Conditions: Ovarian Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 140
Healthy volunteers: no

Brief summary:
This is a phase 3, randomized, multi-center, single dose, open label, pivotal study in patients diagnosed with, or with high clinical suspicion of, ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery.

Detailed description:
The Phase 3 study is to confirm the efficacy of OTL38 in combination with fluorescent light to detect additional Folate Receptor-positive (FR+) ovarian cancer lesions not detected by palpation and visualization under normal light in patients with FR+ ovarian cancer scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery

Arms:
arm 1: Patient injected with OTL38, but does not undergo fluorescent imaging arm 2: Patient injected with OTL38 and undergoes near infrared imaging

Interventions: intervention 1: OTL38 intervention 2: near infrared camera imaging system intervention 3: laparotomy
Intervention descriptions: intervention 1: 0.025 mg/kg of OTL38 in 250ml dextrose 5% in water (D5W) infused intravenously over 60 minutes intervention 2: Infrared imaging used to excite OTL38 for fluorescence intervention 3: primary surgical cytoreduction, interval debulking, or recurrent ovarian cancer surgery

Protocol document:
Prot_000.pdf: 










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Eligibility Criteria Inclusion: 
1. Female patients 18 years of age and older 
2. Have a primary diagnosis, or at high clinical suspicion, of primary ovarian 
cancer (of epithelial type), planned for primary surgical cytoreduction, 
interval debulking, or have recurrent ovarian cancer surgery, and: 
o Who are scheduled to undergo laparotomy for the debulking surgery 
OR 
o Who are scheduled to undergo laparoscopy and pre-authorized to undergo 
laparotomy for the debulking surgery if cancer is detected on the laparoscopy 
3. A negative serum pregnancy test at Screening followed by a negative urine 
pregnancy test on the day of surgery or day of admission for female patients 
of childbearing potential 
4. Female patients 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 for participation in the study 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. Known FR-negative ovarian cancer 
3. Planned surgical debulking via laparoscopy or robotic surgery, with no intent 
of laparotomy. 
4. Patients with known ovarian cancer miliary disease determined pre-
operatively to be inoperable. 
5. Any medical condition that, in the opinion of the investigators, could 
potentially jeopardize the safety of the patient 
6. History of anaphylactic reactions 
7. History of allergy to any of the components of OTL38, including folic acid 
8. Pregnancy or positive pregnancy test 
9. Clinically significant abnormalities on electrocardiogram (ECG) 
10. Presence of any psychological, familial, sociological or geographical 
condition potentially hampering compliance with the study protocol and 
follow-up schedule 
11. Impaired renal function defined as eGFR< 50 mL/min/1.73m2 
12. Impaired liver function defined as values > 3x the upper limit of normal 
(ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), or total bilirubin. 
13. Known Stage IV ovarian cancer with brain metastases 
14. Received an investigational agent in another clinical trial within 30 days prior 
to surgery 
15. Known sensitivity to fluorescent light 
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Table of Contents 
1 PROTOCOL SYNOPSIS .................................................................................................... 4 
2 SCHEDULE OF PROCEDURES ..................................................................................... 12 
3 BACKGROUND INFORMATION .................................................................................. 18 
3.1 
Background ................................................................................................................ 18 
3.2 
Rationale .................................................................................................................... 18 
3.3 
Investigational Product ............................................................................................... 19 
3.4 
Risks and Benefits of OTL38 ...................................................................................... 20 
3.4.1 Risks ............................................................................................................... 20 
3.4.2 Benefits ........................................................................................................... 21 
4 STUDY OBJECTIVES ..................................................................................................... 22 
4.1 
Primary ....................................................................................................................... 22 
4.2 
Secondary ................................................................................................................... 22 
4.3 
Exploratory ................................................................................................................. 22 
5 STUDY DESIGN ............................................................................................................... 23 
5.1 
Overall Investigation Plan ........................................................................................... 23 
5.1.1 Study Assessments .......................................................................................... 23 
5.1.2 Safety assessment ............................................................................................ 24 
5.2 
Eligibility Criteria ....................................................................................................... 24 
5.2.1 Inclusion Criteria ............................................................................................ 24 
5.2.2 Exclusion ........................................................................................................ 25 
5.3 
Patient Enrollment ...................................................................................................... 25 
5.3.1 Randomization ................................................................................................ 26 
5.4 
Patient Discontinuation Criteria .................................................................................. 26 
5.5 
Study Drug Information and Dosage ........................................................................... 26 
5.5.1 Identification and Description of Test Article .................................................. 26 
5.5.2 Packaging and Labeling .................................................................................. 27 
5.5.3 Storage and Handling of Test Article............................................................... 27 
5.5.4 Study Drug Administration ............................................................................. 27 
5.5.5 Camera/Imaging System ................................................................................. 28 
5.5.5.1 
Summary of the Camera/Imaging System Requirements ................... 28 
5.5.5.2 
Quality System Requirements ........................................................... 29 
5.6 
Concomitant Medications ........................................................................................... 30 
5.6.1 Allowed Medications ...................................................................................... 30 
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5.6.2 Prohibited Medications ................................................................................... 30 
5.7 
Schedule of Events ..................................................................................................... 30 
5.7.1 Measurement and Evaluations ......................................................................... 30 
5.7.1.1 
Visit 1 (Screening, up to Day -28) .................................................... 30 
5.7.1.2 
Visit 2-Day of Admission (Day 0) or Day of Surgery (Day 1): ......... 31 
5.7.1.3 
Visit 3 (Day 7 [± 4]): ........................................................................ 33 
5.7.1.4 
Visits 4 (Day 28 [±4]): ...................................................................... 33 
5.7.1.5 
Follow-up (
 ....................................................................... 33 
5.7.2 Interim Analysis .............................................................................................. 34 
5.7.3 Surgical Reporting Schematic ......................................................................... 34 
5.7.4 Post-Surgery Questionnaire ............................................................................. 34 
5.7.5 Pathology Samples .......................................................................................... 34 
5.7.6 Pharmacokinetic Samples ................................................................................ 34 
6 STUDY ENDPOINTS ....................................................................................................... 35 
6.1 
Primary Efficacy ......................................................................................................... 35 
6.2 
Secondary Efficacy ..................................................................................................... 35 
6.3 
Exploratory Efficacy ................................................................................................... 36 
6.4 
Safety ......................................................................................................................... 37 
6.5 
Pharmacokinetics ........................................................................................................ 37 
7 PROCEDURES FOR REPORTING ADVERSE EVENTS ............................................ 38 
7.1 
Adverse Events Definitions ........................................................................................ 38 
7.2 
Reporting of Adverse Events ...................................................................................... 39 
7.2.1 Adverse Events ............................................................................................... 39 
7.2.2 Laboratory Abnormalities ............................................................................... 39 
7.2.3 Serious Adverse Events ................................................................................... 39 
7.2.4 Reporting of Pregnancies ................................................................................ 40 
7.2.5 Disease Progression ........................................................................................ 40 
7.2.6 Overdoses ....................................................................................................... 40 
7.3 
Classification of Adverse Events by Severity .............................................................. 40 
7.4 
Classification of Adverse Events by Relationship to Study Drug Administration ........ 41 
7.5 
Adverse Events Qualifying for Expedited Reporting ................................................... 41 
8 DATA RECORDING, CRF PROCESSING, AND STATISTICAL ANALYSIS ........... 42 
8.1 
Data Recording and CRF Processing .......................................................................... 42 
8.2 
Statistical Methods ..................................................................................................... 42 
8.2.1 Sample Size .................................................................................................... 42 
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8.2.2 Analysis Sets ................................................................................................... 43 
8.2.3 Description of Subgroups to be Analyzed ........................................................ 44 
8.2.4 Subject Demographics, Baseline Disease Status, and Disposition .................... 44 
8.2.5 Efficacy Evaluations ....................................................................................... 44 
8.2.5.1 
Primary Analysis for the Primary Efficacy Endpoint......................... 44 
8.2.5.2 
Sensitivity Analyses for the Primary Efficacy Endpoint .................... 45 
8.2.5.3 
Analytic Methods for Secondary Efficacy Endpoints ........................ 45 
8.2.5.4 
Analytic Methods for Other Endpoints ............................................. 45 
8.2.6 Safety Evaluations........................................................................................... 47 
8.2.6.1 
Adverse Events ................................................................................. 47 
8.2.6.2 
Clinical Laboratory Evaluations........................................................ 47 
8.2.6.3 
Pharmacokinetics.............................................................................. 47 
8.2.6.4 
Vital Signs ........................................................................................ 48 
8.2.6.5 
Physical Examination ....................................................................... 48 
8.2.6.6 
Electrocardiogram ............................................................................ 48 
8.2.6.7 
Pathology and Immunohistochemistry .............................................. 48 
8.2.6.8 
Imaging System ................................................................................ 48 
8.2.6.9 
Prior and Concomitant Medications .................................................. 48 
8.3 
Handling of Missing Data, Subject Withdrawals, and Treatment Failures ................... 49 
8.4 
Interim Analyses ......................................................................................................... 49 
9 ETHICS ............................................................................................................................. 50 
9.1 
Patient Information and Consent ................................................................................. 50 
9.2 
Institutional Review Board ......................................................................................... 50 
10 STUDY ADMINISTRATION ........................................................................................... 51 
10.1 Data ............................................................................................................................ 51 
10.2 Study Record Retention .............................................................................................. 51 
10.3 Patient Anonymity ...................................................................................................... 51 
10.4 Publications ................................................................................................................ 51 
11 INVESTIGATOR’S STATEMENT ................................................................................. 52 
12 REFERENCES .................................................................................................................. 53 
 
 
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List of Appendices 
Appendix 1. 
OTL38 Dose Preparation Manual ....................................................................... 55 
Appendix 2. 
Detailed Description of the Imaging Systems ..................................................... 58 
Appendix 2A. 
System .......................................................... 58 
Appendix 2B. 
Platform...................................................... 70 
Appendix 3. 
Surgical Reporting Forms .................................................................................. 83 
Appendix 3A. 
 ................................................. 83 
Appendix 3B. 
 .................... 84 
Appendix 3C. 
 ................... 85 
Appendix 3D. 
 ........................................... 86 
Appendix 3E. 
 ...................................................... 87 
Table of Figures 
Figure 1. Excitation and Emission Spectra of OTL38 .............................................................. 28 
Figure 2. Classification Table ................................................................................................. 35 
 
