Conditions: Lung Neoplasms Lung Cancer
Keywords: Intraoperative Imaging
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 112
Healthy volunteers: no

Brief summary:
This is a phase 3, multi-center, single dose, open-label, exploratory study in suspected lung cancer patients scheduled to undergo endoscopic or thoracic surgery per CT/PET/MRI or other imaging based on standard of care. This study aims to assess the efficacy of OTL38 and Near Infrared Imaging (NIR) at identifying pulmonary nodules within the operating theater, and to assess the safety and tolerability of single intravenous doses of OTL38.

Detailed description:

Arms:
arm 1: All patients in this arm will receive OTL38 for injection and undergo intraoperative imaging. arm 2: All patients in this arm will receive OTL38 for injection but will not receive intraoperative imaging.

Interventions: intervention 1: OTL38 for Injection intervention 2: Near infrared camera imaging system
Intervention descriptions: intervention 1: Folate analog ligand conjugated with an indole cyanine-like green dye as a solution in vials containing 3 mL at 2 mg/mL intervention 2: Near infrared camera imaging system

Protocol document:
Prot_000.pdf: 












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Eligibility 
Criteria 
Inclusion: 
1. Male and Female subjects 18 years of age and older 
2. Have a primary diagnosis, or a high clinical suspicion, of cancer in the lung 
warranting surgery based on CT/PET or other imaging 
3. Are scheduled to undergo surgical thoracoscopy for diagnostic wedge 
resection followed by anatomic lung resection  
4. Female subjects of childbearing potential or less than 2 years postmenopausal 
agree to use an acceptable form of contraception from the time of signing 
informed consent until 30 days after study completion 
5. Ability to understand the requirements of the study, provide written informed 
consent and authorization of use and disclosure of protected health 
information, and agree to abide by the study restrictions and to return for the 
required assessments 
Exclusion: 
1. Previous exposure to OTL38 
2. Any medical condition that in the opinion of the investigators could potentially 
jeopardize the safety of the subject 
3. History of anaphylactic reactions to folate, including synthetic folic acid 
(pteroylmonoglutamic acid) and contrast agents containing indocyanine green 
for near infrared imaging. Subjects with a medical history of ‘idiopathic 
anaphylaxis’ will require evaluation. 
4. History of allergy to any of the components of OTL38, including folic acid 
5. A positive serum pregnancy test at Screening or a positive urine pregnancy test 
on the day of surgery or day of admission for female subjects of childbearing 
potential 
6. Clinically significant abnormalities on electrocardiogram (ECG) at screening. 
7. Presence of any psychological, familial, sociological condition or geographical 
challenges potentially hampering compliance with the study protocol and 
follow-up schedule 
8. Impaired renal function defined as eGFR< 50 mL/min/1.73m2 
9. Impaired liver function defined as values > 3x the upper limit of normal (ULN) 
for alanine aminotransferase (ALT) or aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), or >2x ULN for total bilirubin except in subjects 
with Gilbert’s syndrome. 
10. Received an investigational agent in another investigational drug or vaccine 
trial within 30 days prior to the administration of study drug 
11. Known sensitivity to fluorescent light 
Number of 
Subjects 
Up to approximately 130 subjects  
Number of 
Investigator Sites 
Up to approximately 15 investigational sites 
















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Table of Contents 
1 
PROTOCOL SYNOPSIS .......................................................................................................4 
2 
SCHEDULE OF ASSESSMENTS ......................................................................................14 
3 
BACKGROUND INFORMATION ....................................................................................20 
3.1 
Background ..................................................................................................................20 
3.2 
Rationale ......................................................................................................................21 
3.3 
Investigational Product ................................................................................................22 
3.3.1 
Prior Clinical Experience ...............................................................................22 
3.3.2 
Phase 1a Study of OTL38 Injection in Healthy Volunteers (CHDR1321A) .23 
3.3.3 
Phase 1b Ovarian Cancer Study (CHDR1321-B) ..........................................23 
3.3.4 
Phase 2 Ovarian Cancer Study (OTL-2016-OTL38-003) ..............................23 
3.3.5 
Phase 2 Lung Cancer Study (OTL-2016-OTL38-005) ..................................24 
3.3.6 
Other Clinical Experience in Lung and Pituitary Cancer: ..............................25 
3.4 
Risks and Benefits of OTL38 ......................................................................................25 
3.4.1 
Risks ...............................................................................................................25 
3.4.2 
Benefits ...........................................................................................................26 
4 
STUDY OBJECTIVES ........................................................................................................27 
4.1 
Primary .........................................................................................................................27 
4.2 
Secondary .....................................................................................................................27 
4.3 
Exploratory ..................................................................................................................28 
4.4 
Safety Objectives .........................................................................................................28 
5 
STUDY DESIGN ..................................................................................................................29 
5.1 
Overall Investigation Plan ............................................................................................29 
5.2 
Eligibility Criteria ........................................................................................................29 
5.2.1 
Inclusion Criteria ............................................................................................29 
5.2.2 
Exclusion Criteria ...........................................................................................29 
5.3 
Study Assessments .......................................................................................................30 
5.4 
Patient Discontinuation Criteria ...................................................................................30 
5.5 
Replacement of Dropouts ............................................................................................31 
5.6 
Study Drug Information and Dosage ...........................................................................31 
5.6.1 
Identification and Description of Test Article ................................................31 
5.6.2 
Packaging and Labeling .................................................................................31 
5.6.3 
Storage and Handling of Test Article .............................................................31 
5.6.4 
Study Drug Administration ............................................................................32 
5.6.5 
Camera/Imaging System ................................................................................32 


