Clinical trial NCT04645797
Conditions: Advanced Colorectal Carcinoma
Sponsor: Apros Therapeutics, Inc
Start date: 2021-01-19; Completion date: 2022-05-07
Enrollment: 11 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
A Phase 1 dose escalation study to evaluate APR003 in patients with advanced colorectal cancer (CRC) with malignant liver lesions

Detailed description:
APR003 is a small molecule TLR7 agonist that concentrates in the GI, and liver with limited systemic exposure. It is designed to increase the therapeutic window of a TLR7 agonist by minimizing the side-effects associated with generalized systemic immune activation and inflammation.

Arms: arm 1: This portion of the study will evaluate the safety and pharmacokinetics of a range of APR003 doses administered once a week for 21 days in subjects with advance colorectal cancer (CRC) with metastases to the liver and to determine the RP2D.
Interventions: intervention 1: APR003
Intervention descriptions: intervention 1: This portion of the study further explores the clinical activity, safety, pharmacokinetics and pharmacology of APR003 monotherapy at the RP2D and to assess the antitumor activity of APR003 in subjects with unresectable CRC with liver metastases.

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol 
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Page 1 of 143 
1.0 
Title Page 
Protocol Number:  
APR003-001 
Title: 
A Phase 1 dose escalation study to evaluate safety, tolerability, 
and pharmacokinetics/pharmacodynamics of APR003 in 
patients with advanced colorectal cancer (CRC) with malignant 
liver lesions 
Sponsor: 
Apros Therapeutics, Inc. 
10210 Campus Point Drive, Suite 150 
San Diego, CA 92121 
USA 
Investigational Product: 
APR003 
Phase: 
1 
Protocol Version and Date: 
1.0, 03 August 2020 
2.0, 16 November 2020 
3.0, 28 January 2022 
GCP Statement: 
This study is to be performed in full compliance with the 
protocol, ICH E6 R(2) Guideline on Good Clinical Practice 
(GCP), and relevant regulatory authority guidance and 
regulations. 
Confidentiality: 
This document is confidential, it contains proprietary 
information of Apros Therapeutics, Inc. Any viewing or 
disclosure of such information that is not authorized in writing 
by the Sponsor is strictly prohibited. Such information may be 
used solely for the purpose of reviewing or performing this 
study.


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SPONSOR SIGNATURE 
Protocol Title: 
A Phase 1 dose escalation study to evaluate safety, tolerability, and 
pharmacokinetics/pharmacodynamics of APR003 in patients with 
advanced colorectal cancer (CRC) with malignant liver lesions 
Protocol Number: 
APR003-001 
This protocol version 3.0 has been reviewed and approved by the Sponsor 
Ron Weitzman M.D. 
Chief Medical Officer 
Date 
28 January 2022
Aaron Weitzman (Dec 14, 2023 17:38 PST)


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date 
Protocol V3.0, Amendment 2 
28 January 2022 
Protocol V2.0, Amendment 1 
16 November 2020 
Original Protocol V1.0 
03 August 2020 
Amendment 3.0, 28 January 2022 
Overall Rationale for the Amendment: 
The Sponsor has introduced the following modifications to protocol V3.0 (Amendment 2); these 
changes are from V2.0 (Amendment 1) and are presented in order of appearance:  
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Section 9.1.3 Direction for 
APR003 Administration 
Section 9.1.3.1 
Premedications 
Appendix 1 Schedule of 
Evaluations 
Add guidance on allowed 
premedication with acetaminophen 
and diphenhydramine 
Safety Measure: such explicit 
guidance will ensure that all patients 
received appropriate premedication 
to minimize the risk of severe 
cytokine release syndrome (CRS) 
and provide clear instructions on 
dose modifications following such 
events 
Section 5.4.3 Clinical 
Experience  
Section 5.4.3.1 Toxicity of 
TLR Therapies  
Section 5.4.3.2 Risk 
Assessment  
Updated Clinical Experience with 
APR003 and other agents in the 
therapeutic class 
Safety Measure: ensure greater 
understanding and knowledge of the 
risk associated with this class of 
therapeutic 


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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Section 6.1 Primary 
Objective and Endpoints 
Section 7.1.1 Dose 
Limiting Toxicities 
(DLTs) 
Endpoint and DLT definition 
updated to included American 
Society for Transplantation and 
Cellular Therapy (ASTCT) grading 
for CRS and immune effector cell-
associated neurotoxicity syndrome 
(ICANS) 
Safety measure: CRS events will be 
reported using more current and 
widely used grading criteria. 
Synopsis 
Section 7.1 Phase 1 
(Dose escalation) 
Section 9.1.3 Directions 
for APR003 
Administration 
Section 12.1.2 Vital 
Signs 
Appendix 1 
Monitoring for CRS for a minimum 
of 6 hours post-dose for the first 
cycle.  If CRS is not observed 
during the first cycle, monitoring is 
not necessary on Day 1 of 
subsequent cycles 
Safety measure: to require 
monitoring for CRS to ensure 
proper monitoring of patients 
during the first and subsequent 
cycles at the discretion of the 
investigator 
Section 9.1.4 APR003 
Dose Modifications and 
Interruptions 
Table 6 and Table 7 
Appendix 1 
Given the potential that a patient 
who undergoes a prolonged 
APR003 treatment interruption may 
experience CRS upon retreatment 
with study drug, patients 
experiencing an APR003 dose 
interruption of greater than or equal 
to 21 consecutive days for any 
reason, should have their safety 
monitoring follow that of Cycle 1 
Day 1 schedule upon retreatment 
with APR003. Thus, as is the case 
in Cycle 1 for new enrollment, 
patients who missed 21 or more 
consecutive days of APR003 
treatment will be monitored for 
CRS with vital signs performed 
every 2 hours for a minimum of 6 
hours post-dose for the first 
resumed cycle.  If CRS is not 
observed during this resumed 
Safety measure to ensure restarting 
of CRS monitoring after a drug 
interruption of 21 consecutive or 
more days upon restarting of 
APR003. 