 
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List of Abbreviations 
Abbreviation 
Definition  
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AEL 
Accessible Emission Limits 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvate transaminase) 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
FITC 
Fluorescein isothiocyanate 
FNR 
False Negative Rate 
FPR 
False Positive Rate 
FR 
Folate Receptor 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation  
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIL 
Miliary disease 
mITT 
Modified Intent-to-Treat 
PK 
Pharmacokinetic(s)  
SAE 
Serious adverse event 
SUSAR 
 Suspected unexpected serious adverse reaction 
TEAE 
Treatment Emergent Adverse Event 
TN 
True Negative 
TP 
True Positive 
TPR 
True Positive Rate 
ULN 
Upper limit of the normal range 
WHO 
World Health Organization 
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3.4.2 
Benefits 
The potential benefits of OTL38 ovarian cancer imaging are: 
• Improved staging of the tumor 
• Removal of more lesions 
• Added assurance of clean margins to excised tumors. 
In a preliminary study by van Dam et al (2011), significantly more lesions were detected by 
surgeons using Folate-FITC than with visual observation alone (34 vs. 7; p < 0.001). Lesions as 
small as 1 mm could be detected and removed. This resulted in better staging of patients as more 
lesions could be visualized but, more importantly, it resulted in greater tumor debulking. Since 
the degree of tumor removal directly affects the prognosis, this was a large potential benefit. This 
would need to be studied with OTL38. Use of OTL38 would not change the surgeon’s option to 
remove additional tissue because of impressions based on experience, visualization, or tactile 
senses. The smallest detectable tumor using OTL38 in the phase 2 study 
 
