Clinical trial NCT03735680
Conditions: Breast Cancer Head and Neck Squamous Cell Carcinoma Colorectal Cancer Prostate Cancer Ovarian Cancer Urothelial Carcinoma Non-small Cell Lung Cancer
Sponsor: OncoNano Medicine, Inc.
Start date: 2019-08-09; Completion date: 2021-11-18
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is to evaluate diagnostic performance, safety and timing of post-dose imaging of ONM-100, an intraoperative fluorescence imaging agent for the detection of cancer in patients with solid tumors undergoing routine surgery.

Detailed description:

Arms: arm 1: All patients in this arm will receive ONM-100 for injection and undergo intraoperative imaging.
Interventions: intervention 1: ONM-100
Intervention descriptions: intervention 1: A polymer micelle covalently conjugated to indocyanine green.

Protocol documents:
Prot_000.pdf: 
OncoNano Medicine, Inc. 
ONM-100 
Title 
Study Drug 
Protocol Amendment 6.0 
Protocol Amendment 5.0 
Protocol Amendment 4.0 
Protocol Amendment 3.1 
Protocol Amendment 3.0 
Protocol Amendment 2.0 
Original Protocol 
Sponsor 
Study Medical Monitor 
Protocol ON-1002 A6.0
NCT03735680
A Phase 2a, single-dose, open-label study to evaluate diagnostic 
perfonnance, safety, and timing ofpostdose imaging ofONM-100, an 
intra.operative fluorescence imaging a.gent for the detection of cancer, in 
patients with solid tumors undergoing routine surge1y 
ONM-100 
03DEC2020 
11JUN2020 
18DEC2019 
18SEP2019 
07AUG2019 
08MAY2019 
25OCT2018 
OncoNano Medicine, Inc. 
Confidentiality Statement: 
This document is a. confidential communication from OncoNano Medicine, Inc. Acceptance of this document constitutes an 
agreement by the recipient(s) that no infonnation contained herein will be published or disclosed without prior written 
approval from OncoNano Medicine, Inc., except that this document may be disclosed to appropriate Institutional Review 
Boards and/or Ethics Collllllittees under the condition that they are also required to maintain confidentiality. 
Protocol Amendment 6.0 
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Table 3: 
Schedule of Assessments and Procedures (Part 1 all cohorts) 
Study Day 
-30 to -1 
0 
1 
(±4h) 
3 
(±24h) 
6 
(±24h) 
28  
(±48h) 
Screeninga 
Pre- 
treatment 
Study Drug  
Administration 
Surgery 
(3±2h or an 
alternate 
imaging 
schedule 
TBD)  
Follow-up 
Informed consent b 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X c 
 
Xd 
 
X 
 
Complete physical examination 
X 
 
 
 
 
 
X 
 
Height, weight, BMI calculation 
X 
X 
 
 
 
 
 
 
Calculate Child-Pugh score 
• 
Encephalopathy 
• 
Ascites  
• 
INR or PT prolongation in seconds 
X 
 
 
 
 
 
 
 
12-lead ECGs 
 
Xe 
Xe 
 
 
 
X 
 
Blood for CMP f, 
X 
Xg 
 
 
X 
X 
X 
X 
Blood for CBC with differentials 
X 
Xg 
 
 
X 
 
X 
X 
Blood for HgbA1C 
X 
Xg 
 
 
 
 
 
 
Pregnancy test h 
X 
 
 
 
 
 
 
X 
Perform test for alcohol i 
 
X 
 
 
 
 
 
 
Karnofsky Performance Status Scale 
X 
X 
 
 
 
 
 
 
Confirm study eligibility 
X 
X 
 
 
 
 
 
 
Administration of ONM-100 j 
 
 
X 
 
 
 
 
 
























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2.0 
TABLE OF CONTENTS 
1.0 
PROTOCOL SYNOPSIS .................................................................................................. 2 
2.0 
TABLE OF CONTENTS ................................................................................................ 28 
3.0 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF TERMS ..... 33 
4.0 
BACKGROUND AND RATIONALE ........................................................................... 36 
4.1 
Nonclinical Studies ................................................................................................ 37 
4.1.1 
Primary Pharmacology.......................................................................... 37 
4.1.2 
Nonclinical Pharmacokinetics .............................................................. 38 
4.1.3 
Toxicology ............................................................................................ 40 
4.1.4 
Dog Patient Study ................................................................................. 42 
4.2 
Clinical Data .......................................................................................................... 44 
4.2.1 
Phase 1 Study (ON-1001) ..................................................................... 44 
4.3 
Summary of Benefits and Risks ............................................................................ 59 
4.3.1 
ONM-100 .............................................................................................. 59 
4.3.2 
Constituents of ONM-100..................................................................... 60 
4.3.3 
Imaging Devices ................................................................................... 60 
4.3.4 
Surgery .................................................................................................. 60 
4.3.5 
ONM-100 Fluorescence-detected Tumors Not Detected by Routine 
Surgery or Pathology ............................................................................ 61 
4.4 
Justification for the Study Design, Dose, and Imaging Schedule .......................... 61 
4.5 
Population to be Studied ........................................................................................ 63 
4.6 
Rationale for Trial Analyses .................................................................................. 63 
4.7 
Statement of Compliance ....................................................................................... 64 
5.0 
STUDY PURPOSE AND OBJECTIVES ...................................................................... 64 
6.0 
STUDY DESIGN ............................................................................................................. 65 
6.1 
Description of the Study ........................................................................................ 65 
6.2 
Number of Patients ................................................................................................ 72 
6.3 
Measures Taken to Minimize Bias ........................................................................ 72 
6.4 
Expected Duration of Patient Participation ........................................................... 72 
6.5 
Method of Treatment Assignment and Blinding ................................................... 73 
7.0 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS ...... 74 
7.1 
Patient Inclusion Criteria ....................................................................................... 74 
7.2 
Patient Exclusion Criteria ...................................................................................... 75 
7.3 
Requalification for Entry ....................................................................................... 76 
7.4 
Patient Withdrawal Criteria ................................................................................... 76 
7.4.1 
Withdrawal from Study Protocol .......................................................... 76 