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Section # and Name 
Description of Change 
Brief Rationale 
dosing cycle, prolonged monitoring 
is not necessary on Day 1 of 
subsequent cycles.  
 
If, however, a patient requires an 
APR003 dose interruption of > 21 
consecutive days due to treatment-
related toxicities, then the patient 
should be discontinued from 
treatment unless otherwise specified 
based on specific toxicities as 
defined in Table 6. 
 
Section 10 Concomitant 
medications 
 
Clarify reporting duration for 
concomitant medication 
Included guidance on the current 
tocilizumab shortage 
Safety Measure: ensure more 
accurate collection of concomitant 
medication data. Make sites aware of 
the current tocilizumab shortage. 
Section 10.1 Permitted 
Concomitant Therapy 
Section 10.1.4 Infection 
Prophylaxis 
Section 10.1.5 Empiric 
Antibiotics 
Section 10.1.6 Blood 
Product Support  
Section 10.1.7 Medication 
for Cytokine Release 
Syndrome (CRS) 
Section 10.1.8 Fever 
Antipyretic Therapy 
Section 10.1.9 Medication 
for Immune Effector Cell 
associated Neurologic 
Syndrome (ICANS) 
Section 10.1.10 
Medication for 
Updated to include additional 
permitted therapy 
Safety Measure: provides explicit 
guidance which medications may 
be/should be used in the setting of 
different adverse events such as 
CRS, or infection. 


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Section # and Name 
Description of Change 
Brief Rationale 
Hemophagocytic 
Lymphohistiocytosis 
(HLH)/ Macrophage 
Activation Syndrome 
(MAS) 
Section 10.1.11 Surgery 
Section 10.1.12 Other 
Concomitant Medications 
to Control Side Effects  
Section 12.1.2 Vital Signs  
Appendix 1 Schedule of 
Evaluations  
Updated vital signs to include 
respiratory rate and oxygen 
saturation; increase frequency for 
monitoring as clinically indicated  
Safety Measure: ensure that all 
patients per protocol will be more 
closely followed for emergence of 
CRS 
Appendix 10 ASTCT 
Grading for Cytokine 
Release Syndrome  
Added  
Safety Measure 
Appendix 11 ACTCT 
Grading of ICANS 
Added 
Safety Measure 
Appendix 12 Immune-
Effector Cell Toxicity 
Assessment and 
Management  
Added 
Safety Measure 
 


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2.0 
Synopsis 
Trial No 
APR003-001 
Title of Study 
A Phase 1 dose escalation study to evaluate safety, tolerability, and 
pharmacokinetics/pharmacodynamics of APR003 in patients with advanced 
colorectal cancer (CRC) with malignant liver lesions 
Sponsor 
Apros Therapeutics, Inc. 
Study Phase 
Phase 1 
Study Sites 
Multiple centers in the United States (US).  
Indications & Study 
Population 
Advanced, unresectable colorectal cancer (CRC) with metastases to the liver. 
Objectives & 
Corresponding 
Endpoints 
Primary Objectives 
To evaluate the safety and tolerability of single-agent APR003 and to establish 
the Recommended Phase 2 Dose (RP2D). Corresponding endpoints include: 
• 
Incidence and nature of Dose Limiting Toxicities (DLTs) 
• 
Incidence, nature, and severity of adverse events graded according to 
NCI CTCAE v5. American Society for Transplantation and Cellular 
Therapy (ASTCT) Grading will be utilized for cytokine release 
syndrome (CRS) (Appendix 10) and immune effector cell-associated 
neurotoxicity syndrome (ICANS) (Appendix 11). 
To characterize the pharmacokinetics (PK) of APR003. Corresponding 
endpoints may include, but are not limited to, the following PK parameters: 
• 
Area under the curve (AUC) from time zero to time t (AUC0-t) 
• 
AUC from time zero to time infinity (AUC0-ꝏ) 
• 
AUC over the dosing interval (AUCtau) 
• 
Maximum concentration (Cmax) 
• 
Time-to-maximum concentration (Tmax) 
• 
Elimination half-life (T1/2) 
• 
Apparent volume of distribution at steady state after administration 
(Vss/F) 
• 
Apparent total plasma clearance (CL/F) 






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(i.e., Cycle 1) and that meets at least one of the non-hematologic or 
hematologic criteria below: 
Non-Hematologic DLT: 
Any ≥ Grade 3 non-hematologic toxicity according to the Common Toxicity 
Criteria for Adverse Events Version 5 (CTCAE v5) except for the following: 
• 
Grade 3 nausea, vomiting, or diarrhea lasting ≤ 72 hrs will not be 
considered a DLT 
• 
Grade 3 fatigue lasting ≤ 7 days 
• 
Grade 3 chills lasting ≤ 72 hrs 
• 
Grade 3 allergic or hypersensitivity reactions lasting ≤ 24 hrs 
• 
Grade 3 increases in total bilirubin of any duration in patients with 
Gilbert’s Syndrome. (Note: Grade 4 increases in bilirubin of any 
duration and in any patient regardless of Gilbert’s Syndrome, will 
constitute a DLT) 
• 
Grade 3 increases in liver transaminases lasting < 7 days (Note: Grade 
3 increases in liver transaminases with concurrent Grade 2 increases in 
bilirubin of any duration, consistent with Hy’s Law, will constitute a 
DLT)  
• 
Any Grade 4 increase in liver transaminases  
• 
Grade 3 or 4 clinical laboratory abnormalities that are reversible to 
≤ Grade 1 or baseline status within 72 hrs that do not require 
continuous monitoring, or that are considered not clinically significant 
by the Principal Investigator 
Hematologic DLT: 
• 
Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5 x 109/L] 
• 
Grade 3 neutropenia (ANC  < 1.0 x 109/L) lasting > 14 days 
• 
≥ Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with a fever 
≥ 38.3ºC) 
• 
Grade 4 thrombocytopenia (< 25.0 x 109/L)  
• 
≥ Grade 3 thrombocytopenia associated with clinically significant 
bleeding 
• 
Any hematologic toxicity resulting in death (i.e. Grade 5) 
In addition, any other AE that is felt to be treatment-limiting in the medical 
opinions of the Principal Investigator and the Sponsor’s Medical Monitor may 
be considered a DLT. 
Treatment of the first 3 patients in each dose level cohort will be staggered 
such that consecutive patients will initiate treatment at least 2 days apart.  
Upon selection of the RP2D, all patients who remain on treatment may have 
the option to be dose modified to receive the RP2D. Intra-patient dose 


