology Parameters: hemoglobin, hematocrit, WBC, platelets, neutrophils, lymphocytes, Monocytes, Eosinophils, Basophils, etc. 
Coagulation parameter: INR, PT, aPTT. Only gradable parameters are included in the table. 
 
 
 


 
 
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Table 14.3.4.2 
Summary of Shift from Baseline to Maximum CTCAE Grade During Treatment Period for Blood Chemistry Tests 
Safety Evaluable 
(N=n)   
 
Blood Chemistry Test 
 
Baseline Severity Grade 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin  
 
Maximum CTCAE Grade [1][2] 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Overall 
Lab Parameter1 (unit) 
 
 
 
 
 
 
Dose 1 
 
 
 
 
 
 
Grade 0 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 1 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 2 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 3 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 4 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 5 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Overall 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
 
 
 
 
 
 
 
Repeat   
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
Grade 0 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 1 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 2 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 3 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 4 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Grade 5 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
Overall 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
nnn( xx.x%) 
 
 
 
 
 
 
 
Lab Parameter2 (unit) 
 
 
 
 
 
 
Cohort1 
 
 
 
 
 
 
[1] Number of patients with both a baseline evaluation and an on-study evaluation used as denominator to calculate percentages. 
[2] Maximum CTCAE Grade was defined as the highest CTCAE Grade reported for a patient after first dose.   
Cross-References: Appendices Listing 16.2.8.2. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Grand total used as denominator to calculate percentages within each dose level. 
Chemistry Parameters: 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. Only gradable 
parameters are included in the table. 
 
 


 
 
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Table 14.3.4.3 
Summary of Absolute Change from Baseline During Treatment Period for Hematology Tests  
Safety Evaluable  
(N=n) 
 
Hematology Test 
                       L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
Timepoint 
 
 
  Dose 1 
 
  Repeat 
 
  Overall 
 
 
 
 
  Statistics 
 
 
 
Actual 
Change 
 
Actual 
Change 
 
Actual 
Change 
 
 
 
 
 
 
Lab Parameter1 (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
Mean 
 
 
 
xx.x  
 
 
xx.x  
 
 
xx.x  
 
 
 
 
 
 
 
Standard Deviation 
 
 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
 
 
 
 
Median 
 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
 
 
 
 
 
Minimum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
Maximum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
 
Timepoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
nnn 
 
nnn 
nnn 
 
nnn 
nnn 
 
 
 
 
 
 
Mean 
 
  
xx.x  
xx.x  
 
xx.x  
xx.x  
 
xx.x  
xx.x  
 
 
  
 
 
Standard Deviation 
 
xx.xx 
xx.xx 
 
xx.xx 
 xx.xx 
 
xx.xx 
xx.xx 
 
 
Median 
 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
  
 
 
Minimum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
Maximum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
REPEAT TIMEPOINTS AS NEEDED 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Lab Parameter2 (unit) 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Baseline 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Cross-Reference: Appendices Listing 16.2.8.1. 
PROGRAMMER’S NOTES: 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Hematology Parameters: hemoglobin, hematocrit, WBC, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils, bands, 
combined other cells, sum of the differentials and coagulation parameters: PT, aPTT, INR.  
Laboratory data for hematology and coagulation were collected at the following scheduled times: Baseline (last pre-treatment value 
from Day -28 to Day 1); for L-DOS47+Pemetrexed/ Carboplatin at Day 1, 8 of Cycle 1 to 4 and End of Treatment (last non-missing value 
recorded off-study but within 30 days post last dose), or immediately after early termination; for L-DOS47 only at Day 1, 8, 15 of 
Cycle x.  
Absolute Change = Visit Value - Baseline Value. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 


 
 
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Table 14.3.4.4 
Summary of Absolute Change from Baseline During Treatment Period for Blood Chemistry Tests 
Safety Evaluable  
(N=n) 
 
Blood Chemistry Test 
                       L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
Timepoint 
 
 
  Dose 1 
 
  Repeat 
 
  Overall 
 
 
 
 
  Statistics 
 
 
 
Actual 
Change 
 
Actual 
Change 
 
Actual 
Change 
 
 
 
 
 
 
Lab Parameter1 (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
Mean 
 
 
 
xx.x  
 
 
xx.x  
 
 
xx.x  
 
 
 
 
 
 
 
Standard Deviation 
 
 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
 
 
 
 
Median 
 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
 
 
 
 
 
Minimum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
Maximum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
 
Timepoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
nnn 
 
nnn 
nnn 
 
nnn 
nnn 
 
 
 
 
 
 
Mean 
 
  
xx.x  
xx.x  
 
xx.x  
xx.x  
 
xx.x  
xx.x  
 
 
  
 
 
Standard Deviation 
 
xx.xx 
xx.xx 
 
xx.xx 
 xx.xx 
 
xx.xx 
xx.xx 
 
 
Median 
 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
  
 
 
Minimum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
Maximum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
REPEAT TIMEPOINTS AS NEEDED 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Lab Parameter2 (unit) 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Baseline 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Cross-Reference: Appendices Listing 16.2.8.2. 
PROGRAMMER’S NOTES:  
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Chemistry Parameters: 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. 
Laboratory data for clinical chemistry was collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-
DOS47+Pemetrexed/ Carboplatin at Day 1, 8 of Cycle 1 to 4 and End of Treatment (last non-missing value recorded off-study but within 
30 days post last dose), or immediately after early termination; for L-DOS47 only at Day 1, 8, 15 of Cycle x. 
Absolute Change = Visit Value - Baseline Value. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 


 
 
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Table 14.3.4.5 
Summary of Change from Baseline for ‘ECG Parameter (units)’ 
Safety Evaluable 
(N=n)   
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
Time Period 
 
 
Dose 1 
 
Repeat 
 
Overall 
 
 
 
 
Statistics 
 
 
 
Actual 
Change 
 
Actual 
Change 
 
Actual 
Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
Mean 
 
 
 
xx.x  
 
 
xx.x  
 
 
xx.x  
 
 
 
 
 
 
 
Standard Deviation 
 
 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
 
 
 
 
Median 
 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
 
 
 
 
 
Minimum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
Maximum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoint 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
nnn 
 
nnn 
nnn 
 
nnn 
nnn 
 
 
 
 
 
 
Mean 
 
  
xx.x  
xx.x  
 
xx.x  
xx.x  
 
xx.x  
xx.x  
 
 
  
 
 
Standard Deviation 
 
xx.xx 
xx.xx 
 
xx.xx 
 xx.xx 
 
xx.xx 
xx.xx 
 
 
Median 
 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
  
 
 
Minimum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
Maximum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
REPEAT AS NEEDED 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
Overall, Maximum Change 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
N 
 
  
nnn 
nnn 
 
nnn 
nnn 
 
nnn 
nnn 
 
 
  
 
 
Mean 
 
  
xx.x  
xx.x  
 
xx.x  
xx.x  
 
xx.x  
xx.x  
 
 
  
 
 
Standard Deviation 
 
  
xx.xx 
xx.xx 
 
xx.xx 
 xx.xx 
 
xx.xx 
xx.xx 
 
 
  
 
 
Median 
 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
  
 
 
Minimum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
Maximum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cross-References: Appendix Listing 16.2.9.4. 
PROGRAMMER’S NOTES:  
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Five tables to be populated: 
For Y=1, ‘ECG Parameter (units)’= HR (beats/min);  


 
 
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For Y=2, ‘ECG Parameter (units)’= PR (msec);  
For Y=3, ‘ECG Parameter (units)’= QT (msec); 
For Y=4, ‘ECG Parameter (units)’= QTc (msec); 
For Y=5, ‘ECG Parameter (units)’= QRS (msec); 
ECG data was collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-DOS47+Pemetrexed/Carboplatin at Day 1, 8 of 
Cycle 1 to 4; and End of Treatment (last non-missing value recorded off-study but within 30 days post last dose), or immediately after 
early termination; for L-DOS47 only at Day 1, 8, 15 of Cycle x. 
Absolute Change = Visit Value - Baseline Value. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Table 14.3.4.6 
Categorical Summary of ‘QT/QTc Parameter’ Interval 
Safety Evaluable 
 (N=n)   
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
 
 
Dose 1 
 
Repeat 
 
Overall 
 
 
 
