Clinical trial NCT04465760
Conditions: Lymphoma Malignant Solid Neoplasm Plasma Cell Myeloma
Sponsor: OHSU Knight Cancer Institute
Start date: 2021-02-25; Completion date: 2021-11-05
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well xisomab 3G3 works in preventing catheter-associated blood clots (thrombosis) in patients with cancer receiving chemotherapy. Many patients with cancer develop blood clots from their catheters and can have pain, swelling, and other symptoms. They also often require blood thinners, which can increase the risk of bleeding. Xisomab 3G3 is type of drug called a monoclonal antibody that may prevent blood clots caused by a catheter in patients receiving chemotherapy.

Detailed description:
PRIMARY OBJECTIVE I. To determine the efficacy of xisomab as measured by the incidence of catheter-associated thrombosis (CAT) in individuals with a central venous catheter.

SECONDARY OBJECTIVE:

I. To evaluate the safety and tolerability of xisomab 3G3 in cancer patients with a PICC or indwelling catheter.

EXPLORATORY OBJECTIVE:

I. Assessment of drug exposure and catheter occlusions leading to medical intervention.

OUTLINE:

Patients receive xisomab 3G3 intravenously (IV) or via catheter within 48 hours of catheter placement. Patients then receive standard of care chemotherapy 2 days later. After approximately 2 weeks, patients undergo standard of care ultrasound for possible CAT.

After completion of study, patients are followed up for 60 days.

Arms: arm 1: Patients receive xisomab 3G3 IV or via catheter within 48 hours of catheter placement. Patients then receive standard of care chemotherapy 2 days later. After approximately 2 weeks, patients undergo standard of care ultrasound for possible CAT.
Interventions: intervention 1: Xisomab 3G3
Intervention descriptions: intervention 1: Given IV or via catheter

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
 
Study Title: 
A Phase II study of Xisomab 3G3, a monoclonal antibody 
preventing the activation of FXI by FXIIa, for the prophylaxis of 
catheter-associated thrombosis.  
Protocol Number:  18976 
Investigational product: xisomab 3G3, AB023 
Version Number:  3.0 
Version Date: 5/25/2021 
Replaces: 2.0 
IND/IDE Status: IND/IDE #  143558 
 
Principal Investigator: Joseph J. Shatzel, MD 
 
Hematology and Oncology / Biomedical Engineering 
Oregon Health & Science University 
3303 S BOND AVE PORTLAND OR 97239, CH13B  
Portland, OR 97239  
Phone: 503-494-6594 
Email: shatzel@ohsu.edu 
  
Sub- 
Investigator(s): 
 
Sven R. Olson MD  
Hematology and Oncology 
Oregon Health & Science University 
3303 S BOND AVE PORTLAND OR 97239, CH13B 
Phone: 503-494-6594 
Email: olsosv@ohsu.edu 
  
Statistician: 
Jeong Youn Lim, PhD  
Biostatistics Shared Resource, 
Knight Cancer Institute 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, KR  
Phone: 503-494-7062 
Fax: 503-346-6931 
Email: limje@ohsu.edu 
IRB Approved 1/27/2023 
NCT# NCT04465760 
 
 
 


 
2 
 
SUMMARY OF CHANGES 
 
# 
Section 
Page(s) 
Change 
Justification 
1. 
see summary of changes memo 
2. 
see summary of changes memo 
3. 
 
 
 
 
4. 
 
 
 
 
5. 
 
 
 
 
 
 


 
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SYNOPSIS 
 
Study Title 
A Phase II study of Xisomab 3G3, a monoclonal antibody 
preventing the activation of FXI by FXIIa, for the prophylaxis of 
catheter-associated thrombosis. 
Protocol # 18976 
Study Center OHSU, single-site   
Clinical Phase Phase 2 – single agent  
Investigational Component Investigational drug: xisomab 3G3 
Interventional Study Type Single-arm 
Précis 
 
Peripherally inserted central catheters (PICCs) and indwelling 
subclavian vein central venous catheters (ie, “Mediports”, “Port-a-
Cath”, or “ports”) are frequently used in ambulatory cancer patients 
requiring chemotherapy, often remaining inserted for weeks to 
months. A major complication of central venous catheters is 
catheter-associated thrombosis (CAT), occurring in over 50% of 
patients. CAT can lead to substantial morbidity including pain, 
swelling, erythema, catheter occlusion, and the potential for 
thrombosis progression mandating anticoagulation. The 
anticoagulant treatment of CAT comes with inherent risks, including 
bleeding, increased healthcare costs surrounding the management 
and replacement of the catheter, and delays in cancer treatment. 
Previous studies have evaluated the role of traditional 
anticoagulants to prevent CAT but have failed to display favorable 
safety and efficacy profiles. Evaluation of contact activation factor 
(F) XII and FXI in device-associated thrombosis has demonstrated 
that inhibiting FXII or FXI reduces these thromboses in multiple 
animal models. FXII appears to be dispensable for hemostasis, as 
individuals with FXII deficiency have no bleeding diathesis, making 
it a promising target for antithrombotic therapy. Xisomab 3G3 is a 
first-in-class monoclonal antibody that binds to the A2 domain of 
FXI, preventing FXII-mediated FXI activation. Xisomab 3G3 has 
been shown to reduce device-associated thrombus formation in 
multiple preclinical models. In this phase 2 study, we will evaluate 
the safety and efficacy of a single dose of 2 mg/kg of xisomab 3G3 
as prophylaxis against CAT in cancer patients having a catheter 
placed, as compared to historical controls. All participants in this 
trial will receive a single dose of xisomab 3G3 near the time of 
catheter placement. Study participants will undergo an upper 
extremity venous duplex ultrasound on day 14 (±4) after catheter 
placement to evaluate the occurrence of CAT (symptomatic or 
asymptomatic).  All anti-cancer therapy provided to the participant 
while on-study will be at the discretion of the treating physician and 
in accordance with institutional guidelines.  Safety follow-up will 
continue for 60 days from the date of catheter insertion, or until 
resolution or stabilization of any clinically significant drug-related 
adverse event, after which they will be considered off-study. 
 
Primary Objectives To evaluate the antithrombotic efficacy of prophylactic xisomab 
3G3 treatment in cancer patients with a central venous catheter. 


 
A randomized phase 2 study of xisomab 3G3 for the prophylaxis of PICC line associated thrombosis.   
IRB# 18976  
Version # 3.0 
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PI: Joseph Shatzel, MD 
 
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Secondary Objectives 
To determine the safety and tolerability of prophylactic xisomab 
3G3 treatment as measured by the incidence and severity of 
adverse events in cancer patients with a central venous catheter. 
Exploratory Objective Assessment of participant coagulation profiles, and the incidence of 
line occlusion requiring medical interventions to obtain patency.  
Primary Endpoints 
The number of participants with catheter-associated thrombosis, as 
defined by the total incidence of symptomatic and asymptomatic 
thrombosis, and thrombotic occlusion leading to device failure  
(start: administration of xisomab; end: Day 18)  
Secondary Endpoints 
The number of subjects with treatment-related adverse events 
(TRAEs) and treatment-emergent adverse events (TEAEs) will be 
summarized using frequency counts  (start: time of consent, end: 
Day 60)  
Exploratory Endpoints 
Quantification of coagulation parameters and assessment of 
catheter occlusion  (start: pre-dose, end: Day 18 [i.e., post-dose]): 
a. Activated partial thromboplastin time (aPTT) 
b. Pharmacokinetic (PK) evaluation 
c. 
Time to symptomatic catheter-associated thrombosis 
d. Proportion of participants with a catheter occlusion requiring 
medical intervention 
 
Number of Participants A total of 50 participants will be enrolled.  
Duration of Therapy 1 day 
Duration of Follow Up 60 days [post catheter placement] 
Key Inclusion Criteria 
• 
Men and women, aged ≥ 18 years and members of all 
races and ethnic groups will be included. 
• 
Participants with any solid tumor malignancy that will undergo 
insertion of a central venous catheter (PICC or indwelling 
subclavian vein central venous catheter) as part of planned 
cancer-directed therapy per institutional standards 
• 
Able to wait 1 day post-study drug infusion before receiving 
cancer-directed therapy.  
• 
ECOG performance status ≤2 
• 
Expected life expectancy of >6 months 
• 
At time of enrollment, must have adequate platelet count 
(>100 x 109/L) 
Key Exclusion Criteria 
• 
Concurrent participation in another therapeutic clinical trial  
• 
Leukemia (lymphoma and myeloma may be included) 
• 
≤72 hours since major surgery  
• 
Abnormal renal function defined by an eGFR < 45 mL/min 
• 
Abnormal hepatic function defined as LFTs (AST, ALT or Total 
Bilirubin) >2x the upper limit of normal or known Child-Pugh 
class B or C cirrhosis.    
• 
Abnormal baseline coagulation profile:  
o INR > 1.5 or aPTT prolonged. 
• 
Prior history of intracranial hemorrhage 
• 
Primary brain tumors or known brain metastasis 


 
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• 
Major extracranial bleed within the last 6 months where the 
cause has not been identified or treated 
• 
Use of oral anticoagulation at enrollment 
• 
Known bleeding diathesis  
• 
At the discretion of the investigator, any other contraindication 
to anticoagulation therapy 
• 
Previously documented hypersensitivity to either the drug or 
excipients  
• 
Participant is pregnant or breastfeeding 
• 
Participant is expected to receive chemotherapy associated 
with a 15% or higher incidence of grade 3-4 thrombocytopenia 
• 
Allergy to heparin and heparin derivatives 
• 
History of venous thromboembolism (VTE) within the last 3 
months.  
 
Investigational Product 
Xisomab 3G3 (2 mg/kg) is a recombinant, humanized, monoclonal 
IgG4 antibody that functions as a contact activation inhibitor and an 
anticoagulant by binding FXI and preventing FXI activation by 
FXIIa. 
 
Statistical Considerations 
The basis for our sample size calculation is the assumption of a 
60% incidence of ultrasound-confirmed CAT (symptomatic or 
screened) over 18 days post-catheter placement in historical 
controls, informed by prior studies of cancer patients with venous 
catheters. A sample size of 50 patients, accounting for a 4% 
efficacy analysis ineligibility rate, was calculated to provide 80% 
power to detect a 20 percentage point decreased incidence of CAT 
at a two-sided alpha level of 0.05.  


 
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SCHEMATIC OF STUDY DESIGN  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... 2 
SYNOPSIS ................................................................................................................................. 3 
SCHEMATIC OF STUDY DESIGN ............................................................................................. 6 
LIST OF TABLES ..................................................................................................................... 12 
LIST OF FIGURES ................................................................................................................... 13 
LIST OF ABBREVIATIONS ...................................................................................................... 14 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 16 
 
Overview of Catheter-Associated Thrombosis .......................................................... 16 
 
Overview of Xisomab 3G3 ........................................................................................ 17 
1.2.1 Mechanism of action ............................................................................................ 17 
1.2.2 Pre-clinical experience ......................................................................................... 17 
1.2.3 Clinical studies of xisomab 3G3 ........................................................................... 18 
 
Rationale .................................................................................................................. 18 
 
Potential Risks and Benefits ..................................................................................... 19 
1.4.1 Known Potential Risks .......................................................................................... 19 
1.4.2 Known Potential Benefits ..................................................................................... 19 
2. STUDY DESIGN AND ENDPOINTS .................................................................................... 20 
 
Description of the Study Design ................................................................................ 20 
2.1.1 Randomization ........................................................ Error! Bookmark not defined. 
2.1.2 Double-Blinding ....................................................... Error! Bookmark not defined. 
 
