Conditions: Advanced Solid Tumor
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 22
Healthy volunteers: no

Brief summary:
A Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety of the Monoclonal Antibody PTX-35 in Patients with Advanced Solid Tumors Refractory to Standard of Care

Detailed description:
This is an open-label, single arm, first-in-human, Phase I study of intravenous administration of PTX-35 to patients with advanced solid tumors refractory to, or ineligible for, or who refuse available SOC. Five escalating dose levels of PTX-35 will be explored using a traditional 3+3 design based on dose-limiting toxicities (DLTs) until optimal immunological dose (OID) or maximum tolerated dose (MTD) is established.

Arms:
arm 1: Dose Level 1: PTX-35 0.01 mg/kg arm 2: Dose Level 2: PTX-35 0.03 mg/kg arm 3: Dose Level 3: PTX-35 0.10 mg/kg arm 4: Dose Level 4: PTX-35 0.30 mg/kg arm 5: Dose Level 5: PTX-35 1.0 mg/kg arm 6: Dose Level 6: PTX-35 3.0 mg/kg

Interventions: intervention 1: PTX-35
Intervention descriptions: intervention 1: Monoclonal antibody PTX-35

Protocol document:
Prot_SAP_000.pdf: 
PTX35-001 
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A Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety of the 
Monoclonal Antibody PTX-35 in Patients with Advanced Solid Tumors Refractory to 
Standard of Care 
 
Protocol No.: 
PTX35-001 
 
IND No.: 
 
139925 
 
Principal Investigator: 
 
Anthony W. Tolcher, MD 
 
 
Sponsor: 
Pelican Therapeutics, Inc. 
8122 Datapoint Drive, Suite 445 
San Antonio, TX 78229 
 
 
Medical Monitor: 
Alan Epstein, MD, JD, MBA, SM 
(703) 472-7289 aepstein@cancerinsight.com 
 
 
Protocol Version: 
4.0 
 
Replaces: 
 
3.0 
Date: 
29 July 2021 
 
 
CONFIDENTIAL 
 
This document contains strictly confidential information and cannot be disclosed or used, 
unless authorized in writing by Pelican Therapeutics. 


PTX35-001 
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INVESTIGATOR’S STATEMENT 
1. 
I have carefully read this protocol entitled “A Phase I, First-in-Human, Dose-Escalation 
Study to Evaluate the Safety of the Monoclonal Antibody PTX-35 in Patients with Advanced 
Solid Tumors Refractory to Standard Care” and agree that it contains all the necessary 
information required to conduct the study.  I agree to conduct this study as outlined in 
the protocol. 
2. 
I understand that this study will not be initiated without approval of the appropriate 
Institutional Review Committee/Independent Ethics Committee (IRB/IEC), and that all 
administrative requirements of the governing body of the Institution will be complied with 
fully. 
3. 
Informed written consent will be obtained from all participants in accordance with 
institutional guidelines, FDA requirements as specified in Title 21 CFR, Part 50, the 
European Union Directive 2001/20/EC and its associated Detailed Guidances, European 
Union GCP Directive 2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 4.8, 
and the terms of the Declaration of Helsinki (2013). 
4. 
I will enroll participants who meet the protocol criteria for entry. 
5. 
I understand that my signature on each completed Case Report Form (CRF) indicates that 
I have carefully reviewed the complete set of CRFs and accept full responsibility for the 
contents thereof. 
6. 
I understand that the information presented in this study protocol is confidential, and I 
hereby assure that no information based on the conduct of the study will be released 
without prior consent from the Sponsor unless this requirement is superseded by the 
Food and Drug Administration, a Competent Authority of the European Union or another 
Regulatory Authority. 
 
Protocol Version 4.0:  29 July 2021 
 
Investigator:   
 
Name: 
 
 
Telephone: 
 
Address: 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
 
 
Sponsor/Representative: 
Signature: 
 
 
Date: 
 
 
 
29 Jul 2021


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TABLE OF CONTENTS 
 
Page No. 
 
INVESTIGATOR’S STATEMENT .................................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................... 3 
CLINICAL STUDY SYNOPSIS ..................................................................................................... 6 
LIST OF ABBREVIATIONS ........................................................................................................ 14 
1.0 
GENERAL INFORMATION ......................................................................................... 17 
1.1 Protocol Number and Title of the Study .................................................................... 17 
1.2 Sponsor ........................................................................................................................ 17 
1.3 Medical Monitor ........................................................................................................... 17 
1.4 Signature Authorization .............................................................................................. 17 
1.5 Principal Investigator and Institution ......................................................................... 17 
2.0 
BACKGROUND INFORMATION ................................................................................ 17 
2.1 Introduction ................................................................................................................. 17 
2.1.1 T lymphocyte Activation and Regulation: Co-Stimulator Molecules ........... 17 
2.1.2 TNFRSF25 and TL1A ........................................................................................ 18 
2.1.3 TNFRSF25 Signaling in CD4 and CD8 T Lymphocytes, and Tumor Growth 
Inhibition ...................................................................................................................... 19 
2.1.4 TNFRSF25: TL1A Signaling and Anti-Cancer Therapy ................................... 20 
2.2 PTX-35 Investigational Product ................................................................................... 20 
2.3 TENIVAC Vaccine .......................................................................................................... 22 
2.4 Preclinical Studies ........................................................................................................ 22 
2.4.1 Primary Pharmacodynamics and Pharmacology ......................................... 23 
2.4.2 Toxicity Studies and Pharmacokinetics ......................................................... 23 
2.5 Rationale for Starting Dose and Treatment Schedule .............................................. 26 
2.6 Potential Risks and Benefits ....................................................................................... 26 
3.0 
TRIAL OBJECTIVES AND PURPOSE ........................................................................... 28 
4.0 
TRIAL DESIGN ............................................................................................................ 29 
4.1 Characteristics of a Well-Conducted Trial .................................................................. 29 
4.2 Overview of Trial Design ............................................................................................. 29 
4.3 Patient Population ....................................................................................................... 30 
4.4 End of Study ................................................................................................................. 30 
4.5 Duration of Therapy .................................................................................................... 30 
4.6 Trial Discontinuation ................................................................................................... 31 
4.7 Investigational Product Accountability/Disposition of Clinical Trial Supplies ......... 31 


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5.0 
SELECTION AND WITHDRAWAL OF PATIENTS ....................................................... 31 
5.1 Inclusion Criteria .......................................................................................................... 31 
5.2 Exclusion Criteria ......................................................................................................... 32 
5.3 Inclusion of Women, Minorities and Children ........................................................... 34 
5.4 Withdrawal Criteria ...................................................................................................... 34 
5.4.1 Withdrawn Patients ......................................................................................... 35 
5.4.2 Replacement of Subjects ................................................................................ 35 
5.5 Study Stopping Criteria ............................................................................................... 35 
6.0 
TREATMENT OF PATIENTS........................................................................................ 36 
6.1 Investigational Product Preparation and Administration ........................................ 36 
6.1.1 Drug Products .................................................................................................. 36 
6.1.2 Dose Escalation Scheme ................................................................................. 37 
6.1.3 Dose-Limiting Toxicity ..................................................................................... 39 
6.1.4 Maximum Tolerated Dose and Optimal Immunological Dose .................... 40 
6.2 Dose Interruptions/Withholding ................................................................................ 40 
6.3 Dose Modification and Management of Immune-Related Adverse Events, Infusion 
Reactions, and Cytokine Release Syndrome ...................................................................... 40 
6.4 Concomitant Treatment .............................................................................................. 42 
6.5 Monitoring Patient Compliance.................................................................................. 42 
7.0 
STUDY EVALUATIONS ............................................................................................... 42 
7.1 Schedule of Assessments ........................................................................................... 42 
7.2 Pre-treatment .............................................................................................................. 45 
7.3 During Treatment ........................................................................................................ 45 
7.3.1 Day 1 of Cycle 1 ............................................................................................... 45 
7.3.2 Days 2, 4, 7, and 10 of Cycle 1 and Cycle 2 .................................................... 46 
7.3.3 Day 1 of Cycle 2 (+ 2 days) .............................................................................. 46 
7.3.4 Day 1 of Cycle 3 and Beyond (+ 2 days) ......................................................... 46 
7.4 30-Day Safety Follow up Visit ...................................................................................... 47 
7.5 Post-Treatment Follow-Up .......................................................................................... 47 
7.6 Survival Follow-up........................................................................................................ 48 
8.0 
STUDY ASSESSMENTS ............................................................................................... 48 
8.1 Safety Assessments ..................................................................................................... 48 
8.1.1 Safety Analysis ................................................................................................. 48 
8.1.2 Reporting of Adverse Events .......................................................................... 48 
8.2 Efficacy Assessments ................................................................................................... 52 
8.2.1 RECIST 1.1 Criteria ........................................................................................... 52 
8.3 Pharmacokinetics ........................................................................................................ 52 
8.4 Analysis of Immunological Effect ............................................................................... 53 
8.5 Analysis of Immunogenicity ........................................................................................ 53 
8.6 Analysis of response to TENIVAC immunization ....................................................... 53 
8.7 Cytokine Analysis ......................................................................................................... 53 


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9.0 
STATISTICS ................................................................................................................. 54 
9.1 Analysis Populations ................................................................................................... 54 
9.2 Endpoints ..................................................................................................................... 54 
9.2.1 Primary ............................................................................................................. 54 
9.2.2 Secondary ........................................................................................................ 54 
9.2.3 Exploratory ...................................................................................................... 55 
9.3 Safety ............................................................................................................................ 55 
9.4 Efficacy .......................................................................................................................... 55 
9.5 Pharmacokinetics ........................................................................................................ 56 
9.6 Immunogenicity ........................................................................................................... 56 
9.7 General and Specific Antigen Immune Expansion .................................................... 56 
9.8 Sample Size .................................................................................................................. 56 
10.0 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................ 57 
10.1 Monitoring of the Study and Regulatory Compliance .............................................. 57 
10.2 Curricula Vitae and Financial Disclosure of Investigators ........................................ 57 
10.3 Protocol Modifications ................................................................................................ 57 
10.4 Publication Policy ......................................................................................................... 57 
11.0 
ETHICAL CONSIDERATIONS ..................................................................................... 58 
11.1 Informed Consent ....................................................................................................... 58 
11.2 Institutional Review Board/Ethics Committee........................................................... 58 
11.3 Patient Privacy ............................................................................................................. 58 
12.0 
DATA HANDLING AND RECORD KEEPING .............................................................. 59 
12.1 Recording of Data ........................................................................................................ 59 
12.2 Study Records .............................................................................................................. 59 
13.0 
REFERENCES .............................................................................................................. 60 
APPENDIX I  - ECOG Performance Status ............................................................................ 61 
APPENDIX II  - Tumor Measurement Based on RECIST 1.1 Criteria.................................. 62 
APPENDIX III - Summary of Changes from Previous Versions ......................................... 65 
 
List of In-text Tables 
Table 1: PTX-35 Dose Levels ....................................................................................................... 38 
Table 2: Schedule of Assessments ............................................................................................. 43 
 
List of In-text Figures 
Figure 1: PTX-35 structure ........................................................................................................... 21 
Figure 2: Schematic of PTX-35 (humanized mAb) development from 4C12 (hamster mAb) 22 
Figure 3: Median (± minimum, maximum) PTX-35 plasma concentrations vs time following 
single dose IV infusion (2.5 min) in cynomolgus monkeys (n=3 per group). .......................... 25 
Figure 4: Current concepts in the diagnosis and management of cytokine release 
syndrome ..................................................................................................................................... 41 


Pelican Therapeutics, Inc. 
Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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CLINICAL STUDY SYNOPSIS 
Name of Sponsor:  
Pelican Therapeutics, Inc. 
8122 Datapoint Drive, Suite 445 
San Antonio, TX 78229  
(917) 892-9996 
Name of CRO: 
Cancer Insight 
Name of finished product:  PTX-35 
Name of active ingredient:  PTX-35 
Title of the study: A Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety of the 
Monoclonal Antibody PTX-35 in Patients with Advanced Solid Tumors Refractory to Standard 
Care 
Protocol number:  PTX35-001 
Investigators and study centers:   
Anthony W. Tolcher, MD 
NEXT Oncology                                      NEXT Oncology 
2829 Babcock Rd, Suite 300                805 W. 37th Street 
San Antonio, Texas 78229                   Austin, Texas 78705 
 
Rachel Sanborn, MD 
Providence Portland Medical Center 
4805 NE Glisan Street 
Portland, OR 97213 
 
Clinical phase:  Phase I 
Objectives:   
Primary: 
• 
To establish the safety profile of PTX-35 in a population of patients with advanced solid 
tumors.  
Secondary: 
• 
To determine the optimal immunological dose (OID), or maximum tolerated dose (MTD), 
of PTX-35. 
• 
To establish the pharmacokinetic profile of PTX-35. 
Exploratory: 
• 
To study the immunological effect generated by PTX-35.  
• 
To evaluate immunogenicity of PTX-35. 
• 
To evaluate preliminary evidence of clinical benefit of PTX-35 in a population of patients 
with advanced solid tumors.  
• 
To evaluate general immunologic expansion: The frequency and expansion of NK, CD4 
and CD8 T cell subsets. 
• 
To measure immune responses to well-characterized first-time exposure or recall antigen. 
• 
To determine specific cytokine expression in response to treatment with PTX-35, or any 
other unspecific inflammatory response.  
 


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Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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Study Overview:   
 
This is an open-label, single arm, first-in-human, Phase I study of intravenous administration of 
PTX-35 to patients with advanced solid tumors refractory to, or ineligible for, or who refuse 
available SOC.  
 
Patients who meet the eligibility criteria will be enrolled to receive intravenous PTX-35 every two 
weeks as well as a single intramuscular injection of TENIVAC vaccine (tetanus and diphtheria 
toxoids adsorbed) on Day 1 of Cycle 1. Upon completion of two cycles of PTX-35, in the absence 
of disease progression or unacceptable toxicity, patients may continue to be treated with PTX-35 
at the same dose and schedule until disease progression, death, and patient withdrawal of 
consent, Investigator’s decision to remove patient, or intolerable toxicity, whichever occurs first. 
 
Seven escalating dose levels of PTX-35 will be explored using a traditional 3+3 design based on 
dose-limiting toxicities (DLTs) until optimal immunological dose (OID) or maximum tolerated dose 
(MTD) is established. The starting dose of PTX-35 is based on the MABEL for Treg activity 
(considered the most sensitive of PTX-35 pharmacodynamic markers) obtained from dose-ranging 
studies conducted in non-clinical animal models. PTX-35 will be administered to patients 
intravenously on Day 1 of each cycle. The length of each cycle is 14 days, and the DLT observation 
period includes the safety data obtained from the first two treatment cycles (4 weeks).  
 
PTX-35 Dose Levels 
Dose level* 
PTX-35 dose 
(mg/kg) 
PTX-35 
Concentration 
(mg/mL) 
PTX-35 Dose  
(mL/kg)  
Number of 
patients 
1 
0.01 mg/kg 
1 mg/mL 
0.01 mL/kg 
3-6 
2 
0.03 mg/kg 
1 mg/mL 
0.03 mL/kg 
3-6 
3 
0.10 mg/kg 
1 mg/mL 
0.10 mL/kg 
3-6 
4 
0.30 mg/kg 
5 mg/mL 
0.06 mL/kg 
3-6 
5 
1.0 mg/kg 
5 mg/mL 
0.20 mL/kg 
3-6 
6 
3.0 mg/kg 
5 mg/mL 
0.60 mL/kg 
3-6 
7 
10 mg/kg 
5 mg/mL 
2.0 mL/kg 
3-6 
*Dose levels 1 through 3 will be administered at a concentration of 1 mg/mL, and dose levels 4 through 7 will be 
administered at a concentration of 5 mg/mL. 
 
At each dose level, 3 patients will be enrolled initially, with treatment initiation staggered by one 
week after the first patient only.  After all 3 patients in a dose level have received the second dose 
of PTX-35 and completed the DLT observation period, the Safety Review Committee (SRC) will 
review the safety data to make a dose escalation decision. If none of these 3 patients experiences 
a DLT, dose escalation may proceed. If 1 of these 3 patients experiences a DLT, the dose level will 
be expanded to at least 6 patients at the same dose level. If <1 out of 6 patients experiences a 
DLT, then the SRC may recommend dose escalation to the next dose level.  If a DLT occurs in 2 or 
more patients in a particular dose level, the maximum tolerated dose (MTD) has been exceeded 
and dose escalation will cease. Up to 3 additional patients will be enrolled at the next lowest dose 
if only 3 patients were treated at that dose level, to confirm safety of that dose. 
 