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10.4.1 
Plasma Concentrations .......................................................................... 94 
10.4.2 
Plasma Concentrations and Blood Volumes over Time ....................... 95 
10.4.3 
Pharmacokinetic Summary Parameters ................................................ 95 
10.5 
Safety Assessments ................................................................................................ 96 
10.5.1 
Safety Parameters.................................................................................. 96 
10.5.2 
Adverse Events ..................................................................................... 97 
10.5.3 
Adverse Event Reporting ...................................................................... 98 
10.5.4 
Definitions............................................................................................. 99 
10.5.5 
Adverse Event Classification .............................................................. 101 
10.5.6 
Dose-limiting toxicity ......................................................................... 105 
10.5.7 
Adverse Event Follow-up ................................................................... 105 
10.5.8 
Adverse Events of Special Interest ..................................................... 105 
10.5.9 
Toxicity Management ......................................................................... 105 
10.5.10 
Risks for Women of Child-Bearing Potential or During Pregnancy .. 105 
11.0 
STATISTICAL METHODS ......................................................................................... 107 
11.1 
Data Management ................................................................................................ 107 
11.2 
Analysis Populations ........................................................................................... 107 
11.3 
Study Population and Patient Characteristics ...................................................... 108 
11.4 
Efficacy Analyses ................................................................................................ 109 
11.5 
Safety Analyses ................................................................................................... 111 
11.6 
Pharmacokinetic Analyses ................................................................................... 111 
11.7 
Determination of Study Sample Size ................................................................... 112 
11.8 
Handling of Dropouts and Missing, Unused, and Spurious Data ........................ 112 
11.9 
Termination Criteria ............................................................................................ 112 
11.10 Deviation Reporting ............................................................................................. 112 
12.0 
INVESTIGATOR REQUIREMENTS ........................................................................ 113 
12.1 
Protocol Adherence ............................................................................................. 113 
12.2 
Electronic Case Report Forms ............................................................................. 113 
12.3 
Source Document Maintenance ........................................................................... 113 
12.4 
Study Monitoring Requirements .......................................................................... 113 
12.5 
Study Completion ................................................................................................ 114 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 114 
14.0 
PROTECTION OF HUMAN SUBJECTS .................................................................. 115 
14.1 
Informed Consent ................................................................................................ 115 
14.2 
IRB/IEC Approval ............................................................................................... 115 
15.0 
DATA HANDLING AND RECORD KEEPING........................................................ 116 






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3.0 
LIST OF ACRONYMS, ABBREVIATIONS AND DEFINITIONS OF TERMS 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
AUC 
area under the time-concentration curve 
AUC0-24, 
AUC0-24hr 
area under the time-concentration curve from time 0 to 24 hours 
AUC0-∞ 
area under the time-concentration curve from time 0 to infinity 
AUC0-last 
area under the time-concentration curve from time 0 to the final sample 
AUCall 
area under the time-concentration curve from time 0 to the last time point (including 
concentration =0) 
BC 
breast cancer 
BLS 
bread loaf slice 
BQL 
below the quantitation limit 
BMI 
body mass index 
C10, C10m 
Concentration at 10 minutes 
CBC 
complete blood count 
CL 
Total body clearance 
Cmax 
maximum plasma concentration  
CMP 
comprehensive metabolic panel 
Conc 
concentration 
CRO 
Contract Research Organization 
CNR 
contrast to noise ratio 
CSE 
clinically significant event 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
EAFUS 
Everything Added to Food in the United States 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FDA 
United States Food and Drugs Administration 
FFPE 
formalin-fixed and paraffin-embedded 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
H/E 
haemotoxylin and eosin 
HED 
human equivalent dose 
HgbA1C 
hemoglobin A1c 