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escalation to the RP2D may be permitted for patients who (1) have not 
experienced a DLT, (2) have not experienced any treatment-related Grade 3 or 
higher AEs and (3) following approval from the Sponsor Medical Monitor. 
Similarly, patients whose dose is above the RP2D may be dose reduced to the 
RP2D following approval from the Sponsor Medical Monitor. All patients 
must have completed at least 3 treatment cycles and have had at least 1 post-
baseline tumor evaluation prior to dose modification. 
The RP2D of APR003 monotherapy may be selected based on one or more of 
the following: (1) the maximum tolerated dose (MTD), which is defined as the 
highest dose level in which the rate of DLTs is <33% in 6 patients, (2) 
maximum administered dose (MAD), defined as the highest dose level tested 
in the study if no MTD is identified, (3) anti-tumor, PK and/or PDx results, 
and/or (4) the occurrence, nature and severity of toxicities occurring after 
Cycle 1. The RP2D will not exceed the MTD. 
Treatment and Long-Term Follow-Up Periods 
During the Treatment Period, APR003 will be administered orally (po) once 
weekly in 21-day cycles. Patients will be monitored for CRS with vital signs 
performed every 2 hours for a minimum of 6 hours post-dose for the first 
cycle.  If CRS is not observed during the first cycle, monitoring is not 
necessary on Day 1 of subsequent cycles. Patients will be evaluated in the 
clinic according to the schedule described in Appendix 1. Patients will be 
permitted to continue on treatment for up to 1 year, or until an early 
discontinuation event, or the sponsor decides to terminate the study, whichever 
occurs first. Reasons for early discontinuation include but are not limited to; 
disease progression (PD), unacceptable toxicity, death, Investigator decision, 
significant protocol violation, patient noncompliance, or withdrawal of 
consent. Due to the potential for pseudoprogression and/or delayed response, 
patients with an initial assessment of PD by RECIST v1.1., should, whenever 
possible, continue on study treatment until disease progression is 
radiologically confirmed. Confirmation of PD is defined as radiographic 
demonstration of progressive disease in two consecutive imaging evaluations 
performed 4-8 weeks apart.  
Upon treatment discontinuation and after the End of Treatment (EOT) visit, 
patients will enter the Long-Term Follow-Up (LTFU) period and be followed 
for disease progression and survival for up to 1 year. 
Evaluation Committees 
The Safety Review Committee (SRC) will review and evaluate the safety of 
APR003 throughout the study. The SRC is comprised of the Sponsor Medical 
Monitor and Principal Investigator from each participating site. The SRC will 


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review and discuss all key safety data and determine whether enrollment into 
the next higher dose level cohort may proceed. 
Number of Patients 
~12-36 patients are planned for this trial.  
Eligibility Criteria 
Inclusion Criteria 
1. Histopathological diagnosis of advanced, unresectable CRC with 
malignant liver lesions.  
2. Age ≥ 18 years at the time of consent. 
3. Patient must have disease that is considered non-surgically resectable. 
4. Patient must have disease that is relapsed or persistent/refractory to at least 
two prior systemic treatment regimens for locally advanced or metastatic 
disease considered to be standard-of-care (SOC). Patients who were 
previously not considered candidates for intensive treatment, who have not 
received SOC agents due to contraindications, and/or who have had <2 
lines of therapy may be eligible with clear documentation and approval 
from the Sponsor Medical Monitor. Specific requirements are outlined 
below: 
a. Patients must have previously received an irinotecan or 
oxaliplatin-based therapy, as well as a targeted antibody therapy 
for metastatic disease 
b. Patients whose tumors are MSI-H/dMMR must have previously 
received checkpoint inhibitor therapy 
5. Has at least 1 malignant lesion that is considered to be measurable 
according to RECIST v1.1 criteria. The lesion site must be measured 
accurately in at least one dimension (longest diameter in the plane of 
measurement to be recorded) with a minimum size of: 
a. 10 mm by CT scan  
b. 10 mm by caliper measurement 
c. 20 mm by chest X-ray 
d. Malignant lymph nodes must be ≥ 15 mm in short axis when 
assessed by CT scan 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1.  
7. Life expectancy of > 3 months. 
8. Adequate organ and marrow function within 14 days of planned treatment 
initiation on Cycle 1 Day 1 (C1D1), as defined below: 