Study Objectives and Endpoints ............................................................................... 20 
2.2.1 Primary objective and Endpoint ............................................................................ 20 
2.2.2 Secondary Objectives and Endpoints ................................................................... 21 
2.2.3 Exploratory Objective and Endpoint ..................................................................... 21 
3. STUDY ENROLLMENT AND WITHDRAWAL ..................................................................... 22 
 
Participant Inclusion Criteria ..................................................................................... 22 
 
Participant Exclusion Criteria .................................................................................... 22 
 
Strategies for Recruitment and Retention ................................................................. 23 
3.3.1 Accrual Estimates ................................................................................................ 24 
3.3.2 Inclusion of Children ............................................................................................. 24 
 
Registration Procedures ........................................................................................... 24 
3.4.1.1 
OHSU Registration ............................................................................... 24 


 
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Participant Screening and Enrollment ....................................................................... 25 
 
Participant Withdrawal or Discontinuation ................................................................. 25 
3.6.1 Handling Participant Withdrawal and Discontinuation ........................................... 25 
 
Off-Study Criteria ...................................................................................................... 25 
3.7.1 Screen Failures .................................................................................................... 26 
 
Study Discontinuation ............................................................................................... 26 
4. INVESTIGATIONAL PRODUCT .......................................................................................... 27 
 
Xisomab 3G3 ............................................................................................................ 27 
4.1.1 Acquisition ............................................................................................................ 27 
4.1.2 Formulation, Appearance, Packaging and Labeling ............................................. 27 
4.1.3 Product Storage and Stability ............................................................................... 27 
4.1.4 Compatibility ........................................................................................................ 27 
4.1.5 Handling ............................................................................................................... 27 
4.1.6 Preparation .......................................................................................................... 27 
4.1.7 Administration ...................................................................................................... 28 
4.1.8 Special Considerations for Administration ............................................................ 28 
4.1.9 Accountability ....................................................................................................... 28 
4.1.10 
Destruction and Return .................................................................................... 29 
5. TREATMENT PLAN............................................................................................................. 30 
 
Dosage and Administration ....................................................................................... 30 
 
Treatment Period ...................................................................................................... 30 
 
Concomitant Medication and Supportive Care Guidelines ........................................ 30 
5.3.1 Infection prophylaxis and treatment ...................................................................... 31 
5.3.2 transfusions of platelets and red blood cells (rBC) ................................................ 31 
5.3.3 anti-platelet agents and anticoagulants ................................................................ 31 
5.3.4 Allergic/Hypersensitivty reactions ......................................................................... 31 
5.3.5 Contraception ....................................................................................................... 31 
5.3.6 Use in Pregnancy ................................................................................................. 32 
5.3.7 Use in Nursing Women ........................................................................................ 32 
 
Precautionary and Prohibited Medications, Treatments, and Procedures ................. 32 
5.4.1 Blood Donation ..................................................................................................... 32 
6. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE OF EVENTS ........................... 33 
 
Study Specific Procedures ........................................................................................ 33 
6.1.1 Medical history ..................................................................................................... 33 
6.1.2 Disease Assessment ............................................................................................ 33 


 
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6.1.3 Medication history ................................................................................................ 33 
6.1.4 Physical examination ............................................................................................ 33 
6.1.4.1 
Vital signs ............................................................................................ 33 
6.1.4.2 
Performance status .............................................................................. 34 
6.1.5 Height and Weight ................................................................................................ 34 
6.1.6 PICC Line Placement ........................................................................................... 34 
6.1.7 Radiographic Imaging Assessments .................................................................... 34 
6.1.8 Ultrasound ............................................................................................................ 34 
6.1.9 Adverse event evaluation ..................................................................................... 34 
6.1.9.1 
Assessment of Major and Clinically Relevant Non-major 
Bleeding ............................................................................................... 35 
 
Laboratory Procedures and Evaluations ................................................................... 35 
6.2.1 Hematology .......................................................................................................... 35 
6.2.2 Biochemistry ........................................................................................................ 35 
6.2.3 Coagulation panel ................................................................................................ 35 
6.2.4 Echocardiogram ................................................................................................... 35 
6.2.5 Pregnancy test ..................................................................................................... 35 
 
Exploratory Studies ................................................................................................... 36 
 
Screening and Baseline Assessments ...................................................................... 36 
 
Assessments During Treatment ................................................................................ 36 
 
End of Treatment Visit .............................................................................................. 37 
6.6.1 Early Termination Visit ......................................................................................... 37 
 
Follow-up .................................................................................................................. 37 
 
Unscheduled Visits ................................................................................................... 37 
 
Schedule of Events ................................................................................................... 38 
7. SAFETY ............................................................................................................................... 40 
 
Specification Of Safety Parameters .......................................................................... 40 
 
Definitions ................................................................................................................. 40 
7.2.1 Adverse Event (AE) .............................................................................................. 40 
7.2.2 Serious Adverse Event (SAE) .............................................................................. 40 
7.2.3 Unanticipated Problems (UP) ............................................................................... 41 
7.2.4 Severity of Event .................................................................................................. 41 
7.2.5 Assessment of Causality Relationship To Study Agent ........................................ 41 
 
Expectedness ........................................................................................................... 41 
 
Adverse Event List .................................................................................................... 42 
7.4.1 Adverse Event List for Xisomab 3G3 .................................................................... 42 


 
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Adverse Event Assessment and Follow-Up .............................................................. 42 
 
Reporting Procedures ............................................................................................... 42 
7.6.1 OHSU IRB Reporting of Unanticipated Problems and Adverse Events ................ 43 
7.6.2 MedWatch Reporting ............................................................................................ 43 
7.6.3 Additional reporting requirements ......................................................................... 43 
7.6.4 Reporting Of Pregnancy ....................................................................................... 43 
 
Study Stopping Rules ............................................................................................... 44 
8. STATISTICAL CONSIDERATIONS ..................................................................................... 45 
 
Analysis Populations ................................................................................................. 45 
 
Description of Statistical Methods ............................................................................. 45 
8.2.1 General Approach ................................................................................................ 45 
8.2.2 Analysis of Primary Endpoint ................................................................................ 45 
8.2.3 Analysis Of The Secondary Endpoints ................................................................. 45 
8.2.4 Analysis Of The Exploratory Endpoints ................................................................ 45 
 
Sample Size, Power, Accrual Rate and Study Duration ............................................ 46 
8.3.1 Sample size and Power ........................................................................................ 46 
 
Measures to Minimize Bias .......................................... Error! Bookmark not defined. 
8.4.1 Randomization Procedures ..................................... Error! Bookmark not defined. 
8.4.2 Breaking the Study Blind ......................................... Error! Bookmark not defined. 
 
Handling of Missing Data .......................................................................................... 46 
9. CLINICAL MONITORING .................................................................................................... 47 
 
OHSU Knight Cancer Institute Data & Safety Monitoring Plan .................................. 47 
 
Clinical Data & Safety Monitoring .............................................................................. 47 
9.2.1 Study Monitoring Requirements ........................................................................... 47 
 
Quality Assurance & Quality Control ......................................................................... 48 
10. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ........................................ 50 
 Source Data/Documents ........................................................................................... 50 
 Participant & Data Confidentiality .............................................................................. 50 
 Data Collection & Storage: Privacy, Confidentiality & Security .................................. 50 
10.3.1 
Future Use of Stored Specimens ..................................................................... 51 
 Maintenance of Records ........................................................................................... 51 
 Publication and Data Sharing Policy ......................................................................... 52 
 Delivery of Progress Reports to Study Funder .......................................................... 52 
11. ETHICS/PROTECTION OF HUMAN PARTICIPANTS ...................................................... 53 


 
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 Ethical Standard ....................................................................................................... 53 
 Institutional Review Board......................................................................................... 53 
 Informed Consent ..................................................................................................... 53 
11.3.1 
Consent Procedures and Documentation ........................................................ 53 
 Protocol Review ........................................................................................................ 53 
 Changes to Protocol ................................................................................................. 54 
12. REFERENCES .................................................................................................................. 55 
APPENDIX A: PERFORMANCE STATUS ............................................................................... 57 
APPENDIX B: CONTRACEPTION ........................................................................................... 58 
 
 
 
 
 


 
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LIST OF TABLES 
 
Table 1. Oregon Population Demographics and Projected Accrual ...........................................24 
 
 
 


 
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Version # 3.0 
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LIST OF FIGURES 
 
Figure 1. Anatomic placement of peripherally inserted central venous catheter. .......................16 
Figure 2. Average dwell time until CAT detection. .....................................................................16 
Figure 3. Effects of Xisomab 3G3 on PT, aPTT and bleeding time in healthy volunteers. .........18 
 
 
 
 


 
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Version # 3.0 
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PI: Joseph Shatzel, MD 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CAT 
Catheter-associated thrombosis 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
HCT 
Hematocrit 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IND 
Investigational new drug application 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IV 
Intravenous 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
PET 
Positron emission tomography 
PI 
Principle Investigator 


 
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IRB# 18976  
Version # 3.0 
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PI: Joseph Shatzel, MD 
 
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PICC 
Peripherally inserted central catheter 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
(a)PTT 
(activated) Partial thromboplastin time 
RBC 
Red blood cell (count) 
RP2D 
Recommended Phase II Dose 
RNI 
Reportable new information 
SAE 
Serious adverse event 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
tPA 
tissue plasminogen activator 
TSMP 
Trial Specific Monitoring Plan 
UA 
Urinalysis 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
WBC 
White blood cell (count) 
 


 
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1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
 
OVERVIEW OF CATHETER-ASSOCIATED THROMBOSIS 
 
Peripherally inserted central catheters (PICCs) and indwelling central catheters are commonly 
used in both hospitalized and ambulatory patients who require centrally acting, or chronic 
intravenous (IV) medications including vasoactive drugs, antibiotics and chemotherapy.  PICC 
lines are inserted through the peripheral veins of the upper 
extremity with the end of the catheter positioned above the 
patient’s right atrium (Figure 1).  PICCs offer many 
conveniences including limiting the need for further 
venipuncture and easy bedside insertion and removal; 
however, they are associated with high rates of 
complications including occlusion and/or mis-positioning, 
infection, and most commonly thrombosis.1  Catheter use is 
exceedingly common in modern health care (Centers for 
Disease Control [CDC] data suggest approximately 30% of 
hospitalized medical patients have a central venous catheter 
placed), and at least 5 million central venous catheters are 
inserted in the US annually. As such, measures to decrease 
common complications would have a large patient impact.2,3  
 
Thrombosis complicates over half of PICC lines. Rates of screened thrombosis vary due to 
heterogeneity in patient population, catheter type, and anticoagulation use, but incidences 
between 50-60% are generally reported at 14 days post insertion, with one study reporting a 
61% incidence at 12-14 days in patients not on anticoagulation, and another 72% at 14-28 
days.4,5  While many of these thromboses remain occult, about 5-7% of patients will develop 
symptomatic thrombosis leading to patient morbidity, increased healthcare utilization and delays 
in medical care.6 Likewise, indwelling central venous catheters (ie, “Mediports”, “Port-a-Cath”, or 
“ports”) are plagued by high rates of thrombosis. Rates of CAT up to 62% have been reported in 
cancer patients not on anticoagulation.7  
 
Cancer patients commonly have central catheters placed to allow for chemotherapy and routine 
laboratory evaluation. Cancer is also a prothrombotic state, leading to a significantly higher risk 
for venous thromboembolism than the general population. Prospective studies specific to cancer 
patients with PICCs receiving weekly screening ultrasounds note a 51.4 % CAT rate, with a 
mean dwell time from PICC insertion to thrombosis of 8-11 
days. (Figure 2).8,9  Multiple prior studies have evaluated 
chemoprophylaxis in cancer patients with central catheters to 
prevent CAT, however traditional anticoagulants have failed 
to display a favorable safety to efficacy ratio. 
 
CAT and its treatment incur significant morbidity and costs. 
Current guidelines from three different professional societies 
all recommend initiation of anticoagulation upon the 
detection of CAT, and continuing anticoagulation for 3-6 
months following catheter removal.10-12  However, this 
strategy incurs a notable bleeding risk.  A systematic review 
of multiple studies of patients with CAT treated with 
anticoagulation found rates of major hemorrhage up to 4.9%, 
with some series reporting bleeding rates approaching 
Figure 1. Anatomic placement of 
peripherally inserted central 
venous catheter.  
Source: Blausen Medical Communications.  
Figure 2. Average dwell time until 
CAT detection.  