Pelican Therapeutics, Inc. 
Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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The conduct and completion of each subsequent dose cohort will follow in similar fashion until 
the MTD is established. Note that if the optimal immunological dose (OID), or observed plateau of 
Treg activity, is determined prior to MTD, further dose escalation may be discontinued by decision 
of the SRC. 
 
Visits and study examinations will be performed per Table 2: Schedule of Assessments. Safety will 
be assessed by frequency of treatment-emergent adverse events (TEAEs), evaluation of clinical 
laboratory parameters (hematology, and biochemistry), weight, vital signs, electrocardiogram 
(ECG), performance status, and physical exam findings. NCI CTCAE version 5.0 will be used to 
grade all toxicities.  
A post-treatment safety visit will be conducted approximately 30 days following the last dose of 
PTX-35. Response to treatment will be assessed according to RECIST 1.1 (APPENDIX II) with 
planned evaluation performed every 8 weeks (+ 1 week) from start of treatment (C1D1).  
 
Target number of patients:  Up to 22 - 34 total patients will be enrolled if all dose levels are 
evaluated. 
Eligibility Criteria 
 
Inclusion Criteria: 
In order to participate in this study, a patient must: 
1. Be willing and have the capacity to sign the written informed consent form. 
2. Be male or female of at least 18 years of age at the time of signing informed consent. 
3. Have a documented diagnosis of metastatic or advanced, unresectable solid tumor 
disease. Patient must have progressed or recurred following standard of care (SOC) 
therapies, or are ineligible for, or who refuse other safe and effective SOC therapies, and 
whom the Investigator believes may benefit from experimental treatment with PTX-35. 
4. Have an acceptable organ function, as defined below: 
a. Albumin ≥ 2.5 g/dL 
b. Total bilirubin < 3.0 × upper limit of normal (ULN), unless patient has Gilbert’s 
syndrome  
c. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × ULN, or 
≤ 5 × ULN in the case of liver metastases  
d. Calculated or measured creatinine clearance > 35 mL/minute per the Cockcroft-
Gault formula  
e. Absolute neutrophil count ≥ 1,500/mm3 
f. 
Hemoglobin ≥ 9 g/dL  
g. Platelet count ≥ 100,000/mm3 
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
(APPENDIX I). 
6. Have life expectancy of at least three months. 
7. Patients, both females and males, of childbearing/reproductive potential must agree to 
use adequate contraception, or continuous abstinence, while included in the trial and for 
six months after the last treatment with PTX-35. 
 


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Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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Exclusion Criteria:  
In order to participate in this study, a patient must not: 
1. Have received any systemic anticancer therapy including small molecules, 
chemotherapy, radiation therapy, monoclonal antibodies or any other experimental 
drug within 4 weeks of first dose of PTX-35. Adjuvant anti-hormonal treatment(s) for 
prior breast cancer or prostate cancer are allowed. (Note: washout for palliative 
radiation therapy is 2 weeks). 
2. Have clinically significant cardiac disease, including: 
a. Onset of unstable angina within 6 months of signing the Informed Consent Form 
(ICF). 
b. Acute myocardial infarction within 6 months of the signing the ICF. 
c. Known congestive heart failure (Grade III or IV as classified by the New York 
Heart Association); and/ or a known decreased cardiac ejection fraction (LVEF) of 
< 45%.  
d. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg 
and/or diastolic blood pressure ≥ 100 mmHg, despite optimal medical 
management. 
3. Have known or clinically suspected leptomeningeal disease. Stable, previously treated 
metastases in the brain or spinal cord, are allowed as long as these are considered 
stable (by CT or MRI), and not requiring systemic corticosteroids. 
4. Have a history of ≥ Grade 3 allergic reactions, or suspected allergy or intolerance to 
monoclonal antibody therapies.  
5. Have a history of suspected cytokine release syndrome (CRS). 
6. Have any known immunodeficiency disorders (testing not required).  
7. Have received prior allogeneic stem cell transplant. 
8. Have ongoing or current autoimmune disease.  Permanent but stable and manageable 
immune related adverse events (irAE) from prior therapies are permissible if prednisone 
equivalent corticosteroid use does not exceed 10 mg/day.  
9. Have any other condition requiring concurrent systemic immunosuppressive therapy 
(other than allowable exceptions which do not exceed 10mg/day of 
prednisone/corticosteroid use).  
10. Have clinically significant active viral, bacterial or fungal infection requiring: 
a. Intravenous treatment with antimicrobial therapy completed less than two 
weeks prior to first dose, or 
b. Oral treatment with antimicrobial therapy completed less than one week prior to 
first dose. 
Prophylactic treatment with antibiotics (e.g., for dental extractions) is allowed. 
11. Have had major surgery (requiring general anesthesia or inpatient hospitalization) within 
four weeks before first administration of PTX-35.  
12. Have had a known tetanus/diphtheria vaccine within the past 10 years. 
13. Have known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ cervical cancer, or 
other cancer for which the patient has been disease-free for at least two years.  
14. Have known previously untreated or symptomatic metastases in the brain or spinal cord 
requiring steroids. Patients with treated and stable CNS metastases may be enrolled 
after approval of the sponsor and/or Medical Monitor. 


Pelican Therapeutics, Inc. 
Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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15. Have any other ongoing significant, uncontrolled medical condition in the opinion of the 
Investigator.  
16. Have known positive serology for human immunodeficiency virus (HIV), hepatitis B, or 
hepatitis C (except in cases of immunity after cured infection). Testing not required. 
17. Have a history of substance abuse, medical, psychological or social conditions that may 
interfere with the patient’s participation in the trial or evaluation of the trial result.  
18. Be a female patient who is pregnant or breast feeding. 
 
Test product, dose and mode of administration:   
PTX-35 is a humanized, affinity matured, IgG2 monoclonal antibody and is a functional agonist of 
human TNFRSF25, a member of the TNF-receptor superfamily that is expressed preferentially by 
activated and antigen-experienced T lymphocytes. 
 
TENIVAC vaccine, Tetanus and Diphtheria Toxoids Adsorbed, is a sterile isotonic suspension of 
tetanus and diphtheria toxoids adsorbed on aluminum phosphate. Each 0.5 mL dose of TENIVAC 
vaccine contains the following active ingredients: Tetanus Toxoid 5 Lf (flocculation units) and 
Diphtheria Toxoid 2 Lf. 
 
Each patient will be administered an intravenous infusion of PTX-35 every 2 weeks during the DLT 
period (2 cycles) based on the dose levels defined in the dose escalation scheme (Section 6.1.2) 
and may, per Investigator discretion, continue treatment every 2 weeks until disease progression 
or unacceptable toxicity, whichever occurs first. 
 
Each patient will also be administered a single 0.5 mL dose of TENIVAC vaccine intramuscularly on 
Day 1 of Cycle 1. TENIVAC should be administered as directed in the package insert. 
 
Dose-Limiting Toxicity (DLT): 
An event will be considered a DLT per NCI CTCAE version 5.0 criteria if it occurs within the DLT 
reporting period and meets at least one of the criteria below: 
• 
Hematological toxicities ≥ Grade 3  
• 
Non-hematological toxicities ≥ Grade 3  
• 
Cytokine release syndrome ≥ Grade 3 
• 
Infusion reaction ≥ Grade 3 
• 
Any ≥ Grade 3 hepatic toxicity meeting Hy's Law criteria, or Total bilirubin ≥2.0 x ULN to 
≤3.0 x ULN for >7 consecutive days, ≥CTCAE G3 total bilirubin, CTCAE G3 AST or ALT for 
>7 consecutive days, or CTCAE G4 AST or ALT 
• 
Any other treatment-emergent toxicity that is considered clinically significant and/or 
unacceptable, and that does not respond to supportive care and results in a disruption 
of the treatment schedule of more than 14 days.  
 
DLT excludes: 
• 
Hematological and non-hematological ≤ Grade 2 unless considered non-acceptable. 
• 
Other Grade 3 self-limited or medically controllable toxicities (e.g., fever without ≥ Grade 
3 neutropenia, lymphopenia, nausea, vomiting, diarrhea, fatigue). Note, such events are 
considered DLT if the abnormality leads to hospitalization or the abnormality persists for 


Pelican Therapeutics, Inc. 
Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
PTX35-001 
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>72 hours despite appropriate interventions (e.g., replacement therapy for electrolyte 
abnormalities, when indicated). 
• 
Electrolyte disturbances that are managed to Grade 1 or less with supplemental therapy. 
 
Any adverse event that is potentially related to PTX-35 and requires discontinuation of treatment 
should be considered a DLT. A DLT will be considered related to PTX-35 treatment unless there is 
a clear, well-documented, relation to intercurrent illness or primary malignant disease. AEs that 
meet the above criteria but occur after the DLT evaluation period will not be defined as DLTs but 
will be reported as AEs/Serious Adverse Events (SAEs), as applicable, and will be reviewed across 
all dose levels during the study to help inform dose escalation decisions.  
 
In case of suspicion of a DLT, the Investigator must inform the Medical Monitor/Sponsor 
immediately. The DLT will be confirmed by the Medical Monitor/Sponsor and a decision must be 
taken by the Sponsor regarding if an ad hoc SRC meeting is required. 
 
Patients who discontinue therapy before completion of 2 cycles (DLT period) for other reasons 
than dose-limiting toxicity will be replaced. Patients who are tolerating PTX-35 will not have to 
discontinue study treatment prematurely due to the occurrence of DLTs in another patient in the 
same cohort, unless decided by the SRC.  
 
Safety Review Committee: 
A Safety Review Committee (SRC) comprised of at least 3 members: one Investigator, a 
representative of Pelican Therapeutics, and the Medical Monitor.  The SRC will evaluate the data 
obtained at each dose level and will recommend whether the dose should be escalated as per 
protocol, revised to a lower level or intermediate level, halted altogether or more patients are 
required at the same dose level to evaluate safety.  
 
Duration of Treatment:   
Upon completion of two cycles (4 weeks), in the absence of disease progression or unacceptable 
toxicity, patients may continue to be treated with PTX-35 at the same dose and schedule until 
disease progression, death, and patient withdrawal of consent, Investigator’s decision to remove 
patient, or intolerable toxicity, whichever occurs first. 
 
At the discretion of the Investigator, and in the absence of clinical deterioration, treatment with 
PTX-35 may continue beyond initial evidence of radiological progression as per Section 8.2.1. 
 
Criteria for Evaluation:   
Primary Endpoints 
• 
Number of Dose-limiting toxicities (DLTs) per NCI CTCAE v5.0. 
• 
Frequency of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) related to PTX-35 during the trial. 
 
Secondary Endpoints 
• 
Optimal Immunological Dose (OID; dose where T-reg plateau is observed) or Maximum 
tolerated dose (MTD; highest dose level at which ≤ 1 patient of at least 6 patients 
experienced a DLT during the first two treatment cycles). 


Pelican Therapeutics, Inc. 
Protocol No. PTX35-001 
Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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• 
Pharmacokinetic parameters will include maximum concentration (Cmax), area under curve 
up to the last measurable concentration (AUClast), trough observed serum concentration 
(Ctrough) and terminal elimination half-life (T1/2λz).  
 
Exploratory Analysis 
Immune phenotype profiling of immune cell subsets will be conducted by flow cytometry in 
peripheral blood at various time-points to assess change from baseline in:  
• 
Percentage of Treg cells (immunological effect) 
• 
Frequency of anti-therapeutic antibody (ATA) titers to PTX-35 (immunogenicity) 
• 
General immunologic expansion: The frequency and expansion of NK, CD4 and CD8 T cell 
subsets  
• 
Specific antigen driven immune expansion: immune responses to a well-characterized 
first-time exposure or recall antigen based on the patient’s HLA type will be measured at 
baseline and on study using ELISA, ELISPOT and flow cytometric methods. 
• 
Specific cytokine expression in response to treatment with PTX-35. 
Clinical benefit will be evaluated where possible for: 
• 
Best Overall Response (BOR), Overall Survival (OS), and Progression-Free Survival (PFS) 
assessed by RECIST 1.1 (APPENDIX II). 
Safety:  
Safety will be assessed throughout the study by means of physical examination, weight, vital signs, 
ECOG performance status, laboratory evaluations (hematology, biochemistry and cytokines), 
electrocardiogram (ECG), and recording of concurrent illness/therapy and treatment-emergent 
adverse events. CTCAE version 5.0 will be used to grade all toxicities. Patients will also be 
monitored for any clinical symptoms associated with elevated cytokine levels. All related adverse 
events will be monitored until resolution or permanent outcome. Concomitant medications will 
be recorded throughout the study.  
 
Cytokines will be monitored during cycle 1 and 2. Cytokines will only be monitored at cycle 3 and 
beyond if patient is symptomatic at time of visit (i.e., flu-like symptoms, fever, or allergic reactions). 
 
Efficacy:  
Clinical benefit (Best Overall Response, Progression-Free Survival, and Overall Survival) will be 
evaluated via radiologic assessments according to RECIST 1.1 (APPENDIX II). 
 
Pharmacokinetics:  
Plasma concentrations of PTX-35 will be measured by ELISA at the following timepoints: pre-dose; 
30min (±2min), 2hr (±5min), 4hr (±5min), 24hr (±2hr), 72hr (±2hr), 144hr (±2hr), 216hr (±2hr) after 
end of PTX-35 infusion for Cycles 1 and 2, and pre-dose at Cycle 3 only. Non-compartmental or 
population pharmacokinetic methods will be used to derive PTX-35 PK parameters, which will be 
summarized using descriptive statistics (mean, standard deviation, median, minimum, 
maximum).  
 
Immunogenicity: Blood samples will be drawn for central analysis of anti-therapeutic antibodies 
(ATA), which will be collected pre-dose on Day 1 of each cycle and at the 30-day follow up visit. 
Samples testing positive in the screening assay will undergo a confirmatory assay to demonstrate 


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that the ATAs are specific for the therapeutic protein product. Samples identified as positive in the 
confirmatory assay will be further characterized in titration and neutralization assays.  
General and Specific Antigen Immune Expansion: Blood samples will be drawn to determine 
each patient’s HLA type (collected pre-dose Cycle 1 Day 1) for exclusive use in determining the 
patients primary or recall response to the TENIVAC vaccine.  Blood samples will also be collected 
pre-dose on Day 1 of each cycle and at the 30-day follow up visit to measure anti-TENIVAC 
antibody titer (TDAR). Blood samples will also be collected pre-dose on Day 1 and Day 7 of Cycles 
1 and 2 as well as at the 30-day follow up visit to measure the general and antigen reactive 
expansion and activity of NK and T cell subsets.  
 
Statistical Methods and Justification of Sample Size:  
All analyses will be descriptive. Categorical variables will be presented with numbers and, if 
meaningful, percentages. Continuous variables will be presented by n, mean, median, standard 
deviation and range (minimum and maximum) as appropriate. Presentations will be by each dose 
level. 
 
Safety Evaluable Population:  All patients who received at least 1 dose of PTX-35. 
 
DLT Evaluable Population:  All patients who receive at least 1 dose of PTX-35 and experience a DLT 
and/or complete the DLT evaluation period. 
 
Efficacy Evaluable Population: All patients with pre-treatment measurable disease by RECIST 1.1, 
who received at least 1 dose of PTX-35 and who had at least one radiological assessment during 
treatment. 
 