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HNSCC 
head and neck squamous cell carcinoma 
ICF 
Informed Consent Form 
ICG 
indocyanine green 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board  
IV 
intravenous, intravenously 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
mean fluorescence intensity 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NIR 
near infrared 
NOAEL 
no-observed-adverse-effect level 
NPV 
negative predictive value 
NSCLC 
non-small-cell lung carcinoma 
ONM-100 
poly(ethyleneoxide)-b-poly(dibutylaminoethyl methacrylate) copolymerindocyanine green 
conjugate 
OTC 
over-the-counter 
PEG 
polyethylene glycol 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PMMA 
polymethylmethacrylate segments 
PPV 
positive predictive value 
SAE 
serious adverse event 
SAER 
Serious Adverse Event Report 
SBR 
specimen-to-background ratio 
SOC 
standard of care 
SOP 
standard operating procedure 
Sponsor 
The sponsor is the party that commissions the organization or performance of the research, for 
example a pharmaceutical company, academic hospital, scientific organization or investigator. 
A party that provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidizing party. 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TBD 
to be determined 
TBR 
tumor-to-background ratio 
TEAE 
treatment-emergent adverse events 
Tmax 
time to maximum plasma concentration  
US 
United States 
Vss 
volume of distribution at steady state 


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Vz 
volume of distribution at terminal phase  
WHO 
World Health Organization 
 
 


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4.0 
BACKGROUND AND RATIONALE 
Approximately 1.7 million new cancer cases are expected to be diagnosed and approximately 610,000 
Americans are expected to die of cancer in 2018 (American Cancer Society, 2018). Despite the 
ongoing improvements in the treatment of solid cancers, disease morbidity remains significantly high 
in the United States (US). Cancer is the second most common cause of death in the US, exceeded only 
by heart disease.  
Treatment guidelines for solid cancers of all stages prominently include surgical removal of the 
primary tumor, as well as at risk or involved lymph nodes, in some cases preceded or followed by 
chemoradiation. Despite the biologic and anatomic differences between these tumor types, the post-
operative margin status is one of the most important prognostic factors of local tumor control and 
therefore the chance for recurrent disease or tumor metastasis (Denaro, 2014; Jonkman, 2007).  
Surgical excision of solid tumors is a balance between oncologic efficacy and minimization of the 
resection of normal tissue, and thus functional morbidity. This also holds true for lymphadenectomy 
performed for diagnostic and therapeutic purposes, often at the same time as the removal of the 
primary cancer. The presence or absence of lymph node metastasis is the most important determinant 
of survival for gastrointestinal cancers, breast cancer, and many other solid cancers (Ferlay, 2015; 
Amit, 2014; d'Alessandro, 2015 ). While physical examination or imaging modalities used for staging 
are successful in detecting enlarged or abnormal nodes and help with surgical treatment plans, for a 
high percentage of patients, lymph node metastasis is present at a level that is too small to be detected 
by current methods, which leads to under-staging. Because occult nodal metastasis is common, elective 
regional nodal dissection and histological examination is standard-of-care (Kim, 2006; Milenovic, 
2014; Pedersen, 2015; Thompson, 2013) for many solid cancers, especially when locally advanced. 
This leads to overtreatment with significant potential for treatment related morbidities (Amezaga, 
2007).  
While pre-operative imaging modalities such as computerized tomography, magnetic resonance 
imaging, and position emission tomography improve early detection and help with surgical planning, 
intraoperatively surgeons still largely rely on inspection and palpation to determine surgical margins in 
real-time with limited accuracy (Alam, 2018).  
Optical imaging strategies have rapidly been adapted to image tissues intra-operatively based on 
cellular imaging, native autofluorescence, and Raman scattering (Dacosta, 2006; Haka, 2006; Mo, 
2009; Schwarz, 2009; Vahrmeijer 2013). The potential advantages of optical imaging include real-time 
feedback and the availability of camera systems that provide a wide view of the surgical field (Gioux, 
2010). Despite some success, one of the major limitations of optical imaging strategies is the lack of 
broad tumor applicability in cancer patients. 
 
 




















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4.2.1.2 
Disposition and Demographic Characteristics 
All patients received a single dose of ONM-100 and completed the study. All patients were included in 
the imaging, PK, and safety analyses. 
Demographic results for the Phase 1a dose-escalation portion of the completed Phase 1 study are 
available for all 15 patients; 3 patients in each of the 5 cohorts (data cut-off date of 15SEP2018). 
Overall, patients were predominately female (80.0%), White (100%), and not Hispanic or Latino 
(100%), with a mean age of 58.1 years and a mean body mass index (BMI) of 26.9 kg/m2 (Table 5).  
Table 5:  
Demographic and Baseline Characteristics 
Demographic or Baseline  
Parameter 
Cohort 1 
0.3 mg/kg 
(N = 3) 
Cohort 2 
0.5 mg/kg 
(N = 3) 
Cohort 3 
0.8 mg/kg 
(N = 3) 
Cohort 4 
0.1 mg/kg 
(N = 3) 
Cohort 5 
1.2 mg/kg 
(N = 3) 
Cancer Type, n 
Breast 
3 
1 
2 
0 
1 
HNSCC 
0 
2 
1 
3 
2 
Age, years 
 Mean 
53.3 
56.7 
61.3 
68.3 
50.7 
 Range 
35-63 
50-69 
53-78 
46-80 
34-70 
Gender, n (%) 
 Male 
0 
1 
0 
1 
1 
 Female 
3 
2 
3 
2 
2 
Ethnicity, n (%) 
 Hispanic or Latino 
0 
0 
0 
0 
0 
 Non-Hispanic or Latino 
3 
3 
3 
3 
3 
Race, n (%) 
 White 
3 
3 
3 
3 
3 
Mean body mass index, kg/m2 
Mean 
30.3 
27.8 
31.1 
22.7 
22.4 
HNSCC = head and neck squamous cell carcinoma 
  