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5.6.6 
Training Requirements ...................................................................................32 
5.6.7 
Tumor to Background Ratio ...........................................................................32 
5.6.7.1 
Summary of the Camera/Imaging System Requirements ..............33 
5.6.7.2 
Quality System Requirements ........................................................34 
5.7 
Prior and Concomitant Medications ............................................................................34 
5.7.1 
Prior Medications ...........................................................................................34 
5.7.2 
Allowed Medications ......................................................................................35 
5.7.3 
Concomitant medications ...............................................................................35 
5.7.4 
Prohibited Medications ...................................................................................35 
5.8 
Schedule of Events .......................................................................................................35 
5.8.1 
Measurement and Evaluations ........................................................................35 
5.8.1.1 
Visit 1 (Screening, up to Day -28) .................................................35 
5.8.1.2 
Visit 2- (Day 0 and/or 1) ................................................................36 
5.8.1.3 
Visit 3-Follow-up (Day 7 [± 4]) .....................................................39 
5.8.1.4 
Visits 4-Follow-up (Day 28 [±4]) ..................................................39 
5.8.2 
Surgical Reporting Schematics .......................................................................39 
5.8.3 
Investigator Post-Surgery Questionnaire (Visit 2b) .......................................39 
5.8.4 
Pathology Samples .........................................................................................39 
5.8.5 
Camera/Imaging System Exposure (NIR Fluorescent Imaging Group Only) 40 
6 
STUDY ENDPOINTS ..........................................................................................................41 
6.1 
Primary .........................................................................................................................41 
6.2 
Secondary .....................................................................................................................41 
6.3 
Exploratory ..................................................................................................................43 
6.4 
Safety ...........................................................................................................................43 
7 
PROCEDURES FOR REPORTING ADVERSE EVENTS .............................................44 
7.1 
Adverse Events Definitions .........................................................................................44 
7.2 
Adverse Device Effects Definitions .............................................................................44 
7.2.1 
Adverse Device Effect ....................................................................................44 
7.2.1.1 
Suspected Adverse Device Effect ..................................................45 
7.2.1.2 
Unanticipated Adverse Device Effect ............................................45 
7.3 
Reporting of Adverse Events .......................................................................................45 
7.3.1 
Adverse Events ...............................................................................................45 
7.3.2 
Laboratory Abnormalities ..............................................................................45 
7.3.3 
Serious Adverse Events ..................................................................................46 
7.3.4 
Reporting of Pregnancies ...............................................................................46 
7.3.5 
Disease Progression ........................................................................................46 


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7.4 
Overdoses .....................................................................................................................46 
7.5 
Classification of Adverse Events by Severity ..............................................................46 
7.6 
Classification of Adverse Events by Relationship to Study Drug Administration ......47 
7.7 
Adverse Events Qualifying for Expedited Reporting ..................................................47 
8 
DATA RECORDING, CRF PROCESSING, AND STATISTICAL ANALYSIS ..........48 
8.1 
Data Recording and CRF Processing ...........................................................................48 
8.2 
Statistical Methods .......................................................................................................48 
8.2.1 
Sample Size Estimation ..................................................................................48 
8.2.2 
Analysis Sets ..................................................................................................48 
8.2.3 
Description of Subgroups to be Analyzed ......................................................49 
8.2.4 
Subject Demographics, Baseline Disease Status, and Disposition .................49 
8.2.5 
Statistical Analysis .........................................................................................50 
8.2.5.1 
Primary Efficacy Endpoints ...........................................................50 
8.2.5.2 
Secondary Efficacy Endpoints .......................................................50 
8.2.5.3 
Exploratory Efficacy Endpoints .....................................................51 
8.2.5.4 
Safety Evaluations .........................................................................51 
8.2.5.5 
Imaging System .............................................................................52 
8.2.5.6 
Prior and Concomitant Medications ..............................................52 
8.2.5.7 
Handling of Missing Data ..............................................................52 
8.2.5.8 
Interim Analyses ............................................................................53 
9 
ETHICS .................................................................................................................................54 
9.1 
Patient Information and Consent .................................................................................54 
9.2 
Institutional Review Board ..........................................................................................54 
10 STUDY ADMINISTRATION .............................................................................................55 
10.1 Data ..............................................................................................................................55 
10.2 Study Record Retention ...............................................................................................55 
10.3 Patient Anonymity .......................................................................................................55 
10.4 Publications ..................................................................................................................55 
11 INVESTIGATOR’S STATEMENT ...................................................................................56 
12 REFERENCES .....................................................................................................................57 
APPENDICES ............................................................................................................................. 59 
Table of Figures 
Figure 1. TBR Imaging ...............................................................................................................32 
Figure 2. Excitation and Emission Spectra of OTL38 ................................................................33 