 
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Version # 3.0 
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25%.13,14  Besides patient morbidity, CAT incurs significant expense. The estimated costs of 
iatrogenic/preventable venous thrombosis in the United States is over $7.5 billion USD 
annually.15  Estimates of the direct medical costs of treating a patient with venous thrombosis 
range from of $12,000 to $15,000 (2014 US dollars).16 
 
Given the significant burden and costs associated with CAT multiple prospective trials17 and 
meta-analysis18 have evaluated the role of prophylactic anticoagulation to prevent CAT.  The 
current literature has failed to show convincing evidence to support routine prophylaxis in all-
comers with central venous catheters, but have shown a concerning risk of bleeding with 
traditional anticoagulants.  In certain high-risk prothrombotic subsets such as cancer patients, 
anticoagulation may be effective at decreasing symptomatic CAT.  One large meta-analysis 
found the absolute incidence of symptomatic CAT was reduced from 6.8% to 3.7% (P<0.001) in 
cancer patients given prophylactic anticoagulation, with 32 patients (95% CI, 21 to 65) needed 
to be treated to prevent one symptomatic event.6  Guidelines from four major cancer 
professional societies recommend against routine prophylactic anticoagulation, however, citing 
insufficient evidence of benefit and prohibitive bleeding risks.19  
 
Given the significant morbidity and financial burden associated with CAT, and the inability of 
traditional anticoagulants to safely prevent CAT, development of prophylactic interventions that 
are effective, but do not increase bleeding risk remains an unmet medical need. 
 
 
OVERVIEW OF XISOMAB 3G3 
 
Xisomab 3G3 is a novel anticoagulant recombinant monoclonal antibody directed against 
coagulation factor XI (FXI).  Please refer to investigator brochure for detailed information.  
 
1.2.1 MECHANISM OF ACTION 
 
The intrinsic pathway of thrombin generation starts with assembly and activation of the contact 
complex comprising FXII, high molecular weight kininogen (HK), prekallikerin (PK), and FXI.20,21  
Activated FXI (FXIa) further activates FIX, which in turn acts with its cofactor (FVIII) to form the 
tenase complex on a phospholipid surface to activate FX, ultimately leading to thrombin 
generation.  Whereas deficiencies of FVIII and FIX lead to haemophilia A and B, respectively, 
individuals lacking FXII, PK, or HK do not bleed abnormally.20  Xisomab 3G3 is a humanized 
IgG4 mouse monoclonal antibody designed to bind to the FXI A2 domain, thus interfering with 
the assembly of the contact activation complex and reducing PK, FXI and FXII interactions and 
activation.  As such, xisomab 3G3 acts as a functional inhibitor of pathological FXIIa by 
preventing prothrombotic contact activation of FXI by FXIIa and FXIa without substantially 
interfering with vasoregulatory activities of FXIIa, enzymatic activity of FXIa, or hemostatic FXI 
feedback activation by thrombin. 
 
1.2.2 PRE-CLINICAL EXPERIENCE 
 
Xisomab 3G3 has been evaluated to examine its binding profile to human tissues as well as its 
ability to induce cytokine release and antibody-dependent cell mediated cytotoxicity.  The safety 
and toxicokinetics of xisomab 3G3 have been evaluated in pivotal single dose studies in both 
rats and cynomolgus monkeys (refer to investigator brochure for details).  In cynomolgus 
monkeys, intravenous administration of xisomab 3G3 (10 mg/kg dose) was associated with a 
group mean terminal elimination half-life (T½) of 31.9 hours (range: 65.9 hours at 2 mg/kg to 212 
h at 50 mg/kg).  No adverse effects were observed up to a maximal dose tested of 50 mg/kg.  
Preclinical data also demonstrate a prolongation of aPTT in all species tested, including in vitro 
studies using human plasma that is expected due to its mechanism of action.   


 
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1.2.3 CLINICAL STUDIES OF XISOMAB 3G3 
 
 
 
The safety of xisomab 3G3 was initially assessed in a phase 1 trial of 21 healthy adults 
(clinicaltrials.gov).  The trial evaluated single dose of xisomab 3G3 at concentrations of 0.1, 0.5, 
2.0 or 5 mg/kg, or placebo.  The primary endpoint was treatment related adverse events.  The 
most common treatment emergent adverse event (TEAE) was productive cough, considered 
unrelated or unlikely treatment related and experienced by 2 (13%) subjects.  All other AEs 
were experienced by 1 subject.  Xisomab 3G3 prolonged activated partial thromboplastin time 
(aPTT) in a dose dependent manner, suggesting effective inhibition of FXI activation by FXIIa, 
while having no appreciable effect on bleeding and prothrombin times (Figure 3). 
 
 
RATIONALE 
 
Contact activation-induced thrombin generation can be initiated by artificial, negatively charged 
surfaces, and has been implicated as a major driver in the development of device associated 
thrombosis.  FXI and FXII may be instrumental in the development of catheter associated 
thrombosis and they could be good therapeutic targets for safe prophylaxis.  Catheters coated 
with a potent inhibitor of FXII activation, corn trypsin inhibitor, significantly delayed the 
development of CAT in vitro and in vivo22, as did knockdown of FXII in mice.23  Antibodies 
targeting FXIIa also prevented thrombosis in a rabbit model of extracorporeal circulation and 
reduced accumulation of clots in blood-perfused membrane oxygenators in baboons.24 FXII 
appears to be completely dispensable for hemostasis, as individuals born FXII deficient have no 
Figure 3. Effects of Xisomab 3G3 on PT, aPTT and 
bleeding time in healthy volunteers.  
Source: Xisomab 3G3 investigator brochure  


 
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bleeding diathesis or other known pathology.25  While individuals born deficient in FXI 
(hemophilia C) can have a mild bleeding diathesis, a human trial using antisense invoked FXI 
deficiency for surgical thromboprophylaxis found that humans significantly deficient in FXI can 
safely undergo orthopedic surgery without any significant increases in bleeding, when compared 
to enoxaparin, and are protected against thrombosis.26  Thus, inhibition of the contact activation 
complex (FXII, FXI, PK and HK), holds promise as a prophylactic intervention to prevent device 
associated thrombosis without increasing bleeding risk. 
 
This study seeks to assess the safety and efficacy of xisomab 3G3 in reducing the occurrence 
of CAT in cancer patients undergoing placement of a central venous catheter. The antibody will 
be administered as a single dose of 2mg/kg within 48 hours (±2 days) of catheter insertion.  This 
dose is based on pharmacokinetic data obtained in the phase 1 trial showing consistent 
evidence of pharmacodynamic effect (elevated aPTT) at day 14 which was normalized by day 
28 (Figure 3).    
 
 
POTENTIAL RISKS AND BENEFITS 
 
1.4.1 KNOWN POTENTIAL RISKS  
 
The safety profile of xisomab 3G3 in humans is still being established.  Xisomab 3G3 functions 
to inhibit, among others, contact activation of the intrinsic blood coagulation cascade. While 
inhibition or lack of FXII, PK, and HK do not appear to impair hemostasis, it is not yet known if 
interference with contact-mediated auto-activation of FXI has clinically relevant antihemostatic 
consequences. This may interfere with hemostatic function, thus increasing the risk for bleeding.  
Results of the completed phase 1 study (n = 21), following administration of xisomab 3G3, 
showed no severe, dose-dependent hemostasis-related adverse effects.  As a humanized 
antibody, participants receiving xisomab 3G3 may develop a variety of acute or delayed allergic 
reactions, such as rash, edema, urticaria, asthma, blood pressure changes, as well as severe 
anaphylaxis.  No severe allergic reactions to xisomab 3G3 were observed in the phase 1 trial.  
Refer to investigator brochure for further details.  
 
1.4.2 KNOWN POTENTIAL BENEFITS 
 
Inhibiting contact activation with xisomab 3G3 may reduce the incidence of CAT in patients that 
have a central venous catheter as part of their planned anti-cancer therapy. This may reduce 
CAT-associated morbidity and unwanted delays in cancer treatment.  It cannot, however, be 
guaranteed that participants in this study will directly benefit from treatment during participation, 
as the clinical trial is designed to provide information about the safety and effectiveness of the 
investigational approach. 
 
 


 
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2. STUDY DESIGN AND ENDPOINTS 
 
 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 8, Statistical Considerations, for additional information regarding statistical 
methods used in this study. 
 
This is a phase 2, single center, single arm trial to assess the safety and efficacy of xisomab 
3G3 in reducing the incidence of CAT in cancer patients undergoing PICC insertion or 
indwelling catheter placement. Participants must meet the inclusion criteria, have none of the 
exclusion criteria, and have provided written informed consent before the conduct of any 
screening tests not performed routinely in their treatment. 
 
A total of 50 participants are planned for enrollment into this study.  Eligibility will be confirmed 
prior to planned PICC line placement or indwelling central venous catheter placement.  Eligible 
participants that are scheduled to have a catheter inserted as part of their planned anticancer 
therapy will be enrolled to receive xisomab 3G3.  Within 48 hours of insertion of the PICC or 
indwelling catheter (i.e. ± 2 days) per institutional standards, participants will undergo IV 
placement and receive a single dose of xisomab 3G3.  Standard procedures for catheter 
maintenance for sterility and patency will be performed each time the catheter is accessed for 
use including 10 to 20 ml of normal saline pulsatile flush before and after use and every 7 days 
in the outpatient setting.  Two days after administration of xisomab 3G3 participants may 
proceed with planned, standard-of-care anticancer treatment in consultation with their treating 
physician and in accordance with institutional guidelines.  The primary objective is to measure 
the efficacy of xisomab 3G3, as determined by the incidence of ultrasound-confirmed CAT (both 
symptomatic and asymptomatic) within 18 days after catheter insertion, compared to historical 
cancer controls.  All participants will undergo duplex venous ultrasound and physical 
examination to evaluate symptomatic or asymptomatic CAT at 14 (± 4) days after catheter 
placement.  If participants develop symptoms suggestive of CAT such as arm pain, swelling, or 
erythema in the arm with the PICC, those participants will undergo standard-of-care workup with 
a unilateral extremity duplex venous ultrasound in the affected arm or leg.  Participants that 
have confirmed CAT or other thrombosis found on imaging, per investigator assessment, will be 
treated at the discretion of their treating physician per institutional guidelines and standards of 
care.  The duplex venous ultrasound assessment will include evaluation of disease history and 
physical exam to further assess possible thrombosis-associated symptoms.  The secondary 
objective is to establish the safety and tolerability of xisomab 3G3 administered near the time of 
central line placement in patients that are diagnosed with and treated for solid tumors.  All 
participants will be followed for 60 days (or until resolution/stabilization of any clinically 
significant drug-related adverse event) from time of catheter insertion to assess for AEs and 
medication use.    
 
 
STUDY OBJECTIVES AND ENDPOINTS 
 
2.2.1 PRIMARY OBJECTIVE AND ENDPOINT 
 
Objective 
Endpoint 
Start  
End  
To determine the efficacy of 
xisomab as measured by 
the incidence of CAT in 
individuals with a central 
venous catheter 
Incidence of CAT  Catheter insertion (Day 
1) 
Day 18 
 


 
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2.2.2 SECONDARY OBJECTIVES AND ENDPOINTS 
 
Objective 
Endpoint 
Start  
End  
To evaluate the safety and 
tolerability of xisomab 3G3 in 
cancer patients with a PICC 
or indwelling catheter  
1. Incidence of major and 
clinically-relevant bleeding 
[refer to Section 6.1.9.1] 
 
2. Incidence of xisomab 3G3-
associated toxicities [per 
CTCAE v5.0]  
Administration 
of xisomab 
3G3 (Day 1 ± 
2 days) 
End of follow-up 
(Day 60) 
 
2.2.3 EXPLORATORY OBJECTIVE AND ENDPOINT 
 
Objective 
Endpoint 
Start  
End  
Assessment of drug 
exposure and catheter 
occlusions leading to 
medical intervention 
Quantification of coagulation profile: 
1. aPTT 
2. PK evaluation 
3. Time to thrombosis (i.e., 
symptomatic CAT) 
4. Proportion of participants 
with a catheter occlusion 
requiring medical 
intervention (i.e., local 
administration of tPA) 
pre-xisomab 
3G3 
administration  
Day 18  
 
 


 
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3. STUDY ENROLLMENT AND WITHDRAWAL 
 
 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Participant or legally authorized representative (LAR) must provide written informed consent 
before any study-specific procedures or interventions are performed.  
2. Men and women, aged ≥ 18 years. 
3. In consultation with PI and treating physician, participant’s cancer-directed therapy allows 
for a 1-day period between administration of study drug and subsequent start of planned 
cancer-directed therapy.  
4. Individuals with a confirmed solid malignancy that will undergo insertion of a PICC line or 
indwelling central venous catheter as part of planned anticancer therapy per institutional 
standards 
5. Must have ECOG performance status ≤ 2 (refer to Appendix A) 
6. At time of enrollment, must have: 
a. Platelet count > 100 x 109/L,  
7. Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.   
Participants of childbearing potential are defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. 
8. Female participants of childbearing potential must agree to use adequate methods of 
contraception (Appendix B) starting with the first dose of study therapy through 90 days after 
the last dose of study therapy.   
Participants of childbearing potential are those who have not been surgically sterilized or 
have not been free from menses for >1 year without an alternative medical cause.  
9. Male participants must agree to use an adequate method of contraception (Appendix B) 
starting with the first dose of study therapy through 90 days after the last dose of study 
therapy.  
 