 
 




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Table 6.  
Overview of Adverse Events 
 
 
Cohort 1 
0.3 mg/kg 
 (N = 3) 
n (%) 
Cohort 2 
0.5 mg/kg 
 (N = 3) 
n (%) 
Cohort 3 
0.8 mg/kg 
 (N = 3) 
n (%) 
Cohort 4 
0.1 mg/kg 
(N = 3) 
n (%) 
Cohort 5 
1.2 mg/kg 
 (N = 3) 
n (%) 
Patients with ≥1 TEAE 
3 (100) 
3 (100) 
3 (100) 
3 (100) 
3 (100) 
Patients with ≥1 TEAE related to study drug 
3 (100) 
0 
0 
0 
0 
Patients with ≥1 SAE 
0 
0 
1 (33.3) 
0 
0 
Patients with ≥1 SAE related to study drug 
0 
0 
0 
0 
0 
Patients with ≥1 severe TEAEs 
0 
1 (33.3) 
1 (33.3) 
0 
0 
Patients with ≥1 severe TEAEs related to study 
drug 
0 
0 
0 
0 
0 
Patients with ≥1 SUSAR 
0 
0 
0 
0 
0 
Patients withdrawn from study due to a TEAE 
0 
0 
0 
0 
0 
Deaths 
0 
0 
0 
0 
0 
SAE = serious adverse event; SUSAR = suspected unexpected serious adverse reaction; TEAE = treatment-emergent adverse events. 
 
 
Table 7: 
Serious and Severe (Grade 3) Adverse Events in Cohorts 1 to 5 
Cohort 
Patient 
Number 
Adverse  
Event 
Study 
Day 
Onset 
Study Day 
of 
Resolution 
Serious 
Severity 
Gradea 
Relationship  
to 
Study Drug 
Action 
Taken 
2  
(0.5 mg) 
ON 
1104 
ALT increased 
1 
16 
No 
3 
Not related 
None 
AST increased 
1 
10 
No 
3 
Not related 
None 
3 
(0.8 mg) 
ON 
1108 
Tracheal 
fistula 
12 
15 
Yes 
3 
Not related 
Surgery 
ALT = alanine aminotransferase; AST = aspartate aminotransferase 
a. 
Severity Grade 1 = mild; Severity Grade 2 = moderate; Severity Grade 3 = severe 
 
 
 


































































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9.0 
STUDY PROCEDURES 
Study procedures should be completed within the windows provided in the Schedule of Assessments 
and Procedures for Part 1 (Figure 1,  
 
Table 3) Part 2 (Figure 1,  
 






























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10.5 
Safety Assessments 
10.5.1 
Safety Parameters 
Safety will be assessed from the signing of the Informed Consent Form (ICF) to Day 28 (±48 hours) in 
Part 1 and to Day 28 (±5 days) in Part 2 and Part 3 postdose through the evaluation of TEAEs, physical 
examinations, vital signs, ECGs, and conventional clinical laboratory data (CMP and CBC with 
differentials) according to the schedule of Assessments and Procedures (Figure 1,  
 
Table 3,  
 


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Table 4/4A, Table  ). Note that the timing provided for postdose assessments and procedures begins 
after infusion of study drug has been completed (ie, time =0 begins at the end of study drug infusion). 
10.5.2 
Adverse Events 
TEAEs will be collected for all patients starting from the start of dosing and through Day 28 (±48 
hours) in Part 1 and through Day 28 (±5 days) in Part 2 and Part 3. The Investigator will assess all 
TEAEs and SAEs and will record the following information on the appropriate eCRF page: 
• Date of onset  
• Date of resolution or stabilization 
• Severity 
• Relationship to study drug  
• Action taken with study medication 
Medically indicated laboratory tests (emergency or unscheduled tests) should be conducted at the local 
laboratory. The Investigator should employ best medical judgment in determining how to manage 
TEAEs and SAEs. Any questions regarding TEAE or SAE management should be directed to the 
Medical Monitor. 
 
 


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10.5.3 
Adverse Event Reporting 
The Sponsor has requirements for expedited reporting of SAEs meeting specific criteria to worldwide 
regulatory authorities. Therefore, the Sponsor must be notified immediately regarding any SAE that 
occurs after informed consent.  
All SAEs must be reported to the Medical Monitor by phone or email within 24 hours of the 
investigational site’s knowledge of the event. 
The study site will also transmit a Serious Adverse Event Report (SAER) to the safety vendor by 
facsimile or email within 24 hours. Contact details will be provided to all sites. An optional initial 
report can be made via telephone, but a completed SAER must still be provided within 24 hours of the 
site’s knowledge of the event. The Investigational site will be provided with SAER forms wherein the 
following information is requested.  
• Patient identification, Investigator name, and site number 
• SAE information: event term, onset date, severity, and causal relationship 
• The outcomes attributable to the event (eg, death, a life-threatening TEAE, inpatient 
hospitalization, prolongation of existing hospitalization, a persistent or significant disability or 
incapacity, or other important medical event[s]) 
• A summary of relevant test results, pertinent clinical laboratory data, and any other relevant 
medical history 
• The date of study drug administration  
• Indicate if the study drug was discontinued or the study drug administration schedule modified 
• Supplemental information may include the following hospital records: laboratory results, radiology 
reports, progress notes, admission and emergency room notes, holding and observation notes, 
discharge summaries, autopsy reports, and death certificates 
In addition, relevant eCRF pages should be appended to communicate relevant study drug and patient 
outcome information. The SAER should be faxed or emailed within 24 hours with as much of the 
above information as available at the time. The following minimum information is required for 
reporting an SAE: patient identification, reporting source, and an event or outcome. Supplemental 
information may be transmitted using a follow-up report and should not delay the initial report. The 
Sponsor may contact the investigational site to solicit additional information or follow up on the event.  
The Investigator must take all therapeutic measures necessary for resolution of the SAE. Any 
medications or procedures necessary for treatment of the SAE must be recorded on the appropriate 
pages of the patient’s eCRF. 
 