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a. Absolute neutrophil count (ANC) ≥ 1,500 cells/μL. Patients must 
not have received growth factors (e.g., G-CSF) within 14 days of 
Screening. 
b. Platelet count ≥ 100,000/μL. Patients must not have received 
platelet transfusions within 14 days of Screening. 
c. Hemoglobin ≥ 8 g/dL. Patients must not have received pRBC 
transfusions within 28 days of Screening.  
d. Total and direct serum bilirubin ≤ 1.5x upper limit of normal 
(ULN). For patients with Gilbert’s Syndrome, total serum bilirubin 
must be ≤ 3x ULN. 
e. AST and ALT ≤ 3x ULN 
f. Serum albumin >3 g/dL.   
g. Prothrombin time (PT) and activated partial thromboplastin time 
(aPTT) ≤ 1.5x ULN. This applies only to patients who are not 
receiving therapeutic anticoagulation. Patients receiving 
therapeutic anticoagulation (e.g., low molecular weight heparin or 
warfarin) should be on a stable dose. 
h. Serum creatinine ≤ 1.5x ULN, or creatinine clearance (CrCl) 
≥ 60 mL/min based on the Cockcroft-Gault formula.  
9. Resolution of all treatment-related toxicities, except alopecia, anemia, and 
peripheral neuropathy, from any previous cancer therapy to ≤ Grade 1 at 
Screening. Patients with ongoing Grade 2 alopecia, anemia and/or 
peripheral neuropathy are eligible. 
10. Female patients must have a negative serum or urine pregnancy test within 
72 hours of Cycle 1 Day 1. Post-menopausal females (> 45 years old and 
without menses for > 1 year) and surgically sterilized females are exempt 
from these requirements. 
11. Patients must agree to use adequate birth control methods from the time of 
informed consent and for up to 6 months following treatment 
discontinuation. 
a. Sexually active females of child-bearing potential must agree to 
use two methods of birth control that includes at least one barrier.  
b. Sexually active males must agree to use an acceptable barrier 
method of birth control.  
c. For patients who are not sexually active: at the discretion of the 
Principal Investigator, sexual abstinence may be considered to be 
an acceptable method of contraception. The Principal Investigator 
should consider the reliability of sexual abstinence in relation to 
the patient’s usual lifestyle. Periodic abstinence (e.g., calendar, 
post-ovulation symptothermal methods, etc.) is not considered to 
be an acceptable method of contraception. 


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12. Willing and able to provide informed consent and to comply with the 
study protocol, in the Investigator’s judgment. 
 
Exclusion Criteria 
1. Chemotherapy, or other systemic small molecule therapy for the treatment 
of the primary malignancy, within 5 half-lives of Cycle 1 Day 1. 
2. Radiation therapy, immunotherapy, or other biological therapy (e.g., 
monoclonal antibodies) within 28 days prior to Cycle 1 Day 1. 
3. Treatment with an unapproved investigational agent or device within 28 
days (or 5 half-lives for small molecule agents) prior to Cycle 1 Day 1. 
4. Presence of clinically significant malignant ascites. 
5. Has a primary immunodeficiency diagnosis (e.g., X-linked 
agammaglobulinemia, common variable immunodeficiency, severe 
combined immunodeficiency, acquired immune deficiency syndrome, 
etc.). 
6. Is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 28 days prior Screening. Intranasal and 
inhaled corticosteroids, or systemic corticosteroids at physiological doses 
(≤ 10 mg/day of prednisone, or an equivalent corticosteroid) are permitted. 
7. Known hypersensitivity to APR003 excipients.  
8. Any other current or previous malignancy within the past three years 
EXCEPT a) adequately treated basal cell or squamous cell skin cancer, b) 
carcinoma in situ of the cervix, c) prostate cancer with stable prostate 
specific antigen (PSA) levels for 3 years, d) or other neoplasm that, in the 
opinion of the Principal Investigator and with the agreement of the 
Sponsor’s Medical Monitor, will not interfere with study-specific 
endpoints. 
9. Current or history of central nervous system (CNS) metastases. 
10. Patients with malignant lesions within the immediate proximity of the 
biliary tract and who, in the opinion of the Principal Investigator, are at 
risk of biliary obstruction. 
11. Active autoimmune disease requiring systemic steroid treatment (e.g., 
disease modifying anti-rheumatic agent, corticosteroids, or other 
immunosuppressive drugs). Physiologic hormone/steroid replacement 


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therapy (e.g., thyroxine, glucocorticoids for treatment of adrenal 
insufficiency) is permitted. 
12. Patients who are unable to receive medication per os (po), or who have 
refractory nausea and/or vomiting, uncontrolled diarrhea, malabsorption 
(e.g., Crohn’s disease, ulcerative colitis, etc.), significant small bowl 
resection or gastric bypass surgery, or other situation that may preclude 
adequate absorption. 
13. Major surgery within 28 days prior to Cycle 1 Day 1. 
14. Active infection requiring parenteral antibiotics, antivirals, or antifungals 
within 14 days of Cycle 1 Day 1. Patients with infections requiring only 
oral antibiotics may be considered following approval by the Sponsor 
Medical Monitor.  
15. Cardiac abnormalities including: 
a. Symptomatic ischemia 
b. Uncontrolled or clinically significant conduction abnormalities (e.g., 
ventricular tachycardia on antiarrhythmics, unstable atrial fibrillation) 
are excluded from enrollment. 1st degree AV block or asymptomatic 
LAFB/RBBB may be eligible for enrollment 
c. Corrected QT interval using Fridericia’s method (QTcF) > 480 ms, 
family history of Long QT syndrome, heart failure, hypokalemia, or 
other risk factor for Torsades de pointes 
d. Myocardial infarction in the previous six months 
e. Congestive heart failure (New York Heart Association class III to IV) 
16. Patients who are pregnant, lactating or breastfeeding. 
17. Patients who are known to have HIV infection/ seropositivity. 
18. Patients with active Hepatitis virus infection (include Hepatitis A, B, 
and/or C). Patients with positive Hepatitis B surface antigen (HBsAg) with 
detected Hepatitis B virus (HBV) DNA or positive Hepatitis C antibody 
with detected Hepatitis C virus (HCV) RNA are excluded. 
19. Patients with active CMV infection/reactivation. 
20. Prior liver or other organ transplantation. 