 
‘QT/QTc Parameter’[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval <=450 msec 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Interval >450 msec 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Interval >480 msec 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
Interval >500 msec 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoint 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval <=450 msec 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Interval >450 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Interval >480 msec 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
Interval >500 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
REPEAT AS NEEDED 
 
  
 
  
 
  
 
  
 
  
 
 
 
 
  
 
  
 
  
 
  
 
  
 
 
Overall, Maximum Interval 
 
  
 
  
 
  
 
  
 
  
 
 
Interval <=450 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Interval >450 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Interval >480 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Interval >500 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
Cross-References: Appendix Listing 16.2.9.4. 
PROGRAMMER’S NOTES: Two tables to be populated: 
For Y=1, ‘QT/QTc Parameter’= QT.  
For Y=2, ‘QT/QTc Parameter’= QTc. 
QT, QTc data was collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-DOS47+Pemetrexed/Carboplatin at Day 1, 
8 of Cycle 1 to 4; and End of Treatment (last non-missing value recorded off-study but within 30 days post last dose), or immediately 
after early termination; for L-DOS47 only at Day 1, 8, 15 of Cycle x. 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Table 14.3.4.7 
Categorical Summary of ‘QT/QTc Parameter’ Interval Change from Baseline 
Safety Evaluable 
 (N=n)   
 
Interval Change from Baseline 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
 
 
Dose 1 
 
Repeat 
 
Overall 
 
 
 
 
‘QT/QTc Parameter’[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Timepoint 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interval Increase <= 30 msec 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Interval Increase > 30 msec 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Interval Increase > 60 msec 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
REPEAT AS NEEDED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall, Maximum Increase 
 
 
 
 
 
 
 
 
Interval Increase <= 30 msec 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
Interval Increase > 30 msec 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
Interval Increase > 60 msec 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
Cross-References: Appendix Listing 16.2.9.4. 
PROGRAMMER’S NOTES:  
Two tables to be populated: 
For Y=1, ‘QT/QTc Parameter’= QT.  
For Y=2, ‘QT/QTc Parameter’= QTc.  
QT, QTc data was collected at Baseline (last pre-treatment value from Day -28 to Day 1); for L-DOS47+Pemetrexed/Carboplatin at Day 1, 
8 of Cycle 1 to 4; and End of Treatment (last non-missing value recorded off-study but within 30 days post last dose), or immediately 
after early termination; for L-DOS47 only at Day 1, 8, 15 of Cycle x. 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Table 14.3.5.1 
Summary of Shift from Baseline to Maximum ECOG Performance Status Score 
Safety Evaluable 
(N=n) 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
Baseline Performance Status (ECOG) 
 
Maximum Score [1][2] 
 
Score 0 
Score 1 
 
 
 
Overall 
 
 
 
 
 
 
 
 
Dose 1 
 
 
 
 
 
 
 
Score 0 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 1 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 2 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 3 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 4 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 5 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Overall 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn (100.0%) 
 
 
 
 
 
 
 
 
Repeat 
 
 
 
 
 
 
 
Score 0 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 1 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 2 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 3 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 4 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 5 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Overall 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn (100.0%) 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
 
 
Score 0 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 1 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 2 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 3 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 4 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Score 5 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn ( xx.x%) 
Overall 
 
nnn ( xx.x%) 
nnn ( xx.x%) 
 
 
 
nnn (100.0%) 
[1] Number of patients with both a baseline evaluation and an on-study evaluation used as denominator to calculate percentages. 
[2] Maximum Score was the highest ECOG Performance Status for a patient after first dose. 
Cross-References: Appendix Listing 16.2.9.3.  
PROGRAMMER’S NOTES: 
Grand total used as denominator to calculate percentages within each dose level. 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
 
 
 


 
 
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Table 14.3.6.1  
Summary of Anti-L-DOS47 Antibodies 
Safety Evaluable 
 (N=n)   
 
 
L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
 
 
Dose 1 
 
Repeat 
 
Overall 
 
 
 
 
Visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 1 (Baseline) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Positive 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
Negative 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
 
  
 
 
Inconclusive 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
 
 
 
 
 
 
 
 
 
 
Positive 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
Negative 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
 
 
Inconclusive 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
Positive 
 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
nnn ( xx.x%) 
 
 
Negative 
 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
  
nnn ( xx.x%) 
 
 
Inconclusive 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
nnn ( xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Number of Patients used as denominator to calculate percentages. 
Cross-References: Appendix Listing 16.2.9.5 
PROGRAMMER’S NOTES:  
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 (Cycle 5 and beyond, Day 1 (predose), at the end of treatment or 
early termination visit, and at the follow-up visit (30 days post last dose). 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Present this table only data is available. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Table 14.3.6.2 
Summary of Titer Values of Anti-L-DOS47 Antibodies 
Safety Evaluable 
(N=n) 
 
 
 
 
L-DOS47 Dose Cohort(µg/kg)+ Pemetrexed/Carboplatin  
 
Visit 
 
 
Dose 1 
Repeat 
Overall 
 
 
 
 
 
 
 
 
Number of Patients 
 
 
nnn 
nnn 
nnn 
 
 
 
 
 
 
 
 
Cycle 1 Day 1 (Baseline) 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
 
 
 
 
 
 
N 
 
 
nnn 
nnn 
nnn 
 
Median 
 
 
xx.x 
xx.x 
xx.x 
 
Minimum 
 
 
xx 
xx 
xx 
 
Maximum 
 
 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
<Repeat for all available visits> 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Only present anti-L-DOS47 antibodies that confirmed positive. Title values listed as ‘<5’ are screened negative for binding 
antibodies. 
Cross-Reference: Appendix Listings 16.2.9.5 
PROGRAMMER’S NOTES: 
 
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 post last dose). 
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Present this table only data is available. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Table 14.3.6.3 
Change from Baseline of Tumour Antigen CEACAM6 
Safety Evaluable 
 (N=n) 
 
 
                       L-DOS47 Dose Cohort (µg/kg) + Pemetrexed/Carboplatin 
 
 
Timepoint 
 
 
  Dose 1 
 
  Repeat 
 
  Overall 
 
 
 
 
  Statistics 
 
 
 
Actual 
Change 
 
Actual 
Change 
 
Actual 
Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 predose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
 
 
nnn 
 
 
nnn 
 
 
 
 
 
 
 
Mean 
 
 
 
xx.x  
 
 
xx.x  
 
 
xx.x  
 
 
 
 
 
 
 
Standard Deviation 
 
 
xx.xx 
 
 
xx.xx 
 
 
xx.xx 
 
 
 
 
 
Median 
 
 
 
xx.x 
 
 
xx.x 
 
 
xx.x 
 
 
 
 
 
 
 
Minimum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
Maximum 
 
 
 
xx 
 
 
xx 
 
 
xx 
 
 
 
 
 
 
 
 
Cycle 4 Day 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
 
 
nnn 
nnn 
 
nnn 
nnn 
 
nnn 
nnn 
 
 
 
 
 
 
Mean 
 
  
xx.x  
xx.x  
 
xx.x  
xx.x  
 
xx.x  
xx.x  
 
 
  
 
 
Standard Deviation 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
xx.xx 
xx.xx 
 
 
Median 
 
  
xx.x 
xx.x 
 
xx.x 
xx.x 
 
xx.x 
xx.x 
 
 
  
 
 
Minimum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
Maximum 
 
  
xx 
xx 
 
xx 
xx 
 
xx 
xx 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
<Repeat for all available visits> 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Cross-Reference: Appendices Listing 16.2.9.6 
PROGRAMMER’S NOTES:  
Tumor antigen (CEACAM6= carcinoembryonic antigen related cell adhesion molecule 6) 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)  
L-DOS47 Dose cohorts = 0.59, 0.78, 1.5/3.0/6.0, 9.0, 12.0 µg/kg. Combine 1.5/3.0/6.0 in one column as only 1 subject is in each of the 
3 dose levels. 
Present this table only if data is available. 
Use protocol specified time windows in protocol Table 10 Schedule of study evaluation. 
 