This is an exploratory, first-in-human trial.  We believe that the sample sizes will be sufficient to 
characterize the initial safety of PTX-35.  No formal sample size calculations have been performed. 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
 
 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
APC 
Antigen-Presenting Cell 
ATA 
AUC 
Anti-Therapeutic Antibody 
Area under Concentration Time Curve 
AUClast 
Area under Concentration Time Curve up to the Last Measurable 
Concentration 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
CDR 
Complementarity-determining regions 
CFR 
Code of Federal Regulations 
Cmax 
Maximum Observed Serum Concentration 
CR  
Complete Response 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CRS 
Cytokine Release Syndrome 
CT 
CTCAE 
Computed Tomography 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T Lymphocyte 
CTLA-4 
Cytotoxic T Lymphocyte-Associated Protein 4 
Ctrough 
Trough Observed Serum Concentration 
DLT 
Dose-Limiting Toxicity 
DR3 
Death Receptor 3 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
Enzyme-linked immunosorbent assay 
FACS 
Fluorescence Activated Cell Sorting 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice Guidelines 
GITR 
Glucocorticoid-Induced TNFR-Related Gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leucocyte Antigen 
ICF 
Informed Consent Form 
ICH 
IEC 
International Council for Harmonization 
Independent Ethics Committee 
Ig 
Immunoglobulin 


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IgSF 
Immunoglobulin Superfamily 
IL 
Interleukin 
IM 
Intramuscular 
IRB 
Institutional Review Board 
IV 
Intravenous 
KD 
Binding Affinity 
Kg 
Lf 
Kilogram 
Flocculation Units 
LVEF 
Left Ventricular Ejection Fraction 
µg 
Microgram 
mAb 
Monoclonal Antibody 
MABEL 
Minimum Anticipated Biological Effect Level 
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
MHC 
Major Histocompatibility Complex 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute  
NKT 
Natural Killer T Cell 
NOAEL 
No Observable Adverse Event Level 
NOEL 
No Observable Effect Level 
NSCLC 
Non-Small Cell Lung Cancer 
OS 
Overall Survival 
OT-I 
Ovalbumin-Specific TCR Transgenic Mouse 
PBMC 
Peripheral Blood Mononuclear Cell 
PD 
Progressive Disease 
PECAM 
Platelet Endothelial Cell Adhesion Molecule 
PETG 
Polyethylene Terephthalate Glycol 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
SAE 
Serious Adverse Event 
SAR 
Suspected Adverse Reaction 
SD 
Stable Disease 
SOC 
Standard of Care 
SRC 
Safety Review Committee 
T1/2λz 
Terminal Elimination Half-Life 
Tconv 
Conventional T Cells 
TCR 
T Cell Receptor 
TDAR 
T Dependent Antibody Response 
TEAE 
Treatment-Emergent Adverse Events 
Tmax 
Time to Peak Serum Concentration 


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TL1A 
Tumor Necrosis Factor–Like Cytokine 1A 
TNF 
Tumor Necrosis Factor 
TNFR 
Tumor Necrosis Factor Receptor 
TNFRSF 
Tumor Necrosis Factor Receptor Superfamily 
TRAMP 
Trf4/Air2/Mtr4p Polyadenylation Complex 
Treg 
Regulatory T Cell 
Tx 
Treatment 
ULN 
Upper Limit of Normal 


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1.0 
GENERAL INFORMATION 
1.1 
Protocol Number and Title of the Study 
Protocol No. PTX35-001 
Protocol Title: A Phase I, First-in-Human, Dose-Escalation Study to Evaluate the Safety of the 
Monoclonal Antibody PTX-35 in Patients with Advanced Solid Tumors 
 
1.2 
Sponsor 
Pelican Therapeutics, Inc. 
8122 Datapoint Drive, Suite 445 
San Antonio, TX 78229 
(917) 892-9996 
 
1.3 
Medical Monitor 
Alan Epstein, MD, JD, MBA, SM 
(703) 472-7289 
aepstein@cancerinsight.com 
 
1.4 
Signature Authorization 
Heat Biologics will sign the protocol. 
 
1.5 
Principal Investigator and Institution 
Anthony W. Tolcher, MD 
NEXT Oncology 
2829 Babcock Rd, Suite 300  
San Antonio, Texas 78229 
 
2.0 
BACKGROUND INFORMATION 
2.1 
Introduction 
2.1.1 T lymphocyte Activation and Regulation: Co-Stimulator Molecules  
T lymphocyte recognition of specific cognate antigenic peptides presented by MHC 
molecules triggers T cell receptor (TCR) signaling. Co-stimulatory and co-inhibitory receptors 
on T cells are required for successful signaling and they play a crucial role in regulating T cell 
activation, subset differentiation, effector function and survival. Following recognition of 
cognate peptide–MHC complexes on antigen-presenting cells (APCs) by the TCR, co-signaling 
receptors often co-localize with TCR molecules, where they synergize with TCR signaling to 


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promote or inhibit T cell activation and function1,2. CD28 is a prototype co-stimulatory TCR 
and its discovery provided evidence for the two-signal model of T cell activation, according 
to which both TCR and co stimulatory signaling are required for full T cell activation.   
 
A large number of co-stimulator molecules have now been identified and most of them 
belong to either the immunoglobulin superfamily (IgSF) or tumor necrosis factor receptor 
superfamily (TNFRSF). The TNFRSF co-stimulatory receptors are structurally related cell 
surface glycoproteins that regulate innate and adaptive immunity. A subgroup of the TNFRSF 
contains a conserved region within the cytoplasmic domain known as the death domain. 
Triggering of death domain-containing members of the TNFRSF can lead to the induction of 
apoptosis via activation of caspase-8 or stimulation of the MAP kinase and NF-kB signaling 
pathways. The T lymphocyte receptor molecules CD27-, OX40- and DR3- mediated co-
stimulation promotes proliferation and survival of both CD4+ and CD8+ effector T cells, 
whereas 4-1BB- and GITR- mediated co-stimulation preferentially enhances the expansion 
and survival of CD8+ effector T cells. The expression of many co-stimulatory and co-inhibitory 
molecules on the surface of T cells is induced following T cell activation and changes in the 
cell surface expression of many of these molecules occur in overlapping fashion as T cells 
proliferate and differentiate. 
 
2.1.2 TNFRSF25 and TL1A 
Tumor necrosis factor (TNF) related superfamily member 25 (TNFRSF25) (also known as 
TRAMP, WSL-1, Apo-3, LARD or DR3), is highly restricted to lymphocyte-rich tissues including 
the spleen, thymus, small intestine and peripheral blood lymphocytes. At a cellular level 
TNFRSF25 is expressed at low levels on naïve CD4+ and at even lower levels on naive CD8+ T 
cells but is up-regulated rapidly on both after activation with TCR engagement with antigen. 
TNFRSF25 is highly and constitutively expressed by CD4+ FoxP3+ T regulatory cells (Treg), 
which may be related to the persistent encounter of thymic-derived Treg with cognate ‘self’ 
antigen.  
 
The only known ligand for TNFRSF25 is TL1A (TNFSF15) and this appears to be a 
monogamous receptor:ligand pair.  TL1A is a type II membrane bound protein but can also 
be processed into a soluble cytokine. TL1A is produced by activated dendritic cells (DCs), 
monocytes, endothelial cells and T cells, and can also be induced by IL-1β or TNFα. TL1A is 
not expressed by resting CD4+ or CD8+ T cells, but can be induced upon activation by TCR 
stimulation or exposure to LPS. TL1A co-stimulates T-cell production of effector cytokines in 
vitro and enhances the accumulation of CD4+ effector T cells within the inflamed tissues in 
autoimmune and inflammatory disease models. TL1A also promotes Treg proliferation and 
attenuates Treg-mediated suppression of non-regulatory CD4+ T cells. In addition, TL1A has 
been shown to co-stimulate invariant NK Tcells and may have a role in enhancing NK cell-
mediated tumor cell killing. 
 


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2.1.3 TNFRSF25 Signaling in CD4 and CD8 T Lymphocytes, and Tumor Growth 
Inhibition 
As mentioned, TNFRSF25 is constitutively and highly expressed by CD4+FoxP3+ Tregs. By 
using a TNFRSF25-specific agonistic monoclonal antibody, 4C12, the effects of TNFRSF25 
signaling on Tregs was studied in vivo in mice. Signaling through TNFRSF25 induced rapid 
and selective expansion of preexisting Tregs in vivo such that they became 30%–35% of all 
CD4+ T cells in the peripheral blood within 4 days. TNFRSF25-induced Treg proliferation was 
dependent upon TCR engagement with MHC class II, IL-2 receptor, and Akt signaling, but not 
upon co-stimulation by CD80 or CD86; it was unaffected by rapamycin3. 
 
While studies have demonstrated a role for TNFRSF25 in regulating CD4+ T cell responses, it 
also has been demonstrated that TNFRSF25 can function as a co-stimulatory receptor for 
CD8+ T cells. Human CD8+ T cells have been found to preferentially express TNFRSF25 
compared to CD4+ T cells, B cells, monocytes, NK cells or dendritic cells. The ectopic 
expression of TL1A on mouse plasmacytomas promotes elimination of tumor cells in a CD8+ 
T-cell dependent manner and renders mice immune to a subsequent challenge with tumor 
cells. 
 
TNFRSF25 triggering in vivo with soluble TL1A promotes the proliferation and accumulation 
of antigen-specific CD8+ T cells as well as their differentiation into CTLs. TNFRSF25 also 
functions as a co-stimulatory receptor for memory CD8+ T cells. Thus, TNFRSF25 triggering 
enhances the secondary expansion of endogenous antigen-specific memory CD8+ T cells. 
These findings suggest that TNFRSF25 agonists, such as soluble TL1A, could potentially be 
used to enhance the immunogenicity of vaccines that aim to elicit human anti-tumor CD8+ T 
cells4. 
 
The effect of TNFRSF25 stimulation by the agonist 4C12, a hamster monoclonal antibody 
(mAb), has been explored using several murine models and treatment approaches. In a study 
of several co-stimulatory agonists in a CT26 murine colon-carcinoma model, it was 
demonstrated that the stimulation of TNFRSF25 by the 4C12 mAb resulted in tumor growth 
inhibition of an equivalent degree as agonists targeting the GITR and OX40 co-stimulator 
receptors. A murine breast cancer model using 4T1 tumor cells demonstrated that following 
cumulative radiation of 30 Gy, similar tumor growth inhibition was achieved with the 
administration of the 4C12 mAb agonist or an OX40 agonist, indicating similar effects 
whether the TNFRSF25 or OX40 co-stimulatory receptors were engaged.  The best activity 
was seen when treatment regimens were combined with anti-TNFRSF25/DR3 4C12 agonist 
antibody, demonstrating proof-of-concept for the combination of current cancer therapies 
with TNFRSF25/DR3 agonists. 
 
Due to the potential of TNFRSF25/DR3 stimulation to expand regulatory T-cells in the 
absence of inflammation/antigen, studies were conducted to measure the systemic (spleen) 
and local (tumor) levels of regulatory T-cells post-4C12 treatment in tumor-bearing animals.  


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In mice with established Lewis Lung Carcinoma (LLC), mice were treated with 4C12 and 
regulatory T-cells were measured in the spleen and tumor over time.  Regulatory T-cells were 
expanded in the spleen but not within the tumor microenvironment (TME).  Neither induced 
(peripheral) nor natural (thymic) regulatory T-cells were expanded in the TME but were found 
elevated systemically. 
There have been clinical explorations of this approach of T cell co-stimulation. The 
mechanisms of action of CD137 (4-1BB), CD134 (OX40), and glucocorticoid-induced TNFR 
(GITR; CD357) co-stimulators depend on a complex interplay of CTL, T-helper cells, regulatory 
T cells, dendritic cells, and vascular endothelium in tumors. Agonist monoclonal antibodies 
specific for CD137 have shown signs of objective clinical activity in patients with metastatic 
melanoma5. 
 
2.1.4 TNFRSF25: TL1A Signaling and Anti-Cancer Therapy 
Pre-clinical work with the 4C12 mAb to stimulate TNFRSF25 has demonstrated antigen driven 
T cell proliferation, increased effector cytokine production, increased CD8+ effector cell 
function and increased survival among murine xenograft models. TNFRSF25 agonism leads 
to a more pronounced ‘memory’ CD8+ cytotoxic T cell activation and TNFRSF25 signaling in T 
cells appears to be dependent upon prior engagement of the TCR, implying an antigen 
specific T cell proliferation. These findings indicate that the incorporation of a TNFRSF25 
agonist such as PTX-35 into anti-cancer therapy could complement checkpoint inhibitors and 
significantly reverse immune suppression in the tumor microenvironment while boosting 
the CD8+ effector arm of the tumor immune response.   
 
2.2 
PTX-35 Investigational Product 
PTX-35 is a humanized, affinity matured, IgG2 monoclonal antibody derived from the 
hamster antibody 4C12, a product of immunization and immortalization as a hybridoma cell 
line. PTX-35 is a functional agonist of human TNFRSF25 (also known as the death receptor 3, 
DR3), a member of the TNF-receptor superfamily that is expressed preferentially by activated 
and antigen-experienced T lymphocytes. 
 
The structure of PTX-35 is shown in Figure 1. 


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Figure 1: PTX-35 structure 
PTX-35 IgG (150 kDa) consists of two heavy and light chains held together by disulfide bonds.  
Fv – antigen-binding variable region; Fab – fragment, antigen-binding region; Fc – fragment, 
crystallizable region 
 
The schematic in Figure 2 illustrates the development of the humanized monoclonal 
antibody, PTX-35 from the hamster monoclonal antibody, 4C12. PTX-35 was developed by a 
humanization process of transferring the complementarity-determining regions (CDRs) of 
the heavy and light chains from the hamster antibody, 4C12, onto a human framework 
backbone. PTX-35 was then matured by amino acid substitution to increase its affinity and 
strength of binding by slight modifications in the variable binding regions of the heavy and 
the light chains. 
 


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Figure 2: Schematic of PTX-35 (humanized mAb) development from 4C12 (hamster mAb) 
 
2.3 
TENIVAC Vaccine 
TENIVAC vaccine, Tetanus and Diphtheria Toxoids Adsorbed, will be used in this study to 
assess the safety and efficacy of PTX-35 administration in the context of immune 
activation/re-activation against a specific set of antigens (TENIVAC) from both a humoral (B 
cell mediated) and cell mediated (T cell) response. TENIVAC is manufactured as a sterile 
isotonic suspension of tetanus and diphtheria toxoids adsorbed on aluminum phosphate. 
Each 0.5 mL dose of TENIVAC vaccine contains the following active ingredients: Tetanus 
Toxoid 5 Lf (flocculation units) and Diphtheria Toxoid 2 Lf. Other ingredients per 0.5 mL dose 
include 1.5 mg of aluminum phosphate (0.33 mg of aluminum) as the adjuvant and ≤5.0 mcg 
of residual formaldehyde.  
 
2.4 
Preclinical Studies 
Key preclinical findings are summarized below. Please refer to the current Investigator's 
Brochure for details of these studies. 
 


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2.4.1 Primary Pharmacodynamics and Pharmacology  
Since human PTX-35 lacks biological activity in mice due to the need for Fc-gamma-receptor 
cross-linking via the Fc portion of the molecule, a mouse-human surrogate antibody was 
generated by genetically splicing the affinity matured CDR variable domains of human 
PTX-35 onto an IgG1 mouse constant region backbone; mPTX-35.  PTX-35 and its mouse 
surrogate mPTX-35 was tested in a series of pharmacology studies that tested target 
engagement and demonstrated biological proof-of-concept: 
• 
Study of the measurement of functional affinity against human Jurkat cell lines, in 
vitro, expressing TNFRSF25/DR3  
• 
In vitro study of PTX-35 co-stimulation in human PBMCs  
• 
Study of the effect of PTX-35 on expansion of Tregs and T cell memory subsets in the 
peripheral blood of monkeys 
• 
Study of mPTX-35 to identify a MABEL and NOEL in mice 
• 
Evaluation of a hamster version of PTX-35 (4C12) in combination with radiation in a 
mouse metastatic breast cancer model  
• 
Evaluation of mPTX-35 in combination with cancer cell vaccine in a mouse model of 
melanoma  
• 
Evaluation of 4C12 anti-tumor activity and regulatory T-cell accumulation in a mouse 
model of Lewis lung carcinoma 
 
These studies demonstrated a dependence on available antigen driven TCR engagement and 
synergistic activity in vivo, for both expansion of CD8+ T cells, as well as delayed outgrowth of 
implanted syngeneic tumors. mPTX-35 also expanded regulatory T-cells confirming target 
engagement giving a pharmacodynamic based MABEL of 0.01 mg/kg and NOEL of 0.001 
mg/kg. This T cell expansion was greatest for the 1 mg/kg dose of mPTX-35 with gp96-Ig cell-
based vaccination and far exceeded any additive value of mPTX-35 and gp96-Ig treatment 
alone. This was also the best dose for vaccine combination for tumor regression, when 
administered simultaneously every two weeks. Additionally, the anti-tumor effects of the 
hamster version of PTX-35 (4C12) was not associated with an accumulation of regulatory 
T-cells in the tumor microenvironment.  
 
2.4.2 Toxicity Studies and Pharmacokinetics 
A PTX-35 safety pharmacology study of the effects of PTX-35 in vitro human PBMC cell culture 
demonstrated that anti-CD3 and PTX-35 stimulated human T-cells in culture does not result 
in the secretion of deleterious cytokines.  