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21. Patients who are receiving treatment with medications that are prohibited 
on study that cannot be discontinued prior to study entry and that are 
considered to be any of the following: 
a. 
Other antineoplastic agents 
b. 
Patients receiving concomitant medications that prolong the QT/QTc 
interval (Appendix 8 in the protocol) are excluded unless such agents 
can be discontinued prior to the initiation of study therapy.  
22. Allergy to meat products or gelatin. 
23. Known psychiatric disorders, substance abuse, or other medical conditions 
that would interfere study compliance or interpretation of study results, or 
that would make the patient inappropriate for entry into the study. 
Study Treatments 
All patients will be treated with APR003, an orally administered agonist of 
TLR7. APR003 will be administered once weekly, on an empty stomach 
(patients must not eat for at least 2 hours before and 1 hour after study drug 
administration). 
Premedication with acetaminophen and diphenhydramine is allowed per 
discretion of the investigator. 
Statistical Methods 
It is anticipated that between ~12-36 patients will be enrolled into this trial.  
Safety Analyses: 
All patients who receive at least one dose of APR003 will be included in the 
safety population. All safety analyses will be performed on the safety 
population.  Adverse Events (AE) will be coded according to the MedDRA 
version 22.1 adverse event dictionary. Results will be tabulated to examine AE 
frequency, organ systems affected, and relationship to study treatment. The 
results of clinically significant laboratory test changes will be evaluated 
similarly. Safety data will be examined on an ongoing basis to ensure safety of 
the study patients and compliance with the trial rules. 
Adverse events leading to dose modifications (i.e., dose reduction, dose 
delayed or dose not administered), as well as AEs leading to treatment 
discontinuation will be summarized and listed. 
Patients who discontinue prior to receiving at least 3 doses of APR003 in 
Cycle 1 for reasons other than a DLT will not be considered evaluable for 
DLTs or the MTD assessment and will be replaced. 




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3.0 
Table of Contents 
1.0 
Title Page .................................................................................. 1 
2.0 
Synopsis .................................................................................... 7 
3.0 
Table of Contents .................................................................. 18 
4.0 
List of Abbreviations and Definitions of Terms ................. 23 
5.0 
Introduction ........................................................................... 27 
5.1 
Background Information on the Disease to be Treated ........................... 27 
5.1.1 
Colorectal Cancer (CRC) ........................................................................ 27 
5.2 
Role of the Immune System and the Liver .............................................. 27 
5.3 
Immune Agonism and Toll-like Receptors (TLRs) ................................. 28 
5.4 
Background Information on the Investigational Product (APR003) ....... 29 
5.4.1 
Non-clinical Experience .......................................................................... 30 
5.4.2 
Selection of the Starting Dose ................................................................. 34 
5.4.3 
Clinical Experience ................................................................................. 34 
5.5 
Program Development ............................................................................. 45 
6.0 
Study Objectives .................................................................... 46 
6.1 
Primary Objectives and Endpoints .......................................................... 46 
6.2 
Secondary Objectives and Endpoints ...................................................... 46 
6.3 
Exploratory Objectives and Endpoints .................................................... 47 
7.0 
Study Design & Plan ............................................................. 47 
7.1 
Phase 1 (Dose escalation) ........................................................................ 48 
7.1.1 
Dose-Limiting Toxicities (DLTs) ............................................................ 48 
7.1.2 
Selection of the Recommended Phase 2 Dose ........................................ 50 
7.1.3 
Intra-patient Dose Modifications ............................................................. 50 
7.2 
Patient Replacement ................................................................................ 50 
7.3 
Evaluation Committees ........................................................................... 50 
7.4 
Study Design Rationale ........................................................................... 51 
7.5 
Early Study Termination ......................................................................... 51 
8.0 
Patient Population and Study Eligibility Criteria .............. 52 
8.1 
Inclusion Criteria ..................................................................................... 52 
8.2 
Exclusion Criteria .................................................................................... 54 
8.3 
Patient Numbering and Treatment Assignment ...................................... 56 


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8.3.1 
Method of Assigning Patients to Treatment Groups ............................... 56 
8.3.2 
Treatment Assignment ............................................................................. 56 
9.0 
Study Treatments .................................................................. 57 
9.1 
Treatments Administered ........................................................................ 57 
9.1.1 
APR003 Description ................................................................................ 57 
9.1.2 
Storage and Labeling ............................................................................... 57 
9.1.3 
Directions for APR003 Administration ................................................... 57 
9.1.4 
APR003 Dose Modifications and Interruptions ...................................... 59 
9.1.5 
APR003 Treatment Compliance .............................................................. 66 
9.1.6 
Investigational Product Accountability ................................................... 66 
9.1.7 
APR003 Disposal and Destruction .......................................................... 66 
9.2 
Warnings and Precautions ....................................................................... 66 
9.2.1 
Elevations in Transaminases and/or Bilirubin ......................................... 67 
9.2.2 
Gastrointestinal Adverse Reactions ......................................................... 67 
9.2.3 
Nephritis and Renal Dysfunction ............................................................ 67 
9.3 
Follow-up for Toxicities .......................................................................... 68 
10.0 
Concomitant Medications ..................................................... 70 
10.1 
Permitted Concomitant Therapy .............................................................. 70 
10.1.1 
Anti-diarrheal Treatment ......................................................................... 71 
10.1.2 
Hematopoietic Growth Factors and Transfusions ................................... 71 
10.1.3 
Anti-Coagulation ..................................................................................... 71 
10.1.4 
Infection Prophylaxis ............................................................................... 71 
10.1.5 
Empiric Antibiotics ................................................................................. 73 
10.1.6 
Blood Product Support ............................................................................ 73 
10.1.7 
Medication for Cytokine Release Syndrome (CRS) ............................... 73 
10.1.8 
Fever (≥ 38.3°C; ≥ 101°F) Antipyretic Therapy ..................................... 74 
10.1.9 
Medication for Immune Effector Cell-Associated Neurologic Syndrome 
(ICANS) .................................................................................................. 74 
10.1.10 
Medication for Hemophagocytic Lymphohistiocytosis 
(HLH)/Macrophage Activation Syndrome (MAS) ................................. 74 
10.1.11 
Surgery .................................................................................................... 75 
10.1.12 
Other Concomitant Medications to Control Side Effects ........................ 75 
10.2 
Permitted Concomitant Therapy to be Used with Caution ...................... 75 