 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Actively receiving treatment in another therapeutic clinical trial  
2. Active acute leukemia (lymphoma and myeloma are allowed) 
3. At time of enrollment, known contraindication to anticoagulation therapy, including: 
a. Clinically significant active bleeding 


 
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b. Individual is within 72 hours of major surgery  
c. Abnormal baseline coagulation tests, including INR > 1.5, or aPTT prolonged 
d. Abnormal renal function defined by an eGFR < 45 mL/min 
e. Abnormal hepatic function defined as LFTs (AST, ALT or Total Bilirubin) >2x the upper 
limit of normal or known Child-Pugh class B or C cirrhosis.    
f. Prior history of intracranial hemorrhage 
g. Primary brain tumors or known brain metastasis 
h. Major extracranial bleed within the last 6 months where the cause has not been 
identified or treated 
i. 
Known bleeding diathesis 
j. 
Use of therapeutic anticoagulation or anti-platelet agents for any indication at enrollment  
k. At the discretion of the investigator, any other contraindication to anticoagulation therapy 
l. 
Presence of a pediatric-sized PICC line  
m. Participant is expected to receive chemotherapy associated with a 15% or higher 
incidence of grade 3-4 thrombocytopenia within 14 days of recieving study drug. 
4. Preexisting intravenous catheter, or indwelling spinal or epidural catheter, at time of 
enrollment that is intended to remain for the duration of study.  Participants may remain 
eligible if existing catheter is to be removed before placement of a catheter for cancer 
directed therapy. Removal of existing catheter should occur at least 24 hours prior to PICC 
or indwelling catheter insertion. 
5. Previously documented hypersensitivity to either the drug or excipients  
6. Psychiatric illness/social situations, or any other condition, that in the opinion of the 
investigator, would limit compliance with study requirements 
7. Participant is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 90 days after the 
last dose of trial treatment. 
 
8. Participant is allergic to heparin or heparin derivatives. 
 
9. Participants with a history of venous thromboembolism within the last 3 months.  
 
 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants for this study will primarily be recruited from hematology and oncology practices 
within OHSU, including affiliated community hematology and oncology (CHO) practices. 
Participants may be identified and referred to this study by their primary treating physician from 
within OHSU/CHO, or from the outside community.  Participants may be identified by a member 
of the patient’s treatment team, the PI, research team, or medical and surgical oncology clinics 
part of OHSU/CHO.  As a member of the treatment team, the investigator will screen their 
patient’s medical records for suitable research study participants and discuss the study and their 
potential for enrolling in the research study.  Referral of potential participants to investigator of 
this study is made as part of standard of care, with the referring physician seeking advice on the 
diagnosis, evaluation, and/or treatment of the patient’s malignancy.   
 


 
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The investigators may also screen the medical records of potential participants with whom the 
investigator does not have a treatment relationship.  This will be done for the limited purpose of 
identifying patients who would be eligible to enroll in the study and to record appropriate contact 
information in order to approach these potential individuals regarding the possibility of 
participating in the study.  Participants may also initiate contact with the investigator through 
information of this study posted on the clinicaltrials.gov website. 
 
3.3.1 ACCRUAL ESTIMATES 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset.  No participant will be excluded from the study on the basis of sex, gender, racial or 
ethnic origin. Male, female and minority volunteers will be recruited for this study from the 
general population and approximately 50% men and 50% women will be studied.  Gender-
nonconforming and gender-fluid individuals as members of the general population will also be 
recruited.  The projected sex, gender, racial, and ethnic composition of the study will represent 
that of the state of Oregon (Table 1).  
 
Table 1. Oregon Population Demographics and Projected Accrual  
Ethnic Category [OR] 
Sex/Gender 
Females 
Males 
Total 
 
n 
% 
n 
% 
n 
% 
Hispanic or Latino 
3 
6.5 
3 
6.3 
6 
12.8 
Not Hispanic or Latino 
22 
44.0 
22 
43.2 
44 
87.2 
Ethnic Category: Total of all participants* 
25 
 
25 
 
50 
100* 
 
Racial Category 
 
American Indian or Alaskan Native 
0 
0.9 
0 
0.9 
1 
1.8 
Asian 
1 
2.3 
1 
2.2 
2 
4.5 
Black or African American 
1 
1.1 
1 
1.0 
1 
2.1 
Native Hawaiian or other Pacific Islander 
0 
0.2 
0 
0.2 
0 
0.4 
White 
22 
44.1 
22 
43.3 
44 
87.4 
Two or more races 
1 
1.9 
1 
1.9 
2 
3.8 
 
Racial Category: Total of all participants* 
25 
50.5 
25 
49.5 
50 
100 
Source: Adapted from U.S. Census Bureau, 2017.  
*Totals may not equal 100 due to rounding. 
 
3.3.2 INCLUSION OF CHILDREN 
 
This study will not include children or adolescents as the safety profile of xisomab 3G3 has not 
been evaluated in a pediatric population.  
 
 
REGISTRATION PROCEDURES 
 
3.4.1.1 OHSU Registration 
 
Participants will be required to give written informed consent to participate in the study before 


 
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any screening tests or evaluations are conducted that are not part of standard care. 
 
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS). At a minimum, registration of OHSU 
participants will include signed copies of the most recently IRB-approved, informed consent 
form and HIPAA authorization. 
 
 
PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant or the participant's legally acceptable representative.  The current Institutional 
Review Board (IRB) approved informed consent must be signed and dated by each participant 
prior to undergoing any study procedures or before any prohibited medications are withheld 
from the participant in order to participate in this study.  
 
Screening will begin once the participant has provided written informed consent to participate in 
the study .  All screening and baseline evaluations will be performed during the screening phase 
(i.e., up to 28 days before catheter placement).  Day 1 of the clinical trial will be when the central 
venous catheter is inserted.  Total accrual of all participants is anticipated to take a total of 36 
months. 
 
 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment.  
 
If a participant withdraws consent, they will be specifically asked if they are withdrawing consent 
to: 
• 
All further participation in the study including any further follow up  
• 
Withdrawal of consent to the use of their study generated data 
• 
Withdrawal to the use of any biological samples 
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study. Information about the reason(s) for discontinuation and collection of 
any new or ongoing AEs and medications should be collected at the time the participant 
withdraws consent.   
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 6, Study 
Procedures/Evaluations And Schedule  
 
3.6.1 HANDLING PARTICIPANT WITHDRAWAL AND DISCONTINUATION 
 
Participants enrolled in this study that withdraw prior to receiving study drug will be replaced.   
 
 
OFF-STUDY CRITERIA 
 
Criteria that can take a participant off-study include: 
• 
Participant requests to be withdrawn from study without further follow-up, 
• 
Participant is lost to follow-up, 
• 
Participant completes study follow-up period, 


 
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• 
Death, 
• 
Screen failure, 
• 
Investigator’s discretion 
 
3.7.1 SCREEN FAILURES 
 
Any participant that has signed the consent form but does not meet the study eligibility criteria, 
or meets study eligibility criteria but terminates their participation prior to receiving study 
treatment, will be considered a screen failure.  The reason for screen failure should be captured 
in the database for each participant failing to meet the eligibility criteria.  
 
 
STUDY DISCONTINUATION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to IRB and manufacturer.  If 
the study is prematurely terminated or suspended, the Investigator will promptly inform the IRB 
and the manufacturer and will provide the reason(s) for the termination or suspension. 
 
Reasons for terminating the study may include the following: 
• 
Incidence or severity of adverse events, in this or other studies, indicates a potential 
health hazard to participants. 
• 
Data that are not sufficiently complete and/or evaluable. 
• 
Investigators do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to manufacturer or 
regulatory authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.    
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor/manufacturer, IRB and/or FDA. 
 


 
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4. INVESTIGATIONAL PRODUCT 
 
A list of the adverse events and potential risks associated with the investigational or other 
agents administered in this study can be found in Section 7.4, Adverse Events. 
 
 
XISOMAB 3G3 
 
Xisomab 3G3 is a humanized IgG4 monoclonal antibody manufactured by Aronora, Inc.  Refer 
to investigator brochure for additional details.  
 
4.1.1 ACQUISITION 
 
Xisomab 3G3 will be supplied by the manufacturer, Aronora Inc., and prepared by the research 
pharmacy services at OHSU per manufacturer instructions.  Following submission and approval 
of the required regulatory documents, a supply of xisomab 3G3 may be ordered from Aronora 
Inc. by completing a Drug Request Form.  
 
4.1.2 FORMULATION, APPEARANCE, PACKAGING AND LABELING  
 
The 146 kDa antibody, xisomab 3G3, is produced as a lyophilized cake that is formulated in 8% 
sucrose, 10 mM histidine, 30 mM arginine HCl, 10 mM methionine, 80 ppm polysorbate 80, and 
has a pH of ~5.2 after reconstitution for intravenous administration.  Xisomab 3G3 is packaged 
in a 10 mL nominal-volume USP-Type I colorless glass vial, stoppered with a bromobutyl rubber 
stopper and capped with an aluminum overseal with a flip-off cap.  Vials containing xisomab 
3G3 will denote drug product as being intended for investigation only. The lyophilized cake 
white is slightly yellow, clear and colorless liquid upon reconstitution. 
 
 
4.1.3 PRODUCT STORAGE AND STABILITY 
 
The lyophilized xisomab 3G3 drug product should be stored upright at 2°C to 8°C.  The drug 
product is stable for 36 months if stored at these conditions.  Exposure to bright light should be 
avoided; standard room illumination does not necessitate any precautions.  Once reconstituted, 
xisomab 3G3 is stable for at least 6 hours when stored at 25°C.   
 
4.1.4 COMPATIBILITY 
 
Lyophilized xisomab 3G3 should be reconstituted in sterile water for injection.   
 
4.1.5 HANDLING 
 
Aseptic technique, use of sterile disposable gloves and hand hygiene according to institutional 
standards.  Manufacturer recommends disinfection of the septum of the injection stoppers using 
a swab with an appropriate disinfectant (based on ethanol or isopropanol).  
 
4.1.6 PREPARATION 
 
Per manufacturer instructions, lyophilized xisomab 3G3 should be reconstituted with 2.6 ml 
sterile water for injection by carefully dispensing diluent into the vial of lyophilizate, trying to 
maintain the product and liquid in the base of the vial to avoid having the powder distribute 
around the walls of the vial.  Gently swirl the vial content until the lyophilized drug product is 
completely dissolved and the solution is homogenous and transparent (not cloudy) when held 
against light.  The final volume should result in 2.8 mL of reconstituted xisomab 3G3 antibody 


 
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drug product for administration.  The final nominal concentration of xisomab 3G3 following 
reconstitution is 15 mg/mL.  Multiple doses may be administered from one drug product vial. 
 
 
4.1.7 ADMINISTRATION 
 
The reconstituted drug product should be administered intravenously via a peripherally inserted 
IV line or via the catheter as a slow bolus (approximately 1 minute) within 48 hours of catheter 
placement (i.e. +/- 2 days).   
 