 
 


 
 
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Appendix 16.2.1.1 
Inclusion/Exclusion Criteria 
All Enrolled (N=n)   
 
Patient 
L-DOS47 Dose Level 
(µg/kg) 
Eligible 
Protocol      
Version Date 
Category 
Identifier 
Waiver Number 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
No 
ddmmmyyyy 
Inclusion  
xx 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
No 
ddmmmyyyy 
Exclusion 
xx 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
No, Waiver 
ddmmmyyyy 
Inclusion  
xx 
xxxx 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
ccc-ppp 
xxx 
Yes 
ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: waivers no longer granted after eCRF update post-March 2018 Helix audit. 
Cross-References: Case Report Form INCLUSION/EXCLUSION CRITERIA (IE) 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
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Appendix 16.2.1.2 
 Patient Disposition 
  All Enrolled (N=n) 
 
Patient 
L-DOS47 Dose 
Level(µg/kg) 
Date Off-Study 
Day[1] 
Reason 
ITT 
Safety Evaluable 
 
Efficacy Evaluable  
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Progressive Disease    Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
No 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Progressive Disease    Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Other:Specify 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
No 
 
No 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Other:Specify 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Reason 
Yes 
Yes 
 
Yes 
 
ccc-ppp 
xxx 
ddmmmyyyy 
xxx 
Other:Specify 
Yes 
Yes 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Day relative to first dose. 
Cross-References: Case Report Form Off-Study Summary (OF). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.1 
Demographic and Disease-Related Characteristics  
Intent-to-Treat (N=n)   
 
 
 
 
 
 
 
 
 
Patient 
L-DOS47 Dose  
Level(µg/kg) 
 Sex 
Date of Birth 
Age (years) 
Race 
Ethnicity 
ICF/Registration Date 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Race 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
ccc-ppp 
xxx 
Gender 
ddmmmyyyy 
xx 
Other/Specify 
Ethnicity 
ddmmmyyyy/ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cross-References: Case Report Form DEMOGRAPHICS (DM). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.1 
Demographic and Disease-Related Characteristics  
Intent-to-Treat (N=n)   
 
 
L-DOS47 Dose  
 
 
Histopathology 
Initial 
Diagnosis 
Duration 
of Disease 
 
Patient 
Level (µg/kg) 
 
 
(Behavior Classification)[1] 
Date 
(months) 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
ccc-ppp 
xxx 
 
 
Histopathology Reported 
ddmmmyyyy 
xxx.x 
 
 
 
 
 
(Histopathology Classification) 
 
 
 
 
 
 
 
 
 
 
 
[1] ICD-O version 3. 
Cross-References: Case Report Form DEMOGRAPHICS (DM). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.2 
Prior Cancer Therapy 
Intent-to-Treat (N=n)   
 
 
L-DOS47 Dose Level 
Regimen 
 
Prior Therapy  
Start 
Stop 
Stop  
Best  
Patient 
(µg/kg) 
Number 
Agent/Treatment 
Type 
Date 
Date 
Day[1] 
Response 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
 
NO PRIOR THERAPY 
 
 
 
 
 
 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
ccc-ppp 
xxx 
x 
Prior Therapy Name 
Type 
ddmmmyyyy 
ddmmmyyyy 
-xx 
 
Response 
 
 
 
 
 
 
 
 
 
 
[1] Day relative to the first dose of study medication or ongoing. 
Cross-References: Case Report Form PRIOR CANCER THERAPY (PT). 
PROGRAMMER’S NOTES: 
Prior Therapy Type includes: Chemotherapy, Hormonal Therapy, Immunotherapy, and Other. 
Best Response includes: Complete Response, Partial Response, Stable Disease, Progressive Disease, Unknown, and Not Applicable.  
When “No Prior Therapy” is indicated, enter “NO PRIOR THERAPY” in the ‘Agent/Treatment’ column. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.3 
Prior Cancer Radiation 
Intent-to-Treat (N=n) 
 
 
L-DOS47 Dose Level 
 
Start 
Stop 
Stop Day 
    
 
Patient 
(µg/kg) 
Site 
Date 
Date 
[1] 
   Best Response 
 
 
 
 
 
 
 
    
 
ccc-ppp 
xxx 
NO PRIOR RADIATION 
 
 
 
    
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
ccc-ppp 
xxx 
Reported Site 
ddmmmyyyy 
ddmmmyyyy 
-xx 
   Response 
 
 
 
 
 
 
 
    
 
[1] Day relative to the first dose of study medication or ongoing. 
Cross-References: Case Report Form PRIOR CANCER RADIATION (PR). 
 
PROGRAMMER’S NOTES: 
When “No Prior Radiation” is indicated, enter “NO PRIOR RADIATION” in the ‘Site’ column. 
Best Response includes: Complete Response, Partial Response, Stable Disease, Progressive Disease, Unknown, and Not Applicable 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.4 
Prior Cancer Surgeries 
Intent-to-Treat (N=n)   
 
 
L-DOS47 Dose Level  
 
 
Procedure 
Day 
 
 
Patient 
(µg/kg) 
Procedure (including site) 
 
Date 
[1] 
Findings (Pathology/Cytology) 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
ccc-ppp 
xxx 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
Procedure Reported and Site 
 
ddmmmyyyy 
xx 
Description of Findings 
 
 
 
 
 
 
 
 
 
[1] Day relative to the first dose of study medication or ongoing. 
Cross-References: Case Report Form  PRIOR CANCER SURGERIES (SG). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Procedure Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.4.5 
Medical History/Baseline Symptoms 
Intent-to-Treat (N=n) 
 
 
 
 
 
   
 
  
 
 
 
   
 
 
 
Condition 
   
 
  
 
 
 
   
Patient 
L-DOS47 Dose 
Date 
 
(Preferred Term) 
   
 
   
Related to 
Therapy    
 
Level (µg/kg) 
Obtained 
Day[1] 
(System Organ Class)[2] 
   Ongoing   Grade 
Study Disease 
Given 
   
 
 
 
   
 
   
 
 
   
ccc-ppp 
 
xxx 
ddmmmyyyy -xx 
Condition 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
   
No 
  Mild 
No 
xxx 
   
 
 
 
 
   
 
   
 
 
   
 
 
 
Condition 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
   
No 
  Moderate 
No 
xxx 
   
 
 
 
 
   
 
   
 
 
   
 
 
 
 
   
 
   
 
 
   
ccc-ppp 
 
xxx 
ddmmmyyyy -xx 
Condition 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
   
Yes 
  Mild 
No 
xxx 
   
 
 
 
   
 
  
 
 
 
   
[1] Day relative to the first dose of study medication or ongoing. 
[2] MedDRA Version 17.1 
Cross-References: Case Report Form MEDICAL HISTORY (MH). 
PROGRAMMER’S NOTES: 
Grade: 1=Mild, 2=Moderate, 3=Severe, Not Applicable, Unknown. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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Appendix 16.2.4.6 
Pregnancy Test  
Intent-to-Treat (N=n)   
 
 
L-DOS47 Dose 
 
Sample 
Cycle/Day 
  
 
 
Patient 
Level (µg/kg) 
Method 
Date 
[1] 
  
Result 
Reason Not Done 
 
 
 
 
 
   
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
ddmmmyyyy 
x/xx 
  
Negative 
 
ccc-ppp 
xxx 
xxx 
NOT PERFORMED 
 
  
 
Post-Menopausal 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
[1] Day relative to the first dose of study medication. 
Cross-References: Case Report Form PREGNANCY (TP). 
PROGRAMMER’S NOTES: 
If Pregnancy Test is not performed, enter “NOT PERFORMED” in the ‘Sample Date’ column. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.5.1.1  
L-DOS47 Administration  
Safety Evaluable (N=n)   
 
 
  
  
 
 Dose 
 
 
 
 
 
 
 
 
    
 
  
Start 
Day  Start Time  Level 
 Lot  Total Dose 
 Dose 
Dose 
Dose 
 
    
Patient 
 Cycle Date 
[1]  /Stop Time  (µg/kg)  No.  Dose Modified  Reduced:Reason Delayed:Reason Interrupted:Reason      
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
   
ccc-ppp 
 x 
Ddmmmyyyy 
 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
 x 
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
ccc-ppp 
 x 
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
 x 
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
  
[1] On-Study day relative to first dose within cycle. 
Cross-Reference: Case Report Form L-DOS47 EXPOSURE (EX). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
LDOS001 
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Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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Appendix 16.2.5.1.2  
Carboplatin Administration  
Safety Evaluable (N=n)   
 
 
  
  
 