in volume. 
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5.1.2 
Safety assessment 
All AEs deemed to be related to OTL38 and of severity graded as mild, moderate or severe will 
be monitored. The following definitions of severity will be considered in this determination: 
• 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. 
• 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. 
Safety assessments will also include changes in labs, vitals, and ECG. 
5.2 
Eligibility Criteria 
5.2.1 
Inclusion Criteria 
To be considered eligible to participate in this study, a patient must meet all the inclusion criteria 
listed below: 
1. Female patients 18 years of age and older 
2. Have a primary diagnosis, or at high clinical suspicion, of primary ovarian cancer 
(of epithelial type), planned for primary surgical cytoreduction, interval debulking, or 
have recurrent ovarian cancer, and: 
• Who are scheduled to undergo laparotomy for the debulking surgery 
OR 
• Who are scheduled to undergo laparoscopy and pre-authorized to undergo laparotomy 
for the debulking surgery if cancer is detected on the laparoscopy 
3. A negative serum pregnancy test at Screening followed by a negative urine pregnancy 
test on the day of surgery or day of admission for female patients of childbearing 
potential 
4. Female patients 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 for 
participation in the study 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 
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5.2.2 
Exclusion 
Patients will be excluded if they meet any of the exclusion criteria listed below: 
1. Previous exposure to OTL38 
2. Known FR-negative ovarian cancer 
3. Planned surgical debulking via laparoscopy or robotic surgery, with no intent of 
laparotomy 
4. Patients with known ovarian cancer miliary disease determined pre-operatively to be 
inoperable 
5. Any medical condition that in the opinion of the investigators could potentially 
jeopardize the safety of the patient 
6. History of anaphylactic reactions 
7. History of allergy to any of the components of OTL38, including folic acid 
8. Pregnancy or positive pregnancy test 
9. Clinically significant abnormalities on the electrocardiogram (ECG) 
10. Presence of any psychological, familial, sociological or geographical condition 
potentially hampering compliance with the study protocol and follow-up schedule 
11. Impaired renal function defined as eGFR< 50 mL/min/1.73m2 
12. Impaired liver function defined as values > 3x the upper limit of normal (ULN) for 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), or total bilirubin. 
13. Known Stage IV ovarian cancer with brain metastases 
14. Received an investigational agent in another clinical trial within 30 days prior to surgery 
15. Known sensitivity to fluorescent light 
5.3 
Patient Enrollment 
Prior to enrolling patients in the study, Sponsor will require copies of the site’s written IRB/IEC 
approval of the protocol, informed consent forms, and all other applicable material. All patients 
must provide informed consent before commencement of study-related procedures. All patient 
who enter the screening period (entry is defined as the point at which the patient signs the 
informed consent) will receive a unique patient identification number that will be used to identify 
the patient throughout the clinical study. 
The patient identification number must remain constant throughout the entire clinical study; it 
must not be changed after initial assignment, even if the patient is rescreened. The patient 
identification number will not necessarily be the same as the randomization number assigned in 
the study. 
A patient will be considered enrolled when the patient signs the informed consent form and 
receives the study drug. 
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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. 
An adverse device effect (ADE) is defined as any untoward and unintended response to a medical 
device, in this study, the camera/imaging system. This definition includes any adverse event 
resulting from insufficiencies or inadequacies in the instructions for use or the deployment of the 
device, as well as any adverse 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. 
A suspected ADE is a subset of all ADEs for which there is a reasonable possibility (ie, 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. 
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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)] 
7.2 
Reporting of Adverse Events 
7.2.1 
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 (including ADEs) 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 (including ADEs) beginning 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 (including ADEs) 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 (including ADEs) 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. 
7.2.2 
Laboratory Abnormalities 
To the extent possible, all 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 
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 and interventions 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. 
7.2.3 
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 7.5 
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below. 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 AEs must be submitted to the IRB/EC in an annual report. 
7.2.4 
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 3 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. 
7.2.5 
Disease Progression 
The progression of the ovarian cancer per se will not constitute an AE. However, if the 
progression of the ovarian cancer meets the criteria for an SAE, then it should be reported as an 
SAE (see Page 2). 
7.2.6 
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. 
7.3 
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. 
• 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 
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7.4 
Classification of Adverse Events by Relationship to Study Drug 
Administration 
The relationship of each AE to the study drug administration or TEAE will be assessed by the 
investigator; after careful consideration, according to the following guidelines: 
Definitely 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 
Probably Related: An adverse event that has a timely relationship to the administration of the 
study drug and follows a known pattern of response, but for which a potential alternative cause 
may be present 
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 
7.5 
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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8.2.6 
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. For all safety assessments, the baseline value will be the last non-missing value 
recorded for a particular safety parameter before exposure to study drug. In general, the analysis 
of safety will be descriptive. No data will be imputed except for partial dates if required to 
determine if an adverse event is treatment emergent or a medication concomitant with exposure 
to study drug. 
8.2.6.1 
Adverse Events 