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List of Abbreviations 
Abbreviation 
Definition  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvate transaminase) 
API 
Active Pharmaceutical Ingredient 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRO 
Contract Research Organization 
CSE 
Clinically Significant Event 
CT 
Computed/Computerized Tomography 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Sets 
FDA 
United States Food and Drug Administration 
FITC 
Fluorescein isothiocyanate 
FN 
False Negative 
FP 
False Positive 
FR 
Folate Receptor 
FPR 
False Positive Rate 
GCP 
Good Clinical Practice 
 
 
 
 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
ICG 
Indole Cyanine Green 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IV 
Intravenous 
KD 
Kilodalton 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 


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Abbreviation 
Definition  
NIR 
Near Infrared 
OTL 
On Target Laboratories 
PPAS 
Per Protocol Analysis Sets 
PET 
Positron-emission tomography 
PHI 
Protected Health Information 
SAP 
Statistical Analysis Plan 
SAE 
Serious adverse event 
SfAS 
Safety Analysis Set 
SUSAR 
Suspected unexpected serious adverse reaction 
TAM 
Tumor Associated Macrophages 
TBR 
Tumor to Background Ratio 
TEAE 
Treatment Emergent Adverse Event 
TN 
True Negative 
TP 
True Positive 
TPR 
True Positive Rate 
ULN 
Upper limit of the normal range 
VATS 
Video-assisted Thoracoscopy 
WHO 
World Health Organization 


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3 
BACKGROUND INFORMATION 
3.1 
Background 
Lung Cancer is the leading cause of cancer related deaths in the United States, with an estimated 
projection of 142,670 lung cancer related deaths for 2019. Of new cases of cancer, lung cancer is 
the second most frequent diagnosis, with an estimated projection of 228,150 newly diagnosed 
cases for 2019 (SEER 2019). Surgery remains the best option for subjects presenting with 
operable Stage I or II cancers, however the five-year survival rate for these candidates remains 
concerningly low at 57.4% for localized disease and 30.8% for regional disease (SEER 2019). 
The rates of local recurrence suggest that surgeons are unable to completely detect and remove 
primary tumor nodules. In addition to the primary nodules, local recurrence can also be attributed 
to synchronous lesions that are not identified on pre-operative imaging and not found during the 
initial surgery (Chang 2007, Fabian 2011). Positive surgical resection margins (the distance from 
the primary tumor to the closest resection margin) also contribute to the recurrence rate 
(Sienel 2007). During video-assisted thoracoscopic surgery (VATS), smaller and deeper nodules 
are not always identified (Cerfolio 2008, Nakashima 2010). To help identify these smaller or 
deeper nodules, methods such as CT-guided hookwire, may be useful in identifying the nodule 
during VATS surgery, but the procedure of inserting the hookwire, can cause severe 
complications including embolism (Suzuki 2014). 
Incomplete resection of non-small-cell lung cancer negatively impacts survival rates 
(Osarogiagbon 2016). Local recurrences are more frequent in patients with segmentectomy than 
lobectomy (Sienel 2007). The risk of recurrence increases if malignant synchronous lesions are 
not identified pre-operatively or during surgery and are not removed (Fabian 2011, Yoon 2006). 
Improved survival after complete resection of synchronous lesions has been shown to be similar 
to that of complete resection of solitary nodules in node-negative patients. Furthermore, this 
holds true even when synchronous lesions occur in the ipsilateral lung, or a different lobe, or 
bilaterally (Chang 2007, Voltolini 2010). 
Positive resection margins are often found in many cancer surgeries including lung cancer 
(Orosco 2018). An increased margin distance has been shown to be associated with a lower risk 
of local recurrence, with a 10-mm margin distance having a 45% lower recurrence risk than a 
5-mm distance (Mohiuddin 2014). In wedge resection for small non–small cell lung cancer, 
increasing the margin distance less than or equal to 15 mm significantly decreased the local 
recurrence risk, with no evidence of additional benefit beyond 15mm (Mohiuddin 2014). 
Therefore, ensuring a negative margin through imaging is important to ensure lower rates of 
recurrence-free disease and thus, overall survival. 
Lung-sparing procedures such as wedge resection or segmentectomy are also important, 
particularly for patients with poor pulmonary reserve. Furthermore, lobectomy to remove 
synchronous lesions has not been shown to improve immediate or long-term survival above lung 
sparing sub-lobar resections (Toufektzian 2014). Intraoperative imaging techniques that increase 
the accurate identification of cancerous synchronous lung lesions may mitigate the need for 
unnecessary lobectomy or pneumonectomy. 




