 Dose 
 
 
 
 
 
 
 
 
    
 
  
Start 
Day  Start Time  Level 
 Lot  Total  
 Dose 
Dose 
Dose 
 
    
Patient 
 Cycle Date 
[1]  /Stop Time  (AUC6 
mg/mL) 
 No.  Dose Dose 
Modified 
 Reduced:Reason Delayed:Reason Interrupted:Reason      
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
   
ccc-ppp 
 x 
Ddmmmyyyy 
 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
 x 
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
ccc-ppp 
 x 
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
 x 
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
  
[1] On-Study day relative to first dose within cycle. 
Cross-Reference: Case Report Form Carboplatin EXPOSURE (EX1). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.5.1.3  
Pemetrexed Administration  
Safety Evaluable (N=n)   
 
 
  
  
 
 Dose 
 
 
 
 
 
 
 
 
    
 
  
Start 
Day  Start Time  Level 
 Lot   
 
 Dose 
Dose 
Dose 
 
    
Patient 
 Cycle Date 
[1]  /Stop Time  (mg/m2)  No.   
Dose 
Modified 
 Reduced:Reason Delayed:Reason Interrupted:Reason      
 
  
 
 
 
 
  
  
 
 
 
  
 
 
 
   
ccc-ppp 
 x 
Ddmmmyyyy 
 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
 x 
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
ccc-ppp 
 x 
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
  
 
 
  
  
  
  
 
  
 
 
 
 
  
 
  
Ddmmmyyyy 
xx 
 HH:MM/HH:MM  xxx 
 xx  xxx 
xxx 
 xxx:xxx 
xxx:xxx 
xxx:xxx 
 
 
  
 
 
 
 
 
  
  
  
  
 
 
 
 
 
 
 
  
[1] On-Study day relative to first dose within cycle. 
Cross-Reference: Case Report Form Pemetrexed EXPOSURE (EX2). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.5.2 
Pharmacokinetic Sampling: Blood  
Safety Evaluable (N=n)   
 
 
Dose Level 
  
 
 
     Sample 
Sample 
Collection 
Patient 
(µg/kg) 
 Cycle 
Day  Planned Time Point 
    Date 
Time 
Status 
 
 
  
 
 
      
 
 
ccc-ppp 
xxx 
 1 
1 
Pre-dose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
End of L-DOS47 infusion  
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
15 min after SOI 
     ddmmmyyyy 
hh:mm 
Not collected 
 
 
  
 
30 min after SOI 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
45 min Postdose 
      
 
 
 
 
  
 
1 hr Postdose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
1.5 hrs Postdose 
      
 
 
 
 
  
 
2 hrs Postdose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
3 hrs Postdose 
      
 
 
 
 
  
 
4 hrs Postdose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
6 hrs Postdose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
24 hrs Postdose 
      
 
 
 
 
  
 
48 hrs Postdose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
 
      
 
 
 
 
 1 
8 
Pre-dose 
     ddmmmyyyy 
hh:mm 
Collected 
 
 
  
 
 
      
 
 
 
 
  
 
 
      
 
 
 
 
  
 
 
      
 
 
 
 
  
 
 
      
 
 
 
 
  
 
 
      
 
 
 
Cross-References: Case Report Forms  PHARMACOKINETICS (PK, PK1, PK2) 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Sample Date” in ascending order within “Patient”. 
Sort “Sample Time” in ascending order within “Sample Date”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.6.1 
Extent of Disease: Target and Non-Target Lesions  
Intent-to-Treat (N=n)   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
Dose Level  
 
Date of 
Day Lesion 
Lesion 
 Organ 
Primary 
 
   
Patient 
(ug/kg) 
Cycle 
Procedure 
[1] Type 
Number 
  
Site 
Procedure 
   
 
 
 
 
 
 
 
  
 
 
   
ccc-ppp 
xxx 
Baseline 
ddmmmyyyy 
-xx Target 
x 
 Other: Specify 
 
xxxx 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
xxxx 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
xxxx 
   
 
 
 
 
 
 
 
  
 
xxxx 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
 
 
  
 
 
   
 
 
x 
ddmmmyyyy 
xx 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
 
 
  
 
 
   
 
 
End-Study 
ddmmmyyyy 
xx 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
Target 
x 
 Reported Organ 
 
 
   
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
Non-Target 
x 
 Reported Organ 
xxxx 
 
   
 
 
 
 
 
 
 
 
 
 
 
   
[1] Baseline day relative to the first dose; On-Study day relative to first dose within cycle; End-Study day relative to last dose. 
Cross-References: Case Report Forms TARGET LESION ASSESSMENT (BT, XT), NON-TARGET LESION ASSESSMENT (BN, XN), NEW LESIONS (NL).       
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portions of patient number. 
Sort “Date” in ascending order within “Patient”. 
Sort “Lesion Type” in descending order within “Date”. 
Sort “Lesion Number” in ascending order within “Lesion Type”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.6.1 
Extent of Disease: Target and Non-Target Lesions  
Intent-to-Treat (N=n)   
 
 
L-DOS47 
 
 
 
 
 
 
Previous 
 
    
 
Dose Level  
 
Date of 
Day Lesion 
Lesion 
Anatomical 
RT 
Progression 
    
Patient 
(µg/kg) 
Cycle 
Performed 
[1] Type 
Number 
Location 
to Lesion 
Since RT? 
    
 
 
 
 
 
 
 
Location 
 
 
    
ccc-ppp 
xxx 
Baseline 
ddmmmyyyy 
xx 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
 
No 
 
    
 
 
 
 
 
 
 
Location 
 
 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
Non-Target 
x 
 
Yes 
xx 
    
 
 
 
 
 
 
 
Location 
 
 
    
 
 
x 
ddmmmyyyy 
xx 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
 
No 
 
    
 
 
 
 
 
 
 
Location 
 
 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
Non-Target 
x 
 
Yes 
xx 
    
 
 
 
 
 
 
 
Location 
 
 
    
 
 
End-Study 
ddmmmyyyy 
xx 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
Location 
No 
 
    
 
 
 
 
 
Target 
x 
 
No 
 
    
 
 
 
 
 
 
 
Location 
 
 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
Non-Target 
x 
Location 
Yes 
xx 
    
 
 
 
 
 
 
 
 
 
 
    
[1] Baseline day relative to the first dose; On-Study day relative to first dose within cycle; End-Study day relative to last dose. 
Cross-References: Case Report Forms TARGET LESION ASSESSMENT (BT, XT), NON-TARGET LESION ASSESSMENT (BN, XN), NEW LESIONS (NL).         
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portions of patient number. 
Sort “Date” in ascending order within “Patient”. 
Sort “Lesion Type” in descending order within “Date”. 
Sort “Lesion Number” in ascending order within “Lesion Type”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Page 
 
Appendix 16.2.6.1 
Extent of Disease: Target and Non-Target Lesions 
Intent-to-Treat (N=n)   
 
 
L-DOS47 
 
 
 
 
 
RECIST 
 
 
Non-Target 
   
 
Dose Level  
 
Date of 
Day Lesion 
Lesion 
Measurement 
Total 
Lesion 
Lesion 
  
Patien
t 
(µg/kg) 
Cycle 
Performed 
[1] Type 
Number 
(mm) 
Sum(mm) Assessable 
Evaluation 
  
 
 
 
 
 
 
 
 
 
 
 
   
ccc-
ppp 
xxx 
Baseline 
ddmmmyyyy 
-xx Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
  
 
 
xx 
 
 
  
 
 
 
 
 Non-Target x 
 
 
 
Present 
  
 
 
 
 
 Non-Target x 
 
 
 
Absent 
  
 
 
 
 
 New Lesion x 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
x 
ddmmmyyyy 
xx Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
  
 
 
xx 
 
 
  
 
 
 
 
 Non-Target x 
 
 
 
 
  
 
 
 
 
 Non-Target x 
 
 
 
Present 
  
 
 
 
 
 Non-Target x 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
End-Study 
ddmmmyyyy 
xx Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
xx 
 
Yes 
 
  
 
 
 
 
 Target 
x 
Not Assessable 
 
Yes 
 
  
 
 
 
 
  
 
 
xx 
 
 
  
 
 
 
 
 Non-Target x 
 
 
 
Present 
  
 
 
 
 
 Non-Target x 
 
 
 