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10.3 
Prohibited Concomitant Therapy ............................................................ 76 
11.0 
Visit Schedule and Assessments ........................................... 77 
11.1 
Study Flow and Visit Schedule ............................................................... 77 
11.1.1 
Screening ................................................................................................. 77 
11.1.2 
Treatment Period ..................................................................................... 78 
11.1.3 
Treatment Discontinuation ...................................................................... 78 
11.1.4 
Long-term Follow-up .............................................................................. 79 
11.1.5 
Withdrawal of Consent ............................................................................ 80 
12.0 
Assessment Types .................................................................. 81 
12.1 
Safety & Tolerability Assessments ......................................................... 81 
12.1.1 
Physical Examination .............................................................................. 81 
12.1.2 
Vital Signs ............................................................................................... 81 
12.1.3 
Height and Weight ................................................................................... 82 
12.1.4 
Performance Status .................................................................................. 82 
12.1.5 
Laboratory Evaluations ........................................................................... 82 
12.1.6 
Electrocardiogram (ECG) ........................................................................ 83 
12.2 
Efficacy Assessments .............................................................................. 86 
12.2.1 
Imaging Requirements ............................................................................. 86 
12.3 
Pharmacokinetic, Pharmacodynamic and Immunogenicity Assessments 87 
12.3.1 
Pharmacokinetic (PK) Assessments ........................................................ 87 
12.3.2 
Pharmacodynamic Assessments .............................................................. 89 
13.0 
Safety Monitoring and Reporting ........................................ 90 
13.1 
Adverse Events ........................................................................................ 90 
13.1.1 
Definitions and Reporting ....................................................................... 90 
13.1.2 
Laboratory Test and Vital Sign Abnormalities ....................................... 91 
13.1.3 
Documenting Adverse Events ................................................................. 91 
13.2 
Serious Adverse Events (SAEs) .............................................................. 92 
13.2.1 
Definitions ............................................................................................... 92 
13.2.2 
SAE Reporting ......................................................................................... 93 
13.3 
Assessment of Severity: AE and SAE Grading ....................................... 93 
13.4 
Assessment of Causality .......................................................................... 94 
13.5 
Pregnancies .............................................................................................. 95 
14.0 
Data Collection and Management ....................................... 96 


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14.1 
Data Confidentiality ................................................................................ 96 
14.2 
Clinical Monitoring ................................................................................. 96 
14.3 
Data Collection ........................................................................................ 97 
14.4 
Database Management and Quality Control ............................................ 97 
15.0 
Statistical Considerations ..................................................... 97 
15.1 
Sample Size Justification ......................................................................... 97 
15.2 
Analysis Populations ............................................................................... 98 
15.2.1 
All Enrolled Population ........................................................................... 98 
15.2.2 
Safety and DLT Evaluable Populations .................................................. 98 
15.2.3 
Efficacy Evaluable Population ................................................................ 98 
15.2.4 
Pharmacokinetic Analysis Population .................................................. 99 
15.3 
Pharmacokinetic and Pharmacodynamic Analyses ................................. 99 
15.3.1 
Pharmacokinetic (PK) Analyses .............................................................. 99 
15.3.2 
Pharmacodynamic (PDx) Analyses ....................................................... 100 
15.4 
Patient Disposition ................................................................................. 100 
15.5 
Demographics ........................................................................................ 100 
15.6 
Baseline Characteristics ......................................................................... 100 
15.7 
Prior and Concomitant Medications ...................................................... 101 
15.8 
Efficacy Analyses .................................................................................. 101 
15.9 
Safety Analyses ..................................................................................... 102 
15.9.1 
Extent of Exposure ................................................................................ 102 
15.9.2 
Adverse Events (AEs) ........................................................................... 102 
15.9.3 
Vital Signs ............................................................................................. 103 
15.9.4 
Laboratory Tests .................................................................................... 103 
15.9.5 
Other Safety Tests ................................................................................. 103 
15.9.6 
Safety Monitoring .................................................................................. 104 
15.10 
Good Clinical Practice ........................................................................... 104 
15.11 
Subject Information and Informed Consent .......................................... 104 
15.12 
Institutional Review Board/Independent Ethics Committee ................. 104 
16.0 
References ............................................................................ 106 
17.0 
Appendices ........................................................................... 109 
Appendix 1.  
Schedule of Evaluations ........................................................................ 109 
Appendix 2.  
Pharmacokinetics (PK) Detailed Schedule of Events ........................... 115 


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Appendix 3.  
Pharmacodynamics (PDx) Detailed Schedule of Events ....................... 116 
Appendix 4.  
Laboratory Evaluations ......................................................................... 117 
Appendix 5.  
RECIST v1.1 Response Assessment ..................................................... 119 
Appendix 6.  
iRECIST Response Assessment ............................................................ 131 
Appendix 7.  
QTcF Calculation .................................................................................. 135 
Appendix 8.  
Concomitant Medications to be Used with Caution .............................. 136 
Appendix 9.  
QT prolonging Medications to be used with Caution ........................... 138 
Appendix 10.   ASTCT Grading for Cytokine Release Syndrome1 ............................... 140 
Appendix 11.   ASTCT GRADING OF ICANS1 ........................................................... 141 
Appendix 12.   Immune-Effector Cell Toxicity Assessment and Management ............. 143 
 