 


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10.5.4 
Definitions 
10.5.4.1 
Adverse Event 
An AE means any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. A TEAE (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (eg, a clinically meaningful abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a drug and does not imply any judgment about 
causality. A TEAE can arise with any use of the drug (eg, off-label use, use in combination with 
another drug) and with any route of administration, formulation, or dose, including an overdose. 
Laboratory abnormalities should not be recorded as TEAEs or SAEs unless they are associated with 
clinical signs or symptoms or require medical intervention. However, each laboratory abnormality (eg, 
clinically meaningful changes detected on hematology, CMP) independent from any underlying 
medical condition that requires medical or surgical intervention, or that leads to interruption of study 
drug infusion or discontinuation, must be recorded as a TEAE or SAE if applicable. If the laboratory 
abnormality is part of a clinical condition or syndrome, it should be recorded as the syndrome or 
diagnosis rather than as the individual laboratory abnormality. In addition, laboratory abnormalities or 
other abnormal test assessments (eg, ECGs) that are associated with signs or symptoms must be 
recorded as TEAEs or SAEs if they meet the definition of a TEAE (or SAE) as described in Section 
10.5.4.1 (or Section 10.5.4.4). 
Conditions resulting from the surgical resection will be considered TEAEs if they meet the criteria 
described above. 
10.5.4.2 
Suspected Adverse Reaction 
A suspected adverse reaction is any TEAE for which there is a reasonable possibility that the drug 
caused the TEAE. For the purposes of Investigational New Drug safety reporting, ‘‘reasonable 
possibility’’ means there is evidence to suggest a causal relationship between the drug and the TEAE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any TEAE caused by a drug. 
10.5.4.3 
Life-Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction 
A TEAE or suspected adverse reaction is considered ‘‘life threatening’’ if, in the view of either the 
Investigator or Sponsor, its occurrence places the patient or patient at immediate risk of death. It does 
not include a TEAE or suspected adverse reaction that, had it occurred in a more severe form, might 
have caused death. 
 
 


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10.5.4.4 
Serious Adverse Event or Serious Suspected Adverse Reaction 
A TEAE 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 TEAE (see definition of TEAE provided in Section 10.5.4.1)  
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
• 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 or patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias, or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
As the study population consists of oncologic patients, progression of a patient’s pre-existing disease 
will not be considered an SAE. In addition, an elective hospital admission will not be considered an 
SAE. Conditions resulting from the surgical resection will be considered SAEs if they meet the criteria 
described above. 
10.5.4.5 
Unexpected Adverse Event or Unexpected Suspected Adverse Reaction 
A TEAE or suspected adverse reaction is considered ‘‘unexpected’’:  
• If it is not listed in the Investigator’s Brochure or is not listed at the specificity or severity that has 
been observed, or  
• If an Investigator’s Brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended  
• If it is not listed in the prescribing information (for marketed products) 
 
 
 


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For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater severity) 
if the Investigator’s Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, 
cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the Investigator’s Brochure listed only cerebral vascular accidents.  
‘‘Unexpected,’’ as used in this definition, also refers to TEAEs or suspected adverse reactions that are 
mentioned in the Investigator’s Brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
10.5.5 
Adverse Event Classification 
10.5.5.1 
Relationship to Investigational Drug 
The Investigator’s assessment of causality must be provided for all TEAEs (serious and non-serious) 
(Table 11). An Investigator’s causality assessment is the determination of whether there exists a 
reasonable possibility that the study drug caused or contributed to a TEAE.  
These criteria, in addition to good clinical judgment, should be used as a guide for determining the 
causal assessment. If the event is believed to be unrelated to study drug administration, then an 
alternative explanation should be provided. 
Table 11:  
Guidelines for Assessing Relationship of Event to Study Drug
 
 
Not related 
The event is most likely produced by other factors such as the patient’s 
clinical condition, intercurrent illness, or concomitant drugs, and does not 
follow a known response pattern to the study drug, or the temporal 
relationship of the event to study drug administration makes a causal 
relationship unlikely. 
Possibly related 
The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but 
is more likely produced by other factors such as the patient's clinical 
condition, intercurrent illness, or concomitant drugs. 
Probably related 
The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, but 
could be explained by other factors such as the patient's clinical condition, 
intercurrent illness, or concomitant drugs. 
Definitely related 
The event follows a reasonable temporal sequence from the time of drug 
administration, and/or follows a known response pattern to the study drug, 
and cannot be reasonably explained by other factors such as the patient's 
clinical condition, intercurrent illness, or concomitant drugs. 
 