Present 
  
 
 
 
 
 
 
 
 
 
 
 
  
[1] Baseline day relative to the first dose; On-Study day relative to first dose within cycle; End-Study day relative to last dose. 
Cross-References: Case Report Forms TARGET LESION ASSESSMENT (BT, XT), NON-TARGET LESION ASSESSMENT (BN, XN), NEW LESIONS (NL). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portions of patient number. 
Sort “Date” in ascending order within “Patient”. 
Sort “Lesion Type” in descending order within “Date”. 
Sort “Lesion Number” in ascending order within “Lesion Type”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 


 
 
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Appendix 16.2.6.2 
Cycle Response Assessment  
Intent-to-Treat (N=n) 
 
 
L-DOS47 
 
 
 
 
 
 
 
 
 
Dose Level 
 
Date of 
Day Target Lesion 
Non-Target 
New  
Symptomatic 
Deterioration Overall Response 
Patient (µg/kg) 
Cycle 
Procedure [1] Response 
Lesion Response[2] Lesions Deterioration Date 
For This Cycle 
 
 
 
 
  
 
 
 
 
 
ccc-ppp xxx 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
 
 
End-Study ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
ccc-ppp xxx 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
Yes 
ddmmmyyyy 
Stable Disease 
 
 
x 
ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
 
 
End-Study ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
ccc-ppp xxx 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
End-Study ddmmmyyyy xx Progression 
Progression 
No 
No 
 
Progression 
ccc-ppp xxx 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Stable Disease 
NON-CR/NON-PD 
No 
No 
 
Stable Disease 
 
 
x 
ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
 
 
End-Study ddmmmyyyy xx Complete Response Complete Response 
No 
No 
 
Complete Response 
 
 
 
 
 
 
 
 
 
 
 
[1] On-Study day relative to first dose within cycle; End-Study day relative to last dose. 
[2] NON-CR/NON-PD=Neither complete response nor disease progression 
Cross-References: Case Report Form CYCLE RESPONSE ASSESSMENT (RS). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portions of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.6.3 
Patient Listing for Duration of Clinical Benefit (CR or PR or SD) 
Intent-to-Treat (N=n) 
 
Patien
t 
/Age/S
ex 
L-DOS47 
Dose 
Level(µg/k
g) 
Date of 
First Dose 
Date of 
First CR[1] 
Date of 
First PR[1] 
Date of SD[1] 
Date of 
Progression (PD) 
Date of 
Censoring 
Duration of 
Clinical 
Benefit (day) [2] 
 
 
 
 
 
 
 
 
 
ccc-
ppp 
xx/x 
xx 
ddmmmyyyy 
ddmmmyyyy 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
ccc-
ppp 
xx/x 
xx 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
ccc-
ppp 
xx/x 
xx 
ddmmmyyyy 
 
 
ddmmmyyyy 
ddmmmyyyy 
 
xxx 
 
 
 
 
 
 
 
 
 
ccc-
ppp 
xx/x 
xx 
ddmmmyyyy 
 
ddmmmyyyy 
 
 
ddmmmyyyy 
xxx 
 
 
 
 
 
 
 
 
 
ccc-
ppp 
xx/x 
xx 
ddmmmyyyy 
ddmmmyyyy 
 
 
 
 
xxx 
 
 
 
 
 
 
 
 
 
[1] CR = complete response, PR = partial response, SD= stable disease 
[2] Duration of Clinical Benefit is calculated from date of first (CR or PR or SD) to first date of recurrence or objectively 
documented PD (not including symptomatic deterioration) or death due to any cause. For a patient without evidence of objective disease 
progression or death, duration of clinical benefit will be censored at the date of the last evaluable tumor assessment. Only patients 
with a SD or confirmed CR or PR are included in the analysis. 
Cross-Reference:  Case Report Forms: RECIST Cycle Response Assessment (RS) 
PROGRAMMER’S NOTES: 
Data used in the SAS Life Table procedure. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portions of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
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Appendix 16.2.7.1 
Adverse Events 
Safety Evaluable (N=n) 
 
 
L-DOS47 
 Adverse Event 
 
 
Onset 
 
  
 
 
 
 
 
 
Patient Dose Level  (MedDRA Preferred Term) 
 
Onset/ Resolved 
Therapy   Maximum 
Serious 
Drug 
 Action Outcome 
 
(µg/kg) 
 (MedDRA System Organ Class)[1] 
DLT Day[2] Dates 
Given   Grade 
[3] 
Related  [4] 
[5] 
 
 
 
 
 
 
 
   
 
 
 
 
 
ccc-ppp 
 
xxx 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
No xx/xx 
ddmmmyyyy 
ddmmmyyyy 
No 
  Mild 
x 
Probable  x 
x 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
Yes xx/xx 
ddmmmyyyy 
ongoing 
No 
  Moderate 
x 
Probable  x 
x 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
  
 
 
 
 
   
 
 
  
 
ccc-ppp 
 
xxx 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
No xx/xx 
 
ddmmmyyyy 
Yes 
  Mild 
x 
Possible  x 
x 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
[1] MedDRA Version 17.1. 
[2] On-Study day relative to first dose. 
[3] Serious: 1=Not Serious, 2=Results in Death, 3=Life threatening, 4=Hospitalization, 5=Significant Disability,                 
             6=Congenital Anomaly or Birth Defect, 7=Other Medically Important Event. 
[4] Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 6 = Dose  
    Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued. 
[5] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with sequelae, 5=Fatal, 
    6=Unknown. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Maximum Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
Drug Relationship: 1=Unrelated, 2=Unlikely, 3=Possible, 4=Probable, 5=Definite. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Onset Date” in ascending order within “Patient”.  
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
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Appendix 16.2.7.2.1 
Treatment-Emergent Adverse Events Leading to Dose Reduction  
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration 
of AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =2. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.2 
Treatment-Emergent Adverse Events Leading to Dose Interruption  
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 Dose 
Level (µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
xx/xx 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =3. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.3 
Treatment-Emergent Adverse Events Leading to Dose Delay 
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =4. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.4 
Treatment-Emergent Adverse Events Leading to Dose Reduction and Interruption 
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =5. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.5 
Treatment-Emergent Adverse Events Leading to Dose Delay and Reduction 
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =6. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.6 
Treatment-Emergent Adverse Events Leading to Dose Delay and Interruption 
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =7. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.7 
Treatment-Emergent Adverse Events Leading to Dose Delay, Reduction and Interruption 
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =8. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.2.8 
Treatment-Emergent Adverse Events Leading to Dose Discontinuation  
Safety Evaluable 
(N=n) 
 
Patient 
 
L-DOS47 
Dose Level 
(µg/kg)  
Adverse Event 
(MedDRA Preferred Term) 
Onset/Day 
[1] 
Last 
Dose 
to Onset 
[2] 
Treatment 
Duration 
[3] 
Duration of 
AE 
[4] 
Serious  
Drug 
Relationship 
 
 
 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
Yes 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
ccc-ppp 
 
xxx 
ADVERSE EVENT 
xx/xx 
xx 
xx 
xx 
No 
Relationship 
 
 
(MedDRA Preferred Term) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Onset day relative to first dose. 
[2] Last Dose to Onset calculated in days. 
[3] Treatment Duration calculated from first dose to treatment discontinuation.  
[4] Duration of Adverse Event calculated in days from the Onset Date to the Resolution Date. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Use Action Code =9. Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 
6 = Dose Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued.    
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.3 
Patients With Incomplete Adverse Event Information Excluded From Summary Tables 
Safety Evaluable (N=n) 
 
 
 
  
  
 
 
  
 
 
 
 
 
 
 
L-DOS47 
 Adverse Event 
  
Onset 
 
  
 
 
 
 
 
 
Patient Dose Level  (MedDRA Preferred Term) 
 Onset/Day Resolved 
Therapy   Maximum Serious 
Drug 
 Action Outcome 
 
(µg/kg) 
 (MedDRA System Organ Class)[1] 
DLT [2] 
Dates 
Given   Grade 
[3] 
Relationship  [4] 
[5] 
 
 
 
 
 
 
 
   
 
 
 
 
 
ccc-ppp 
 
xxx 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
No xx/xx 
ddmmmyyyy 
ddmmmyyyy 
No 
  Mild 
x 
 
 x 
x 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
Yes xx/xx 
ddmmmyyyy 
ongoing 
No 
  Moderate 
x 
Probable 
  