List of Tables 
Table 1. 
 Enrollment by Dose Level ...................................................................... 36 
Table 2. 
 Frequency of All Adverse Events Regardless of Causality .................... 37 
Table 3. 
 Adverse Events by Dose Level ............................................................... 40 
Table 4. 
 Risk Assessment for APR003 ................................................................ 43 
Table 5. 
 Planned Dose Levels .............................................................................. 48 
Table 6. 
 APR003 Dose Modification and Supportive Care Guidelines for 
Treatment-Related Toxicities .................................................................. 61 
Table 7. 
 Follow-up Evaluations for Selected Toxicities ...................................... 68 
Table 8. 
 Eastern Cooperative Oncology Groups Performance Status (ECOG) ... 82 
Table 9. 
 ECG Values of Potential Clinical Concern ............................................ 85 
Table 10. 
 Imaging Assessments and Collection ..................................................... 87 
Table 11. 
 Definitions of Adverse Events Severity ................................................. 94 
Table 12. 
 Time Point Response: Patients with Target (± Non-target) Disease .... 127 
Table 13. 
 Time Point Response: Patients with Non-target Disease Only ............ 128 
Table 14. 
 Best Overall Response .......................................................................... 130 
Table 15. 
 Comparison of RECIST v1.1 and iRECIST ......................................... 131 
Table 16. 
 Drugs and Foods to be used with Caution while on Study ................... 136 
Table 17. 
 QT Prolonging Medications to be used with Caution while on Study .......  
 ............................................................................................................... 138 
 


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4.0 
List of Abbreviations and Definitions of Terms 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ADA 
Anti-drug antibodies 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ASTCT 
American Society for Transplantation and Cellular Therapy  
AUC 
area under the curve 
AUC0-t 
area under the curve from time zero to time t 
AUC0-ꝏ 
area under the curve from time zero to time infinity 
AUCtau 
area under the curve over the dosing interval 
AV 
atrioventricular 
BCG 
Bacillus Calmette-Guerin 
 
CL/F 
total plasma clearance 
C1D1 
Cycle 1 Day 1 
C2D1 
Cycle 2 Day 1 
CapeOX 
Capecitabine/Oxaliplatin 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentration 
CMV 
cytomegalovirus 
CNS 
central nervous system 
CR 
complete response 
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRS 
cytokine release syndrome  
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DC 
dendritic cell 
DCR6 
Disease Control Rate at 6 months 
DLT 
Dose Limiting Toxicity 


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dMMR 
deficient mismatch repair 
DOR 
Duration of Response 
DRF 
dose-range finding 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FOCBP 
females of child-bearing potential 
FOLFIRI 
FU/Leucovorin/Irinotecan 
FOLFOX 
FU/Oxaliplatin/Leucovorin 
FOLFOXIRI 
FU/Oxaliplatin/Leucovorin/Irinotecan 
FU 
fluorouracil  
G-CSF 
granulocyte-colony stimulating factor 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIV 
human immunodeficiency virus 
ICANS 
immune effector cell-associated neurotoxicity syndrome  
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IFN 
interferon 
IL 
interleukin 
INR 
international normalized ratio 
IP10 
Interferon-γ-inducible protein 10 
IRB 
Institutional Review Board 
iRECIST 
Response Evaluation Criteria in Solid Tumors in immunotherapy trials 
IV 
intravenous(ly) 
LAFB 
left anterior fascicular block 
LTFU 
Long-Term Follow-Up 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
major histocompatibility complex 
MLN 
mesenteric lymph node 


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MMR 
Measles/Mumps/Rubella 
MMRV 
Measles/Mumps/Rubella/Varicella 
MSI-H 
microsatellite instability-high 
MSI-L 
microsatellite instability-low 
MSS 
microsatellite stable 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NK 
natural killer 
ORR 
objective response rate 
OS 
Overall Survival 
PAMP 
pathogen-associated molecular patterns 
PD 
Progressive Disease 
PDx 
pharmacodynamic(s) 
PD1 or PD-1 
programmed cell death protein 1 
PD-L1 
programmed death ligand 1 
PET 
positron emission tomography 
PFS 
Progression Free Survival 
PK 
pharmacokinetic(s) 
PO 
per os (oral administration) 
PR 
partial response 
pRBC 
packed red blood cell 
PSA 
prostate specific antigen 
PT 
prothrombin time 
QTcF 
corrected QT interval using Fridericia’s method 
RBBB 
right bundle branch block 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SD 
standard deviation 
SOC 
standard of care 
SRC 
Safety Review Committee 
T1/2 
elimination half-life 
TIL 
tumor-infiltrating lymphocyte 
TLR 
toll-like receptor 


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Tmax 
time to maximum concentration 
TNF-α 
tumor necrosis factor-α 
ULN 
Upper limit of normal 
Vss/F 
volume of distribution at steady state after administration 