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PTX-35 was tested in a series of toxicology safety studies in mouse and monkey:  
• 
Tissue-cross reactivity against human, mouse and monkey  
o PTX-35 tissue cross-reactivity against mouse, human, monkey TNFRSF25/DR3 
was performed to justify species selection for toxicology studies. 
• 
28-day toxicology study in mice with toxicokinetics  
o PTX-35 was administered via an intraperitoneal injection at doses of 0 (control 
article), 10, 50, 100 and 200 mg/kg to Crl:CD (ICR) mice on two occasions during 
a 28-day study with a 4-week recovery period. 
o No PTX-35-related adverse clinical signs, changes in hematology or clinical 
chemistry parameters, macroscopic findings or changes in organ weighs.  No 
changes in myeloid:erythroid ratio. 
o NOAEL for mouse was determined to be 200 mg/kg with a combined male and 
female Cmax of 2,440 µg/mL, Tmax of 24 hours and AUC(0-216 
hrs.) 
390,000 hr*µg/mL on day 15. 
o Tmax of PTX-35 ranged between 8-72 hours.  Systemic exposure increased with 
dose between 50 and 200 mg/kg [Cmax 644 – 2,440 µg/mL and AUC(0-216 hrs.) of 
91,100 – 390,000 hr*µg/mL averaged for male and female animals for day 15].  
Presence of ATA was observed in only one animal and this did not affect 
exposure. 
• 
2-week dose range finding toxicology study in monkey with toxicokinetics  
o Animals were dosed PTX-35 at 1, 10, 50 and 96 mg/kg, by bolus IV injection, 
once every 2 weeks, for a total of 2 weeks. 
o PTX-35 was well tolerated up to 96 mg/kg/dose; there were no PTX-35-related 
clinical observations, or changes to body weights, qualitative food 
consumption, clinical chemistry, coagulation, and urinalysis parameters at any 
dose levels evaluated. 
o NOAEL of 96 mg/kg/dose with corresponding Cmax of 2,590 µg/mL and AUC(0-t) 
of 261,500 hr*µg/mL for male and female combined. 
o Animals in each dose group were ATA negative on day 36, except at the lowest 
dose level (1 mg/kg/dose), in which both animals were ATA positive and 
appeared to affect exposure. 
• 
8-week toxicology study with toxicokinetics in monkey with NOAEL of 100 mg/kg  
o PTX-35 was administered at 10, 60, 100 mg/kg by IV bolus injection once every 
2 weeks over an 8-week period (total of 4 doses). 


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o There were no PTX-35-related clinical signs, or changes in body weights or 
qualitative food consumption. There were no PTX-35-related effects on eyes, 
electrocardiogram, coagulation, clinical chemistry, or urinalysis parameters, or 
bone marrow cytology; nor were there any PTX-35-related gross necropsy or 
histopathologic findings, or changes in absolute or relative organ weights. 
o NOAEL of 100 mg/kg/dose with a Cmax of 217 to 2,660 µg/mL and AUC(0-336 hrs.) 
of 24,500 to 298,000 µg*hr/mL at day 43 for doses 10 to 100 mg/kg. 
o Systemic exposure to PTX-35 did not appear to consistently change greater 
than 2-fold following repeated administration of PTX-35. Animals in the lowest 
dose group (10 mg/kg) were positive for ATA which influenced exposure. 
 
The pharmacokinetics of PTX-35 drug substance (DS) and drug product (DP) when 
administered by slow bolus intravenous injection on a single occasion were determined for 
the two formulations (DS; group 1 and DP; group 2) in monkeys. Overall, these two 
formulations showed relatively similar pharmacokinetic values (Figure 3) suggesting the 
addition of polysorbate 80 to the DS has little effect on PTX-35 exposure. Apparent terminal 
half-life (T1/2λz) of PTX-35 drug product (Group 2) was 163 hours, with the volume of 
distribution at steady-state (Vss) of 58.4 mL/kg. 
 
 
 
Figure 3: Median (± minimum, maximum) PTX-35 plasma concentrations vs time following 
single dose IV infusion (2.5 min) in cynomolgus monkeys (n=3 per group). 
 


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2.5 
Rationale for Starting Dose and Treatment Schedule 
The starting dose rationale for this current study is derived from non-clinical study in mice 
that generated a minimum anticipated biological effect level (MABEL) and no observable 
effect level (NOEL) for mouse-human surrogate antibody, mPTX-35. mPTX-35 was used as an 
alternative to human PTX-35, in mice, due to the poor binding affinity (KD) of human IgG for 
mouse Fc-γ receptors. The MABEL was determined to be 0.01 mg/kg for mPTX-35 with the 
NOEL being 0.001 mg/kg. This study also established the pharmacologically active dose as 
the dose between 0.1 and 10 mg/kg, with 10 mg/kg being the highest dose given without 
reversing the intended effect. This 0.01 mg/kg starting dose considers the calculated MABEL 
in mice using a mouse-human surrogate that shares the same complementary determining 
region (CDR) binding as that of human PTX-35 with a functionally comparable mouse Fc.  This 
proposed dose is 20,000-fold below the 200 mg/kg NOAEL as determined in mice, and 
10,000-fold below the 100 mg/kg NOAEL as determined in monkey.     
 
Thus, the suggested starting dose in patients is 0.01 mg/kg of PTX-35 administered every 
2 weeks. This dose represents the MABEL dose in mice with a 10,000 to 20,000-fold safety 
factor based on monkey and mouse toxicity studies. Five dose levels of PTX-35 will be 
explored using half-logarithmic dose escalation increments, using a traditional 3+3 design 
based on DLTs until MTD is established, as described in Section 6.1.2. 
 
2.6 
Potential Risks and Benefits 
As this is the first-in-man study of PTX-35, no human data regarding the safety or potential 
benefit of PTX-35 is available. PTX-35 is a functional agonist of human TNFRSF25 (also known 
as the death receptor 3, DR3), a member of the TNF-receptor superfamily that is expressed 
preferentially by activated and antigen-experienced T lymphocytes. No other agonistic 
antibody targeting TNFSRF25 has been evaluated in clinical studies previously.  
 
Other TNFRSF agonistic antibodies, including OX-40, 4-1BB/CD137, CD27, CD40, have been 
evaluated in clinical studies. For example, a recent integrated safety analysis of urelumab, 
an agonist anti-CD137 monoclonal antibody, showed that urelumab was relatively well 
tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related 
AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by 
the induction of IFN-inducible genes and cytokines6. Another anti-CD137 monoclonal 
antibody, utomilumab, appears well tolerated, and most common treatment-related adverse 
events observed in a Phase I clinical study were fatigue, pyrexia, decreased appetite, 
dizziness, and rash (<10% of patients). Only one (1.8%) patient experienced a Grade 3-4 
treatment-related adverse event (fatigue), and no clinically relevant elevations in 
transaminases were noted7. In a Phase I randomized study of KHK4083, an anti-OX40 
monoclonal antibody, in patients with mild to moderate plaque psoriasis, the most frequent 
treatment-related AEs observed were mild or moderate chills (9.1%), and infusion/injection 
site reactions (7.3%). No clinically meaningful or dose-related changes from baseline in 


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laboratory values, vital signs, ECG recordings or physical examinations were observed8. The 
Phase I study of varilumab, an agonistic antibody targeting CD27, the treatment-related 
adverse events were generally Grade 1 or 2 in severity, with 1 dose-limiting toxicity 
(asymptomatic Grade 3 hyponatremia), but no high-grade immune-related adverse events9. 
 
Cytokine release syndrome (CRS) is a potentially life-threatening toxicity that has been 
observed following administration of natural and bispecific antibodies and, more recently, 
following adoptive T-cell therapies for cancer. 
 
No relevant toxicity of PTX-35 has been observed in a series of dedicated toxicology safety 
studies (mice and monkeys). Based on the experience with other antibodies, infusion 
reactions may occur. Manipulation of immune checkpoints may, theoretically, trigger 
immune-related adverse reactions and/or cytokine release syndrome but based on 
experience with other agonists of the TNFRSF, this risk appears limited with PTX-35. 
 


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3.0 
TRIAL OBJECTIVES AND PURPOSE 
Primary: 
• 
To establish the safety profile of PTX-35 in a population of patients with advanced 
solid tumors.  
 
Secondary: 
• 
To determine the optimal immunological dose (OID), or maximum tolerated dose 
(MTD) of PTX-35.  
• 
To establish the pharmacokinetic profile of PTX-35. 
 
Exploratory: 
• 
To study the immunological effect generated by PTX-35. 
• 
To evaluate immunogenicity of PTX-35. 
• 
To evaluate preliminary evidence of clinical benefit of PTX-35 in a population of 
patients with advanced solid tumors.  
• 
To evaluate general immunologic expansion: The frequency and expansion of NK, 
CD4 and CD8 T cell subsets. 
• 
To measure immune responses to well-characterized first-time exposure or recall 
antigen. 
• 
To determine specific cytokine expression in response to treatment with PTX-35, or 
any other unspecific inflammatory response.  


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Phase I Study of PTX-35 in Patients with Solid Tumors 
 
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4.0 
TRIAL DESIGN 
4.1 
Characteristics of a Well-Conducted Trial 
The following characteristics of an adequate and well-conducted trial will be implemented: 
 
1. 
The Investigators will be well qualified by scientific training and experience. 
2. 
Detailed Case Report Forms (CRFs) will be completed for every patient. 
3. 
Requirements for institutional ethics review as set forth by the appropriate 
Institutional Review Board/Independent Ethics Committee (IRB/IEC), Title 21 Code of 
Federal Regulations (CFR) Part 56, the European Union Directive 2001/20/EC and its 
associated Detailed Guidances, European Union GCP Directive 2005/28/EC, the ICH 
Guideline for Good Clinical Practice, Sections 3 and 4, and the terms of the Declaration 
of Helsinki (2013), will be followed. 
4. 
Requirements for informed consent in accordance with institutional guidelines, FDA 
requirements as specified in Title 21 CFR, Part 50, the European Union Directive 
2001/20/EC and its associated Detailed Guidances, European Union GCP Directive 
2005/28/EC, the ICH Guideline for Good Clinical Practice, Section 4.8, and the terms 
of the Declaration of Helsinki (2013), will be followed. 
5. 
Safety data will be recorded and evaluated. 
6. 
Routine monitoring visits will be conducted by the Sponsor’s representative to ensure 
data accuracy. 
7. 
Drug accountability will be strictly maintained. 
8. 
This trial will be conducted according to Good Clinical Practice (GCP), the protocol and 
applicable regulatory requirements. 
 
4.2 
Overview of Trial Design 
This is an open-label, single arm, first-in-human, Phase I study of the intravenous 
administration of PTX-35 to patients with advanced solid tumors refractory to, or ineligible 
for, or who refuse, SOC therapy.  
 
Patients who meet the eligibility criteria will be enrolled to receive intravenous PTX-35 every 
two weeks as well as a single intramuscular injection of TENIVAC vaccine on Day 1 of Cycle 1. 
Upon completion of two cycles of PTX-35, in the absence of disease progression or 
unacceptable toxicity, patients may continue to be treated with PTX-35 at the same dose and 
schedule until disease progression, death, and patient withdrawal of consent, Investigator’s 
decision to remove patient, or intolerable toxicity, whichever occurs first. At the discretion of 
the Investigator, and in the absence of clinical deterioration, treatment with PTX-35 may 
continue beyond initial evidence of radiological progression as per Section 8.2.1. 


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Seven escalating dose levels of PTX-35 will be explored using a traditional 3+3 design based 
on DLTs (dose-limiting toxicities) until optimal immunological dose (OID) or maximum 
tolerated dose (MTD) is established. The starting dose of PTX-35 is based on the MABEL for 
Treg activity (considered the most sensitive of PTX-35 pharmacodynamic markers) obtained 
from dose-ranging studies conducted in non-clinical animal models. PTX-35 will be 
administered to patients intravenously on Day 1 of each cycle. The length of each cycle is 14 
days, and the DLT period includes the safety data obtained from the first two treatment 
cycles (4 weeks).  
 
4.3 
Patient Population 
This study will enroll adult male and female patients of age ≥ 18 years with metastatic or 
advanced, unresectable solid tumor types, who have progressed or recurred following 
standard of care (SOC) therapies, or are ineligible for, or refuse, other safe and effective SOC 
treatment.  
 
4.4 
End of Study 
The end of the study is defined as the date of the last visit of the last patient participating in 
the trial. 
 
4.5 
Duration of Therapy 
Upon completion of the first two treatment cycles (i.e., 4 weeks, with at least 2 doses of PTX-
35), in the absence of disease progression and unacceptable toxicity, patients may continue 
to be treated with PTX-35 at the same dose and schedule until disease progression, death, 
patient’s withdrawal of consent, Investigator’s decision to remove patient, or intolerable 
toxicity, whichever occurs first. 
 
At the discretion of the Investigator, and in the absence of clinical deterioration, treatment 
with PTX-35 may continue beyond initial evidence of radiological progression as per 
Section 8.2.1. 
 


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4.6 
Trial Discontinuation  
For reasonable cause, either the Investigator or the Sponsor may terminate this study 
prematurely. Written notification of the termination is required. Conditions that may warrant 
termination include, but are not limited to: 
 
• 
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study. 
• 
Failure of the Investigator to enter patients at an acceptable rate. 
• 
Insufficient adherence to protocol requirements (non-compliance). 
• 
Lack of evaluable and/or complete data. 
• 
Decision to modify the developmental plan of the drug. 
• 
A decision on the part of the Sponsor to suspend or discontinue development of the drug. 
 
Section 5.5 Study Stopping Criteria lists events that warrants immediate stop of treatment 
until reviewed by the Safety Review Committee. This assessment may also result in trial 
discontinuation (equivalent to first bullet above). 
 
4.7 
Investigational Product Accountability/Disposition of Clinical Trial Supplies 
Investigational Product (IP) accountability records will be maintained for all clinical trial 
supplies. 
 
All unused clinical trial supplies will be destroyed per the institution’s standard operating 
procedure, or returned to the Sponsor or designee. Destruction and/or return of IP and trial 
supplies must be documented, and the documentation will be reviewed by/sent to the 
Sponsor or their Designee.  
 
5.0 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1 Inclusion Criteria 
Patients must meet all of the following inclusion criteria before they will be allowed to 
participate in the trial: 
1. Be willing and have the capacity to sign the written informed consent form. 
2. Be male or female of at least 18 years of age at the time of signing informed consent. 
3. Have a documented diagnosis of metastatic or advanced, unresectable solid tumor 
disease. Patient must have progressed or recurred following standard of care (SOC) 
therapies, or are ineligible for, or who refuse, other safe and effective SOC therapies, and 
whom the Investigator believes may benefit from experimental treatment with PTX-35. 


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4. Have an acceptable organ function, as defined below: 
a. Albumin ≥ 2.5 g/dL 
b. Total bilirubin < 3.0 × upper limit of normal (ULN) unless patient has Gilbert’s 
syndrome.  
c. Alanine transaminase (ALT) and aspartate transaminase (AST) ≤ 3.0 × ULN, or ≤ 5 
× ULN in the case of liver metastases.  
d. Calculated or measured creatinine clearance > 35 mL/minute per the Cockcroft-
Gault formula. 
e. Absolute neutrophil count ≥ 1,500/mm3 
f. Hemoglobin ≥ 9 g/dL.  
g. Platelet count ≥ 100,000/mm3 
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 
(APPENDIX I). 
6. Have life expectancy of at least three months. 
7. Patients, both females and males, of childbearing/reproductive potential must agree to 
use adequate contraception, or continuous abstinence, while included in the trial and for 
six months after the last treatment with PTX-35. 
 
5.2 Exclusion Criteria 
Patients MUST NOT enter the trial if they meet any of the following exclusion criteria: 
1. Have 
received 
any 
systemic 
anticancer 
therapy 
including 
small 
molecules, 
chemotherapy, radiation therapy, monoclonal antibodies or any other experimental drug 
within 4 weeks of first dose of PTX-35. Adjuvant anti-hormonal treatment(s) for prior 
breast cancer or prostate cancer are allowed. (Note: washout for palliative radiation 
therapy is 2 weeks). 


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2. Have clinically significant cardiac disease, including: 
a. Onset of unstable angina within 6 months of signing the Informed Consent Form 
(ICF). 
b. Acute myocardial infarction within 6 months of the signing the ICF. 
c. Known congestive heart failure (Grade III or IV as classified by the New York Heart 
Association); and/or a known decreased cardiac ejection fraction (LVEF) of < 45%.  
d. Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or 
diastolic blood pressure ≥ 100 mmHg, despite optimal medical management. 
3. Known or clinically suspected leptomeningeal disease. Stable, previously treated 
metastases in the brain or spinal cord, are allowed as long as these are considered 
stable (by CT or MRI), and not requiring systemic corticosteroids. 
4. Have a history of ≥ Grade 3 allergic reactions, or suspected allergy or intolerance to 
monoclonal antibody therapies.  
5. Have a history of suspected cytokine release syndrome (CRS).  
6. Have any known immunodeficiency disorders (testing not required).  
7. Have received prior allogeneic stem cell transplant. 
8. Have ongoing or current autoimmune disease.  Permanent but stable and manageable 
immune related adverse events (irAE) from prior therapies are permissible if prednisone 
equivalent corticosteroid use does not exceed 10 mg/day.  
9. Have any other condition requiring concurrent systemic immunosuppressive therapy 
(other 
than 
allowable 
exceptions 
which 
do 
not 
exceed 
10mg/day 
of 
prednisone/corticosteroid use).  
10. Have clinically significant active viral, bacterial or fungal infection requiring: 
a. Intravenous treatment with antimicrobial therapy completed less than two weeks 
prior to first dose, or 
b. Oral treatment with antimicrobial therapy completed less than one week prior to 
first dose. 
Prophylactic treatment with antibiotics (e.g., for dental extractions) is allowed. 
11. Have had major surgery (requiring general anesthesia or inpatient hospitalization) within 
four weeks before first administration of PTX-35.  