 
 


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10.5.5.2 
Severity  
All TEAEs will be graded for severity. Adverse events will be graded by the Investigator using a 
numerical score according to the defined National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) Version 5.0 (2017). Adverse events not specifically defined in the NCI 
CTCAE will be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined in Table 12. 
The Investigator will use the terms: Mild, Moderate, Severe, Life Threatening, or Death to describe the 
maximum intensity of the TEAE. For purposes of consistency, these intensity grades are defined as 
follows: 
Table 12:  
Guidelines for Severity Assessments 
Grade 1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADLa 
Grade 3 
Severe 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADLb 
Grade 4 
Life 
threatening 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death 
Death related to an adverse event 
ADL = activities of daily living 
a. 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
b. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
 
 




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10.5.5.3.1 
Serious Adverse Event Definition Clarifications 
• Death is an outcome of an AE, and not an AE in itself 
• All deaths during study drug administration or occurring within 21 (±1) days after administration 
of study drug, regardless of cause or relationship, must be reported 
• “Occurring at any dose” does not imply that the patient is actively receiving study drug at the time 
of the event 
• “Life-threatening” means that the patient was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death, had it occurred with greater 
severity. 
• Complications that occur during hospitalizations are AEs. If an AE prolongs hospitalization, it is an 
SAE. 
• “In-patient hospitalization” means the patient has been formally admitted to a hospital for medical 
reasons, for any length of time. This may or may not be overnight. It does not include presentation 
and care within an emergency department (although an emergency department visit may define a 
medically important event, which is also considered an SAE). 
• The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, and 
other clinical information. In such cases, the diagnosis should be documented as the TEAE or SAE, 
rather than as the individual signs or symptoms. 
10.5.5.4 
Suspected Unexpected Serious Adverse Reactions 
Adverse reactions are all untoward and unintended responses to an investigational product related to 
any dose administered. Unexpected adverse reactions are SUSARs if the following 3 conditions are 
met: 
1. The event must be serious (Section 10.5.5.3) 
2. There must be a certain degree of probability that the event is a harmful and an undesirable 
reaction to the medicinal product under investigation, regardless of the administered dose 
3. The adverse reaction must be unexpected, that is to say, the nature and severity of the adverse 
reaction are not in agreement with the product information as recorded in 
a. Summary of Product Characteristics for an authorized medicinal product 
b. Investigator’s Brochure 
The sponsor or sponsor designee will report SUSARs according to details provided in the study’s 
Safety and Medical Management Plan (or equivalent). The expedited reporting will occur not later than 
15 days after the sponsor has first knowledge of the adverse reactions. For fatal or life-threatening 
cases, the term will be maximal 7 days for a preliminary report with another 8 days for completion of 
the report. 


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10.5.6 
Dose-limiting toxicity 
DLT is defined as any TEAE of Grade 2 or greater that is considered by the Investigator to be possibly 
related, probably related, or definitively related to ONM-100 treatment (Section 10.5.5.1) and not to 
surgery, anesthesia, or other study procedures. Toxicity will be graded according to the NCI-Common 
Terminology Criteria for Adverse Events (CTCAE) (Sibille 2010). TEAEs will be followed closely 
during the study to identify any potential DLTs. In Part 1, safety results for each cohort will be 
reviewed by the Internal Safety Review Committee. Escalation to doses higher than those previously 
tested will not occur until the safety of lower doses has been confirmed following review by the 
Internal Safety Review Committee. 
10.5.7 
Adverse Event Follow-up 
All unresolved TEAEs (“ongoing” at end of study) will be followed by the study staff until resolution 
or deemed stable. 
For total bilirubin >1.5×ULN on ≥2 consecutive assessments, assess fractionated bilirubin. If liver 
function tests (ALT, AST, AP, total bilirubin, fractionated bilirubin) show an abnormal elevation 
(>1.5×ULN), retest weekly until the values have returned to baseline or stabilized.  
10.5.8 
Adverse Events of Special Interest 
There were no TEAEs of special interest in the Phase 1 study (Section 4.2.1.3).  
10.5.9 
Toxicity Management  
The Investigator should employ best medical judgment in determining how to manage TEAEs. Any 
questions regarding TEAE management should be directed to the Medical Monitor. 
10.5.10 
Risks for Women of Child-Bearing Potential or During Pregnancy 
The risks of ONM-100 administration during pregnancy have not been evaluated. Pregnant and 
lactating females are excluded from this study.  
Male patients and female patients of child-bearing potential (ie, premenopausal women with intact 
reproductive organs and women <2 years after menopause) must agree to and comply with using 
medically acceptable contraception including surgical sterilization (eg, hysterectomy, bilateral 
oophorectomy, bilateral tubal ligation), intrauterine device, oral contraceptive, contraceptive patch, 
long acting injectable contraceptive, partner’s vasectomy, double-barrier method (condom or 
diaphragm plus spermicide or condom plus diaphragm), or abstinence during the trial and for 6 months 
thereafter. 
 