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infrared imaging. Patients with a medical history of ‘idiopathic anaphylaxis’ will require 
evaluation. 
4. History of allergy to any of the components of OTL38, including folic acid 
5. A positive serum pregnancy test at Screening or a positive urine pregnancy test on the 
day of surgery or day of admission for female subjects of childbearing potential 
6. Clinically significant abnormalities on electrocardiogram (ECG) at screening. 
7. Presence of any psychological, familial, sociological condition or geographical 
challenges potentially hampering compliance with the study protocol and follow-up 
schedule 
8. Impaired renal function defined as eGFR< 50 mL/min/1.73m2 
9. Impaired liver function defined as values > 3x the upper limit of normal (ULN) for 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), or >2x ULN for total bilirubin excluding those patients with 
Gilbert’s syndrome. 
10. Received an investigational agent in another investigational drug or vaccine trial within 
30 days prior to the administration of study drug 
11. Known sensitivity to fluorescent light 
5.3 
Study Assessments 
The assessments for this study are listed in Section 5.8. 
5.4 
Patient Discontinuation Criteria 
Although a single dose of study drug is infused on Day 1, a patient may be withdrawn from the 
study for any of the following reasons: 
• Request of the patient or patient’s representative 
• AEs or adverse device effects (ADEs) based on the judgment of the Investigator 
• The Investigator decides that it is in the patient’s best interest 
• The patient is noncompliant with the protocol 
• Lost to follow-up 
• Death 
If a subject is withdrawn at any time, the reason(s) will be recorded on the relevant page of the 
electronic case report form (eCRF). 
Patients discontinued due to AEs or ADEs will be monitored until resolution or stability of the 
event based on the judgment of the investigator. 




















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5.8.5 
Camera/Imaging System Exposure (NIR Fluorescent Imaging Group Only) 
A camera/imaging system will be used to identify tumor lesions under fluorescence prior to 
surgical excision of lesions, and again after surgical excision of lesions to identify persistent 
lesions. The Investigator will record the start and stop time for each in situ exposure to 
fluorescence imaging (pre-resection, post-initial resection, other [give reason]) in the eCRF. The 
total time of fluorescence will be calculated automatically. 
Back table imaging will not be included in the fluorescence exposure time. 
Status 
Time On 
Fluorescent Light 
Time Off 
Fluorescent Light 
Before surgical excision 
 
 
After initial surgical excision 
 
 
Other (explain reason) 
 
 








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7 
PROCEDURES FOR REPORTING ADVERSE EVENTS 
7.1 
Adverse Events Definitions 
The Investigator will monitor the occurrence of AEs during the course of the study that will end 
with Visit 4. 
The following definitions of terms are guided by the United States Code of Federal Regulations 
(21 CFR 312.32(a)) and are included here. 
Adverse event is any untoward medical occurrence in a patient associated with the use of a drug 
in humans, whether or not considered drug related. 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, "reasonable 
possibility" means there is evidence to suggest a causal relationship between the drug and the 
adverse event. Suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
Unexpected adverse event (adverse drug experience) or (suspected) adverse reaction means any 
adverse event or (suspected) adverse reaction that is not listed in the investigator brochure or is 
not listed at the specificity or severity that has been observed. 
An AE or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: Death, a life- threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
An adverse event is considered “life-threatening” if, in the view of either the investigator or 
sponsor, its occurrence places the patient at immediate risk of death. It does not include an 
adverse event that, had it occurred in a more severe form, might have caused death. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is any (suspected) adverse reaction 
(any adverse event for which there is a reasonable possibility that the drug caused the adverse 
event) that is both serious and unexpected. 
7.2 
Adverse Device Effects Definitions 
7.2.1 
Adverse Device Effect 
An ADE is defined as any untoward and unintended response to a medical device, in this study, 
the camera/imaging system. This definition includes any event resulting from insufficiencies or 
inadequacies in the instructions for use or the deployment of the device, as well as any event that 
is the result of a user error [ISO 14155-1:2003 (E) 3.1]. 
All ADEs noted during the study will be reported in the eCRF. 


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7.2.1.1 
Suspected Adverse Device Effect 
A suspected ADE is a subset of all ADEs for which there is a reasonable possibility (i.e., evidence 
to suggest a causal relationship between the device and the ADE) that the device caused the event. 
Suspected ADE implies a lesser degree of certainty about causality than adverse device effect. 
7.2.1.2 
Unanticipated Adverse Device Effect 
An unanticipated ADE is any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
application, or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects [21 CFR 812.3 (s)]. 
7.3 
Reporting of Adverse Events 
7.3.1 
Adverse Events 
The safety of all patients enrolled in this study will be recorded from the time of study drug 
administration and throughout the course of the study that will end with Visit 4. 
All AEs will be recorded in the appropriate section of the eCRF. Patients withdrawn from the 
study because of AEs will be followed by the investigator until the outcome is determined. When 
appropriate, additional written reports and documentation will be provided. 
All AEs beginning during or after the exposure to study drug must be reported to the sponsor or 
its designee if the onset of the AE was before Visit 4. All AEs that are judged by the investigator 
to be not related to study drug need not be reported to the sponsor or its designee after Visit 4. 
All AEs that are judged by the Investigator to be related to study drug administration must be 
reported to the sponsor or its designee regardless of how much time has elapsed since the last 
exposure to study drug. 
7.3.2 
Laboratory Abnormalities 
To the extent possible, all clinically significant laboratory abnormalities observed during the 
course of the study will be included under a reported AE describing a clinical syndrome 
(e.g., elevated blood urea nitrogen and creatinine in the setting of an AE of “renal failure” or 
elevated ALT/AST in the setting of an AE of “hepatitis”). In these cases (e.g., an AE of renal 
failure), the laboratory abnormality itself (e.g., elevated creatinine) does not need to be recorded 
as an AE. 
In the absence of a reported AE identifying a clinical syndrome that encompasses the observed 
clinically significant laboratory abnormality that “isolated” laboratory abnormality itself should 
be reported as an AE. 
Patients experiencing AEs or laboratory abnormalities will be assessed and appropriate 
evaluations performed until all parameters have returned to baseline levels, or are consistent with 
the patient’s then-current physical condition, in the opinion of the investigator. 