 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
  
 
xx/xx 
 
 
   
 
 
  
 
ccc-ppp 
 
xxx 
 ADVERSE EVENT 
(MedDRA Preferred Term) 
(MedDRA System Organ Class) 
No  
 
ddmmmyyyy 
Yes 
  Mild 
x 
 
  
x 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
[1] MedDRA Version 17.1. 
[2] On-Study day relative to first dose. 
[3] Serious: 1=Not Serious, 2=Results in Death, 3=Life threatening, 4=Hospitalization, 5=Significant Disability,6=Congenital Anomaly 
    or Birth Defect, 7=Other Medically Important Event. 
[4] Action Taken: 1 = None, 2 = Dose Reduced, 3 = Dose Interrupted, 4= Dose Delayed, 5 = Dose Reduced and Interrupted, 6 = Dose  
    Delayed and Reduced, 7 = Dose Delayed and Interrupted, 8 = Dose Delayed, Reduced, Interrupted, 9 = Dose Discontinued. 
[5] Outcome: 1=Recovered/Resolved, 2=Recovering/Resolving, 3=Not Recovered/Not Resolved, 4=Recovered/Resolved with sequelae, 5=Fatal,  
    6=Unknown. 
Cross-References: Case Report Form ADVERSE EVENTS (AE). 
PROGRAMMER’S NOTES: 
Maximum Grade: 1=Mild, 2=Moderate, 3=Severe, 4=Life threatening, 5=Fatal. 
Drug Relationship: 1=Unrelated, 2=Unlikely, 3=Possible, 4=Probable, 5=Definite. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Onset Date” in ascending order within “Patient”.  
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.4 
Death Summary  
Safety Evaluable (N=n)   
 
 
L-DOS47 Dose 
Date of 
 
    
Patient 
Level (µg/kg) 
Death 
Primary Cause of Death 
    
 
 
 
 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
ccc-ppp 
xxx 
ddmmmyyyy 
Cause of Death Reported on CRF 
    
 
 
 
 
    
 
 
 
 
    
 
 
 
 
    
 
Cross-References: Case Report Form DEATH SUMMARY (DS).  
PROGRAMMER’S NOTES: 
Present for every death record in the database. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.7.4 
Death Summary  
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
 
Treatment  
First Dose 
Last Dose 
Off-Study 
    
 
Dose Level  
Date of 
Date of 
Date of 
Date of 
Duration 
to Death 
to Death 
to Death 
    
Patient 
(µg/kg) 
Death 
First Dose 
Last Dose 
Off-Study 
[1] 
(days) 
(days) 
(days) 
    
 
 
 
 
 
 
 
 
 
 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
ccc-ppp 
xxx 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
xx 
xx 
    
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
    
[1] Treatment duration calculated from the first dose of study medication to treatment discontinuation. 
Cross-References: Case Report Forms DEATH SUMMARY (DS), L-DOS47 EXPOSURE (EX), OFF-STUDY SUMMARY (OF).  
PROGRAMMER’S NOTES: 
Present for every death record in the database. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.8.1 
Clinical Laboratory Tests - Hematolog 
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Level  
Sample 
Sample 
Day Lab 
Laboratory Test 1[2] 
 
Laboratory Test 2[2] 
Patient 
(µg/kg) 
Cycle/Day 
Date 
Time 
[1] Code Results 
Normal Range 
Units 
 Results 
Normal Range 
Units  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm 
-xx 
xxxx xx.x H G1  
xx.x - xx.x 
unit  xx.x H G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm 
-xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x L G1  
xx.x - xx.x 
unit  xx.x L G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study day relative to the first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last 
dose. 
[2] Reported Result: H = High (Above Normal Range), L = Low (Below Normal Range); Calculated CTCAE 4.0 Grade 1 to 4. 
Cross-References: Case Report Form HEMATOLOGY (HM). 
PROGRAMMER’S NOTES: 
Repeat page as required.  
Include following Hematology Tests: hemoglobin, hematocrit, WBC, platelets, neutrophils, lymphocytes, monocytes, eosinophils, 
basophils, bands, combined other cells, sum of the differentials. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date” in ascending order within “Patient”. 
 L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Page 1 of x 
 
Appendix 16.2.8.2 
Clinical Laboratory Tests - Blood Chemistry 
Safety Evaluable (N=n)   
 
 
 
DoseLevel  
Sample 
Day Lab 
Laboratory Test 1[2] 
 
Laboratory Test 2[2] 
Patient Fasted (ug/kg) 
Cycle 
Date        Time [1] Code Results Normal Range Units  
 Results Normal Range Units 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
ccc-ppp xxx 
xxx 
x 
Ddmmmyyyy  hh:mm -xx xxxx xx.x 
H 
G1  
xx.x - xx.x 
Unit  
 xx.x 
H 
G1  
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit 
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit 
 xx.x 
xx.x - xx.x 
Unit 
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
EOT 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
ccc-ppp xxx 
xxx 
x 
Ddmmmyyyy  hh:mm -xx xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
L 
G1  
xx.x - xx.x 
Unit  
 xx.x 
L 
G1  
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit 
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
x 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
EOT 
Ddmmmyyyy  hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
Unit  
 xx.x 
xx.x - xx.x 
Unit  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study day relative to the first dose; On-Study day relative to first dose within cycle; End of treatment day relative to 
last dose. 
[2] Reported Result: H = High (Above Normal Range), L = Low (Below Normal Range); Calculated CTCAE 4.0 Grade 1 to 4. 
Cross-References: Case Report Form BLOOD CHEMISTRY (BC). 
PROGRAMMER’S NOTES: 
Repeat page as required.  
Include following Blood Chemistry Tests: : 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. 
Data is presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date” in ascending order within “Patient”.  
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Final Version 2.0  Date: 17 January 2019  
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Page 1 of x 
 
Appendix 16.2.8.3 
Clinical Laboratory Tests - Coagulation  
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Level 
 
Sample 
Sample Day Lab 
Laboratory Test 1[2] 
 
Laboratory Test 2[2] 
Patient 
(µg/kg) 
Cycle/Day 
Date 
Time 
[1] Code Results 
Normal Range 
Units  Results 
Normal Range 
Units  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm 
-xx xxxx xx.x H G1  
xx.x - xx.x 
unit  xx.x H G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm 
-xx xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x L G1  
xx.x - xx.x 
unit  xx.x L G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm 
xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study day relative to the first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last 
dose. 
[2] Reported Result: H = High (Above Normal Range), L = Low (Below Normal Range); Calculated CTCAE 4.0 Grade 1 to 4. 
Cross-References: Case Report Form COAGULATION (GA). 
PROGRAMMER’S NOTES: 
Repeat page as required.  
Include following Coagulation Tests: INR, PT, aPTT. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date” in ascending order within “Patient”.  
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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FINAL – ddmmmyy:hh:mm 
LDOS001 
Page 1 of x 
 
Appendix 16.2.8.4 
Clinical Laboratory Tests – Urinalysis 
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Level 
 
Sample 
 
Day Lab 
Laboratory Test 1[2] 
 
Laboratory Test 2[2] 
Patient 
(µg/kg) 
Cycle/Day 
Date 
Time 
[1] Code Results 
Normal Range 
Units  Results 
Normal Range 
Units  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm -xx xxxx xx.x H G1  
xx.x - xx.x 
unit  xx.x H G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm -xx xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x L G1  
xx.x - xx.x 
unit  xx.x L G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study day relative to the first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last 
dose. 
[2] Reported Result: H = High (Above Normal Range), L = Low (Below Normal Range); Calculated CTCAE 4.0 Grade 1 to 4.  
Cross-References: Case Report Form URINALYSIS (US).  
PROGRAMMER’S NOTES: 
Repeat page as required.  
Include following Urinalysis Tests: Occult blood, glucose, total protein, ketones, Bilirubin. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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Confidential – Entire Page 
 
 
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FINAL – ddmmmyy:hh:mm 
LDOS001 
Page 1 of x 
 
Appendix 16.2.8.5 
Other Clinically Significant Laboratory Results  
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose Level 
 
Sample 
 
Day Lab 
Laboratory Test 1[2] 
 