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12. Have had a known tetanus/diphtheria vaccine within the past 10 years. 
13. Have known additional malignancy that is active and/or progressive requiring treatment; 
exceptions include basal cell or squamous cell skin cancer, in situ cervical cancer, or other 
cancer for which the patient has been disease-free for at least two years.  
14. Have known previously untreated or symptomatic metastases in the brain or spinal cord 
requiring steroids. Patients with treated and stable CNS metastases may be enrolled after 
approval of the sponsor and/or Medical Monitor. 
15. Have any other ongoing significant, uncontrolled medical condition in the opinion of the 
Investigator.  
16. Have known positive serology for human immunodeficiency virus (HIV), hepatitis B, or 
hepatitis C (except in cases of immunity after cured infection). Testing not required. 
17. Have a history of substance abuse, medical, psychological or social conditions that may 
interfere with the patient’s participation in the trial or evaluation of the trial result.  
18. Be a female patient who is pregnant or breast feeding. 
5.3 
Inclusion of Women, Minorities and Children 
Both men and women and members of all races and ethnic groups are eligible for this study. 
Children are not eligible for this study because the safety and tolerability of the proposed 
administration schedule has not been determined in adults. 
 
5.4 
Withdrawal Criteria 
Protocol therapy will be discontinued at any time if any of the following situations occur: 
1. Progressive disease (not including unconfirmed radiographic PD if Investigator opts to 
continue treatment as outlined in section 8.2.1).  
2. Adverse event. 
• 
The development of toxicity which, in the Investigator’s judgment, precludes further 
therapy.  
• 
 Unacceptable adverse event(s). 
• 
 Intercurrent illness that prevents further administration of treatment. 
3. Withdrawal by subject. 
4. Lost to follow-up. 
5. Non-compliance. 
6. At the discretion of the Investigator/physician decision. 


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7. Death. 
8. Pregnancy. 
9. Study termination. 
 
5.4.1 Withdrawn Patients  
When a patient is removed from the study, the Investigator will clearly document the reason 
in the medical record and complete the appropriate case report form page describing the 
reason for discontinuation. In addition, every effort should be made to complete the 
appropriate assessments listed in Section 7.4. 
 
Patients lost to follow-up will be withdrawn from the study. Patients will be declared “lost to 
follow-up” if the last contact date has exceeded two years, and/or the site has documented 
three attempts to contact the patient by telephone and/or certified letter to last known 
address. 
 
5.4.2 Replacement of Subjects 
Patients who discontinue due to toxicity (related to PTX-35) during the 4-week DLT window 
of observation of Cycle 1 and Cycle 2, or who do not receive all doses due to toxicity in Cycle 
1 and Cycle 2, will not be replaced. Patients who discontinue or who do not receive at least 
two doses of PTX-35 for any reason other than toxicity during Cycle 1 and 2 will be replaced. 
Note, that all patients who receive PTX-35 will be included in assessment of DLT per 
Section 6.1.3.  
 
5.5 
Study Stopping Criteria 
If any of the following occur, administration of PTX-35 will be temporarily or permanently 
stopped, pending a review by the Safety Review Committee. During that time, no drug can 
be administered to any patient, until a decision is made. 
• 
Any Death (other than progressive disease) that is at least possibly related to the 
study agent(s) 
• 
Occurrence of two or more grade 4 events that are at least possibly related to the 
study agent(s) 
 
Conditions that may warrant trial termination are listed in Section 4.6 
 


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6.0 
TREATMENT OF PATIENTS 
6.1 
Investigational Product Preparation and Administration 
6.1.1 Drug Products 
6.1.1.1 PTX-35 
PTX-35 is a humanized, affinity matured, IgG2 monoclonal antibody and is a functional 
agonist of human TNFRSF25, a member of the TNF-receptor superfamily that is expressed 
preferentially by activated and antigen-experienced T lymphocytes. 
 
The drug substance is manufactured by KBI Biopharma (Durham, NC) and formulated in 20 
mM histidine (pH 6.5) and 250 mM sorbitol at a target of 25 mg/mL and stored frozen at -80°C 
in PETG bottles. 
 
The final drug product is reformulated and filled at Integrity Bio (Camarillo, CA) at a final 
concentration of 10 mg/mL in 20 mM histidine (pH 6.0), 250 mM sorbitol and 0.01% 
polysorbate 80 and stored at 2–8°C.  
 
PTX-35 will be administered via intravenous infusion according to the dose levels in the dose 
escalation scheme (Section 6.1.2) on Day 1 of each cycle. The dose will be calculated using 
the weight obtained during Screening. The weight obtained at each dosing visit is to be 
reviewed prior to dispensing IP. If the patient’s weight changes by >10% during the course of 
the study, the drug dose should be recalculated. Recalculation of drug dose on each 
treatment day regardless of percentage of body weight change is also allowed, if required 
per institutional dosing policy. The dosing solution should include additional volume to 
account for dose losses due to administration set priming. PTX-35 should be diluted with 
0.9% sodium chloride for injection under aseptic conditions to the appropriate concentration 
according Table 1: PTX-35 Dose Levels. Dose levels 1 through 3 will be administered at a 
concentration of 1 mg/mL, and dose levels 4 through 7 will be administered at a 
concentration of 5 mg/mL. Diluted Investigational Product should be infused with a 
MedFusion 3500 syringe pump (or equivalent) with compatible polypropylene syringe 
connected to Smith’s Medical FS116 60” PVC tubing with 0.22 micron in-line filter and 0.7 mL 
priming volume. [Note that the total priming volume to be used during administration will 
be 1.0 mL to ensure filter saturation.] The rate of infusion should be approximately 1 mL per 
minute. Please refer to the study Investigational Product Manual for full administration 
details. 
 


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Each patient must remain in clinic for a 6-hour safety observation period after the first cycle 
of PTX-35 infusion. Afterwards, the Investigator may reduce the observation period to 
2 hours for the remaining cycles according to the following criteria: 
• 
Absence of any significant safety concerns following a complete review of all clinical 
and laboratory data for all treated subjects at the given dose level and the preceding 
dose levels, 
• 
Absence of any late-onset (>2 hours post dose) infusion-related reactions or IRR 
symptoms that continue beyond 2 hours post-dose, and lack of any severe or serious 
IRRs, 
 
6.1.1.2 TENIVAC Vaccine 
TENIVAC vaccine is a suspension available in 0.5 mL single-dose for injection. TENIVAC 
vaccine is a sterile isotonic suspension of tetanus and diphtheria toxoids adsorbed on 
aluminum phosphate. Each 0.5 mL dose of TENIVAC vaccine contains the following active 
ingredients: Tetanus Toxoid 5 Lf (flocculation units) and Diphtheria Toxoid 2 Lf. Other 
ingredients per 0.5 mL dose include 1.5 mg of aluminum phosphate (0.33 mg of aluminum) 
as the adjuvant and ≤5.0 mcg of residual formaldehyde. 
  
TENIVAC will be administered via intramuscular injection on Day 1 of Cycle 1 only and will be 
administered per the current product package insert.  
 
If any serious adverse reaction occurs these may be treated per institutional practice, as 
noted in Section 6.4 Concomitant Treatment. 
 
6.1.2 Dose Escalation Scheme 
Escalating doses of PTX-35 will be administered to patients via intravenous infusion on Day 
1 of each cycle.  
 
Upon completion of two cycles (4 weeks), in the absence of disease progression or 
unacceptable toxicity, patients may continue to be treated with PTX-35 at the same dose and 
schedule until disease progression, death, and patient withdrawal of consent, Investigator’s 
decision to remove patient, or intolerable toxicity, whichever occurs first. At the discretion of 
the Investigator, treatment with PTX-35 may continue beyond initial evidence of radiological 
progression as per Section 8.2.1. 
 
Seven escalating dose levels of PTX-35 will be explored using a traditional 3+3 design based 
on DLTs (dose-limiting toxicities) until MTD (maximum tolerated dose) or optimal 
immunological dose (OID) is established. The starting dose of PTX-35 is based on the MABEL 
for Treg activity (considered the most sensitive of PTX-35 pharmacodynamic markers) 
obtained from dose-ranging studies conducted in non-clinical animal models. PTX-35 will be 
administered to patients intravenously on Day 1 of each cycle. The length of each cycle is 


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14 days, and the DLT observation period includes the safety data obtained from the first two 
treatment cycles (4 weeks).  
Table 1: PTX-35 Dose Levels 
Dose level* 
PTX-35 dose 
(mg/kg) 
PTX-35 
Concentration 
(mg/mL) 
PTX-35 Dose  
(mL/kg)  
Number of 
patients 
1 
0.01 mg/kg 
1 mg/mL 
0.01 mL/kg 
3-6 
2 
0.03 mg/kg 
1 mg/mL 
0.03 mL/kg 
3-6 
3 
0.10 mg/kg 
1 mg/mL 
0.10 mL/kg 
3-6 
4 
0.30 mg/kg 
5 mg/mL 
0.06 mL/kg 
3-6 
5 
1.0 mg/kg 
5 mg/mL 
0.20 mL/kg 
3-6 
6 
3.0 mg/kg 
5 mg/mL 
0.60 mL/kg 
3-6 
7 
10 mg/kg 
5 mg/mL 
2.0 mL/kg 
3-6 
*Dose levels 1 through 3 will be administered at a concentration of 1 mg/mL, and dose levels 4 through 7 will be 
administered at a concentration of 5 mg/mL. 
 
At each dose level, 3 patients will be enrolled, with a minimum waiting period of one week 
after treatment initiation of the first patient only.  The remaining subjects in the dose level 
will be treated with no stagger.  After all 3 patients in a dose level have received the second 
dose of PTX-35 and completed the DLT observation period, the Safety Review Committee 
(SRC) will review the safety data to make a dose escalation decision.  If none of these 3 
patients experiences a DLT, dose escalation may proceed.  If 1 of these 3 patients 
experiences a DLT, the dose level will be expanded to at least 6 patients at the same dose 
level.  If <1 out of 6 patients experiences a DLT, then the SRC may recommend dose 
escalation to the next dose level.  If a DLT occurs in 2 or more patients in a particular dose 
level, the maximum tolerated dose (MTD) has been exceeded and dose escalation will cease. 
Up to 3 additional patients will be enrolled at the next lowest dose if only 3 patients were 
treated at that dose level, to confirm safety of that dose.  
 
The conduct and completion of each subsequent dose cohort will follow in similar fashion 
until the MTD is established. Note that if the optimal immunological dose (OID), or observed 
plateau of Treg activity, is determined prior to MTD, further dose escalation may be 
discontinued by decision of the SRC. 
 
Visits and study examinations will be performed per Table 2: Schedule of Assessments. 
Safety will be assessed by frequency of treatment-emergent adverse events (TEAEs), 
evaluation of clinical laboratory parameters (hematology and biochemistry), weight, vital 
signs, electrocardiogram (ECG), performance status, and physical exam findings. NCI CTCAE 
version 5.0 will be used to grade all toxicities.  
 
A post-treatment safety visit will be conducted approximately 30 days following the last dose 
of PTX-35. Response to treatment will be assessed according to RECIST 1.1 with planned 
evaluation performed every 8 weeks (± 1 week) from the start of treatment (C1D1). 


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6.1.3 Dose-Limiting Toxicity 
An event will be considered a DLT per NCI CTCAE version 5.0 criteria if it occurs within the 
DLT reporting period during Cycle 1 and Cycle 2 (i.e., 4 week evaluation period following the 
initial administration of PTX-35) and meets at least one of the criteria below: 
• 
Hematological toxicities ≥ Grade 3  
• 
Non-hematological toxicities ≥ Grade 3  
• 
Cytokine release syndrome ≥ Grade 3 
• 
Infusion reaction ≥ Grade 3 
• 
Any ≥ Grade 3 hepatic toxicity meeting Hy's Law criteria, or total bilirubin ≥2.0 x ULN 
to ≤3.0 x ULN for >7 consecutive days, ≥CTCAE G3 total bilirubin, CTCAE G3 AST or ALT 
for >7 consecutive days, or CTCAE G4 AST or ALT 
• 
Any other treatment-emergent toxicity that is considered clinically significant and/or 
unacceptable, and that does not respond to supportive care and results in a 
disruption of the treatment schedule of more than 14 days.  
 
DLT excludes: 
• 
Hematological and non-hematological ≤ Grade 2 unless considered non-acceptable. 
• 
Other Grade 3 self-limited or medically controllable toxicities (e.g., fever without 
≥ Grade 3 neutropenia, lymphopenia, nausea, vomiting, diarrhea, fatigue). Note, such 
events are considered DLT if the abnormality leads to hospitalization or the 
abnormality 
persists 
for 
>72 
hours 
despite 
appropriate 
interventions 
(e.g., replacement therapy for electrolyte abnormalities, when indicated).  
• 
Electrolyte disturbances that are managed to Grade 1 or less with supplemental 
therapy. 
 
Any adverse event that is potentially related to PTX-35 and requires discontinuation of 
treatment should be considered a DLT.  A DLT will be considered related to PTX-35 treatment 
unless there is a clear, well-documented relation to intercurrent illness or primary malignant 
disease. AEs that meet the above criteria but occur after the DLT evaluation period will not 
be defined as DLTs but will be reported as AEs/Serious Adverse Events (SAEs), as applicable, 
and will be reviewed across all cohorts during the study to help inform dose escalation 
decisions.  
 
In case of suspicion of a DLT, the Investigator must inform the Medical Monitor/Sponsor 
immediately. The DLT will be confirmed by the Medical Monitor/Sponsor and a decision must 
be taken by the Sponsor regarding if an ad hoc SRC meeting is required. 
 


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Patients who discontinue therapy before completion of 2 cycles (DLT period) for other 
reasons than dose-limiting toxicity will be replaced. Patients who are tolerating PTX-35 will 
not have to discontinue study treatment prematurely due to the occurrence of DLTs in 
another patient in the same cohort, unless decided by the SRC. 
 
6.1.4 Maximum Tolerated Dose and Optimal Immunological Dose 
The MTD will be defined as the highest dose level at which ≤ 1 patient of at least 6 patients 
experienced a DLT during the first two treatment cycles. The OID will be defined as the dose 
level where increasing doses of PTX-35 do not result in increases in Treg activity (i.e., a 
plateau of Treg activity is observed). If the OID is reached prior to the MTD, further dose 
escalations may be discontinued by decision of the SRC. 
 
6.2 
Dose Interruptions/Withholding  
Investigational Product may be withheld from a patient based on the Investigator‘s decision 
in the event of intercurrent illness, adverse event, administrative reasons, or other reasons. 
If the patient‘s condition subsequently improves, or the situation that resulted in withholding 
study drug rectifies itself, the Investigator may resume study treatment as soon as possible, 
unless the delay is more than 4 weeks. 
 
Dosing should be delayed for any DLT-equivalent toxicity and possible CTCAE > Grade 2 
adverse events considered related to study medication. At the Investigator’s discretion, study 
treatment may recommence when the toxicity has resolved to Grade 2 or less. Immune 
related reactions or allergy should resolve to ≤ Grade 1. 
 
Treatment should be discontinued if a TEAE has not resolved (to acceptable grade) after 
≤ 4 weeks. 
 
6.3 
Dose Modification and Management of Immune-Related Adverse Events, 
Infusion Reactions, and Cytokine Release Syndrome 
One level dose reduction per the dose escalation scheme, for toxicity is allowed. If the toxicity 
is equivalent to a DLT (see Section 6.1.3) then continued treatment at a lower dose level 
needs approval by the sponsor and/or SRC. 
 
If immune related adverse events occur, these should be managed according to the 
ASCO2018 guideline for immune checkpoint inhibitors10, and therapy should be continued 
with close monitoring for Grade 1 toxicities, with the exception of some neurologic, 
hematologic, and cardiac toxicities. For Grade 2 toxicities, corticosteroids may be 
administered, and dose should be held until resolution of the AE. Grade 3-4 toxicities 
treatment with PTX-35 should be discontinued and treatment with high-dose corticosteroids 
initiated. 