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7.3.3 
Serious Adverse Events 
Instructions for reporting Serious Adverse Events (SAE) and Suspected Unexpected Serious 
Adverse Reactions (SUSAR) are found on Page 2. A written report of all SAEs that occur after 
the administration of study drug and during the study (ending with Visit 4) must be submitted to 
the IRB/ethics committee (EC) and the Sponsor. SAEs/SUSARs must be reported to the Sponsor 
within 24 hours for a determination of expedited reporting to FDA, as described in Section 7.7. 
In all SAE reports, the investigator will advise whether or not the SAE is judged to be related to 
study drug administration. SAEs that occur after Visit 4 and are not reasonably associated with 
study drug do not require reporting per the instructions given below. All SAEs that are judged by 
the investigator to be at least possibly related to study drug administration must be reported to 
the sponsor or its designee regardless of how much time has elapsed since the last exposure to 
study drug. All SAEs must be submitted to the IRB/EC in an annual report per local reporting 
guidelines. 
7.3.4 
Reporting of Pregnancies 
If a patient becomes pregnant during the course of the study, the investigator or site personnel 
must notify the Medical monitor (see Page 2 for details) within 5 working days after the 
investigator or site personnel become aware of the pregnancy. If an SAE occurs in conjunction 
with the pregnancy, then the reporting time frame for an SAE must be met. 
7.3.5 
Disease Progression 
The progression of lung cancer (in patients diagnosed as such) per se will not constitute an AE. 
However, if the progression of the lung cancer meets the criteria for an SAE, then it should be 
reported as an SAE (see Page 2). 
7.4 
Overdoses 
Overdoses should be reported as a protocol violation. If an overdose results in an AE, the CRF 
AE page should be completed, and source documents included. If the overdose results in an 
SAE, then SAE reporting should be followed using the specific CRF pages with overdose 
information entered in the narrative section. All available clinical information relevant to 
overdose, including signs and symptoms, laboratory findings, and therapeutic measures or 
treatments administered, should be summarized and discussed. 
7.5 
Classification of Adverse Events by Severity 
The investigator must categorize the severity of each AE according to the following: 
• Mild: Awareness of signs or symptoms, but easily tolerated and are of minor irritant type. 
Symptoms do not require therapy or a medical evaluation; signs and symptoms are 
transient. 


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• Moderate: Events introduce a low level of inconvenience or concern to the participant, 
but are usually improved by simple therapeutic measures; moderate experiences may 
cause some interference with functioning 
• Severe: Events generally require systemic drug therapy or other treatment; they are 
usually incapacitating 
• Life-Threatening: Risk of imminent death requiring immediate intervention. 
7.6 
Classification of Adverse Events by Relationship to Study Drug 
Administration 
The relationship of each AE to the study drug administration will be assessed by the investigator; 
after careful consideration, according to the following guidelines: 
Related: An adverse event that has a timely relationship to the administration of the study drug 
and follows a known pattern of response for which no alternative cause is present or may be 
excluded. 
Possibly Related: An adverse event that has a timely relationship to the administration of the 
study drug, follows no known pattern of response, but a potential alternative cause does not exist 
Not related: An adverse event for which there is evidence that it is definitely related to a cause 
other than the study; in general, no timely relationship to the administration of the drug exists, or 
if so, the event does not follow a pattern of response and an alternative cause is present 
7.7 
Adverse Events Qualifying for Expedited Reporting  
All SUSARs, SAEs and unanticipated adverse device effects must be reported to On Target 
Laboratories or designee by telephone and in writing as soon as practical, but at least within 
24 hours of initial report. 
The investigator must report fatal and life-threatening SUSARs to the IRB within 7 calendar 
days of the initial receipt of information. On Target Laboratories or designee will report fatal and 
life-threatening SUSARs to the regulatory authorities and all investigators within 7 calendar days 
of the initial report of information. 
The investigator must report non-fatal and non-life-threatening SUSARs to the IRB within 
15 calendar days of the initial receipt of information. On Target Laboratories or designee will 
report non-fatal and non-life-threatening SUSARs to the regulatory authorities and all 
investigators within 15 calendar days of the initial report of information. 
The investigator must report all unanticipated adverse device effects to the IRB within 
10 calendar days of the initial receipt of information. On Target Laboratories or designee will 
report all unanticipated adverse device effects to the regulatory authorities and all investigators 
within 10 working days of the initial report of information. 