Adverse events occurring prior to exposure to OTL38 administration will be provided 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 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 potential ADEs will also be 
provided. 
8.2.6.2 
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. 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. 
8.2.6.3 
Pharmacokinetics 
The pharmacokinetics of OTL38 will be estimated by fitting compartmental pharmacokinetic 
models to the serial plasma concentration-time (Ct) data using established methods including 
maximum likelihood parameter estimation and nonlinear mixed-effects (NLME) modeling 
approaches, with the patient serving as the random effect. Various structural PK and error 
models will be fit to data using a qualified, standard software package. Primary PK parameters 
will be estimated at the population level and for individual patients as post-hoc empirical 
Bayesian estimates (EBEs). The actual primary parameters may vary depending on the supported 
model, but are likely to include systemic clearance (CL), volumes of distribution of the central 
and peripheral compartment(s) (Vc, Vp), distributional clearance (CLd), or derivatives thereof. 
Inter-patient variability in select PK parameters will be assessed as part of the model, as will the 
residual error. Secondary parameters may include, but are not limited to: model predicted 
maximum concentration (Cmax), time of Cmax (Tmax), area under the concentration-time curve 
(AUC) to the last time point (AUClast) and to infinity (AUCinf), and the terminal elimination half-
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life (T1/2). The model predicted Ct profiles and observed Ct data will be presented as figures for 
the population and individual level. Individual primary EBE and secondary parameters will be 
presented as listings at the patient level. 
Potential covariates explaining inter-subject PK variability, and their influence upon PK 
parameters, will be initially screened using a two-stage approach with standard parametric 
statistical tests on the individual patient EBEs, focusing on CL. Covariates of interest will include 
baseline demographic values (e.g. height, weight, age, BSA, BMI, race), and laboratory values 
predictive of renal or hepatic function (e.g. BUN, creatinine, calculated creatinine clearance or 
GFR, AST, ALT, alkaline phosphatase, albumin, and total bilirubin). If warranted, a single stage 
approach with direct incorporation of covariates into the NLME PK model may be undertaken 
using a forward addition - backward deletion method at an alpha level of 0.05. 
The final model PK parameter estimates, and any bootstrapped results, will be reported as a 
table, including the estimates, their standard errors, or confidence intervals. The covariate 
coefficient estimates, their standard errors, and the associated P values for those significant at the 
alpha level of 0.05 will be tabulated. Relationships between covariates and PK parameters will 
be graphically presented as figures. Additional details will be found in the PK analysis plan 
(PKAP). 
8.2.6.4 
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. 
8.2.6.5 
Physical Examination 
Physical examination results will be provided in line listings only. 
8.2.6.6 
Electrocardiogram 
Electrocardiogram results will be provided in line listings only. 
8.2.6.7 
Pathology and Immunohistochemistry 
Pathology and immunohistochemistry results will be provided in line listings. 
8.2.6.8 
Imaging System 
Times on and off for the imaging system for each subject will be provided in line listings. 
8.2.6.9 
Prior and Concomitant Medications 
The prior and concomitant medications will be coded to identify the drug class and preferred 
drug name. Concomitant medications will include all medications that started, or were 
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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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10 STUDY ADMINISTRATION 
10.1 Data 
All information regarding the nature of the proposed investigation provided by the Sponsor or 
Study Monitor to the Investigator (with the exception of information required by law or regulations 
to be disclosed to the IRB, the patient, or the appropriate regulatory authority) must be kept in 
confidence by the Investigator. 
All data recorded during the study must be available for audit against source data and for 
compliance with GCP and specific protocol requirements. Monitoring of the study progress and 
conduct will be ongoing. The Investigator will be responsible for the following: 
• Monitoring study conduct to ensure that the rights of patients are protected; 
• Monitoring study conduct to ensure trial compliance with GCP guidelines; and 
• Monitoring accuracy, completion, and verification from source documents of study data. 
10.2 Study Record Retention 
US FDA regulations (21 CFR 312.62[c]) and the ICH Guideline for GCP (section 4.9 of that 
guideline) require that records and source documents pertaining to the conduct of this study and 
the distribution of investigational drug, including eCRFs, consent forms, laboratory test results, 
and medication inventory records, must be retained by the Investigator for 2 years after the last 
marketing application approval in an ICH region or for at least 2 years since formal discontinuation 
of clinical development of the investigational product. All state and local laws for retention of 
records also apply. The Investigator agrees to adhere to the document retention procedures by 
signing the protocol. 
10.3 Patient Anonymity 
The anonymity of participating patients must be maintained. Patients will be identified by their 
initials and an assigned patient number on eCRFs, and other documents submitted to the Study 
Monitor. Documents that will not be submitted to the Study Monitor and that identify the patient 
(e.g., the signed informed consent document), must be maintained in strict confidence by the 
Investigator, except to the extent necessary to allow auditing by the appropriate regulatory 
authority, the Study Monitor, or Sponsor representatives. 
10.4 Publications 
Following completion of the study, the results from the entire study, followed by the results from 
subsets of the study, may be reported at a scientific meeting and/or be published in a scientific 
journal. On Target Laboratories, Inc. will support these activities and will work with the 
Investigator(s) to determine how the meeting abstract, presentation and/or manuscript is written 
and edited, the number and order of authors, the meeting and/or journal to which it will be 
submitted, and other related activities. On Target Laboratories, Inc. acknowledges the right of 
the Investigator(s) to publish the results of this study after the entire study has been completed, 
but also reserves the right to a 30-day window to review the publication for regulatory 
compliance as well as for protection of its intellectual property. 
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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 (OTL38) for Intra-operative Imaging of 
Folate Receptor- Positive Ovarian Cancer”, 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 patients. 
 