 


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Patients must be instructed to inform the Investigator immediately if they or their partner become 
pregnant during the study. Female partners of male patients must complete informed consent to allow 
the investigator to follow them for the outcome of the pregnancy.  
In the event of a confirmed pregnancy, the following actions should be taken: 
• Study drug should be discontinued immediately  
• The pregnancy should be reported to the Medical Monitor within 24 hours of notification using the 
applicable Pregnancy Report Form 
• The Investigator should counsel the patient regarding the possible effects of prior ONM-100 
exposure on the fetus and the need to inform the study site of the outcome of the pregnancy 
• The patient must be monitored until the immediate postnatal period or until termination of the 
pregnancy. The outcome should be reported to the Medical Monitor using the Pregnancy Outcome 
or Abnormal Pregnancy Outcome form. 
Pregnancy is not an AE, in and of itself. However, any pregnancy complication or elective termination 
of a pregnancy for medical reasons will be recorded as an AE or SAE. A spontaneous abortion is 
always considered an SAE and will be reported as described in the TEAE and SAE sections. 
Furthermore, any SAE occurring as an adverse pregnancy outcome poststudy must be reported to the 
Medical Monitor. 
 
 




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Table 4/4A, and Table ). 
11.3 
Study Population and Patient Characteristics 
The study population and patient characteristics will be analyzed in the Safety population. 
Demographics (including age, gender, race, ethnicity, and BMI), medical history (prior therapies with 
dates, histology, localization and classification of cancer, prior treatment outcome), and administration 
of study drug will be summarized using descriptive statistics.  
Surgical care (including type, duration, and outcome) and tumor characteristics (including 
morphology, size, and margin status) will be summarized using descriptive statistics. 
 
 






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11.5 
Safety Analyses 
The safety analyses will be assessed in the Safety Population.  
Adverse events, vital signs, ECGs, and conventional clinical laboratory data (CMP and CBC with 
differentials) will be summarized using descriptive statistics. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.1. The incidence of TEAEs will be presented by system organ class and preferred term, by 
relationship to study drug, by severity, and by whether or not they resulted in alteration of 
administration of or discontinuation of study drug. A TEAE is defined as an AE that occurs during or 
after study drug administration and up through 28 days (±48 hours) in Part 1 or 28 days (±5 days) in 
Part 2 after administration of study drug. In addition, the incidence of SAEs and TEAEs leading to 
discontinuation of study drug will be presented by system organ class, preferred term, and relationship 
to study drug.  
Descriptive statistics for clinical laboratory test results and vital signs, and for changes from Baseline, 
will be presented by time point. Baseline is defined as the measurement closest to, but before, the 
administration of study drug. Incidences of potentially clinically meaningful clinical laboratory results 
and vital signs, determined based on normal ranges and percentage changes from Baseline, will also be 
summarized by time point. The number and percentage of abnormal ECGs will be provided by time 
point.  
11.6 
Pharmacokinetic Analyses 
The PK analyses will be assessed in the Pharmacokinetic Population.  
Plasma concentration-time profiles will be constructed for each patient and each dosing cohort. Plasma 
concentration values will be summarized at each time point using mean, standard deviation, median, 
and range. 
Summary PK parameters will be summarized using mean, standard deviation, median, and range. 
 
 




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12.0 
INVESTIGATOR REQUIREMENTS 
12.1 
Protocol Adherence 
The Investigator must adhere to the protocol as detailed in this document and agree that the Sponsor 
must approve any change to the protocol before seeking approval from the IRB/IEC. The Investigator 
will be responsible for enrolling only those patients who have met the protocol inclusion and exclusion 
criteria. 
12.2 
Electronic Case Report Forms 
The eCRF will be supplied by the contract research organization or designee for the recording of all 
information and study data as specified by this protocol. All eCRFs must be completed by trained 
study personnel. The Investigator is responsible for ensuring that the eCRF data are entered and 
completed in a timely manner.  
Once all data queries and issues have been resolved for each patient, the Investigator will electronically 
sign each patient’s eCRF to attest to the accuracy of the data.  
12.3 
Source Document Maintenance 
Source documents are defined as documentation related to original observations and activities of a 
clinical investigation. Source documents may include, but are not limited to, study progress notes, 
study- or patient-specific e-mail correspondence, computer printouts, clinical laboratory data, and 
recorded data from automated instruments. All source documents produced in this study will be 
maintained by the Investigator and made available for inspections by the Sponsor and by regulatory 
authorities. The original signed ICF for each participating patient shall be filed with records kept by 
the Investigator, and a signed and dated copy will be given to the patient. In all cases, subject 
confidentiality must be maintained in accordance with local regulatory requirements. 
12.4 
Study Monitoring Requirements 
An authorized Sponsor representative will conduct site visits to inspect study data, patients’ medical 
records, and eCRFs in accordance with ICH guidelines, GCPs, and the foreign regulations and 
guidelines, as applicable. A monitor will be utilized for monitoring ongoing drug accountability and 
adherence to protocol procedures. 
The Investigator will allow representatives of the Sponsor and regulatory authorities to inspect 
facilities and records relevant to this study. 
 