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8.2.5.3 
Exploratory Efficacy Endpoints 
In general, exploratory efficacy endpoints will be descriptive. 
8.2.5.4 
Safety Evaluations 
Safety will be evaluated using the Safety Analysis Set and will include treatment emergent 
adverse events (TEAEs), adverse device effects (ADEs), serious adverse events (SAEs), vital 
signs, physical examinations, clinical laboratory measurements, electrocardiograms, and 
concomitant medications. Treatment emergent adverse events are adverse events occurring 
during or after study drug exposure. Adverse device effects occur during or after exposure to the 
imaging device and classified as device effects by the Investigator. In general, the analysis of 
safety will be descriptive. No data will be imputed except for partial dates if required to 
determine if a medical event is a TEAE or a medication concomitant with exposure to study 
drug. 
In general, the baseline value will be considered the last non-missing value recorded for a 
particular safety parameter before exposure to study drug. Where relevant, changes from baseline 
summaries will also include the change from screening to pre-infusion. 
8.2.5.4.1 
Adverse Events and Adverse Device Effects 
For subjects in the Safety Analysis Set, medical events occurring after the signing of informed 
consent but prior to exposure to OTL38 administration will be considered a study AE, but not a 
treatment emergent AE (TEAE). It is anticipated that study AEs will be sparse and presented in 
line listings. Treatment emergent adverse events (TEAEs) will be summarized via the MedDRA 
system organ class and preferred term using subject incidence rates. Data will be tabulated by 
severity, physician assessment of the relationship to study drug, serious TEAEs, and TEAEs 
leading to death or study withdrawal. Further description of TEAEs may be defined by temporal 
onset to study drug infusion. Additional summaries of TEAEs identified as ADEs will also be 
provided. 
8.2.5.4.2 
Clinical Laboratory Evaluations 
The analysis of laboratory parameters will include descriptive statistics for the change from 
baseline to each post-baseline study visit as well as shifts from baseline to each post-baseline 
study visit for categorical lab parameters. 
In addition, shift tables (i.e., low-normal-high at baseline versus low-normal-high at last visit 
will be provided where appropriate. Urinalysis and pregnancy results will not be summarized but 
will be provided in a data listing. For all relevant laboratory data, values above or below normal 
limits will be flagged along with the direction of abnormality in line listings. 
8.2.5.4.3 
Vital Signs 
Vital signs will be summarized via descriptive statistics similar to that described above for 
clinical laboratory evaluations with regard to changes from baseline. 






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9 
ETHICS 
The study will be conducted in compliance with applicable ICH guidelines, the ICH E6 GCP 
guideline, and regulations, guidelines, and applicable laws of the locale and countries where the 
study is conducted. The study will be conducted with the approval of a duly constituted IRB/EC in 
accordance with the requirement of United States regulation Title 21 CFR Part 56 - Institutional 
Review Boards. The nature and risks of the study will be fully explained to each patient and 
written consent obtained in accordance with the requirements of 21 CFR 50 - Protection of Human 
Subjects. Patients will be informed of their rights, including the right to withdraw from the study 
at any time. 
9.1 
Patient Information and Consent 
A properly executed, written informed consent in compliance with national and local regulations 
and GCP guidelines will be obtained from each patient prior to entering the study or performing 
any study-related procedures that are not part of the patient’s standard care. The Investigator will 
submit a copy of the informed consent document to the IRB/EC for review and approval before 
patients are enrolled. The Investigator will provide a copy of the signed informed consent to the 
patient and the original will be maintained in the patient’s medical record. 
9.2 
Institutional Review Board 
The Investigator will provide the IRB/EC with all requisite material, including a copy of the 
protocol, IB, and the informed consent document. The study will not be initiated until the 
IRB/EC provides written approval of the protocol and the informed consent document and until 
approved documents have been obtained by the Investigator, and copies received by the Sponsor. 
Appropriate reports on the progress of this study by the Investigator will be made to the IRB/EC 
and the Sponsor in accordance with the applicable government regulations and in agreement with 
the Sponsor. 




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11 INVESTIGATOR’S STATEMENT 
I have read the protocol entitled “A Phase 3, Randomized, Single dose, Open-Label Study to 
Investigate the Safety and Efficacy of OTL38 Injection for Intraoperative Imaging of Folate 
Receptor Positive Lung Nodules” and agree that it contains all necessary details for carrying out 
the study as described. I will conduct this protocol as outlined therein and will make a reasonable 
effort to complete the study within the time designated. I will provide copies of the protocol and 
access to all information furnished by On Target Laboratories, Inc. to study personnel under my 
supervision. I will discuss this material with them to ensure they are fully informed about the drug 
and the study. I understand that the study may be terminated or enrollment suspended at any time 
by On Target Laboratories, Inc., with or without cause, or by me if it becomes necessary to protect 
the best interests of the study subjects. 
 