Signature of Investigator 
 Date (day/month/year) 
Printed Name of Investigator 
 Site Number 
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12 REFERENCES 
Al Rawahi T, Lopes AD, Bristow RE, Bryant A, Elattar A, Chattopadhyay S, Galaal K. Surgical 
cytoreduction for recurrent epithelial ovarian cancer. Cochrane Database Syst Rev. 
2013(2):CD008765. doi: 10.1002/14651858.CD008765.pub3. 
Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival effect of maximal 
cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. 
J Clin Oncol. 2002;20(5):1248-59. doi: 10.1200/JCO.2002.20.5.1248. 
Crane LM, Arts HJ, van Oosten M, Low PS, van der Zee AG, van Dam GM, Bart J. The effect 
of chemotherapy on expression of folate receptor-alpha in ovarian cancer. Cell Oncol (Dordr). 
2012;35(1):9-18. doi: 10.1007/s13402-011-0052-6. 
Eisenkop SM, Friedman RL, Wang H-J. Complete Cytoreductive Surgery Is Feasible and 
Maximizes Survival in Patients with Advanced Epithelial Ovarian Cancer: A Prospective Study. 
Gynecologic Oncology. 1998;69(2):103-8. doi: https://doi.org/10.1006/gyno.1998.4955. 
Fitzmaurice GM, Laird NM, Ware JH. Applied Longitudinal Analysis. 2nd ed. Hoboken, NJ: 
John Wiley & Sons; 2011. 
Hilbe JM. Modeling Count Data. Cambridge: Cambridge University Press; 2014. 
Ibeanu OA, Bristow RE. Predicting the outcome of cytoreductive surgery for advanced ovarian 
cancer: a review. Int J Gynecol Cancer. 2010;20 Suppl 1:S1-11. doi: 
10.1111/IGC.0b013e3181cff38b. 
Kalli KR, Oberg AL, Keeney GL, Christianson TJ, Low PS, Knutson KL, Hartmann LC. Folate 
receptor alpha as a tumor target in epithelial ovarian cancer. Gynecol Oncol. 2008;108(3):619-
26. doi: 10.1016/j.ygyno.2007.11.020. 
Kosary CL. Cancer of the Ovary. In: Ries LAG YJ, Keel GE, Eisner MP, Lin YD, Horner M-J, 
editor. SEER Survival Monograph: Cancer survival among adults: US SEER program, 1988-
2001, patient and tumor characteristics. Bethesda, MD: National Cancer Institute, SEER 
Program, NIH 2007. 
Leamon CP, Low PS. Membrane folate-binding proteins are responsible for folate-protein 
conjugate endocytosis into cultured cells. Biochemical Journal. 1993;291(3):855-60. doi: 
10.1042/bj2910855. 
Markert S, Lassmann S, Gabriel B, Klar M, Werner M, Gitsch G, Kratz F, Hasenburg A. Alpha-
folate receptor expression in epithelial ovarian carcinoma and non-neoplastic ovarian tissue. 
Anticancer Res. 2008;28(6A):3567-72. 
Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP. Folate receptor expression in 
carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal 
Biochem. 2005;338(2):284-93. doi: 10.1016/j.ab.2004.12.026. 
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Ross JF, Chaudhuri PK, Ratnam M. Differential regulation of folate receptor isoforms in normal 
and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications. 
Cancer. 1994;73(9):2432-43. 
SEER. Surveillance Epidemiology and End Results US National Cancer Institute; 2016 [cited 
2016 15 August]. Available from: http://seer.cancer.gov/statfacts/html/ovary.html. 
Shih KK, Chi DS. Maximal cytoreductive effort in epithelial ovarian cancer surgery. J Gynecol 
Oncol. 2010;21(2):75-80. doi: 10.3802/jgo.2010.21.2.75. 
Toffoli G, Russo A, Gallo A, Cernigoi C, Miotti S, Sorio R, Tumolo S, Boiocchi M. Expression 
of folate binding protein as a prognostic factor for response to platinum-containing 
chemotherapy and survival in human ovarian cancer. Int J Cancer. 1998;79(2):121-6. 
van Dam GM, Themelis G, Crane LM, Harlaar NJ, Pleijhuis RG, Kelder W, Sarantopoulos A, de 
Jong JS, Arts HJ, van der Zee AG, Bart J, Low PS, Ntziachristos V. Intraoperative tumor-
specific fluorescence imaging in ovarian cancer by folate receptor-alpha targeting: first in-human 
results. Nat Med. 2011;17(10):1315-9. doi: 10.1038/nm.2472. 
van Melick RGM, Bakker D, Meester RJC, Cilia G, Löwik CWG, editors. DLP technology's 
pivotal role in O2view's versatile medical projection/illumination device. SPIE MOEMS-
MEMS; 2010: SPIE. 
Weitman SD, Lark RH, Coney LR, Fort DW, Frasca V, Zurawski VR, Kamen BA. Distribution 
of the Folate Receptor GP38 in Normal and Malignant Cell Lines and Tissues. Cancer Research. 
1992;52(12):3396-401. 
 