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All patients should be observed for infusion-related reactions (e.g., back pain, fever and/or 
shaking chills, flushing and/or itching, alterations in heart rate and blood pressure, dyspnea 
or chest discomfort, skin rashes, or anaphylaxis).  For Grade 1-2 reactions, the infusion 
should be temporarily interrupted and then resumed when symptoms are resolved. If 
symptoms have not resolved in 15 minutes treatment with acetaminophen and/or 
antihistamines may be administered per institutional standard at the discretion of the 
investigator. Premedication prior to subsequent doses is allowed and should be considered. 
Grade 3 or 4 infusion related reactions should be managed per institutional standards 
(e.g., IM epinephrine, followed by IV diphenhydramine and ranitidine, and IV glucocorticoid), 
and treatment with PTX-35 should be permanently discontinued. 
 
Cytokine release syndrome (CRS) is associated with elevated circulating levels of several 
cytokines including interleukin (IL)-6 and interferon γ, and uncontrolled studies demonstrate 
that immunosuppression using tocilizumab, an anti-IL-6 receptor antibody, with or without 
corticosteroids, can reverse the syndrome. However, because early and aggressive 
immunosuppression could limit the efficacy of the immunotherapy, current approaches seek 
to limit administration of immunosuppressive therapy to patients at risk for life-threatening 
consequences of the syndrome. The treatment algorithm suggested by Lee et al11 outlined 
in Figure 4 should be used to manage such reactions. 
 
 
Figure 4: Current concepts in the diagnosis and management of cytokine release 
syndrome 


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6.4 
Concomitant Treatment  
Patients must not receive any other concurrent anti-cancer therapy, including investigational 
agents while on study treatment.  
 
Unexpected serious adverse reactions, including for example severe allergic reactions, may 
be treated according to standard-of-care and institutional practice without limitations, 
including antihistamines, corticosteroids, cytokine antagonists, antipyretics and analgesics.  
 
While on treatment in the study, use of the type of medications specified below should be 
avoided. PTX-35 will be temporarily stopped for the period of time these medications are 
used.  
 
• 
Immunosuppressive agents (i.e., methotrexate, azathioprine, and TNFα blockers), 
except to treat a PTX-35-related adverse event  
• 
Systemic corticosteroids > 10 mg daily prednisone equivalent  
 
Ocular, intra-articular, intranasal, and inhalational corticosteroids are allowed. 
 
For patients with bone metastases requiring medication for treatment and/or prevention of 
skeletal-related events bisphosphonates are permissible but RANK-ligand inhibitors, such as 
Denosumab are prohibited throughout the trial. 
 
Supportive treatment may include anti-emetic, anti-diarrheal, anti-pyretic, anti-histamines, 
analgesics, antibiotics, and blood products. At the discretion of the treating physician, 
patients may receive anti-histamine prophylaxis according to the standard of care in clinical 
practice. 
 
6.5 
Monitoring Patient Compliance 
This study will be monitored by Pelican Therapeutics or its designee according to ICH E6 
guidelines of GCP. The study site monitor will regularly visit the study sites to ensure that the 
study is conducted according to the protocol and GCP principles. 
 
 
7.0 
STUDY EVALUATIONS 
 
7.1 
Schedule of Assessments 
Study visit and assessment schedule are summarized in Table 2 and described in Sections 7.2 
through 7.6.


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Table 2: Schedule of Assessments 
Study procedures 
Pre-
Treatment 
Study Treatment 
Follow-Up 
Cycle 1 
Cycle 2 
Cycle ≥3 
D1 
30-Day 
Safety 
Follow-Up 
Post-
Treatment 
Follow-Up 
(q8 wks) 
Survival 
Follow-Up  
(q12 wks) 
D1 
D2  
D4 
D7 
D10 
 
D1 
D2  
D4 
D7 
D10 
 
Informed consent 
×a 
  
  
  
  
   
  
  
  
  
   
  
  
  
  
Medical history 
×a 
  
  
  
  
  
  
  
  
  
   
  
  
  
  
Physical exam 
×a 
×c 
  
  
  
  
× 
  
  
  
  
× 
× 
  
  
Weight 
×a 
×c 
  
  
  
  
× 
  
  
  
   
× 
× 
  
  
Vital signs 
×a 
×d 
  
  
  
  
×d 
  
  
  
   
×d 
× 
  
  
ECOG performance status 
×b 
×c 
  
  
  
  
× 
  
  
  
   
× 
× 
  
  
ECGe 
×a 
×c 
  
  
  
   
× 
  
  
  
   
× 
  
  
  
Tumor measurementf 
×a 
Every 8 weeks (± 1 week) from C1D1 until PD or change in cancer treatment 
N/A  
Hematologyg 
×b 
×c 
  
  
  
  
× 
  
  
  
  
× 
× 
  
  
Serum chemistryh 
×b 
×c 
  
  
  
   
× 
  
  
  
   
× 
× 
  
  
Pregnancy test i 
×b 
  
  
  
  
  
  
  
  
  
   
  
  
  
  
Confirmation of eligibility 
× 
× 
  
  
  
  
  
  
  
  
  
  
  
  
  
PTX-35 administrationj 
  
× 
  
  
  
  
× 
  
  
  
   
× 
  
  
  
TENIVAC administration 
  
× 
  
  
  
   
  
  
  
  
  
  
  
  
  
Blood sample for HLAk 
  
× 
  
  
  
  
  
  
  
  
  
  
  
  
  
Blood sample for PKl 
  
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
×l 
  
  
  
Blood sample for cytokines 
  
×m 
  
  
  
  
×m 
  
  
  
   
×m 
  
  
  
Blood sample for ATA and 
anti-TENIVAC titer n 
  
× 
  
  
  
   
× 
  
  
  
   
× 
× 
  
  
Blood sample for 
immunological effecto 
  
× 
  
  
× 
  
× 
  
  
× 
   
  
× 
  
  
Prior/concomitant medications 
review 
×a 
× 
× 
× 
× 
× 
× 
×  
 × 
×  
×  
× 
× 
×p 
×p 
Adverse Event assessment 
  
× 
× 
× 
× 
×  
× 
×  
×  
×  
×   
× 
× 
×q 
×q 
Survival Status 
  
  
  
  
  
   
  
  
  
  
   
  
  
  
×r 
 


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Footnotes to Schedule of Assessments 
a. Within 28 days prior to study treatment initiation. 
b. Within 7 days prior to study treatment initiation. 
c. If performed within 3 days of Cycle 1 Day 1, these tests do not need to be repeated unless clinically indicated. 
d. Vital signs, including blood pressure, heart rate, respiration rate, and temperature. During Cycle 1 and 2: prior to PTX-35 administration 
and at 30 min (±5 min) and 1h (±5 min) after end of PTX-35 infusion. Other cycles: only prior to PTX-35 administration.  
e. 12-lead ECGs (in triplicate) to be performed with patient in a semi-recumbent position at screening and on Day 1 of each cycle prior to PTX-35 
administration. 
f. 
Tumor measurement per RECIST 1.1. Baseline tumor assessment should be performed within 28 days prior to study treatment 
initiation. Patients will be evaluated every 8 weeks (±1 week) from C1D1 until disease progression, regardless of dose delays. 
g. Hematology, including hemoglobin, WBC with differential, and platelet count (Approximately 5 mL blood per draw).  
h. Serum chemistry including: sodium, potassium, chloride, CO2, BUN, creatinine, glucose, calcium, albumin, total protein, total bilirubin, 
AST, ALT, alkaline phosphatase, TSH (Approximately 5 mL blood per draw).  
i. 
For women of childbearing potential only, a negative serum or urine β-hCG must be documented within 7 days prior to first dose of 
PTX-35. 
j. 
PTX-35 is administered as an IV infusion. Each patient must remain in clinic for a 6-hour safety observation period after the end of the 
PTX-35 infusion unless the SRC reduces the required observation period. 
k. HLA sample will be collected pre-dose at Cycle 1 only. 
l. 
PK samples will be collected at the following timepoints: pre-dose; 30min (±5min), 2hr (±5min), 4hr (±5min), 24hr (±2hr), 72hr (±2hr), 
144hr (±2hr), 216hr (±2hr) after end of PTX-35 infusion for Cycles 1 and 2, and pre-dose at Cycle 3 only. 
m. Cytokine blood sample collection at the following timepoints during Cycle 1 and 2: prior to PTX-35 administration and at 2 hr (+5min) 
after end of PTX-35 infusion. Collection at cycle 3 and beyond is only required if the patient is symptomatic (i.e., flu-like or allergic 
reactions) prior to PTX-35 infusion and at 2 hr (+5min) after end of PTX-35 infusion.  
n. Pre-dose blood sample collection to monitor development of anti-therapeutic antibodies (ATA) and anti-TENIVAC antibody titer. 
o. Blood sample collection for immunological effect; Day 1 (prior to PTX-35 administration) and Day 7 for Cycle 1 and Cycle 2, and 30-Day 
Safety Follow-Up only.  
p. In post-treatment and survival follow-up, concomitant medications limited to subsequent anti-cancer therapy. 
q. If > 30 days since last dose, only record AEs if deemed related to Investigational Product 
r. 
Survival status and subsequent anti-cancer therapy information will be collected approximately every 12 weeks in a clinic visit or by 
telephone/electronic communication, from the time of disease progression or initiation of new anti-cancer treatment until death.  


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7.2 
Pre-treatment 
Within 28 days from C1D1: 
• 
Sign written informed consent 
• 
Medical history including prior cancer treatments, prior surgeries (requiring an 
overnight hospitalization), and pre-existing clinical signs and symptoms 
• 
Record prior medications (taken within 30 days of C1D1) 
• 
Complete physical exam 
• 
Weight 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) 
• 
ECG (a standard 12-lead ECG in triplicate, approximately 2 to 5 minutes apart) is 
taken while patient is in a semi-recumbent position) 
• 
Imaging for tumor measurements by RECIST 1.1 (APPENDIX II) 
• 
Confirmation of eligibility 
 
Within 7 days from C1D1: 
• 
ECOG performance status (APPENDIX I) 
• 
Blood draw for hematology 
• 
Blood draw for serum chemistry  
• 
Pregnancy test for women of childbearing potential 
 
7.3 
During Treatment 
7.3.1 Day 1 of Cycle 1 
• 
Eligibility must be re-verified before dosing on Day 1 
• 
Physical exam (may be done within 3 days prior) 
• 
Weight (may be done within 3 days prior) 
• 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature) at 3 
timepoints: pre-dose, at 30 min (±5 min), and at 1hr (±5 min) after end of PTX-35 
infusion 
• 
ECG (a standard 12-lead ECG in triplicate, approximately 2 to 5 minutes apart) taken 
while patient is in a semi-recumbent position (may be done within 3 days prior) 
• 
ECOG performance status (may be done within 3 days prior)  
• 
Blood draw for hematology (may be done within 3 days prior) 
• 
Blood draw for serum chemistry tests (may be done within 3 days prior) 
• 
Blood sample for pharmacokinetics at 4 timepoints: pre-dose; 30min (±5 min), 2hr 
(±5 min) and 4hr (±5 min) after end of PTX-35 infusion 
• 
Blood sample for cytokines at 2 timepoints: pre-dose, and 2hr (± 5 minutes) after 
end of PTX-35 infusion 
• 
Blood sample for anti-therapeutic antibodies (ATA) and anti-TENIVAC antibody titer 
(pre-dose) 
• 
Blood sample for immunological effect (pre-dose) 


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• 
Blood sample for HLA (pre-dose) 
• 
PTX-35 administration and observation period 
• 
TENIVAC administration 
• 
Concomitant medications review 
• 
Adverse event assessment 
 
7.3.2 Days 2, 4, 7, and 10 of Cycle 1 and Cycle 2 
• 
Blood sample for pharmacokinetics at the following post-dose time points: 
Day 2 - 24hr (±2hr), Day 4 – 72hr (±2hr), Day 7 – 144hr (±2hr) and Day 10 – 216hr 
(±2hr) 
• 
Blood sample for immunological effect (Day 7 only) 
• 
Concomitant medications review 
• 
Adverse event assessment 
 
7.3.3 Day 1 of Cycle 2 (+ 2 days) 
• 
Physical exam  
• 
Weight  
• 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature): pre-dose; 
30 min (±5 min) and 1hr (±5 min) after end of PTX-35 infusion 
• 
ECG (a standard 12-lead ECG in triplicate (approximately 2 to 5 minutes apart) taken 
while patient is in a semi-recumbent position 
• 
ECOG Performance status  
• 
Blood draw for hematology 
• 
Blood draw for serum chemistry tests 
• 
Blood sample for pharmacokinetics at 4 timepoints: pre-dose; 30min (±5 min), 2hr 
(±5 min) and 4hr (±5 min) after end of PTX-35 infusion 
• 
Blood sample for cytokines at 2 time points: pre-dose and 2hr (±5 min) after end of 
PTX-35 infusion 
• 
Blood sample for anti-therapeutic antibodies (ATA) and anti-TENIVAC antibody titer 
(pre-dose) 
• 
Blood sample for immunological effect (pre-dose) 
• 
PTX-35 administration and observation period 
• 
Concomitant medications review 
• 
Adverse event assessment 
 
7.3.4 Day 1 of Cycle 3 and Beyond (+ 2 days) 
• 
Physical exam  
• 
Weight  
• 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature): prior to 
PTX-35 infusion 


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• 
ECG (a standard 12-lead ECG in triplicate, approximately 2 to 5 minutes apart) taken 
while patient is in a semi-recumbent position 
• 
ECOG Performance status  
• 
Blood draw for hematology 
• 
Blood draw for serum chemistry tests 
• 
Blood draw for pharmacokinetics (C3D1 pre-dose only) 
• 
Blood sample for cytokines (ONLY IF PATIENT IS SYMPTOMATIC) at 2 time points: 
pre-dose and 2hr (±5 min) after end of PTX-35 infusion 
• 
Blood sample for anti-therapeutic antibodies (ATA) and anti-TENIVAC antibody titer 
(pre-dose) 
• 
PTX-35 administration and observation period 
• 
Concomitant medications review 
• 
Adverse event assessment 
• 
Imaging for tumor measurements by RECIST 1.1 via CT scans or MRI (every 8 weeks 
± 1 week from C1D1 until disease progression)  
 
7.4 
30-Day Safety Follow up Visit  
The following assessments will be performed at 30 days ± 3 days of the last administration 
of PTX-35 for all patients who are off study treatment: 
 
• 
Physical exam  
• 
Weight  
• 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature)  
• 
ECOG Performance status  
• 
Blood draw for hematology 
• 
Blood draw for serum chemistry tests 
• 
Blood draw for immunological effect 
• 
Blood sample for anti-therapeutic antibodies (ATA) and anti-TENIVAC antibody titer 
• 
Concomitant medications review 
• 
Adverse event assessment 
 
7.5 
Post-Treatment Follow-Up 
Any patient that stops treatment (or starts new anti-cancer treatment) for any reason other 
than progressive disease will enter the Post-Treatment Follow-Up period, which refers to the 
time between last dose of PTX-35 and disease progression.  The following assessments will 
be performed every 8 weeks from the date of last scan (±1 week) during the Post-Treatment 
Follow-Up period: 
 
• 
Imaging for RECIST 1.1 tumor measurements via CT scan or MRI every 8 weeks (±1 
week) 
• 
Concomitant medications review, limited to subsequent anti-cancer therapy 


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• 
Adverse event assessment (only if deemed related to PTX-35) 
 
7.6 
Survival Follow-up 
The Survival Follow-Up period refers to the time between disease progression (or initiation 
of anti-cancer treatment) and patient death. Survival status and subsequent anti-cancer 
therapy will be collected approximately every 12 weeks in a clinic visit, or by 
telephone/electronic communication. Patients who withdraw consent for study procedures 
should still be followed for survival and/or public records searched as per FDA guidance 
issued October 2008 entitled “Guidance for Sponsors, Clinical Investigators, and IRBs: Data 
Retention When Subjects Withdraw from FDA-Regulated Clinical Trials”. 
 
8.0 
STUDY ASSESSMENTS 
8.1 
Safety Assessments 
8.1.1 Safety Analysis 
Safety data will be summarized for the safety evaluable population. These data will include 
Treatment emergent adverse events (TEAEs) and laboratory parameters.  Adverse event 
terms will be coded using the most current version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA).  
 
8.1.2 Reporting of Adverse Events 
8.1.2.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily have 
a causal relationship with the treatment.  An adverse event can be any unfavorable and 
unintended sign (including a laboratory finding), symptom or disease temporally associated 
with the use of an Investigational Product, whether or not related to the Investigational 
Product.  
 
The AE reporting period starts on Cycle 1 Day 1 after the first dose of PTX-35. If an AE occurs 
before the first dose of study drug it will be captured as baseline and considered part of 
medical history unless it directly related to a study procedure (in which case it may be 
reported as an AE).  At each evaluation, patients should be interviewed in a non-directed 
manner to elicit potential adverse reactions from the patient. The occurrence of an adverse 
event will be based on changes in the patient’s physical examination, laboratory results, 
and/or signs and symptoms. 
 