Signature of Investigator 
 Date (day/month/year) 
Printed Name of Investigator 
 Site Number 






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APPENDICES 
Appendix 1. Detailed Description of the 
 60 
Appendix 2. Detailed Description of the 
 ........................................... 73 
Appendix 3. Surgical Reporting Schematics (SAMPLE) ........................................................... 84 
Appendix 4. Back Table Analysis (SAMPLE) ........................................................................... 86 
 
 


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Appendix 1. 
Detailed Description of the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


























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Appendix 2. 
Detailed Description of the 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
















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Appendix 3. 
Surgical Reporting Schematics (SAMPLE) 


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Appendix 4. 
Back Table Analysis (SAMPLE) 
 

SAP_001.pdf: 
On Target Laboratories, Inc. 
Cytalux™ (pafolacianine) injection 
Clinical Study Report OTL-2019-OTL38-007 
Version 1.0 
 
Confidential 
16. APPENDICES 
16.1 
STUDY INFORMATION 
16.1.9 
Documentation of Statistical Methods and Interim Analysis Plans 
Statistical Analysis Plan, Version 4.0, 29 July 2021 




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Table of Contents 
List of Abbreviations ...................................................................................................................... 4 
1 
Introduction ........................................................................................................................... 5 
2 
Study Objectives .................................................................................................................... 5 
2.1 
Primary Objective ......................................................................................................... 5 
2.2 
Secondary Objectives.................................................................................................... 5 
2.3 
Exploratory Objectives ................................................................................................. 6 
2.4 
Safety Objectives .......................................................................................................... 6 
3 
Overall Study Design ............................................................................................................. 7 
4 
Study Population ................................................................................................................... 7 
5 
Treatment Assignment .......................................................................................................... 7 
6 
Sample Size Determination ................................................................................................... 8 
7 
General Analysis and Reporting Conventions .................................................................... 8 
8 
Analysis SETS ........................................................................................................................ 9 
8.1 
Full Analysis Set (FAS) ................................................................................................ 9 
8.2 
Per Protocol Analysis Set (PPAS) ................................................................................ 9 
8.3 
Safety Analysis Set (SfAS) ........................................................................................... 9 
9 
Subject Disposition and Protocol Deviations ...................................................................... 9 
9.1 
Subject Disposition ....................................................................................................... 9 
9.2 
Protocol Deviations ..................................................................................................... 10 
10 Subject Demographics and Baseline Characteristics ....................................................... 10 
11 Measurements of Treatment Compliance ......................................................................... 10 
12 Efficacy Evaluations ............................................................................................................ 10 
12.1 Primary Efficacy Endpoint ......................................................................................... 10 
12.2 Secondary Efficacy Endpoints .................................................................................... 11 
12.3 Exploratory Endpoints ................................................................................................ 13 
12.4 Safety Endpoints ......................................................................................................... 13 
13 Statistical Analysis Methods for Efficacy .......................................................................... 14 
13.1 Analytic Methods for the Primary Efficacy Endpoint ................................................ 14 
13.1.1 Sensitivity Analyses for the Primary Efficacy Endpoint ............................... 14 
13.1.2 Description of Subgroups to be Analyzed ..................................................... 15 
13.2 Analytic Methods for Secondary Efficacy Endpoints ................................................ 16 
 
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13.3 Analytic Methods for Exploratory Endpoints ............................................................. 17 
13.4 Handling of Missing Data and Subject Withdrawals .................................................. 18 
13.5 Investigator Post-Surgery Questionnaire .................................................................... 18 
14 Safety Evaluations ............................................................................................................... 18 
14.1 Overview of Safety Analysis Methods ....................................................................... 18 
14.1.1 Imputation of Partial Adverse Event Dates ................................................... 18 
14.2 Extent of Exposure ...................................................................................................... 19 
14.3 Adverse Events ........................................................................................................... 19 
14.4 Deaths, Serious Adverse Events and Adverse Events ................................................ 21 
14.5 Clinical Laboratory Evaluations ................................................................................. 21 
14.6 Vital Signs, Physical Exams and ECGs ...................................................................... 21 
14.7 Pathology and Immunohistochemistry ....................................................................... 22 
14.8 Imaging System .......................................................................................................... 22 
14.9 Prior and Concomitant Medications ........................................................................... 22 
14.10 Pregnancy Test Results ............................................................................................... 22 
15 Interim Analyses and Data Monitoring ............................................................................. 22 
16 Changes to the Analyses Planned in the Protocol or Statistical Analysis Plan .............. 23 
17 Randomization Plan ............................................................................................................ 23 
 
 
18 References ............................................................................................................................ 25 
 