4.1.8 SPECIAL CONSIDERATIONS FOR ADMINISTRATION  
 
Xisomab 3G3 is to be administered at a fixed dose of 2 mg/kg. The participant’s weight should 
be measured prior to administration.  To calculate the exact volume of concentrated solution 
needed for the dose, apply the following equation: 
 
𝑉𝑉𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑(𝑚𝑚𝑚𝑚) = [𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷 (𝑚𝑚𝑚𝑚/𝑘𝑘𝑘𝑘) 𝑥𝑥 𝐵𝐵𝐵𝐵𝐵𝐵𝐵𝐵 𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡 (𝑘𝑘𝑘𝑘)]
15 (𝑚𝑚𝑚𝑚/𝑚𝑚𝑚𝑚)
  
 
Example: for a 70 kg patient dosed at 2 mg/kg, then: 
 
𝑉𝑉𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑(𝑚𝑚𝑚𝑚) = 
ቂ2 ቀ
𝑚𝑚𝑚𝑚
𝑘𝑘𝑘𝑘ቁ𝑥𝑥 70 (𝑘𝑘𝑘𝑘)ቃ 
15 ቀ
𝑚𝑚𝑚𝑚
𝑚𝑚𝑚𝑚ቁ
= 9.3 𝑚𝑚𝑚𝑚 𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥𝑥 3𝐺𝐺3 
 
To calculate the number of vials needed for the dose follow these steps: 
 
𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 (𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣𝑣) = 𝑉𝑉𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑(𝑚𝑚𝑚𝑚)
2.8 𝑚𝑚𝑚𝑚 
 
If result is obtained with decimals, it should be rounded up to the nearest upper unit 
 
Example: for a 70 kg patient dosed at 2 mg/kg, the calculated patient dose is 3.3 vials, then 4 
vials should be used to obtain the volume of concentrated solution. 
 
4.1.9 ACCOUNTABILITY 
 
RPS will maintain a careful record of the inventory and disposition of the study agent. (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage).   
 
Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities or other oversight bodies. 
 
The Investigator or designee will collect and retain all used, unused, and partially used 
containers of study medication until full accounting has been completed.  The Investigator or 
designee must maintain records that document: 
• Investigational product delivery to the study site. 
• The inventory at the site. 


 
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• Use by each participant including unit counts from each supply dispensed. 
• Return of investigational product to the Investigator or designee. 
• Destruction or return of investigational product for final disposal. 
 
These records should include dates, quantities, batch/serial numbers (if available), and the 
unique code numbers (if available) assigned to the investigational product and study 
participants. 
 
The investigational product must be used only in accordance with the protocol.  The Investigator 
will also maintain records adequately documenting that the participants were provided the 
correct study medication specified. 
 
Completed accountability records will be archived by the site. At the completion of the study, the 
Investigator or designee will oversee shipment of any remaining study drug back to Aronora Inc. 
for destruction according to institutional standard operating procedures. If local procedures 
mandate site destruction of investigational supply, prior written approval must be obtained from 
Aronora Inc. 
 
4.1.10 DESTRUCTION AND RETURN 
 
At the end of the study unused supplies of study drug should be destroyed according to 
institutional policies.  Drug supplies will be counted and reconciled in full at the site with all 
monitoring procedures complete before destruction.  Destruction will be documented in the Drug 
Accountability Record Form. 


 
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5. TREATMENT PLAN 
 
 
DOSAGE AND ADMINISTRATION 
 
Treatment will be administered on an out-patient basis.  Reported adverse events and potential 
risks are described in Section 7.4, Adverse Event List.   
 
 
Enrolled participants will receive a single fixed dose of xisomab 3G3 (2 mg/kg) through a 
peripheral IV or the inserted catheter within 48 hours of catheter placement (i.e. ± 2 days). If 
Xisomab 3G3 is administered prior to D1 catheter placement, eligibility must be confirmed prior 
to study drug administration. Participants will be monitored for at least 1 hour on the day of 
xisomab 3G3 administration for adverse events. Participants not receiving study drug or 
catheter placement as scheduled, may be rescheduled if within allowable screening window 
(i.e., no more than 28 days from consent). Participants receiving study drug but have a delay in 
placement of the catheter beyond 48 hours from time of xisomab administration, will not be 
considered evaluable for efficacy analysis (per Section 8.1), but will be followed for xisomab 
3G3-associated toxicities (per Section 6.7).  
 
Two (2) days after participants receive study drug they may proceed to undergo planned 
anticancer therapy per standard of care.  Administration of planned cancer-directed therapy may 
not occur earlier than 2 days from time of giving study drug.  The type(s) and frequency of 
administration of anticancer drug(s) comprising the participants’ anticancer treatment regimen is 
at the discretion of treating physician and should be recorded in the CRF.   
 
Consistent with institutional standards, participants may at any time during the study receive a 
standard of care workup with an ultrasound if they develop symptoms the investigator (or 
treating physician) believes to be suggestive of CAT, including arm pain and swelling or 
erythema in the same arm as the catheter.  In such cases, the participant may receive 
antithrombotic therapy, at the discretion of their treating physician, per institutional guidelines. 
 
 
TREATMENT PERIOD  
 
After administration of a single, fixed dose of xisomab 3G3 (2 mg/kg) within 48 hours of catheter 
placement (with this placement defining Day 1), participants will undergo an end of treatment 
visit on Day 14 (± 4 days). 
 
 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Medications required to treat AEs, treat cancer, manage cancer symptoms, concurrent diseases 
and supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are 
allowed in general.  The participant must be told to notify the investigational site about any new 
medications begun after the start of the study treatment.  All medications or nutritional/herbal 
supplements known to interact with study agent should be excluded.  Prohibited medications 
must be stopped within 2 weeks or 1 half life (whicever is shorter) of investigational agent 
Regimen Description 
Agent 
Dose 
Route** 
Schedule 
Xisomab 3G3 
2 mg/kg 
IV (via catheter) Single dose administered within 48 hours of 
catheter placement (± 2 days). 
.  
**Study drug should be administered as a slow bolus (approximately 1 minute). 


 
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administration. If the medication or supplement cannot be discontinued or replaced, the subject 
should be excluded from this study.  Each participant’s medication and supplement profile 
should be reviewed by investigator and/or an oncology trained pharmacist to ensure compliance 
with this aspect of care. All medications known to interact with the study drug should be avoided 
after day 18.   
 
5.3.1 INFECTION PROPHYLAXIS AND TREATMENT 
 
In general, participants with a documented infectious complication should receive oral or IV 
antibiotics or other anti-infective agents as considered appropriate by the Investigator for a 
given infectious condition, according to standard institutional practice.   
 
5.3.2 TRANSFUSIONS OF PLATELETS AND RED BLOOD CELLS (RBC) 
 
Blood, plasma, platelet or red blood cell transfusions are permitted as medically necessary per 
institutional guidelines.  The decision for platelet or red blood cell transfusions should be done in 
collaboration with study investigator and participant’s treating physician.  The occurrence of any 
transfusion occurring prior to end of treatment visit on Day 14 (± 4 days) should be recorded in 
(e)CRF. Abnormal, clinically significant bleeding may be managed at the discretion of the 
physician.  Antifibrinolytic agents such as transexamic acid may be used in the event of major 
bleeding events, and bleeding refractory to this may be managed with recombinant factor VIIa 
(Novo7) or prothrombin complex concentrates, at the discretion of the treating physician and in 
consultation with study PI.  
 
5.3.3 ANTI-PLATELET AGENTS AND ANTICOAGULANTS 
 
Anti-platelet agents and anticoagulants are permitted only as medically necessary, in case of 
new thrombosis, and managed per institutional guidelines. Standard of care anticoagulation 
may be started at any time in conjunction with xisomab 3G3 if deemed warranted by the treating 
physician. Anti-platelet agents and/or anticoagulants may not be given prior to administration of 
xisomab 3G3. The decision regarding use of antithrombotics should be done in collaboration 
with study investigator and participant’s treating physician. Participants should be carefully 
monitored for bleeding risks. The use of any anti-platelet agents or anticoagulants occurring 
prior to end of treatment visit should be recorded in (e)CRF.   
 
5.3.4 ALLERGIC/HYPERSENSITIVTY REACTIONS 
 
‘Allergic/hypersensitivity reactions’ or ‘cytokine release syndrome/acute infusion reaction’, per 
CTCAE v5.0, are defined as AEs related to xisomab 3G3 with onset typically within hours from 
the start of the study drug infusion. Symptoms should be managed per institutional guidelines as 
appropriate (e.g., antihistamines, corticosteroids, NSAIDs, and IV fluids).  
 
5.3.5 CONTRACEPTION 
 
The study agent described within this protocol may have adverse effects on a fetus in utero.  
Non-pregnant, non-breast-feeding women of child-bearing potential may be enrolled if they are 
willing to use adequate methods of birth control (Refer to Appendix B) or are considered highly 
unlikely to conceive.  
 
Highly unlikely to conceive women are defined as:  
 


 
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1. Surgically sterilized, or  
2. Women will be considered post-menopausal if they have been amenorrheic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
a. Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).  
b. Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
3. Not heterosexually active for the duration of the study.  
 
Participants should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study individuals must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in Section 7.6.  If there is any 
question that a participant will not reliably comply with the requirements for contraception, they 
should not be entered into the study. 
 
5.3.6 USE IN PREGNANCY 
 
If a participant inadvertently becomes pregnant while on treatment with study agent, the study 
site will contact the participant at least monthly and document the participant’s status until the 
pregnancy has been completed or terminated.  The pregnancy will be recorded on the (e)CRF 
and reported by the Investigator to the IRB (refer to Section 7.6.4). 
 
5.3.7 USE IN NURSING WOMEN 
 
It is unknown whether study agent is excreted in human milk. Since many drugs are excreted in 
human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
 
 
PRECAUTIONARY AND PROHIBITED MEDICATIONS, TREATMENTS, AND 
PROCEDURES  
 
Antithrombotic agents (Warfarin, heparin products, direct oral anticoagulants) should be avoided 
while on study (except for standard of care heparin/tPA flushes if required for catheter 
maintenance/occlusion).  Elective invasive procedures should be delayed until completion of the 
initial 18 day drug efficacy evaluation period.   
 
5.4.1 BLOOD DONATION  
 
Participants must not donate blood during treatment with study drug and for 1 month following 
initial administration. 
 


 
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6. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE OF EVENTS 
 
All study visits and laboratory procedures, where possible, should be conducted as part of 
scheduled standard of care visits.   
 
 
STUDY SPECIFIC PROCEDURES 
 
6.1.1 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee.  In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any condition diagnosed within the prior 10 years that are considered to be clinically significant 
by the Investigator.  Details regarding the participant’s cancer will be recorded separately and 
not listed as medical history. 
 
6.1.2 DISEASE ASSESSMENT 
 
The Investigator or qualified designee will obtain prior and current details regarding the 
participant’s cancer. 
 
6.1.3 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history.  
 
6.1.4 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits. 
The physical exam at baseline should include a complete physical exam per institutional 
standards.  All other physical exams after baseline will include an evaluation of any AEs, or any 
previously reported symptoms, or prior physical examination findings. 
 
A physical examination may include evaluating: weight, general appearance, head, ears, eyes, 
nose, throat, neck, skin, cardiovascular system, respiratory system, gastrointestinal system, and 
nervous system.  For the purposes of assessing CAT, physical exam should include 
assessment of participant arm pain and swelling or erythema in the same arm as the catheter. 
 
A physical exam to be conducted: as part of screening visit; within 24hrs or day of single dose of 
study treatment; and at EOT.  If screening visit occurs within 24hrs of study treatment 
administration, provider visit does not need to be repeated. All physical examinations will also 
include: 
 
6.1.4.1 Vital signs  
 
Vitals to be collected include BP, HR, temperature, and oxygen saturation by pulse oximetry.  
Unless noted otherwise, vitals will be obtained during each study visit incorporating a physical 
exam.  Significant findings that were present prior to the signature of the informed consent must 
be included in the Medical History (e)CRF page.  Significant new findings that begin or worsen 
after beginning study treatment must be recorded on the Adverse Event (e)CRF page.  
 


 
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6.1.4.2 Performance status  
 
Unless noted otherwise, ECOG status (per Appendix A) will be obtained during each study visit 
incorporating a physical exam. 
 
6.1.5 HEIGHT AND WEIGHT  
 
Weight must be collected on the day of enrollment. 
 
6.1.6 CATHETER PLACEMENT 
 
Placement of the PICC in participants will be performed according to institutional guidelines. 
Ultrasound may be used to guide the placement of the PICC, and may include use of local 
anesthetic.  The specific type of PICC (e.g., single or double lumen, brand) will be determined 
by participants’ treatment management team based on needs of their planned anticancer 
therapy.   
 
Placement of indwelling central venous catheters in participants will be performed according to 
institutional guidelines. Ultrasound may be used to guide the placement of the indwelling 
catheter and may include use of local anesthetic. The specific type of indwelling catheter will be 
determined by participants’ treatment management team based on needs of their planned 
anticancer therapy.   
 