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APPENDIX 1. OTL38 DOSE PREPARATION MANUAL 
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SAP_001.pdf: 
On Target Laboratories, Inc. 
Clinical Study Report Appendices 
OTL-2016-OTL38-006 
OTL38 (Pafolacianine Sodium) 
16.1.9 Documentation of Statistical Methods 
 
OTL-2016-OTL38-006 Statistical Analysis Plan V1, Dated 16 May 2017 
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STATISTICAL ANALYSIS PLAN 
Study Title: 
A Phase 3, Randomized, Single Dose, Open-Label Study 
to Investigate the Safety and Efficacy of OTL38 Injection 
(OTL38) for Intra-operative Imaging of Folate Receptor 
Positive Ovarian Cancer. 
Sponsor: 
On Target Laboratories, LLC 
Protocol No.: 
OTL-2016-OTL38-006 
Protocol Version/Date 
Version 1, 16 May 2017 
Phase of Development: 
3 
Analysis Plan Version/Date: 
Version 1, 16 May 2017 
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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 Objects .......................................................................................................... 5 
3 Overall Study Design .............................................................................................................. 6 
4 Study Population ..................................................................................................................... 6 
5 Treatment Assignment ........................................................................................................... 6 
6 Sample Size Determination .................................................................................................... 7 
7 General Analysis and Reporting Conventions ..................................................................... 8 
8 Analysis Populations ............................................................................................................... 8 
8.1 Full Analysis Set (FAS) ................................................................................................... 8 
8.2 Per Protocol Analysis Set (PPAS) .................................................................................... 8 
8.3 Safety Analysis Set (SAS)................................................................................................ 9 
8.4 Evaluable Lesions ............................................................................................................ 9 
8.5 Pharmacokinetic Analysis Set .......................................................................................... 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 ............................................................................................................. 11 
12.1 Primary Efficacy Endpoint ............................................................................................. 11 
12.2 Secondary Efficacy Endpoints ....................................................................................... 11 
12.3 Exploratory Endpoints .................................................................................................... 12 
12.4 Safety Endpoints ............................................................................................................ 13 
12.5 Pharmacokinetic Endpoints ............................................................................................ 13 
13 Statistical Analysis Methods for Efficacy ........................................................................... 14 
13.1 Analytic Methods for the Primary Efficacy Endpoint ................................................... 14 
13.1.1 Description of Subgroups to be Analyzed ......................................................... 14 
13.1.2 Sensitivity Analyses for the Primary Efficacy Endpoint ................................... 15 
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13.2 Analytic Methods for Secondary Efficacy Endpoints .................................................... 15 
13.3 Analytic Methods for Exploratory Endpoints ................................................................ 15 
13.3.1 Sensitivities, False Positive Rates, and Positive Predictive Values ................... 15 
13.3.2 Proportion of Subjects With at Least One Additional Lesion Detected by 
OTL38 and Fluorescent Light Not Detected by Normal Light – Various 
Lesion Types ...................................................................................................... 16 
13.3.3 Number of Additional Lesions Detected by OTL38 and Fluorescent Light 
Not Detected by Normal Light – Various Lesion Types ................................... 16 
13.3.4 Surgical Plan Changes ....................................................................................... 17 
13.3.5 Pharmacokinetics ............................................................................................... 17 
13.3.6 
 17 
13.4 Handling of Missing Data and Subject Withdrawals ..................................................... 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 of Special Interest ..................... 20 
14.5 Clinical Laboratory Evaluations ..................................................................................... 20 
14.6 Vital Signs, Physical Exams and ECGs ......................................................................... 20 
14.7 Pathology and Immunohistochemistry ........................................................................... 20 
14.8 Imaging System .............................................................................................................. 21 
14.9 Prior and Concomitant Medications ............................................................................... 21 
15 Interim Analyses and Data Monitoring .............................................................................. 21 
16 Changes to the Analyses Planned in the Protocol or Statistical Analysis Plan ............... 21 
References ..................................................................................................................................... 22 
 