 
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List of Abbreviations 
Abbreviation 
Definition 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CSE 
Clinically Significant Event (CSE) 
CSR 
Clinical Study Report 
CTDB 
Clinical Trial Database 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FN 
False Negative 
FP 
False Positive 
FPR 
False Positive Rate 
FR- 
Folate Receptor Negative 
FR+ 
Folate Receptor Positive 
 
 
ICF 
Informed Consent Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
NIR 
Near Infrared  
PPAS 
Per Protocol Analysis Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SfAS 
Safety Analysis Set 
TBR 
Tumor to Background Ratios 
TEAE 
Treatment Emergent Adverse Event 
TN 
True Negative 
TP 
True Positive 
TPR 
True Positive Rate 
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experiencing any treatment-emergent AE will also be provided. All percentages will use the 
number of subjects in the SfAS set as the denominator. An exception will be the presentation of 
ADEs which will use all subjects undergoing fluorescent light imaging as the denominator. If a 
subject has more than one AE within a system organ class, the subject will be counted only once 
in that system organ class. If a subject has more than 1 AE that codes to the same preferred term, 
the subject will be counted only once for that preferred term. 
Treatment-emergent AEs will also be summarized by the maximum relationship to study drug as 
determined by the Principal Investigator as well as the maximum severity of the event. Relationship 
to study drug will be scored as Related, Possibly Related, or Not Related. Related AEs will be 
classified as those scored as Related or Possibly Related. Severity will be rated as per CTCAE 
v5.0: 
• 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated. 
• 
Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling;  
• 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
• 
 Grade 5 Death related to AE 
If a subject experiences more than 1 AE within system organ class or preferred term, that subject 
will be counted only once for that event under the maximum severity or most related category 
within the relevant category. In the event that the relationship to study drug or the severity of the 
event is missing, for tabulation purposes the maximum relationship will be assumed, and a Grade 
3 (Severe) level of severity will be assumed.  
Adverse Events of Special Interest (AESIs) will be captured and analyzed.  An AESI is defined as an 
infusion related reaction and will be identified through the following mechanisms to include all AEs 
that meet the following criteria:  
 
 
AE that are not considered procedural in nature (Procedural complications and 
administration related problems will be excluded and defined as any AE with a preferred 
term of “procedural complication” or “infusion site discomfort” will be excluded.)  
 
AND meets at least one of the following:  
 
• AE that resulted in interruption of study drug infusion in the study drug administration data 
(study drug administration CRF; was infusion interrupted = yes; reason for interruption = 
AE)  
• AE that resulted in study drug interruption or study drug withdrawal in the AE data (all AEs 
with an action taken with study drug =drug interrupted, or drug withdrawn)  
• AE that started during the study drug infusion as per the recoded start time (AEs with a start 
date of Study Day 1 AND a start TIME within the infusion window as defined as start time > 
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infusion start time and ≤ infusion stop time; AEs that have the same start time as the study 
drug infusion will not be counted)  
• AE presumed to start during the study drug infusion as per the recorded start/stop dates and 
assigned relatedness (AEs without a recorded start time, that have both a start date and stop 
date of Study Day 1, and are indicated as Related or Possibly Related for their relationship to 
OTL38 Infusion)  
 AE that started during the study drug infusion as per the recoded start time which abate 
after infusion being stopped or reduced. 
Incidence of TEAEs will be summarized by age group, race, and gender if there are sufficient 
numbers of subjects within these subgroups. Otherwise only line listings will be provided. 
All AEs will be presented in data listings for subjects. If required, the line listings will distinguish 
between adverse events occurring after signing the ICF but prior to exposure to study drug, and 
TEAEs. If a partial date was imputed, the line listings will include both the observed and imputed 
date. Imputations for missing relationships and severities of AEs will not be included in the line 
listings. 
14.4 Deaths, Serious Adverse Events and Adverse Events 
Treatment-emergent serious AEs (SAEs), TEAEs leading to early study withdrawal, and TEAEs 
resulting in death (included in the serious definition) will be summarized for all subjects in the 
SfAS. Summary tables will reflect the number and percentage of subjects experiencing at least 1 
TEAE in each system organ class and preferred term within each AE subset (serious, leading to 
early study withdrawal, or death). In addition, the number of subjects experiencing any TEAE in 
the respective subset will be reported. 
Adverse events leading to early study withdrawal, AEs resulting in death, and SAEs will also be 
presented in data listings. 
14.5 Clinical Laboratory Evaluations 
The analysis of laboratory parameters will include descriptive statistics for the baseline and all 
post-baseline visits as well as the changes from baseline at each visit. Baseline distributions and 
shifts from baseline to each post-baseline study visit for categorical lab parameters will also be 
provided. Where relevant, as noted above, changes from baseline summaries will include a 
change from screening to pre-infusion. 
Urinalysis data will not be summarized but will be provided in a data listing. For all relevant 
laboratory data, values above or below normal limits will be flagged along with the direction of 
abnormality in line listings. 
14.6 Vital Signs, Physical Exams and ECGs 
The analysis of vital signs and physical exams will be summarized via descriptive statistics similar 
to that described above for clinical laboratory evaluations. Vital signs and physical exams will 
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