Laboratory Test 2[2] 
Patient 
(µg/kg) 
Cycle/Day 
Date 
Time 
[1] Code Results 
Normal Range 
Units  Results 
Normal Range 
Units  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm -xx xxxx xx.x H G1  
xx.x - xx.x 
unit  xx.x H G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
hh:mm -xx xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x L G1  
xx.x - xx.x 
unit  xx.x L G1  
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
x/xx 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
EOT 
ddmmmyyyy 
hh:mm xx 
xxxx xx.x 
xx.x - xx.x 
unit  xx.x 
xx.x - xx.x 
unit  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study day relative to the first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last 
dose. 
[2] Reported Result: H = High (Above Normal Range), L = Low (Below Normal Range); Calculated CTCAE 4.0 Grade 1 to 4.  
Cross-References: Case Report Form Other Clinically Significant Laboratory Results (UL).  
PROGRAMMER’S NOTES: 
Repeat page as required.  
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Reporting and Analysis Plan 
Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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Confidential – Entire Page 
 
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FINAL – ddmmmyy:hh:mm 
LDOS001 
Page 1 of x 
 
Appendix 16.2.9.1 
Physical Examination 
Safety Evaluable (N=n)   
 
 
L-DOS47  
 
Examination 
Day 
 
 
 
Significant 
 
 
 
 
Patient 
Dose Level(µg/kg) 
 
Cycle/Day 
Date 
[1] 
 
 
 
Findings 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ccc-ppp 
xxx 
 
Pre-Study 
 
ddmmmyyyy 
-xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
EOT 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
ccc-ppp 
xxx 
 
Pre-Study 
 
ddmmmyyyy 
-xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
EOT 
 
ddmmmyyyy 
xx 
 
 
 
Yes 
 
 
 
 
ccc-ppp 
xxx 
 
Pre-Study 
 
ddmmmyyyy 
-xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
x/xx 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
EOT 
 
ddmmmyyyy 
xx 
 
 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Pre-Study Day relative to first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last 
dose. 
Cross-References: Case Report Form PHYSICAL EXAMINATION (PE). 
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
LDOS001 
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Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
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All rights reserved 
174 
Confidential – Entire Page 
 
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FINAL – ddmmmyy:hh:mm 
LDOS001 
Page 1 of x 
 
Appendix 16.2.9.2 
Vital Signs  
Safety Evaluable (N=n) 
 
 
L-DOS47 
 
 
 
  
 
 
Blood Pressure 
 
 
 
    
 
Dose 
Level 
 
Date 
Scheduled  
  
Day  
(mmHg) 
Temperature Pulse 
Respiration 
Rate 
Pulse Oximetry 
    
Patient (µg/kg) 
Cycle/Day  Performed  
Timepoint  
Time  [1]  Systolic Diastolic (unit) 
(beats/min) (/min) 
(%) 
    
 
 
 
 
 
 
   
 
 
 
 
 
 
    
ccc-ppp xxx 
x/xx 
ddmmmyyyy 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
ddmmmyyyy 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
ddmmmyyyy 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
Timepoint 
 
hh:mm  xx  
xxx 
xx 
xx.x  
xxx 
xx 
xx 
    
 
 
 
 
 
 
 
   
 
 
 
 
 
 
    
 
 
 
 
 
 
   
 
 
 
 
 
    
[1] Pre-Study day relative to first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last dose.  
Cross-References: Case Report Forms SCREENING VITAL SIGNS and VITAL SIGNS (VS, VSx). 
PROGRAMMER’S NOTES: 
When “Not done” is indicated, enter “NOT DONE” in the ‘Time’ column. 
Add records for “Other unscheduled timepoints” within a day if necessary. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date Performed” in ascending order within “Patient”. Sort “Time” in ascending order within “Date”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
LDOS001 
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Final Version 2.0  Date: 17 January 2019  
Copyright© 2019 by Theradex, Princeton NJ 
 
1068R18DEC.002 
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FINAL – ddmmmyy:hh:mm 
LDOS001 
Page 2 of x 
 
Appendix 16.2.9.2 
Vital Signs 
Safety Evaluable (N=n) 
 
 
L-DOS47 
 
 
 
   
  Body 
 
   
 
 
Dose Level 
 
Date 
Scheduled 
 
  
Day    Weight Height 
   
BSA 
Patient 
(µg/kg)* 
Cycle 
/Day Performed 
 Timepoint 
 Time 
 [1]    (kg) 
(cm)[2] 
   
(mA2) 
 
 
 
 
 
 
 
 
   
 
 
 
     
ccc-ppp 
xxx 
x/xx 
ddmmmyyyy 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
ddmmmyyyy 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
ddmmmyyyy 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
Timepoint 
 
hh:mm  
xx 
   xx.x 
xxx 
xx.x 
     
 
 
 
 
 
 
 
 
 
   
 
 
 
     
 
 
 
 
 
 
 
 
 
   
 
 
 
     
 
 
 
 
 
 
 
 
   
 
 
     
[1] Pre-Study day relative to first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last dose 
[2] Completed at screening only. 
Cross-References: Case Report Forms SCREENING VITAL SIGNS and VITAL SIGNS (VS, VSx). 
PROGRAMMER’S NOTES: 
When “Not done” is indicated, enter “NOT DONE” in the ‘Time’ column. 
Add records for “Other unscheduled timepoints” within a day if necessary. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date Performed” in ascending order within “Patient”. Sort “Time” in ascending order within “Date”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.9.3 
ECOG Performance Status  
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
  
 
Dose Level 
 
Date 
Day  
Patient 
(µg/kg) 
Cycle/Day 
Performed [1] ECOG Performance Status 
 
 
 
 
  
ccc-ppp 
xxx 
Pre-Study 
ddmmmyyyy -xx 0 Fully active, able to carry on all pre-disease activities without restriction. 
 
 
x/xx 
ddmmmyyyy xx 1 Restricted in physically strenuous activity but ambulatory and able to carry work 
of a light or sedentary nature, e.g., light house work, office work. 
 
 
x/xx 
ddmmmyyyy xx 2 Ambulatory and capable of all self-care but unable to carry out work activities. 
Up and about more than 50% of waking hours. 
 
 
x/xx 
ddmmmyyyy xx 3 Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
 
x/xx 
ddmmmyyyy xx 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
 
End Study 
ddmmmyyyy xx 5 Dead. 
 
 
 
 
  
ccc-ppp 
xxx 
Pre-Study 
ddmmmyyyy -xx 0 Fully active, able to carry on all pre-disease activities without restriction. 
 
 
x/xx 
ddmmmyyyy xx 1 Restricted in physically strenuous activity but ambulatory and able to carry work 
of a light or sedentary nature, e.g., light house work, office work. 
 
 
x/xx 
ddmmmyyyy xx 2 Ambulatory and capable of all self-care but unable to carry out work activities. 
Up and about more than 50% of waking hours. 
 
 
x/xx 
ddmmmyyyy xx 3 Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
 
 
x/xx 
ddmmmyyyy xx 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 
 
End Study 
ddmmmyyyy xx 5 Dead. 
 
 
 
 
 
 
[1] Day relative to the first dose; End of treatment day relative to last dose. 
Cross-References: Case Report Form PERFORMANCE STATUS (ES).  
PROGRAMMER’S NOTES: 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc” portion of patient number. 
Sort “Date Performed” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.9.4 
Electrocardiogram  
Safety Evaluable (N=n) 
 
 
L-DOS47 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
Dose Level Cycle/ 
Date 
Planned 
 
  
Day  Heart Rate PR 
QT 
QTc 
 
QRS 
  
Patient (µg/kg) 
Day 
 Performed  
Timepoint  
Time  [1]  (beats/min) (msec) 
(msec) 
(msec)  
(msec)   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
ccc-ppp xxx 
Screening ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
 
  
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
x/xx 
ddmmmyyyy 
Pre-dose 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
Pre-Dose 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
Pre-Dose 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
ccc-ppp xxx 
Screening ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  
xx 
xx 
xx.x 
xxx 
xxx 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
[1] Pre-Study day relative to first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last dose.  
Cross-References: Case Report Forms ELECTROCARDIOGRAM (EG). 
PROGRAMMER’S NOTES: 
When “Not done” is indicated, enter “NOT DONE” in the ‘Time’ column. 
Add records for “Other unscheduled timepoints” within a day if necessary. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date Performed” in ascending order within “Patient”. Sort “Time” in ascending order within “Date”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.9.4 
Electrocardiogram 
Safety Evaluable (N=n) 
 