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All adverse events (except Grade 1 and 2 laboratory abnormalities that do not require an 
intervention), regardless of causal relationship, are to be recorded in the case report form 
and source documentation.  The Investigator must determine the intensity of any adverse 
events according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0 and their causal relationship. Those AEs not covered by these criteria will be 
graded as follows:  
1. 
Mild: Discomfort noticed, but no disruption of normal daily activity. Prescription drug 
not ordinarily needed for relief of symptom but may be given because of personality 
of patient. 
2. 
Moderate: Discomfort sufficient to reduce or affect normal daily activity. Patient is 
able to continue in study; treatment for symptom may be needed. 
3. 
Severe: Incapacitating, severe discomfort with inability to work or to perform normal 
daily activity. Severity may cause cessation of treatment with test drug; treatment for 
symptom may be given and/or patient hospitalized. 
4. 
Life-Threatening: Symptom(s) place the patient at immediate risk of death from the 
reaction as it occurred; it does not include a reaction that, had it occurred in a more 
serious from, might have caused death. 
5.  
Fatal: Event caused the death of the patient.  
Adverse events will be followed until resolution or stabilization while the patient remains on-
study.  Once the patient is removed from study, events thought to be related to the 
Investigational Product will be followed until resolution or stabilization, unless, in the 
Investigator’s opinion the event is unlikely to resolve due to the patient’s underlying disease, 
or until the patient starts a new treatment regimen or the patient is lost to follow-up. 
 
8.1.2.2 Attribution Definitions 
An adverse event is considered to be associated with the use of the Investigational Product 
if the attribution is determined as possible or definite. Attribution of AEs will be recorded in 
the CRF as: 
 
• 
Unrelated: The AE is clearly not related to the study treatment. 
• 
Possible: The AE may be related to the study treatment. 
• 
Definite: The AE is clearly related to the study treatment. 
 


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8.1.2.3 Definition of an Unexpected Adverse Event 
An unexpected adverse event is defined as any adverse drug experience, the specificity or 
severity of which is not consistent with the current Investigator Brochure; or, if an 
Investigator Brochure is not required or available, the specificity or severity of which is not 
consistent with the risk information described in this protocol or in the regulatory agency 
study authorization application.   
 
Unexpected, as used in this definition, refers to an adverse drug experience that has not 
been previously observed (e.g., included in the Investigator’s Brochure) rather than from the 
perspective of such experience not being anticipated from the pharmacological properties 
of the pharmaceutical product. 
 
8.1.2.4 Serious Adverse Event (SAE) 
A serious adverse event is defined as any untoward medical occurrence that at any dose: 
1. 
Results in death, 
2. 
Is life-threatening (i.e., the patient was at risk of death at the time of the event. It does 
not refer to an event which hypothetically might have caused death if it was more 
severe), 
3. 
Requires in-patient hospitalization or prolongation of existing hospitalization 
excluding that for pain management, disease staging/re-staging procedures, or 
catheter placement unless associated with other serious events, 
4. 
Results in persistent or significant disability/incapacity, or 
5. 
Is a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based on appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Disease Progression, or death as a result of disease progression, are not considered to be 
SAEs. However, if the progression of the underlying disease is greater than what would 
normally be expected as part of the natural course of the disease under study for the patient, 
or if the Investigator considers that there was a causal relationship between treatment with 
study drug or protocol design/procedures and the disease progression, then it must be 
reported as an SAE.  
 


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8.1.2.5 Pregnancy 
Any pregnancy detected during the study, or that occurs within 30 days after stopping study 
medication, must be reported immediately to the Investigator. Pregnancy, in and of itself, is 
not regarded as an adverse event, unless there is suspicion that study medication may have 
interfered with the effectiveness of a contraceptive medication. If the patient becomes 
pregnant while on-study, the study drug should be immediately discontinued. Pregnancy 
information about a female patient or a female partner of a male patient should be reported 
immediately from the time the Investigator first becomes aware of a pregnancy or its 
outcome. This will be performed by the Investigator per instructions from the Sponsor or its 
designee.  
 
Any pregnancy complication, spontaneous abortion, elective termination of a pregnancy for 
medical reasons, outcome of stillbirth, congenital anomaly/birth defect, or serious adverse 
event in the mother will be recorded as an SAE and will be reported as described in 
Section 8.1.2.6.  
 
8.1.2.6 Reporting of Serious Adverse Events 
Adverse events classified as serious require expeditious handling and reporting to Sponsor 
or its designee to comply with regulatory requirements. 
 
For any serious adverse event (SAE) that occurs while a patient is on-study; within 30 days of 
the last study drug administration, regardless of any opinion as to the relationship of the SAE 
to the study drug; or if any SAE that the Investigator feels is related to the study drug occurs 
later than 30 days after the last study drug administration, the Sponsor or its designee must 
be notified immediately (within 24 hours of becoming aware of the event). 
 
8.1.2.7 Safety Data Review 
8.1.2.7.1 Safety Review Committee 
A Safety Review Committee (SRC) comprised of at least three members – one Investigator, a 
representative from Pelican Therapeutics and the Medical Monitor will evaluate the data 
obtained at each dose level including a review of all adverse events (serious and non-serious 
adverse events) as they are reported by the study site. The SRC will recommend whether the 
dose should be escalated as per protocol, revised to a lower level or intermediate level, 
halted altogether or more patients are required at the same dose level to evaluate safety.  
 
Ad-hoc SRC meetings may be called for by both the SRC and Sponsor any time during the 
study if DLTs are observed and/or new safety data warrants immediate action to the conduct 
of the trial (including events defined by the Study Stopping Criteria in Section 5.5). 
 


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The conclusion of the SRC meeting will be documented in meeting minutes. The outcome of 
the SRC meeting will be communicated to all Investigators. 
 
8.2 
Efficacy Assessments 
Patient’s disease status will be monitored by clinical and radiological assessment (CT scans 
or MRI) as per RECIST 1.1 criteria where applicable. Patient response per RECIST 1.1 will be 
evaluated as complete response, partial response, stable disease, or progressive disease. 
 
For the purpose of this study, patients will be evaluated after every 8 weeks ± 1-week from 
C1D1, regardless of any delays in treatment cycles. In the event objective response (PR or 
CR) is noted, changes in tumor measurements must be confirmed by repeat assessments 
that should be performed at least 4 weeks after the criteria for response are first met. For 
stable disease (SD), follow-up measurements must meet the SD criteria at least 6 weeks after 
study entry.  
 
8.2.1 RECIST 1.1 Criteria 
Response and progression will be evaluated in this study using the international criteria 
(version 1.1) proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) 
Committee12 (see APPENDIX II).  
 
Immune response may be a delayed effect, and in immuno-oncology, treatment beyond first 
progression is commonly used in situations where clinical progression is asymptomatic 
and/or is not likely to result in life-threatening complications with further progression. 
Therefore, at the discretion of the Investigator the treatment with PTX-35 may continue 
despite evidence of radiologic disease progression, and in the absence of clinical 
deterioration, if the investigator considers this of a potential clinical benefit for the patient, 
and if the following terms are met: i) no decline in performance status, ii) absence of rapid 
disease progression or threat to vital organs or critical anatomical sites (e.g., CNS metastasis, 
respiratory failure due to tumor compression, spinal cord compression) requiring urgent 
alternative medical intervention, and iii) no significant, unacceptable or irreversible toxicities 
related to study treatment. 
 
8.3 
Pharmacokinetics  
Plasma concentrations of PTX-35 will be measured by ELISA at the following timepoints: 
pre-dose; 30min (±5min), 2hr (±5min), 4hr (±5min), 24hr (±2hr), 72hr (±2hr), 144hr (±2hr), 
and 216hr (±2hr) after end of PTX-35 infusion for Cycles 1 and 2, and pre-dose at Cycle 3 
only. An approximate 1 mL sample will be collected for each timepoint. 
 


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8.4 
Analysis of Immunological Effect 
Immune-phenotyping of patient’s peripheral blood sample will be performed by flow 
cytometry, which may include but is not limited to surface and intracellular markers that 
define naïve T cells (CD4 and CD8), central memory T cells (CD4 and CD8), effector T cells 
(CD4 and CD8), memory T cells (CD4 and CD8),  senescent T cells (cytotoxic and helper), 
terminal differentiated senescent T cells (cytotoxic and helper), natural killer (NK) cells, 
natural killer T cells (NKT), T regulatory cells, proliferative T regulatory cells, activated T cells 
(helper and cytotoxic), proliferative T cells (helper and cytotoxic), T cell markers of exhaustion 
(helper and cytotoxic; CTLA-4, PD-1, TIGIT, TIM3).  
 
Immune phenotype profiling to determine proportions of NK and T cell subsets for levels of 
antigen activation, memory and exhaustion will be performed from blood samples 
(approximately 23 mL) collected on Day 1 (prior to PTX-35 administration) and Day 7 for Cycle 
1 and Cycle 2, and at the 30-Day Safety Follow-Up visit.  
 
8.5 
Analysis of Immunogenicity 
Approximately 2 mL of blood samples will be drawn for central analysis of anti-therapeutic 
antibodies (ATA), at the following time-points: 
• 
All Cycles (pre-dose) 
• 
30-Day Safety Follow-Up Visit 
 
Samples testing positive in the screening assay will undergo a confirmatory assay to 
demonstrate that the ATAs are specific for the therapeutic protein product. Samples 
identified as positive in the confirmatory assay will be further characterized in titration and 
neutralization assays. 
 
8.6 
Analysis of response to TENIVAC immunization 
Blood samples collected for immunogenicity will also be used for central analysis of tetanus 
antibodies, at the following time-points: 
• 
All Cycles (pre-dose) 
• 
30-Day Safety Follow-Up Visit 
 
8.7 
Cytokine Analysis 
Approximately 2 mL of blood samples will be collected at the following time-points during 
Day 1 of Cycle 1 and Cycle 2 for determination of serum cytokines (e.g., IL-2, IL-4, IL-6, IL-8, 
IL-10, IL-12, IL-17, IL-22, TNF-α, TGF-β, IFN-γ and TL1A). 
• 
Day 1: Pre-dose 
• 
Day 1: 2hr ± 5 minutes from end of PTX-35 infusion 
 


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For Cycle 3 and beyond cytokine testing will only be performed if the patient is 
symptomatic at the time of visit (i.e., flu-like symptoms, fever, or allergic reactions).  
 
9.0 
 STATISTICS 
Demographic data and disease-related characteristics will be summarized using descriptive 
statistics.  Categorical variables will be summarized with incidence and percent. Continuous 
variables will be summarized with n, mean, median, standard deviation and range (minimum 
and maximum) as appropriate. Data will be presented by each dose cohort. All patient data 
will be presented in data listings.   
 
9.1 
Analysis Populations 
Safety Evaluable Population:  All patients who received at least 1 dose of PTX-35. 
 
DLT Evaluable Population:  All patients who receive at least 1 dose of PTX-35 and experience 
a DLT and/or complete the DLT evaluation period. 
 
Efficacy Evaluable Population: All patients with pre-treatment measurable disease by RECIST 
1.1, who received at least 1 dose of PTX-35 and who had at least one radiological assessment 
during treatment. 
 
9.2 
Endpoints 
9.2.1 Primary 
• 
Number of Dose-limiting toxicities (DLTs) per NCI CTCAE v5.0. 
• 
Frequency of treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs) related to PTX-35 during the trial. 
 
9.2.2 Secondary  
• 
Optimal Immunological Dose (OID; dose where T-reg plateau is observed) or 
Maximum tolerated dose (MTD; highest dose level at which ≤ 1 patient of at least 6 
patients experienced a DLT during the first two treatment cycles). 
• 
Pharmacokinetic parameters will include maximum concentration (Cmax), area under 
curve up to the last measurable concentration (AUClast), trough observed serum 
concentration (Ctrough) and terminal elimination half-life (T1/2λz).  
 


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9.2.3 Exploratory 
Immune phenotype profiling of immune cell subsets will be conducted by flow cytometry in 
peripheral blood at various time-points to assess change from baseline in:  
• 
Percentage of Treg cells (immunological effect) 
• 
Frequency of anti-therapeutic antibody (ATA) titers to PTX-35 (Immunogenicity) 
• 
General immunologic expansion: The frequency and expansion of NK, CD4 and CD8 
T cell subsets  
• 
Specific antigen driven immune expansion: immune responses to a well-
characterized first-time exposure or recall antigen based on the patient’s HLA type 
will be measured at baseline and on study using ELISA, ELISPOT and flow cytometric 
methods. 
• 
Specific cytokine expression in response to treatment with PTX-35. 
Clinical benefit will be evaluated where possible for: 
• 
Best Overall Response, Overall Survival and Progression-Free Survival assessed by 
RECIST 1.1. 
 
9.3 
Safety 
Safety will be assessed throughout the study by means of physical examination, weight, vital 
signs, ECOG performance status, laboratory evaluations (hematology, biochemistry and 
cytokines), electrocardiogram (ECG), and recording of concurrent illness/therapy and 
treatment-emergent adverse events. CTCAE version 5.0 will be used to grade all toxicities. All 
related adverse events will be monitored until resolution or permanent outcome. 
Concomitant medications will be recorded throughout the study.  
 
Cytokines will be monitored during cycle 1 and 2. Patients will also be monitored for any 
clinical symptoms associated with elevated cytokine levels. Cytokines will only be monitored 
at cycle 3 and beyond if patient is symptomatic (i.e., flu-like symptoms, fever, or allergic 
reactions). 
 
Safety data will be summarized for the safety evaluable population. These data will include 
Treatment emergent adverse events (TEAEs) and laboratory parameters.  Adverse event 
terms will be coded using the most current version of Medical Dictionary for Drug Regulatory 
Activities (MedDRA).  
 
9.4 
Efficacy 
Assessment of tumor response will be performed every 8 weeks (± 1 week) from C1D1 until 
disease progression according to RECIST 1.1 (APPENDIX II). Best overall response (BOR), 
Overall Survival (OS) and Progression-Free Survival (PFS) will be determined for each patient. 
 


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9.5 
Pharmacokinetics 
Plasma concentrations of PTX-35 will be measured by ELISA at the following timepoints at 
Cycle 1 and 2: pre-dose, and 30min (±5min), 2hr (±5min), 4hr (±5min), 24hr (±2hr), 72hr (±2hr), 
144hr (±2hr), and 216hr (±2hr) after end of PTX-35 infusion. Plasma concentrations of PTX-
35 will also be measured at the following timepoint for Cycle 3: pre-dose. 
 
Non-compartmental or population pharmacokinetic methods will be used to derive PTX-35 
PK parameters, which will be summarized using descriptive statistics (mean, standard 
deviation, median, maximum, minimum).  
 
9.6 
Immunogenicity 
Blood samples will be drawn for central analysis of anti-therapeutic antibodies (ATA), which 
will be collected pre-dose on Day 1 of each cycle and at the 30-day follow up visit. Samples 
testing positive in the screening assay will undergo a confirmatory assay to demonstrate that 
the ATAs are specific for the therapeutic protein product. Samples identified as positive in 
the confirmatory assay will be further characterized in titration and neutralization assays. 
 
9.7 
General and Specific Antigen Immune Expansion 
Blood samples will be drawn to determine each patient’s HLA type (collected pre-dose 
Cycle 1 Day 1) for exclusive use in determining the patients primary or recall response to 
the TENIVAC vaccine.  Blood samples will also be collected pre-dose on Day 1 of each cycle 
and at the 30-Day Safety Follow-Up visit to measure anti-TENIVAC antibody titer (TDAR). 
Blood samples will also be collected pre-dose on Day 1 and Day 7 of Cycles 1 and 2 as well 
as at the 30-Day Safety Follow-Up visit to measure the general and antigen reactive 
expansion and activity of NK and T cell subsets. 
 
9.8 
Sample Size 
This is an exploratory trial and therefore no sample size calculations have been performed. 
The target number of patients (22 - 34 patients) is based on the planned number of dose 
escalation cohorts required to identify the OID or MTD. Based on response observed in 
patients at different dose levels and/or in patients with a particular tumor type, the study 
protocol may be amended to allow for cohort expansion of patients with specific 
characteristics.   
 