 
6.1.7 RADIOGRAPHIC IMAGING ASSESSMENTS 
 
All diagnostic and treatment-associated imaging (e.g., MRI, CT, PET) will be performed as 
clinically indicated in accordance with institutional standards for managing a participant’s 
cancer.  Per institutional standards, the use of additional imaging modalities such as the use of 
contrast venography for assessing CAT or lumen patency is also permitted as clinically 
indicated.  Findings from these studies may be collected.  
 
6.1.8 ULTRASOUND  
 
Per institutional standards, catheters are evaluated for possible CAT via venous duplex 
ultrasonography 14 (±4) days from time of catheter placement (which will be ±2 days from 
administration of study agent). Venous duplex ultrasonagraphy to occur as part of EOT visit, 
prior to provider visit. Assessment will include compression imaging of all the accessible 
portions of the internal jugular, innominate, subclavian, axillary, cephalic and basilic veins, as 
well as color Doppler of the internal jugular, subclavian and axillary veins. VTE will be 
diagnosed based on non-compressibility of a vein segment and/or abnormal color Doppler 
patterns. Whether the presence of CAT in a participant is symptomatic or asymptomatic at time 
of ultrasound evaluation will be noted in CRF as part of assessment.  
 
6.1.9 ADVERSE EVENT EVALUATION  
 
Toxicities and adverse experiences will be assessed at each visit using the CTCAE v5.0.  
Safety will be monitored by assessing physical examination, vital signs, and weight, 
performance status, hematology, chemistry, coagulation, and pregnancy, as well as collecting of 
the AEs and medications at study visits. 
 


 
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Adverse events will be monitored from the time the participant signs the informed consent form, 
but will not be included for analysis if occurring before the study agent is given. Participants will 
be instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  All AEs (serious and non-serious) must be recorded in the medical record 
and (e)CRFs regardless of the assumption of a causal relationship with the study drug; 
however, known AEs associated with a participant’s planned anticancer treatment regimen will 
not be collected except for the development of grade 3-4 thrombocytopenia.  For details on AE 
collection and reporting, refer to Section 7, Safety.   
 
6.1.9.1 Assessment of Major and Clinically Relevant Non-major Bleeding  
 
Bleeding will be defined using the International Society of Thrombosis and Hemostasis definition 
of major bleeding for clinical investigations of anti-hemostatic medicinal products in nonsurgical 
patients (i.e., fatal bleeding, critical organ bleeding such as CNS bleeding, or bleeding causing a 
fall in hemoglobin of 20 g/L or more) and clinically relevant non-major bleeding (i.e., bleeding 
that does not fit the former definition of major bleeding but prompts medical attention).27 
 
 
LABORATORY PROCEDURES AND EVALUATIONS 
 
All laboratory procedures and evaluations will occur at times indicated in Section 6.9, Schedule 
of Events.  
 
6.2.1 HEMATOLOGY 
 
A complete blood count (CBC) with differential will be collected, per institutional standards, and 
should include : RBC, hematocrit, hemoglobin, platelet, white blood cell (WBC), and WBC 
differential. 
 
6.2.2 BIOCHEMISTRY  
 
Comprehensive metabolic panel (CMP), including: Na, K, Cl, CO2, BUN, Creatinine, Ca, 
Glucose, Albumin, Total protein Alkaline Phosphatase, total bilirubin, aspartate 
aminotransferase (AST), and alanine aminotransferase (ALT).  
 
6.2.3 COAGULATION PANEL 
 
Activated Partial Thromboplastin Time (aPTT) and pro-thrombin time (INR) are required at 
screening (baseline) and on Day 14 (±4 days) study visit.  Results from any other coagulation 
test performed as clinically indicated will also be captured.  
 
6.2.4 ECHOCARDIOGRAM 
 
Required only as clinically indicated.  
 
6.2.5 PREGNANCY TEST  
 
For women of childbearing potential, a serum or urine pregnancy test will be done within 72 
hours prior to receiving study drug.  If the urine pregnancy test is positive, a serum pregnancy 
test must be performed per institutional standards.  
 


 
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EXPLORATORY STUDIES 
 
Research blood specimens will be collected for additional coagulation studies (e.g., PT/INR, and 
aPTT) and drug PK evaluation.   
 
i) Collection of Specimens 
 
The research blood draws will occur as noted in Section 6.9, Schedule of Events.  The research 
blood draw should be collected in a blue top (3.2% sodium citrate) tube.  Collection of research 
blood should occur before collection of samples in additive-containing tubes such as the EDTA, 
heparin, or clot activator tubes.   
 
ii) Transport of Specimens 
 
Within 3 hours from time of collection, whole blood research samples should be transported at 
room temperature to Shatzel Laboratory: 
 
3303 S Bond Ave, CHH13033,  
Portland OR 97239 
 
iii) Handling of Specimen 
 
Whole blood samples should be centrifuged at a speed of 1500g for at least 15 minutes to 
achieve platelet poor plasma.  Plasma is to be transferred into a polypropylene vial being careful 
to avoid the buffy coat.  Specimens can be stored at -70°C until ready for analysis.  
 
iv) Site Performing Studies  
 
Coagulation assays will be performed in the investigator’s laboratory.   
 
 
SCREENING AND BASELINE ASSESSMENTS 
 
A screening (consultation) visit may occur as part of standard of care.  If a participant is eligible 
for the study after review of key inclusion/exclusion criteria, additional screening and/or baseline 
visits will be scheduled while staff members are requesting insurance authorization to 
participate in a clinical trial.  The following will be reviewed at initial screening visit:  
• 
Clinical history and physical exam (per standard of care) 
• 
Informed consent obtained and documented 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis.  Consent 
must be obtained before initiation of any clinical screening procedures that are performed solely 
for the purpose of determining eligibility for this research study.  Evaluations performed as part 
of routine care before informed consent can be utilized as screening evaluations if done within 
the defined time period.  
 
 
ASSESSMENTS DURING TREATMENT 
 
Specific on-study assessments are listed in the Section 6.9, Schedule of Events.  Visits should 
occur on Day 1 and Day 14 (±4 days).   The Day 14 (±4 days) visit will include an ultrasound, as 
well as corresponding history and physical exam. The presence of CAT, either symptomatic or 
asymptomatic, at time of assessment should be recorded in (e)CRF. 
 


 
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For all other assessments: under certain circumstances (e.g., clinic holiday, inclement weather) 
scheduled visits may be delayed by no more than 4 days, or may occur earlier than scheduled 
by no more than 4 days.   
 
 
END OF TREATMENT VISIT 
 
An end of treatment visit should occur on Day 14 (±4 days) after catheter placement and include 
assessments listed in Section 6.9, Schedule of Events.   
 
If a participant does not reach the end of treatment due to transition to hospice or death, an end 
of treatment visit will not be conducted.   
 
6.6.1 EARLY TERMINATION VISIT 
 
Participants should be evaluated within 10 days after terminating participation, or evaluated 
prior to the initiation of any other off-study interventional therapy.  Early termination 
assessments are listed in the Section 6.9, Schedule of Events.   
 
 
FOLLOW-UP 
 
Participants with AE(s) that require hospitalization will be followed until resolution or stabilization 
of the AE.  Participants will be followed until 60 days from date of catheter placement, initiation 
of off-study anticoagulation treatment, or death, whichever occurs first (see Section 6.9, 
Schedule of Events). 60 day follow-up can be performed by phone or chart review.  
 
 
UNSCHEDULED VISITS 
 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed (e.g., laboratory or clinical assessments) at those visits should be recorded in 
(e)CRF.   
 


 
38 
 
 
SCHEDULE OF EVENTS  
 
Visit Days*  
 
Screening** 
On-Study Treatment  
End of Treatment Visit  
Day 14 (±4 days) 
Follow-Up 
Day 60 (±4 days) 
 
Days -28 to -3 
Day 1  
 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Catheter placementA 
 
X 
 
 
Xisomab 3G3  
 
X 
 
 
Medical history  
X 
 
 
 
Medication history 
X 
 
 
 
Physical ExaminationC 
X 
XG 
X 
 
Radiographic Imaging 
Per investigator’s discretion, as clinically indicated 
UltrasoundD 
 
 
X 
 
Hematology 
X 
 
 
 
Biochemistry 
X 
 
 
 
Coagulation 
X 
 
X 
 
Pregnancy testE 
X 
 
 
 
AE assessment and 
ConmedsB,F 
X 
X 
X 
X 
Research blood 
draw/Assessment for 
ImmunogenicityH 
X 
X 
X 
 
ElectrocardiogramI 
X 
As clinically indicated  
* Ideally the clinic visit and all the study requirements should be performed as indicated. 
** Enrolled participants will receive a single fixed dose of xisomab 3G3 (2 mg/kg) through a peripheral IV or the inserted catheter within 48 hours of catheter 
placement (i.e. ± 2 days). If Xisomab 3G3 is administered prior to D1 catheter placement, eligibility must be confirmed prior to study drug administration. 
A Placement of the catheter in participants will be performed according to institutional guidelines. Ultrasound may be used to guide the placement of the 
catheter, and may include use of local anesthetic. 
B For concomitant medications – enter new medications started during the trial through the end of treatment visit. 
C All physical exams will include assessing vital signs, weight and ECOG performance status.  
D  Per institutional standards, study participants will be evaluated for CAT via planned ultrasound 14 ±4 days after catheter insertion.  Additional ultrasound 
evaluations may occur at any time during the study based on treating physician and PI discretion; however, only ultrasounds performed within 18 days from 
catheter placement will be included when computing CAT incidence. Ultrasound to occur as part of EOT, prior to provider visit.  
E For women of reproductive potential, a serum pregnancy test should be performed within 3 days prior to first dose of trial treatment. Serum pregnancy test 
should be performed by the local study site laboratory per institutional guidelines, and repeated if required.  


 
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Visit Days*  
 
Screening** 
On-Study Treatment  
End of Treatment Visit  
Day 14 (±4 days) 
Follow-Up 
Day 60 (±4 days) 
 
Days -28 to -3 
Day 1  
 
F AEs and laboratory safety measurements will be graded per NCI CTCAE version 5.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for 
 seriousness. Report grade 3 and 4 hematological and non-hematological SAEs (related and unrelated to trial treatment) occurring up until 60 days after 
catheter placement. AE evaluation includes assessment of major and clinically-relevant non-major bleeding per Section 6.1.9.1. 
GStudy visit to occur within 24hrs or day of single dose of study treatment. If screening visit occurs within 24hrs of study treatment administration, D1 provider 
visit does not need to be repeated. 
HBlood will be collected and batched on day 14 for Immunogenicity assessment.  The Day 1 blood draw should be obtained any time prior to study drug 
administration.  
IElectrocardiogram will be obtained at screening and as clinically indiciated.   
 
 


 
40 
 
7. SAFETY 
 
 
SPECIFICATION OF SAFETY PARAMETERS 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. Safety assessments will be based on medical review of adverse events and the results of 
safety evaluations at specified time points as described in Section 6.9, Schedule of Events.  Any 
clinically significant adverse events persisting at the end of treatment visit will be followed by the 
Investigator until resolution/stabilization or death, whichever comes first. 
 
 
DEFINITIONS 
 
7.2.1 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant before and during their participation in an investigational study, in 
conjunction with the use of the investigational product, whether or not considered intervention-
related (21 CFR 312.32 (a)). In general, this includes signs or symptoms experienced by the 
participant from the time of signing the informed consent to completion of the study.   
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 
treatment.  
 
7.2.2 SERIOUS ADVERSE EVENT (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of the Investigator, it 
results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient 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 participant and/or participant 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 in-patient hospitalization, or 
• 
The development of drug dependency or drug abuse.  
 


 
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7.2.3 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 
1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
7.2.4 SEVERITY OF EVENT 
 
The Investigator will grade the severity of each AE using, when applicable, the current version 
of the CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
• Grade 1 – Mild; asymptomatic or mild symptoms, or clinical or diagnostic observations only; 
intervention not indicated.  
• Grade 2 – Moderate; minimal, local or noninvasive intervention indicated, or limiting age-
appropriate instrumental activities of daily living (ADL)  
• Grade 3 – Severe or medically significant but not immediately life-threatening, or 
hospitalization or prolongation of hospitalization indicated, or disabling, or limiting self-care 
ADL.  
• Grade 4 – Life-threatening consequences, or urgent intervention indicated.  
• Grade 5 – Death related to AE. 
 