 
L-DOS47 
 
 
 
  
 
 
 
 
 
 
  
 
 
Dose Level  
Date 
Planned 
 
  
Day  Clinical 
If abnormal,  
 
 
  
 
Patient (µg/kg) 
Cycle/Day  Performed  
Timepoint  
Time  [1]  Significance details 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
   
ccc-ppp xxx 
Screening   ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
 
  
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
x/xx 
ddmmmyyyy 
Pre-dose 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
Pre-Dose 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
Pre-Dose 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1 hr post 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
1.5 hrs post  
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  xx  Normal 
Details 
 
 
 
 
 
  
 
ccc-ppp xxx 
Screening 
ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
  
 
 
 
 
ddmmmyyyy 
 
 
hh:mm  -xx  Normal 
Details 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
[1] Pre-Study day relative to first dose; On-Study day relative to first dose within cycle; End of treatment day relative to last dose.  
Cross-References: Case Report Forms ELECTROCARDIOGRAM (EG). 
PROGRAMMER’S NOTES: 
When “Not done” is indicated, enter “NOT DONE” in the ‘Time’ column. 
Add records for “Other unscheduled timepoints” within a day if necessary. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Date Performed” in ascending order within “Patient”. Sort “Time” in ascending order within “Date”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 
 


 
 
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Appendix 16.2.9.5 
Immunogenicity Data of L-DOS47 
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
  
    
  
Patient 
Dose Level 
Cycle 
Date 
Time 
  
   ELISA 
  
 
(µg/kg) 
Day (day) 
Collected  
Collected 
 Titer 
   Result 
  
 
 
 
 
  
 
  
 
ccc-ppp 
 
xxx 
x/xx (xx) 
ddmmmyyyy 
HH:MM 
 xxxx 
   Negative 
   
 
 
 
 
 
  
    
   
 
 
 
ddmmmyyyy 
HH:MM 
 xxxx 
   Positive 
   
 
 
 
 
 
  
    
   
 
 
 
 
 
  
    
   
 
 
 
 
 
  
    
   
ccc-ppp 
 
xxx 
x/xx (xx) 
ddmmmyyyy 
 
 xxxx 
   Inconclusive 
   
 
 
 
 
  
 
  
 
[1] Day relative to the first dose of study medication. 
[2] WHO-DD version June 2013. 
Cross-References: Case Report Form ANTIBODY TESTING (AT). 
PROGRAMMER’S NOTES: 
When “None” is indicated, enter “NO CONCOMITANT MEASURES” in the ‘Drug Name or Treatment’ column. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Present only data is available. 
 
 
 


 
 
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Appendix 16.2.9.6 
Immunogenicity Data of Tumour Antigen (CEACAM6) 
Safety Evaluable (N=n)   
 
 
L-DOS47 
 
 
 
  
    
  
Patient 
Dose Level 
Cycle 
Date 
Time 
  
   ELISA 
  
 
(µg/kg) 
Day (day) 
Collected  
Collected 
 Titer 
   Result 
  
 
 
 
 
  
 
  
 
ccc-ppp 
 
xxx 
x/xx (xx) 
ddmmmyyyy 
HH:MM 
 xxxx 
   Negative 
   
 
 
 
 
 
  
    
   
 
 
 
ddmmmyyyy 
HH:MM 
 xxxx 
   Positive 
   
 
 
 
 
 
  
    
   
 
 
 
 
 
  
    
   
 
 
 
 
 
  
    
   
ccc-ppp 
 
xxx 
x/xx (xx) 
ddmmmyyyy 
 
 xxxx 
   Inconclusive 
   
 
 
 
 
  
 
  
 
[1] Day relative to the first dose of study medication. 
[2] WHO-DD version June 2013. 
Cross-References:  
PROGRAMMER’S NOTES: 
When “None” is indicated, enter “NO CONCOMITANT MEASURES” in the ‘Drug Name or Treatment’ column. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
Present only data is available. 
 
 
 


 
 
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Appendix 16.2.10.1 
Concomitant Measures 
Safety Evaluable (N=n)   
 
 
L-DOS47 
  
Start Day 
 Drug Name or Treatment 
 
   
  
Patient 
Dose Level 
 Start Date 
Stop Day 
 (WHO-DD Preferred Term) 
 
  Reason 
  
 
(µg/kg) 
 Stop Date 
[1] 
 (WHO-DD ATC Class Category Level II)[2] 
Route 
  For Use 
  
 
 
 
 
  
 
  
 
ccc-ppp 
 
xxx 
 ddmmmyyyy 
Ongoing 
-xx 
 Concomitant Measure 
(WHO-DD Preferred Term) 
(WHO-DD ATC Class Category Level II) 
Route 
  Reason 
   
 
 
  
 
  
 
   
   
 
 
 ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
 Concomitant Measure 
(WHO-DD Preferred Term) 
(WHO-DD ATC Class Category Level II) 
Route 
  Reason 
   
 
 
  
 
  
 
   
   
 
 
 ddmmmyyyy 
ddmmmyyyy 
xx 
xx 
 Concomitant Measure 
(WHO-DD Preferred Term) 
(WHO-DD ATC Class Category Level II) 
Route 
  Reason 
   
 
 
  
 
  
 
   
   
ccc-ppp 
 
xxx 
 ddmmmyyyy 
Ongoing 
-xx 
 Concomitant Measure 
(WHO-DD Preferred Term) 
(WHO-DD ATC Class Category Level II) 
Route 
  Reason 
   
 
 
 
 
  
 
  
 
[1] Day relative to the first dose of study medication. 
[2] WHO-DD version June 2013. 
Cross-References: Case Report Form CONCOMITANT MEASURES (CM). 
PROGRAMMER’S NOTES: 
When “None” is indicated, enter “NO CONCOMITANT MEASURES” in the ‘Drug Name or Treatment’ column. 
Data will be presented in mixed case for formatted variables and upper case only for unformatted variables. 
Sort “Patient” in ascending order using “ppp”, and then “ccc”  portion of patient number. 
Sort “Start Date” in ascending order within “Patient”. 
L-DOS47 Dose Level = 0.59, 0.78, 1.5, 3.0, 6.0, 9.0, 12.0 µg/kg. 
 
 


 
 
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List of CSR Appendices 
The following appendices apply to the CSR. This RAP provides the listings for Appendix 
16.2.  
  
Appendix 
 
Description 
16.1 
 
Study Information  
16.1.1 
 
Protocol and protocol amendments 
16.1.2 
 
Sample case report form  
16.1.3 
 
List of IECs or IRBs and representative written information for patient 
and sample consent forms 
16.1.4 
 
List and description of investigators and other important participants 
in the study + CVs 
16.1.5 
 
Signatures of principal investigator(s) and sponsor representatives  
16.1.6 
 
Listing of patients receiving test drug(s)/investigational product(s) 
from specific batches, where more than one batch was used 
16.1.7 
 
Randomization scheme and codes 
16.1.8 
 
Audit certificates 
16.1.9 
 
Documentation of statistical methods 
16.1.10 
 
Documentation of inter-laboratory standardization methods and 
quality assurance procedures if used 
16.1.11 
 
Publications based on the study 
16.1.12 
 
Important publications referenced in the report 
16.2 
 
Patient Data Listings  
16.2.1 
 
Patient accountability (includes Discontinued Patients and 
Inclusion/Exclusion Criteria) 
16.2.3 
 
Patients excluded from the efficacy analysis 
16.2.4 
 
Demographic data and baseline characteristics 
16.2.5 
 
Compliance and/or drug concentration data  
16.2.6 
 
Individual efficacy response data 
16.2.7 
 
Adverse event listings  
16.2.8 
 
Individual laboratory measurements by patient  
16.2.9 
 
Other safety listings (Vital Signs, ECG, Physical Exam etc.) 
16.2.10 
 
Concomitant medications 


 
 
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16.2.11 
 
Comments 
16.3 
 
Case Report Forms 
16.3.1 
 
CRFs for deaths, other serious adverse events, and withdrawals for 
adverse events 
16.3.2 
 
Other CRFs submitted  
16.4 
 
Archival Individual Patient Data Listings