 
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List of Abbreviations 
Abbreviation 
Definition 
AE 
Adverse Event 
ADE 
Adverse Device Effect 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
FAS 
Full Analysis Set 
FN 
False Negative 
FP 
False Positive 
FR+ 
Folate Receptor Positive 
FPR 
False Positive Rate 
GLMM 
Generalized Linear Mixed Model 
IC 
Informed Consent 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
ML 
Maximum Likelihood 
NB2 
Negative Binomial 2 
PPAS 
Per Protocol Analysis Set 
PPV 
Positive Predictive Value 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
SD 
Standard Deviation 
TEAE 
Treatment Emergent Adverse Event 
TN 
True Negative 
TP 
True Positive 
TPR 
True Positive Rate 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) provides detailed information and guidance regarding the 
planned analyses to be conducted to address the trial objectives outlined in protocol OTL-2016-
OTL38-006, Version 1 dated May 16, 2017, “A Phase 3, Randomized, Single Dose, Open-Label 
Study to Investigate the Safety and Efficacy of OTL38 Injection (OTL38) for Intra-operative 
Imaging of Folate Receptor Positive Ovarian Cancer”. Should an amendment to the finalized SAP 
become necessary prior to conducting the analysis, the Sponsor or its representatives will 
document any amendments including the date of the change and the rationale. Additional analyses 
beyond those planned in the SAP will be identified and described in the clinical study report 
(CSR). Draft tables, listings and figures will be provided in a separate document. 
The statistical analysis, data integrity processes, and computer software validation will follow the 
SOPs provided by the Contract Research Organization conducting the operational aspects of the 
trial and should follow the statistical principles as outlined in ICH E91. 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to confirm the efficacy of OTL38 in combination with 
fluorescent light to detect additional Folate Receptor-positive (FR+) ovarian cancer lesions not 
detected by palpation and visualization under normal light in patients with FR+ ovarian cancer 
scheduled to undergo primary surgical cytoreduction, interval debulking, or recurrent ovarian 
cancer surgery. 
2.2 
Secondary Objectives 
The secondary objectives are: 
• To estimate the proportion of folate positive ovarian cancer patients in whom all lesions 
detected by fluorescent light only are histologically negative, the patient level False 
Positive Rate (FPRp) 
• To estimate the Sensitivity and False Positive Rate for OTL38 in combination with 
fluorescent light with respect to the detection of FR+ ovarian cancer lesions confirmed 
by 
 pathology. 
• To assess the safety of using OTL38 and 
 Imaging System for 
intraoperative imaging with OTL38. 
2.3 
Exploratory Objects 
The exploratory objectives are: 
• 
 