7.2.5 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY AGENT  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and their clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definite – The AE is clearly related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unrelated –The AE is clearly NOT related to the study treatment. 
 
 
EXPECTEDNESS 
 
The Sponsor-investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study agent. 
 


 
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ADVERSE EVENT LIST  
 
7.4.1 ADVERSE EVENT LIST FOR XISOMAB 3G3 
 
Detailed information about the risks and expected AEs of xisomab 3G3 may be found in the 
current edition of the manufacturer’s investigator brochure.  In brief, 10 (48%) of 21 subjects 
experienced a total of 20 treatment emergent adverse events (TEAEs), of which 7 (44%) of 16 
subjects received xisomab 3G3 and 3 (60%) of 5 subjects were exposed to placebo.  A total of 3 
(19%) subjects receiving xisomab 3G3 experienced 5 events that were suspected to be possibly 
treatment-related by the PI.  The highest incidence of TEAEs by organ system was skin and 
subcutaneous tissue disorders, experienced by 3 (19%) xisomab 3G3-treated subjects and 1 
(20%) placebo subject.  The most common TEAE in this study was productive cough, 
experienced by 2 (13%) xisomab 3G3-treated subjects.  All other TEAEs were experienced by 1 
subject each.  The majority of events (17) were mild (Grade 1) in severity and 3 were moderate 
(Grade 2).  Moderate events included increased diastolic BP, productive cough, and upper 
respiratory tract infection. 
 
 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All AEs including local and systemic reactions not meeting the criteria for SAEs 
will be captured on the appropriate CRF, except for AEs definitely attributable to participant’s 
planned anti-cancer treatment regimen.  Information to be collected includes event description, 
time of onset, clinician’s assessment of severity, seriousness, expectedness, relationship to 
study product (assessed only by those with the training and authority to make a diagnosis), and 
date of resolution/stabilization of the event.  All AEs occurring while on study must be 
documented appropriately regardless of relationship.  All AEs will be followed to adequate 
resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE.  However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode.  At each study visit, the Investigator will 
inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization.  
 
The Investigator will record all reportable events with start dates occurring any time after 
informed consent is obtained until 60 days post study agent dose  or until the participant 
receives alternative anticoagulant therapy, whichever occurs first.  Any SAE that occurs after 
treatment with alternative anticoagulant therapy will be reported only if the Investigator or 
current treating physician has assessed the SAE as related to the study treatment.  Adverse 
events will be evaluated using the current version of the CTCAE v5.0. 
  
 
REPORTING PROCEDURES 
 


 
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7.6.1 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 
 
Per regulatory requirements, if an event is assessed by the Sponsor Institution as a Serious 
Unexpected Adverse Reaction (SUSAR), it is the responsibility of the Sponsor Institution to 
submit the SUSAR to Regulatory Authorities according to applicable regulations.  In addition, 
the SUSAR will be distributed to the Investigators/sites utilizing a Council for International 
Organizations of Medical Sciences (CIOMS) report form, or the MedWatch 3500A form).  The 
Investigator/site will submit a copy of the report to their respective IRB or IEC per the governing 
institutional requirements and in compliance with local laws and guidelines. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801). At a minimum, events 
requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IND safety reports 
that require a change to the protocol or consent,  
• 
New FDA black box warning,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
7.6.2 MEDWATCH REPORTING  
 
The Sponsor is required to report AEs to the FDA through the MedWatch reporting program, 
even if the trial involves a commercially available agent.  Adverse events to be reported include 
any UPs (i.e., not listed in the package insert) and any SAEs with a suspected association to the 
investigational product. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified in the 
investigational new drug/biologic regulations using Form FDA 3500, the MedWatch Voluntary 
Reporting form (available here), or completed online.  A copy of Form FDA 3500 and supporting 
materials will be kept on file in the study regulatory binder.  
 
7.6.3 ADDITIONAL REPORTING REQUIREMENTS 
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible, but in no event later than 7 calendar days after 
initial receipt of the information.  All other serious unexpected experiences associated with the 
use of the study treatment will be reported to FDA as soon as possible, but in no event later 
than 15 calendar days after initial receipt of the information.  All events reported to the FDA will 
also be reported to Aronora Inc. within 24 hours of reporting. 
 
7.6.4 REPORTING OF PREGNANCY 
 


 
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To ensure participant safety, each pregnancy in a participant on study treatment must be 
reported within 24 hours of learning of its occurrence.   The investigator must report the event to 
the IRB or other oversight entity per institutional policies/requirements. The PI will assess the 
event and report to the manufactuerer and any other entity as warranted.  
 
 
The pregnancy should be recorded on a CRF and reported by the Investigator to the Aronora 
Inc.  Pregnancy follow-up should be reported using the same form.  Any SAE experienced 
during pregnancy must be reported.  If while on study treatment a participant’s sexual partner 
becomes pregnant, the pregnancy and pregnancy outcomes must also be reported as 
described above.  Consent to report information regarding the pregnancy should be obtained 
from the pregnant individual. 
 
The investigator must follow the pregnancy to determine outcome, including spontaneous, or 
voluntary termination, details of the birth, and the presence or absence of any birth defets, 
congenital abnormalities, or any pregnancy- or childbirth0 related and/or newborn 
complications.  
 
 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected. 
• 
Death suspected to be related to study agent 
 


 
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8. STATISTICAL CONSIDERATIONS 
 
Refer to Section 2.1, Description of the Study Design for a detailed description of the study 
design and endpoints.   
 
 
ANALYSIS POPULATIONS  
 
An intent to treat (ITT) analysis set consists of all participants who consent and enroll in the trial 
regardless of whether they are exposed to the study drug.  An efficacy analysis set consists of 
participants who have placement of a catheter, receive xisomab 3G3 within 48 hours of catheter 
placement, and have at least one CAT assessment (i.e., ultrasound and physical exam) by Day 
18 of the study.  A safety analysis set consists of all participants who are exposed to the single 
dose of study drug.   
 
 
DESCRIPTION OF STATISTICAL METHODS 
 
8.2.1 GENERAL APPROACH 
 
This is a single arm phase II trial to assess the efficacy of xisomab 3G3 in reducing the 
incidence of CAT over 18 days after catheter placement.  This study will enroll 50 patients with 
non-leukemic cancer who are to undergo placement of a central venous catheter and who can 
wait 2 days from xisomab infusion before initiating antineoplastic therapy.   
 
8.2.2 ANALYSIS OF PRIMARY ENDPOINT 
 
Using the efficacy analysis set, the incidence of ultrasound-detected CAT (including both 
symptomatic and asymptomatic clots) in the first 18 days after catheter insertion will be 
assessed and reported with a 95% CI. CAT incidence will also be separately estimated for each 
general catheter type (i.e., PICC vs. indwelling port).   
 
8.2.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
 
The incidence of major or clinically relevant non-major bleeding (defined in Section 6.1.9.1), 
along with 95% CI, will be assessed using the safety analysis set. The proportion of safety set 
participants with these bleeding events will also be separately estimated for each catheter type.   
 
The incidence of xisomab 3G3-associated toxicities will be assessed using the safety analysis 
set.  Descriptive statistics of safety will be presented using CTCAE v5.0. All on-study AEs (from 
time of consent), treatment-related AEx (from time of xisomab infusion), SAEs, and treatment-
related SAEs will be tabulated using worst grade per NCI CTCAE v5.0 criteria by system organ 
class and preferred term.  On-study abnormal lab parameters including hematology, chemistry, 
liver function, and renal function will be summarized using worst grade NCI CTCAE v5.0 criteria. 
 
8.2.4 ANALYSIS OF THE EXPLORATORY ENDPOINTS 
 
Descriptive statistics will be used to present results of coagulation measures (i.e., platelet count, 
PT/INR, and aPTT), drug PK, and incidence of catheter occlusion requiring medical therapy 
(specifically, local administration of tPA). The proportion of participants with symptomatic 
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will be reported for those (expected few) participants with symptomatic CAT.  All exploratory 
endpoints will additionally be analyzed within each catheter type (i.e., PICC vs. indwelling 
central venous catheter).   
 
 
SAMPLE SIZE, POWER, ACCRUAL RATE AND STUDY DURATION 
 
8.3.1 SAMPLE SIZE AND POWER 
Based on the central venous catheter thrombosis rates and other parameters (e.g., population 
type, thrombosis evaluation period) in prior studies4,5,7, the sample size calculation makes the 
assumption of a 60% incidence of ultrasound-confirmed CAT (i.e., both symptomatic and 
asymptomatic) over 18 days post- catheter placement in cancer patients not treated with 
xisomab. A sample size of 50 participants, accounting for a 4% efficacy ineligibility rate, is 
sufficient to provide 80% power to detect a 20 percentage point reduction in the incidence of 
CAT at a two-sided α of 0.05.  
 
 
 
HANDLING OF MISSING DATA 
 
Every attempt will be made to obtain data at the defined time points as described in the primary 
and secondary endpoint descriptions (section 2.2) and the schedule of events (section 6.9).  If 
the data are not sufficient to analyze specific endpoints, the participant’s data may be excluded 
entirely or partially, depending on the specific endpoints in question and in consultation with the 
biostatistician.  No missing data will be imputed.  Whenever possible, all available data will be 
included in the analysis.  A sample size for each analysis will be clearly stated along with the 
reason for exclusion, if any participant is excluded from the analysis due to missing data. 
 
 


 
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9. CLINICAL MONITORING 
 
 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN 
 
This study is under the oversight of the Knight Cancer Institute’s Data Safety and Monitoring 
Committee (DSMC) as described in the Knight’s institutional Data and Safety Monitoring Plan 
(DSMP).  The Knight DSMP outlines the elements required to ensure the safety of clinical trial 
participants, the accuracy and integrity of the data and the appropriate modification of cancer-
related clinical trials for which significant benefits or risks have been discovered or when the 
clinical trial cannot be successfully concluded.  The Knight DSMP also describes the methods 
and procedures for ensuring adequate oversight of cancer-related research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The Knight DSMC reviews and monitors study progress, toxicity, safety, and other data for this 
study.  The DSMC will address any issue that raises questions about data integrity or trial 
participant safety with the Investigator and study team.  Should any major concern arise, the 
Knight DSMC may recommend corrective action, and determine whether to suspend or 
terminate the study. 
 
The Knight DSMC evaluates each protocol to determine the risk profile of the trial design.  This 
assessment establishes trial reporting requirements commensurate with risk, and also directs 
the scope and frequency of Quality Assurance audits.  The DSMC may adapt report and audit 
requirements at any time, if indicated (refer to the Knight DSMP for additional details on 
reporting and audit frequency).  The Investigator will submit trial-specific data reports for the 
DSMC to assess toxicity and safety data; the report must provide the DSMC with such 
information as: up-to-date participant accrual; treatment regimen information; current dose level 
information; AEs and SAEs reported by category; summary of any death on study; unexpected 
AEs that have been reported; AEs of special or clinical interest; deviations from the approved 
protocol; that have been reported eligibility exceptions; any inspection, audit, or monitor report; 
publications and/or developments that may affect scientific validity, subject safety or the ethics 
of the trial, and a summary of trial status.  The study team will provide other information (e.g. 
scans, laboratory values) upon request.  
 
 
CLINICAL DATA & SAFETY MONITORING 
 
As part of the Quality Assurance plan and in full agreement with NIH policy that states all clinical 
trials require monitoring to ensure the safety of study participants and the validity and integrity of 
the data, monitoring will be a continuous, ongoing and multifaceted process.  This includes 
external review by the DSMC and IRBs, as well as internal data quality control, review and 
evaluation.  Site monitoring visits are central to this process, and will include reporting to 
appropriate individuals with oversight responsibilities.STUDY MONITORING REQUIREMENTS 
The Investigator is responsible for ensuring that the study is conducted in accordance with the 
protocol, Declaration of Helsinki, GCP, and applicable regulatory requirements, and that valid 
data are entered into the (e)CRFs.  To achieve this objective, the monitor’s duties are to aid the 
Investigator and, at the same time, the Sponsor in the maintenance of complete, legible, well 
organized and easily retrievable data. Monitoring visits will be performed during the study to 


 
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ensure that the rights and well-being of human participants are protected, that the reported trial 
data are accurate, and that the conduct of the trial is in compliance with the protocol, GCP, and 
applicable regulatory requirements.  
 