 


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12.5 
Study Completion 
The Sponsor requires the following data and materials before a study can be considered complete or 
terminated: 
• Laboratory findings, clinical data, and all special test results from Screening throughout the study 
until the Follow-up visit  
• eCRFs (including data queries) properly completed by appropriate study personnel and signed and 
dated by the Investigator 
• Copies of complete drug accountability records (drug inventory log and an inventory of returned or 
destroyed clinical material) 
• Copies of protocol amendments and IRB/IEC approval and notification, if appropriate 
• A summary of the study prepared by the Investigator (an IRB/IEC summary letter is acceptable) 
 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Written standard operating procedures (SOPs) will be followed to ensure that the study is conducted 
and data are generated, documented (recorded), and reported in compliance with the protocol, GCP, 
and the applicable regulatory requirements. Quality control will be applied to each stage of data 
handling. Regular monitoring, as defined in ICH GCP, Section 1.8, “The act of overseeing the progress 
of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the 
protocol, SOPs, GCP, and the applicable regulatory requirement(s)”, will be conducted throughout the 
conduct of the study. 
The purpose of monitoring is to verify that: 
• Rights and well-being of the human patients are protected 
• The reported study data are accurate, complete, and verifiable from source documents 
• The conduct of the study is in compliance with the currently approved protocol/amendment(s), 
with GCP, and with the applicable regulatory requirements 
• Monitoring is an integral role in the quality control of a clinical trial and is designed to verify the 
quality of the study 
To fulfill the Quality Assurance requirements of GCP, audits will be conducted to assess and assure 
the reliability and integrity of a study’s quality control systems and recognized standards. 
The purpose of an audit is to: 
• Ensure participant safety 
• Assure compliance to study protocol procedures, regulatory requirements, and SOPs 
• Assure data quality 
 


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14.0 
PROTECTION OF HUMAN SUBJECTS 
This study will be conducted in compliance with the ICH Technical Requirements for Registration of 
Pharmaceuticals for Human Use including ICH E6 GCP (2016), the ethical principles of the 
Declaration of Helsinki (2013), US FDA Code of Federal Regulations Title 21 Food and Drugs (2018), 
and any additional national or IRB/IEC-required procedures. 
14.1 
Informed Consent 
This study will be conducted in compliance with ICH E6 GCP (2016): Consolidated Guidelines 
pertaining to informed consent. Patients will give written consent to participate in the study at the first 
visit, before initiation of any study-related procedures, after having been informed about the nature and 
purpose of the study, participation and termination conditions, risks, and benefits. If a patient is unable 
to provide written informed consent, the patient’s legally acceptable representative may provide 
written consent, as approved according to institution-specific guidelines. The ICF must be signed and 
dated by the patient, or the patient’s legally acceptable representative, before study participation. A 
copy of the ICF must be provided to the patient or the patient’s legally acceptable representative. If 
applicable, it will be provided in certified translation for non-English-speaking patients. Signed ICFs 
must remain in the patient’s study file and be available for verification by Sponsor at any time. 
14.2 
IRB/IEC Approval 
This protocol, the ICF, and all relevant supporting data must be submitted to the IRB/IEC for approval. 
The protocol, ICF, and any advertisement used to recruit study patients must be approved by the 
IRB/IEC. Approval by the IRB/IEC of the protocol and ICF must be obtained before the study may be 
initiated. 
The Investigator is responsible for informing the IRB/IEC of any changes made to the protocol, and to 
advise them, at least once a year, about the progress of the study. The Investigator is also responsible 
for notifying the IRB/IEC of any significant TEAEs that occur during the study. 
 
 












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19.0 
APPENDICES  
APPENDIX 1:  
KARNOFSKY PERFORMANCE STATUS SCALE 
Karnofsky Status 
Karnofsky Grade 
Normal, no complaints 
100 
Able to carry on normal activities. Minor signs or symptoms of disease 
90 
Normal activity with effort 
80 
Care for self. Unable to carry on normal activity or to do active work 
70 
Requires occasional assistance, but able to care for most of his needs 
60 
Requires considerable assistance and frequent medical care 
50 
Disabled. Requires special care and assistance 
40 
Severely disabled. Hospitalization indicated though death nonimminent 
30 
Very sick. Hospitalization necessary. Active supportive treatment 
necessary 
20 
Moribund 
10 
Dead 
0 
 
 
 
 


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APPENDIX 2: CHILD-PUGH SCORE 
The Child-Pugh score employs 5 clinical measures of liver disease. Each measure is scored 1 to 3, with 
1 indicating the least severe and 3 indicating the most severe score. The sum of the 5 measures is the 
total Child-Pugh point score. 
Parameter 
Points 
1 
2 
3 
Ascites 
None 
Medically controlled 
Poorly controlled 
Encephalopathy a 
None 
Medically controlled 
Poorly controlled 
Total bilirubin (mg/dL) 
<2 
2 – 3 
>3 
Albumin (g/dL) 
>3.5 
2.8 – 3.5 
<2.8 
International Normalized Ratio 
OR 
PT prolongation in seconds 
<1.7 
 
<4 
1.7 – 2.3 
 
4 – 6 
>2.3 
 
>6 
a. 
If sedated, use last known encephalopathy status before sedation.