                                                            
1 Guidance for Industry: E9 Statistical Principles for Clinical Trials. September 1998. 
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7 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
The following is a list of general analysis and reporting conventions to be applied for this study. 
• Baseline will be defined as the last recorded non-missing observation prior to exposure to 
study drug. 
• Categorical variables will be summarized using counts (n) and percentages (%) and will 
be presented in the form “n (xx.x)”. Percentages will be based on the relevant total category 
count excluding missing data if not otherwise mentioned. To ensure completeness, where 
relevant, summaries for categorical and discrete variables will include all categories, even 
if no patients had a response in a particular category. 
• Continuous variables will be summarized using mean, SD, minimum, maximum, median, 
and number of patients. The mean and median will be reported to one more level of 
precision than the original observations, and the SD will be reported to 2 more levels of 
precision than the original observations. The minimum and maximum will be the same 
precision as the original data. 
• For tests of hypotheses, the associated p-value and confidence interval (CI) will be 
reported, where applicable. All p-values will be rounded to 3 decimal places; p-values 
that round to “0.000” will be presented as “<0.001”. 
• Dates will be displayed as ddmmmyyyy (e.g., 24Jan2005). 
• Age (in years) will be calculated using the date of birth and the date of informed consent 
as (date of informed consent – date of birth) / 365.25. 
8 
ANALYSIS POPULATIONS 
The following definitions will be used to derive the analysis sets for the study. 
8.1 
Full Analysis Set (FAS) 
The FAS for the primary analysis of the primary endpoint will include patients exposed to 
OTL38 and randomized to undergo fluorescent imaging (OTL38+Imaging) who: 
• Were evaluated under both normal light and fluorescent light imaging, and 
• Had central pathology and histology confirmation for at least one FR+ Ovarian Cancer 
lesion detected under normal light or fluorescent light imaging 
For the evaluation of the primary efficacy endpoint, only the evaluable lesions contributed by 
FAS subjects will be considered (see Section 8.4). The FAS will also be referred to as the 
modified Intent-to-Treat (mITT) analysis set. 
8.2 
Per Protocol Analysis Set (PPAS) 
The per protocol analysis set will include all patients meeting the FAS criteria in addition to the 
following criteria: 
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• The number and percent of patients who did not complete the study and the reason for 
early withdrawal overall and by randomized group assignment 
Patients will be considered enrolled if they sign the informed consent (IC) and are exposed to 
study drug. Patients who signed the IC and receive study drug will serve as the denominator 
for the calculation of percentages. An exception will be the percentages calculated for early 
withdrawal reasons which will be based on the number of patients not completing the study. 
A data listing for all enrolled patients with regard to disposition will also be provided. 
Patients who sign the IC but are not exposed to study drug will not be represented in any further 
analyses or line listings. 
9.2 
Protocol Deviations 
All protocol deviations will be recorded on the protocol deviation case report from (eCRF) and 
will be reported in line listings. Major protocol deviations will be identified prior to database 
freeze for the final analysis of endpoints other than 
 (see Section 15; Interim Analyses 
and Data Monitoring). Major protocol deviations will be analyzed by aggregate summary and 
line listings. For aggregate summaries, data will be presented overall and by randomized group 
assignment and for each analysis population. If the number of major protocol deviations is small, 
aggregate summaries will not be presented. 
10 SUBJECT DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Descriptive statistics for patient demographics and baseline disease status will be provided. 
Demographics will be grouped by patients exposed to OTL38, patients randomized to no 
fluorescent light imaging, and patients randomized to undergo fluorescent light imaging, and 
overall randomized groups. If all patients exposed to OTL38 are subsequently randomized, the 
separate category for patients exposed to OTL38 may be omitted. Demographic variables will 
include, but are not limited to: age, sex, and race/ethnicity. 
Baseline characteristics will include, but are not limited to: medical history, ovarian cancer 
history, ovarian cancer type, ovarian cancer stage, height, weight, and body mass index (BMI). 
Summaries will be tabulated for the mITT (FAS) group and the Safety Analysis Set. Individual 
demographic and baseline characteristics data will also be presented in line listings. 
11 MEASUREMENTS OF TREATMENT COMPLIANCE 
Study drug is administered as a single infusion. The number of patients signing the IC but not 
receiving study drug will be presented in the disposition summary. For patients exposed to study 
drug, the dose received will be listed in the study drug administration line listing. 
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13.3.4 Surgical Plan Changes 
The proportion of patients in whom the Pre-Fluorescence Surgical Plan was changed based on 
fluorescent imaging, both prior to initiation of the surgical procedure and upon reimaging of the 
surgical field after the surgical procedure immediately prior to surgical closure, will be estimated 
along with 95% CIs. 
13.3.5 Pharmacokinetics  
The pharmacokinetics (PK) of OTL38 will be estimated by fitting compartmental 
pharmacokinetic models to the serial plasma concentration-time (Ct) data using established 
methods including maximum likelihood parameter estimation and nonlinear mixed-effects 
(NLME) modeling approaches, with the patient serving as the random effect. Various structural 
PK and error models will be fit to data using a qualified, standard software package. Primary PK 
parameters will be estimated at the population level and for individual patients as post-hoc 
empirical Bayesian estimates (EBEs). The actual primary parameters may vary depending on the 
supported model, but are likely to include systemic clearance (CL), volumes of distribution of 
the central and peripheral compartment(s) (Vc, Vp), distributional clearance (CLd), or derivatives 
thereof. Inter-patient variability in select PK parameters will be assessed as part of the model, as 
will the residual error. Secondary parameters may include, but are not limited to: model predicted 
maximum concentration (Cmax), time of Cmax (Tmax), area under the concentration-time curve 
(AUC) to the last time point (AUClast) and to infinity (AUCinf), and the terminal elimination half-
life (T1/2). The model predicted Ct profiles and observed Ct data will be presented as figures for 
the population and individual level. Individual primary EBE and secondary parameters will be 
presented as listings at the patient level. 
Potential covariates explaining inter-subject PK variability, and their influence upon PK 
parameters, will be initially screened using a two-stage approach with standard parametric 
statistical tests on the individual patient EBEs, focusing on CL. Covariates of interest will include 
baseline demographic values (e.g. height, weight, age, BSA, BMI, race), and laboratory values 
predictive of renal or hepatic function (e.g. BUN, creatinine, calculated creatinine clearance or 
GFR, AST, ALT, alkaline phosphatase, albumin, and total bilirubin). If warranted, a single stage 
approach with direct incorporation of covariates into the NLME PK model may be undertaken 
using a forward addition - backward deletion method at an alpha level of 0.05. 
The final model PK parameter estimates, and any bootstrapped results, will be reported as a table, 
including the estimates, their standard errors, or confidence intervals. The covariate coefficient 
estimates, their standard errors, and the associated P values for those significant at the alpha level 
of 0.05 will be tabulated. Relationships between covariates and PK parameters will be graphically 
presented as figures. Additional details will be found in the pharmacokinetics analysis plan 
(PKAP). 
13.3.6 
 
Descriptive summary statistics for 
 pre-surgery (baseline), post-surgery, and the 
change from pre-surgery will be calculated along with the percent change. In addition, the number 
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Protocol No. OTL-2016-OTL38-006 
Statistical Analysis Plan 
 
Version 1.0, 16 May 2017 
Confidential 
Page 20 of 22 
Incidence of TEAEs will also by summarized by age group, race, and gender if there is sufficient 
numbers of patients within these subgroups. Otherwise only line listings will be provided. 
All AEs will be presented in data listings for safety patients. If required, the line listings will 
distinguish between adverse events occurring 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 of Special 
Interest 
Treatment-emergent serious AEs (SAEs), TEAEs leading to early study withdrawal, and TEAEs 
resulting in death will be summarized for all patients in the safety analysis set. Summary tables 
will reflect the number and percentage of patients 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 patients experiencing any TEAE in the respective subset 
will be reported. The tabular summary will be sorted by descending order of overall incidence. 
Adverse events leading to early study withdrawal, AEs resulting in death, and SAEs will also be 
presented in data listings. Treatment-emergent AEs of special interest are those classified as 
infusion reactions which will be separately tabulated, or listed separately if numbers are not 
sufficient for meaningful summary statistics. 
14.5 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. 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. 
14.6 Vital Signs, Physical Exams and ECGs 
The analysis of vital signs will include descriptive statistics for the change from baseline to each 
post-baseline study visit. Vital signs will also be included in line listings and flagged for 
abnormal values. Results for physical exams and ECGs will be provided in line listings only. 
14.7 Pathology and Immunohistochemistry 
Pathology and immunohistochemistry results will be included in line listings only. 
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