Details of monitoring activities, including designation of assigned monitoring entities, scope of 
monitoring visits, timing, frequency, duration of visits, and visit reporting, will be included in a 
separate Trial-Specific Monitoring Plan (TSMP). 
 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory.  
The Investigator agrees that the monitor will be permitted to conduct monitoring visits at 
appropriate intervals.  The Investigator agrees to provide all relevant information and 
documentation as requested by the monitor, including access to all original study documents 
and source data, including access to electronic medical records and/or source documents if 
necessary.  The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
 
The monitor will conduct source data review and verification as outlined in the TSMP, and 
following each visit will generate a report summarizing the visit findings. 
 
Regardless of monitoring entity, the OHSU Sponsor-investigator is ultimately, singularly 
responsible for overseeing every aspect of the design, conduct, and final analysis of this 
investigation and for governing trial conduct at all participating sites. 
 
If at any time Investigator noncompliance is discovered at OHSU or any participating site, the 
Sponsor-investigator shall promptly either secure compliance or end the Investigator’s 
participation in the study. 
 
Independent audits may be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
that monitoring practices are adequate and in compliance with the monitoring plan, and that 
evidence of ongoing investigator oversight is present. 
 
 
QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
All clinical trials at the Knight are required to have a DSMP.  All clinical work conducted under 
this protocol is subject to ICH GCP guidelines.  This includes inspection of study-related records 
by the lead site, sponsor, its designee, or health authority representatives at any time. 
 
Quality assurance (QA) audit activities will occur as detailed in the Knight institutional DSMP.  
All discrepancies, queries, deviations, observations, and findings of non-compliance will be 
compiled into a final audit report.  The PI must review and assess each finding, and generate a 
response to the audit report that incorporates a Corrective and Preventative Action (CAPA) 
plan.  The CAPA must analyze root cause(s) of noncompliance to determine the appropriate 


 
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changes to correct and resolve issues, and prevent recurrence. 
 
Quality Control (QC) activities will occur to monitor and ensure the safety of study participants 
and the validity and integrity of data.  Monitoring will be a continuous, ongoing and multifaceted 
process.  This includes review by the Knight DSMC and IRBs, as well as internal data quality 
control, review and evaluation.  Site monitoring visits are central to this process, and will include 
reporting to appropriate individuals with oversight responsibilities. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 
 


 
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10. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data.  The Investigator will maintain adequate case 
histories of study participants, including accurate (e)CRF and source documentation. 
 
 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives. Individual participants and their research data will be identified by a unique 
coded identifier consisting of numbers. The study data entry and study management systems 
used by clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives. At the end of the study, or after the 
appropriate period of record retention stated in Section 10.4, all study databases will be de-
identified and archived within the Knight Cancer Institute. 
 
 
DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 


 
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procedures. 
 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be 
identified by code only. Specifically, each consenting participant will be assigned a unique 
coded identifier consisting of numbers. This identifier will be associated with the participant 
throughout the duration of their participation in the trial. The coded identifier will also be used to 
identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon. Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC) system on OHSU secure servers, which facilitates information being stored 
in a unified format and location.  To further preserve confidentiality, PHI in the EDC system will 
be limited to just birth date and visit dates. The web-accessible EDC system is password 
protected and encrypted with role-based security, and administered by designated informatics 
staff within OHSU or Knight Cancer Institute. All users of the database are assigned a unique 
ID, username, and password and must complete training appropriate to their role before they 
are authorized to enter, access, and store data in the database.  
 
Data from correlative studies will be entered into the EDC system by study personnel at OHSU. 
All other electronic data extracts will be stored only on OHSU computers and restricted drives, 
limited only to study investigators and staff with authorization to access the data. Quality 
assurance will be conducted as outlined in Section 9.3, Quality Assurance & Quality Control. 
 
10.3.1 FUTURE USE OF STORED SPECIMENS 
 
Each participant who signs consent will be assigned a unique coded identifier consisting of 
numbers.  This identifier will be associated with the participant throughout the duration of their 
participation in the trial.  The coded identifier will be used to identify any participant specific 
samples.  As part of this study, blood samples collected for the purposes of this protocol will be 
stored until they can be analyzed and will then be destroyed, unless the participant consents to 
remaining blood samples being stored indefinitely in the Shatzel laboratory and further analyzed 
to address scientific questions and/or development of biological tests related to coagulation. 
 
 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 
Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified.  It is the responsibility of the sponsor to inform the Investigator when these 
documents no longer need to be retained. 


 
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If the Investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution or another investigator at 
OHSU. Records must be maintained according to institutional or FDA requirements.  
 
 
PUBLICATION AND DATA SHARING POLICY 
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  
 
 
DELIVERY OF PROGRESS REPORTS TO STUDY FUNDER 
 
Upon the request of Aronora, Inc., the Institution will submit oral or written reports on the 
progress of the Study as provided by this protocol.  Within one hundred and twenty (120) days 
following the completion or termination of the study, Institution will furnish Aronora, Inc., with a 
final report detailing the results of the Study. 


 
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11. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 312, and/or the ICH E6. 
 
 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval.  Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study.  All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50.  Documentation of the consent process and a copy of the signed 
consent shall be maintained in the participant’s medical record.  
 
11.3.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation.  Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate.  Consent forms will be IRB-approved and the participant will be asked to read 
and review the document.  The Investigator will explain the research study to the participant and 
answer any questions that may arise.  All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing.  The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate.  The participant will sign the informed consent 
document prior to any procedures being done specifically for the study.  The participants may 
withdraw consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the participants for their records.  The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
 
PROTOCOL REVIEW 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study.   
 


 
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CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and approved by the CRRC and IRB, before the 
revision or amendment may be implemented.  The only circumstance in which the amendment 
may be initiated without regulatory approval is for a change necessary to eliminate an apparent 
and immediate hazard to the participant.  In that event, the Investigator must notify the IRB (and 
FDA if under an IND) within 5 business days after the implementation.  
 
An Investigator who holds an IND application must also notify the FDA of changes to the 
protocol per 21 CFR 312.  


 
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12. REFERENCES 
 
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2. 
Climo, M., et al. Prevalence of the use of central venous access devices within and 
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3. 
Gallieni, M., Pittiruti, M. & Biffi, R. Vascular access in oncology patients. CA: a cancer 
journal for clinicians 58, 323-346 (2008). 
4. 
Itkin, M., et al. Peripherally inserted central catheter thrombosis--reverse tapered versus 
nontapered catheters: a randomized controlled study. Journal of vascular and 
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5. 
Paauw, J.D., et al. The incidence of PICC line-associated thrombosis with and without 
the use of prophylactic anticoagulants. JPEN. Journal of parenteral and enteral nutrition 
32, 443-447 (2008). 
6. 
D'Ambrosio, L., Aglietta, M. & Grignani, G. Anticoagulation for Central Venous Catheters 
in Patients with Cancer. New England Journal of Medicine 371, 1362-1363 (2014). 
7. 
Monreal, M., et al. Upper extremity deep venous thrombosis in cancer patients with 
venous access devices--prophylaxis with a low molecular weight heparin (Fragmin). 
Thrombosis and haemostasis 75, 251-253 (1996). 
8. 
Liu, Y., et al. Peripherally inserted central catheter thrombosis incidence and risk factors 
in cancer patients: a double-center prospective investigation. Therapeutics and Clinical 
Risk Management 11, 153-160 (2015). 
9. 
Fletcher, J.J., Stetler, W. & Wilson, T.J. The clinical significance of peripherally inserted 
central venous catheter-related deep vein thrombosis. Neurocritical care 15, 454-460 
(2011). 
10. 
Kearon, C., et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert 
Panel Report. Chest 149, 315-352 (2016). 
11. 
Schiffer, C.A., et al. Central venous catheter care for the patient with cancer: American 
Society of Clinical Oncology clinical practice guideline. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology 31, 1357-1370 (2013). 
12. 
Sousa, B., et al. Central venous access in oncology: ESMO Clinical Practice 
Guidelines†. Annals of Oncology 26, v152-v168 (2015). 
13. 
Baumann Kreuziger, L., Onwuemene, O., Kolesar, E., Crowther, M. & Lim, W. 
Systematic review of anticoagulant treatment of catheter-related thrombosis. Thrombosis 
Research 136, 1103-1109 (2015). 
14. 
Jones, M.A., et al. Characterizing resolution of catheter-associated upper extremity deep 
venous thrombosis. Journal of vascular surgery 51, 108-113 (2010). 
15. 
Mahan, C.E., Holdsworth, M.T., Welch, S.M., Borrego, M. & Spyropoulos, A.C. Deep-
vein thrombosis: a United States cost model for a preventable and costly adverse event. 
Thrombosis and haemostasis 106, 405-415 (2011). 
16. 
Grosse, S.D., Nelson, R.E., Nyarko, K.A., Richardson, L.C. & Raskob, G.E. The 
economic burden of incident venous thromboembolism in the United States: A review of 
estimated attributable healthcare costs. Thromb Res 137, 3-10 (2016). 
17. 
Karthaus, M., et al. Dalteparin for prevention of catheter-related complications in cancer 
patients with central venous catheters: final results of a double-blind, placebo-controlled 


 
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phase III trial. Annals of oncology : official journal of the European Society for Medical 
Oncology 17, 289-296 (2006). 
18. 
Akl, E.A., et al. Anticoagulation for people with cancer and central venous catheters. The 
Cochrane database of systematic reviews, Cd006468 (2014). 
19. 
Sousa, B., et al. Central venous access in oncology: ESMO Clinical Practice Guidelines. 
Annals of oncology : official journal of the European Society for Medical Oncology 26 
Suppl 5, v152-168 (2015). 
20. 
Palta, S., Saroa, R. & Palta, A. Overview of the coagulation system. Indian Journal of 
Anaesthesia 58, 515-523 (2014). 
21. 
Seligsohn, U. Factor XI deficiency in humans. Journal of thrombosis and haemostasis : 
JTH 7 Suppl 1, 84-87 (2009). 
22. 
Yau, J.W., et al. Selective depletion of factor XI or factor XII with antisense 
oligonucleotides attenuates catheter thrombosis in rabbits. Blood 123, 2102-2107 
(2014). 
23. 
Yau, J.W., et al. Corn trypsin inhibitor coating attenuates the prothrombotic properties of 
catheters in vitro and in vivo. Acta biomaterialia 8, 4092-4100 (2012). 
24. 
Larsson, M., et al. A factor XIIa inhibitory antibody provides thromboprotection in 
extracorporeal circulation without increasing bleeding risk. Science translational 
medicine 6, 222ra217 (2014). 
25. 
Renne, T., Schmaier, A.H., Nickel, K.F., Blomback, M. & Maas, C. In vivo roles of factor 
XII. Blood 120, 4296-4303 (2012). 
26. 
Buller, H.R., et al. Factor XI antisense oligonucleotide for prevention of venous 
thrombosis. The New England journal of medicine 372, 232-240 (2015). 
27. 
Schulman, S. & Kearon, C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. Journal of thrombosis and 
haemostasis : JTH 3, 692-694 (2005). 


 
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APPENDIX A: PERFORMANCE STATUS 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of self’s needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 


 
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APPENDIX B: CONTRACEPTION 
 
Females of childbearing potential who are sexually active with a non-sterilized male partner or 
partners of male participant must use 2 highly effective method of contraception. These include: 
levonorgestrel-releasing intrauterine system (e.g., Mirena®), copper intrauterine device, and 
hormonal methods. Appropriate hormonal contraceptives include:  Etonogestrel-releasing 
implants (e.g. Implanon® or Norplant®), ethinylestradiol/etonogestrel-releasing intravaginal 
devices (e.g. NuvaRing®), medroxyprogesterone injection (e.g., Depo-Provera®), normal and 
low dose combined oral contraceptive pill, norelgestromin/ethinylestradiol-releasing transdermal 
system (e.g. Ortho Evra®), progesterone based oral contraceptive pill using desogestrel (NB, 
Cerazette® is currently the only highly effective progesterone-based)  
 
Non-sterilized male participants, or partners of female participant, must use male condom plus 
spermicide throughout this period.  Cessation of birth control after this point should be 
discussed with a responsible physician.  Abstaining from sexual activity for the total duration of 
the drug treatment and the drug washout period is an acceptable practice for both female and 
male participants; however, periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of birth control.  Female participant should also refrain from 
breastfeeding throughout this period.