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10.0 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
10.1 Monitoring of the Study and Regulatory Compliance 
The Sponsor, or designee, will make an initiation site visit to each institution to review the 
protocol and its requirements with the Investigator(s), inspect the drug storage area, fully 
inform the Investigator of his/her responsibilities and the procedures for assuring adequate 
and correct documentation. During the initiation site visit the case report forms (CRFs) will 
be reviewed. Other pertinent study materials will also be reviewed with the Investigator’s 
research staff.  During the course of the study, the monitor will make regular site visits in 
order to review protocol compliance, examine CRFs and individual patient’s medical records 
and assure that the study is being conducted according to pertinent regulatory 
requirements. All CRF entries will be verified with source documentation.  The review of 
medical records will be done in a manner to assure that patient confidentiality is maintained.  
 
10.2 Curricula Vitae and Financial Disclosure of Investigators  
All Principal Investigators will be required to provide a current signed and dated curriculum 
vitae, a completed FDA Form 1572 and a financial disclosure statement to Sponsor or its 
designee. All Sub-Investigators will be required to provide a current curriculum vitae and a 
financial disclosure statement to Sponsor or its designee. 
 
10.3 Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval 
of the Sponsor or the Sponsor’s representative. Any such changes which may affect a 
patient’s treatment or informed consent, especially those increasing potential risks, must 
receive prior approval by the IRB/EC. The exception to this is where modifications are 
necessary to eliminate an immediate hazard to trial subjects, or when the change involves 
only logistical or administrative aspects of the trial (e.g., change in monitor, change in 
telephone number). Other administrative revisions which may impact the clinical portion of 
a study will be duly reported to the IRB/EC by the Principal Investigator. 
 
10.4 Publication Policy 
The publication of the results of the study will be subject to the terms and conditions of the 
clinical trial agreement between the Sponsor and Investigators. Sponsor approval is required 
for publication of any data from this trial.  
 


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11.0 ETHICAL CONSIDERATIONS 
11.1 Informed Consent 
The Investigator will obtain written informed consent from each patient, or their authorized 
representative, participating in the study. The form must be signed, witnessed, and dated. 
The informed consent form will contain all the Essential Elements of Informed Consent set 
forth in 21 CFR, Part 50, the European Union Directive 2001/20/EC and its associated Detailed 
Guidances, European Union GCP Directive 2005/28/EC, the ICH Guideline for Good Clinical 
Practice, Section 4.8, and the terms of the Declaration of Helsinki (2013). Copies of the signed 
document should be given to the patient and filed in the Investigator’s study file, as well as 
the patient’s medical record if in conformance with the institution’s Standard Operating 
Procedures.  
 
11.2 Institutional Review Board/Ethics Committee 
The study will not be initiated without approval of the appropriate Institutional Review 
Board/ Ethics Committee (IRB/EC) and compliance with all administrative requirements of 
the governing body of the institution. This protocol, consent procedures, and any 
amendments must be approved by the IRB/EC in compliance with current regulations of the 
FDA and the European Union as applicable and in accordance with ICH/GCPs. A letter of 
approval will be sent to the Sponsor prior to initiation of the study and when any subsequent 
modifications are made. The IRB/EC will be kept informed by the Investigator, Sponsor, or its 
designee, as required by national regulations, as to the progress of the study as well as to 
any serious and unexpected adverse events.  
 
11.3 Patient Privacy  
In order to maintain patient confidentiality, all case report forms, study reports and 
communications relating to the study will identify patients by initials and assigned patient 
numbers; patients should not be identified by name.  In accordance with local, national, or 
federal regulations, the Investigator will allow the Sponsor or designee personnel access to 
all pertinent medical records in order to verify the data gathered on the case report forms 
and to audit the data collection process. Regulatory agencies such as the US Food and Drug 
Administration (FDA) may also request access to all study records, including source 
documentation for inspection. Clinical information will not be released without the written 
permission of the patient as outlined in the patient consent form. 
 


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12.0 DATA HANDLING AND RECORD KEEPING 
 
12.1 Recording of Data 
Data collected during the study will be entered in the patient’s Case Report Form (CRF) by 
the investigational site staff. The staff will keep records of the patient’s visit in the files 
considered as source documents for the site, e.g., hospital chart, research chart. The 
Investigator will be responsible for the recording of all data on the CRF and for submitting 
the data to the Sponsor or their designee in a timely manner. Should any value be 
significantly different from normal, the Investigator will comment in the appropriate sections 
provided in the CRF.  
 
The Investigator will provide access to his/her original records to permit a representative 
from the Sponsor to verify the proper transcription of data. To facilitate photocopying, 
entries must be recorded legibly in black ink only. Erroneous entries will be crossed out with 
a single line, so as to remain legible.  The correct value will be entered above the error and 
then initialed and dated by the person authorized to make the correction. 
 
12.2 Study Records 
U.S. Federal laws require that an Investigator maintain all study records for the indication 
under investigation for two years following the date a Product Licensing Application is 
approved or, if no application is to be filed or if the application is not approved for such 
indication, until two years after the investigation is discontinued and the FDA is notified. 
 
 


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13.0 REFERENCES 
1.  
Smith-Garvin JE, Koretzky GA, Jordan MS. T Cell Activation. Annu Rev Immunol. 
2009;27(1):591-619. doi:10.1146/annurev.immunol.021908.132706 
2.  
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. 
Nat Rev Immunol. 2013;13(4):227-242. doi:10.1038/nri3405 
3.  
Schreiber TH, Wolf D, Tsai MS, et al. Therapeutic Treg expansion in mice by TNFRSF25 
prevents allergic lung inflammation. J Clin Invest. 2010;120(10):3629-3640. 
doi:10.1172/JCI42933 
4.  
Slebioda TJ, Rowley TF, Ferdinand JR, et al. Triggering of TNFRSF25 promotes CD8+ T-
cell responses and anti-tumor immunity. Eur J Immunol. 2011;41(9):2606-2611. 
doi:10.1002/eji.201141477 
5.  
Melero I, Hirschhorn-Cymerman D, Morales-Kastresana A, Sanmamed MF, Wolchok 
JD. Agonist antibodies to TNFR molecules that costimulate T and NK cells. Clin Cancer 
Res. 2013;19(5):1044-1053. doi:10.1158/1078-0432.CCR-12-2065 
6.  
Segal NH, Logan TF, Hodi FS, et al. Results from an integrated safety analysis of 
urelumab, an agonist anti-CD137 monoclonal antibody. Clin Cancer Res. 
2017;23(8):1929-1936. doi:10.1158/1078-0432.CCR-16-1272 
7.  
Segal NH, He AR, Doi T, et al. Phase i study of single-agent utomilumab (PF-
05082566), a 4-1bb/cd137 agonist, in patients with advanced cancer. Clin Cancer Res. 
2018;24(8):1816-1823. doi:10.1158/1078-0432.CCR-17-1922 
8.  
Papp KA, Gooderham MJ, Girard G, Raman M, Strout V. Phase I randomized study of 
KHK4083, an anti-OX40 monoclonal antibody, in patients with mild to moderate 
plaque psoriasis. J Eur Acad Dermatology Venereol. 2017;31(8):1324-1332. 
doi:10.1111/jdv.14313 
9.  
Burris HA, Infante JR, Ansell SM, et al. Safety and Activity of Varlilumab, a Novel and 
First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors. J 
Clin Oncol. 2017;35(18):2028-2036. doi:10.1200/JCO.2016.70.1508 
10.  
Brahmer JR, Lacchetti C, Schneider BJ, et al. irAE_guideline_JCliOnc2018. J Clin Oncol. 
2018;36(17):JCO.2017.77.638. doi:10.1200/JCO.2017.77.6385 
11.  
Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and 
management of cytokine release syndrome. Blood. 2014;124(2):188-195. 
doi:10.1182/blood-2014-05-552729 
12.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
doi:10.1016/j.ejca.2008.10.026 


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APPENDIX I  - ECOG Performance Status 
 
 
 
       Grade 
 
 
 
0 
 
Fully active, able to carry on all pre-disease performance without 
restriction. 
 
 
1 
 
Restricted in physically strenuous activity but ambulatory and 
able to carry out work of a light or sedentary nature, e.g., light 
housework, office work. 
 
 
2 
 
Ambulatory and capable of all self-care but unable to carry out 
any work activities.  Up and about more than 50% of waking 
hours. 
 
 
3 
 
Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
 
 
4 
 
Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
 
 
5 
 
Dead. 
 
 
 
 
 


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APPENDIX II  - Tumor Measurement Based on RECIST 1.1 Criteria 
See the international criteria proposed by the Response Evaluation Criteria in Solid Tumors 
(RECIST) Committee, version 1.112 for additional details on RECIST 1.1. 
 
Measurable disease will be defined as the presence of at least one measurable lesion that 
can be accurately measured in at least one dimension with the longest diameter a minimum 
size of: 
• 
>10mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 
10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
 
For malignant lymph nodes to be considered pathologically enlarged and measurable, a 
lymph node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5mm). At baseline and in follow-up, only the short axis 
will be measured and followed.   
 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with ≥10 to <15 mm short axis) as well as truly non-measurable lesions, will be 
considered 
non-measurable. 
Lesions 
considered 
truly 
non-measurable 
include: 
leptomeningeal disease; ascites; pleural/pericardial effusion; inflammatory breast disease; 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical exam that is not measurable by reproducible imaging techniques. 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
All baseline evaluations should be performed as close as possible to the treatment start and 
never more than 4 weeks before the beginning of the treatment. The same method of 
assessment and the same technique should be used to characterize each identified and 
reported lesion at baseline and during follow-up.  Imaging based evaluation should always 
be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. Clinical lesions will only be considered 
measurable when they are superficial and ≥10 mm diameter as assessed using calipers (e.g., 
skin nodules). For the case of skin lesions, documentation by color photography including a 
ruler to estimate the size of the lesions is recommended. 
 
Baseline Documentation of Target and Non-Target Lesions 
All measurable lesions up to a maximum of 5 lesions total (and a maximum of two lesions 
per organ) representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. 
 


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Target lesions should be selected on the basis of their size (lesions with the longer diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements.  
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes 
are to be included in the sum, only the short axis is added into the sum.  The baseline sum 
diameters will be used as reference to further characterize the objective tumor response of 
the measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified 
as non-target lesions and should also be recorded at baseline. Measurements are not 
required, and these lesions should be followed as “present” or “absent”, or in rare cases 
“unequivocal progression”.   
 
Evaluation of Target Lesions using RECIST 1.1 Criteria 
NOTE: In addition to the information below, also see section 4.3.2 in the international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee, version 
1.112 for special notes on the assessment of target lesions.  
 
Complete response (CR) − Disappearance of all target lesions.  Any pathological lymph node 
(LN) (whether target or non-target) must have decreased in short axis to <10mm. 
 
Partial response (PR) − At least a 30% decrease in the sum of the LD of the target lesions 
taking as reference the baseline sum LD. 
 
Progressive Disease (PD) − At least a 20% increase in the sum of the LD of the target lesions 
taking as reference the smallest sum LD recorded since the treatment started including 
baseline if that is the smallest on study.  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5mm.  The appearance of one or 
more new lesions also constitutes PD. 
 
Stable disease (SD) − Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as references the smallest sum LD since the treatment started. 
 
Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
Complete response (CR) − Disappearance of all non-target lesions and normalization of 
tumor marker levels.  All LN must be non-pathological in size (< 10mm short axis).   
 
Non-complete response (non-CR)/non-progression (non-PD) − Persistence of one or more 
non-target lesion(s) or/and maintenance of tumor marker level above the normal limits. 


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Progressive disease (PD) − Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
Evaluation of Best Overall Response using RECIST 1.1 Criteria 
The best overall response is the best response recorded from the start of the study 
treatment until the end of treatment provided the confirmation criteria are met. To be 
assigned a status of PR or CR, changes in tumor measurements must be confirmed by repeat 
studies that should be performed > 4 weeks after the criteria for response are first met. If a 
CR/PR cannot be confirmed the original "response" should be considered stable disease. The 
best overall response will be defined according to the following table: 
 
Overall 
Response 
First Time 
Point 
Overall 
Response 
Subsequent 
Time Point 
BEST Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PR1 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
CR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
PR 
NE2 
SD provided minimum criteria for SD duration met, otherwise, 
NE2 
NE 
NE2 
NE2 
1 If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, makes the disease PD at that point (since disease must have 
reappeared after CR).  Best response would depend on whether minimum duration for SD was met.  
However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions were likely still 
present and in fact the patient had PR, not CR at the first time point.  Under these circumstances, the 
original CR should be changed to PR and the best response is PR.  
 
2 NE=unevaluable  
 
 


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APPENDIX III - Summary of Changes from Previous Versions 
Changes from Protocol v2.1 
Section # and Title 
Page(s) # 
Description 
5.1 Inclusion Criteria; 
Synopsis 
8, 27 
• Continuous abstinence included in addition to 
contraception for participants of child-bearing 
potential 
6.1.1.1 PTX-35 
30 
• Clarification that patient weight from screening 
should be used for all visit dose calculations (unless 
there is a 10% weight change from screening 
requiring recalculation), or unless institutional 
policy dictates otherwise. 
6.1.3 Dose-Limiting 
Toxicity; Synopsis 
9, 33 
• Updated DLT definition to exclude Grade 3 
lymphopenia 
7.0 Study Evaluations  
37-41 
• Corrections made to Table 2 (Schedule of 
Assessments) and list of study visit procedures to 
address inconsistencies and clarify required 
evaluations. 
Table 2, Schedule of 
Assessments Footnote ‘R’;  
7.6 Survival Follow-Up 
38, 41 
• Added electronic communications as a method of 
contact for survival follow up. 
8.4 Analysis of 
Immunological Effect; 8.5 
Analysis of 
Immunogenicity;  
8.6 Analysis of Response 
to TENIVAC immunization;  
8.7 Cytokine Analysis 
45-46 
• Minor clarification of blood sample collection 
requirements. 
• Revised cytokine 2hr post-dose collection timepoint 
to 2hr ±5 minutes from end of PTX-35 infusion, for 
consistency and clarity. 
Various throughout 
Various 
• Revised all timepoint references of PTX-35 “post-
dose” to “after end of PTX-35 infusion” for clarity. 
Various throughout 
Various 
• Minor formatting changes 
 
Changes from Protocol v2.0 
Section # and Title 
Page(s) # 
Description 
Synopsis 
7 – 9 
• Verbiage updated to match protocol body; the 
synopsis was erroneously not updated in Protocol 
v2.0. 
• Exclusion criteria renumbered to start with #1. 
Title Page and 1.3 Medical 
Monitor 
1, 15 
• Added name and contact information of Medical 
Monitor. 
4.2 Trial Design and 6.1.2 
Dose Escalation Scheme 
26, 33 
• 28 days changed to 4 weeks. 
• 2 weeks changed to 14 days. 


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6.1.1.1 PTX-35 
32 
• Clarification added to avoid confusion between the 
0.7 mL priming volume associated with the infusion 
set, and the 1.0 mL priming volume required in the 
Investigational Product Manual. 
7.2 Pre-Treatment 
40 
• Added detail regarding collection of medical history 
and prior medications. 
7.3.4 Day 1 of Cycle 3 and 
Beyond 
41 
• Removed the minus two (-2) day option for visit 
window schedule to ensure that a cycle will not be 
shorter than 14 days. 
Appendix III 
58 
• Added Summary of Changes from previous 
version. 
Throughout- Various 
Throughout 
• Removal of the word ‘chemokine’ and associated 
list of cytokines for consistency throughout 
document. 
 
Changes from Protocol v3.0 
Section # and Title 
Page(s) # 
Description 
Title Page and 1.3 Medical 
Monitor 
1, 17 
• Medical Monitor changed from Vance Sohn, MD to 
Alan Epstein, MD, JD, MBA, SM 
Investigators and Study 
Centers 
6 
• Added Rachel Sanborn, MD and study centers in 
Austin and Portland 
Study Overview 
7 
• Updated to reflect total of 7 dose levels and added 
cohorts 6 and 7 to table 
Target Number of Patients 
8 
• Updated number of patients from 15 to 30 to 22 to 
34 
4.2 Overview of Trial 
Design 
29 
• Updated to reflect total of 7 dose levels 
6.1.1.1 PTX-35 
35 
• Updated from dose levels 4 and 5 to dose levels 4 
through 7 and clarified to permit Investigator to 
shorten observation period after first treatment 
cycle 
6.1.2 Dose Escalation 
Scheme 
36, 37 
• Updated to reflect total of 7 dose levels and added 
cohorts 6 and 7 to table and clarified dose stagger 
after first patient only 
7.1 Table 2  
44 
• Footnote l 30-minute pk time point corrected time 
window from ± 2 minutes to ± 5 minutes 
8.3 Pharmacokinetics 
52 
• Corrected 30-minute pk time point window from ± 2 
minutes to ± 5 minutes 
9.5 Pharmacokinetics 
55 
• Corrected 30-minute pk time point window from ± 2 
minutes to ± 5 minutes 
9.8 Sample Size 
56 
• Updated sample size from 15 to 30 to 22 to 34