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5.0 
Introduction 
5.1 
Background Information on the Disease to be Treated 
The liver is a common major organ site of cancer metastasis, particularly for tumors of the 
gastrointestinal tract including colorectal cancer (CRC). The immunosuppressive 
microenvironment of the liver is thought to play a key role in the lack of anti-tumor 
immunity in patients with liver lesions and the lack of tumor response to checkpoint 
inhibition with anti-programmed cell death protein 1 (anti-PD1) agents (Joyce & Fearon 
2015, Brodt 2016). Although a number of other tumor types, both gastrointestinal (GI) and 
non-GI, involve metastases to the liver, this first-in-human (FIH) trial of APR003 will focus 
on CRC with liver metastases. 
5.1.1 
Colorectal Cancer (CRC) 
CRC is the third most common cancer world-wide and the second leading cause of cancer-
related death in the developed world (Ferlay 2015, Siegel 2017). Among CRC patients, more 
than 50% with advanced and/or unresectable disease will develop liver metastasis during the 
course of their disease (Tomlinson 2007), the majority of which will not be considered 
surgically resectable at the time of diagnosis. For patients with advanced and/or unresectable 
disease or those whose disease recurs following surgical resection, a variety of systemic 
chemotherapy regimens are typically used. For initial therapy of metastatic disease in 
patients who qualify for intensive therapy, the National Comprehensive Cancer 
Network (NCCN) guidelines suggest 1 of 5 regimens: 5-fluorouracil 
(FU)/Oxaliplatin/Leucovorin (FOLFOX), FU/ Leucovorin/Irinotecan (FOLFIRI), 
Capecitabine/Oxaliplatin (CapeOX), infusional 5-FU/Leucovorin or capecitabine or 
FU/Oxaliplatin/Leucovorin/Irinotecan (FOLFOXIRI). Despite the availability of these 
intensive chemotherapeutic regimens for advanced CRC, progression-free survival and 
overall survival remain poor; approximately 8.6 months progression-free survival; 17-month 
overall survival in patients treated with FOLFOX or CapeOX ± cetuximab (Maughan 2011). 
Furthermore, CRC remains largely non-responsive to PD-1 blockade, except for a small 
subset of patients whose tumors demonstrate microsatellite instability (i.e., “MSI-high”) and, 
consequently, have an extremely high mutational burden (Le 2015).  
5.2 
Role of the Immune System and the Liver 
The ability of the liver to suppress systemic antigen-specific T cell responses, so called 
“liver tolerance”, has been well described in the literature in the context of both liver 


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transplantation and exposure of antigens through the portal circulation (Crispe 2006). 
Recently, the presence of liver metastasis was associated with decreased progression-free 
survival in both melanoma and non-small cell lung carcinoma patients treated with 
pembrolizumab. Furthermore, liver metastasis was associated with reduced 
CD8+ tumor-infiltrating lymphocytes (TILs) within distant non-hepatic, metastatic 
lesions (Tumeh 2017). Therapies directed at reducing the tolerogenic bias of the liver and 
inducing a local increase in immune-modulatory cytokines may have a role in promoting the 
anti-tumor immune response needed for the successful treatment of liver metastases and 
associated distant metastases with cancer immunotherapies like anti-PD-1 antibodies.  
5.3 
Immune Agonism and Toll-like Receptors (TLRs) 
Toll-like receptors (TLRs) are a family of proteins that detect a wide range of conserved 
pathogen-associated molecular patterns (PAMPs) and are key drivers of innate immune 
activation. TLR7 is highly expressed in plasmacytoid dendritic cells and B lymphocytes and 
is located within the endosome where it normally functions as a sensor for single-stranded 
viral RNA. Activation of TLR7 results in enhanced antigen processing and presentation 
mechanisms, the upregulation of costimulatory molecules critical for cross-priming of 
cytotoxic T cells, and the production of a myriad of cytokines, such as type I and type II 
interferons (IFNs), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-12. In 
addition, TLR7 activation promotes the production of chemokines, such as interferon-γ-
inducible protein 10 (IP10), which further function to bridge the gap between innate and 
adaptive immunity by attracting monocytes, macrophages, T cells, natural killer (NK) cells, 
and dendritic cells (Prinz 2003, Dufour 2002, Schwabe 2006, Lee 2007). 
Several small molecule TLR agonists have demonstrated potential therapeutic efficacy 
against malignant disorders (Smith 2018). The TLR7 agonist, imiquimod, has previously 
demonstrated the ability to promote a local anti-tumor immune response when administered 
topically and is approved for the treatment of superficial basal cell carcinoma (Aldara® 
package insert). The anti-tumor effect of imiquimod is multifactorial and is hypothesized to 
act by recruitment of tumor-infiltrating plasmacytoid DCs and macrophages activated by 
cytokines and chemokines that ultimately drive increased major histocompatibility 
complexes (MHC)-I expression and CD8+ TILs in basal cell carcinoma (Walter 2010).  
TLR7 activation in the liver of patients with malignancies that are metastatic to the liver may 
similarly lead to innate immune activation, release of tumor-associated antigens and, 
ultimately, enhanced anti-tumor immune responses. Specifically, a strong innate immune 
activator may convert the immunosuppressive liver/tumor microenvironment into a locally 
immunogenic state, leading to both a reversal of liver tolerance and generation of tumor-


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specific T cell responses both locally and systemically. Thus, the successful development of 
effective synthetic innate immune activators may expand the fraction of patients that can 
respond to immunotherapies, such as anti-PD-1 blockade.  
Numerous approaches to developing synthetic innate immune agonists that effectively 
mimic PAMPs have been employed over the past decade. Currently, there are over 20 innate 
immune agonists that are undergoing development in clinical trials for cancer therapy 
(Braunstein 2018). The majority of these innate immune agonists elicit dramatic changes to 
the tumor microenvironment by increasing IFN response genes, increasing leukocyte 
infiltration, and in particular, enhancing the tumor-specific CD8+ T cell response to drive 
tumor eradication (Aznar 2017). Unfortunately, clinical applications of low molecular 
weight TLR7 agonists have largely been limited due to broad and systemic exposure of this 
class of compounds driving immune cell activation in many tissues that result in high levels 
of systemic cytokines that contribute to tolerability issues and potential “TLR tolerance” 
(Dudek 2007, Engel 2011, Bourquin 2011). The Sponsor is developing a small molecule 
TLR7 agonist, APR003, that concentrates in the GI, liver, and kidneys, with limited 
systemic exposure. This approach is designed to increase the therapeutic window of a TLR7 
agonist by minimizing the side-effects associated with generalized systemic immune 
activation and inflammation.  
5.4 
Background Information on the Investigational Product (APR003) 
The APR003 drug product is a capsule, which contains the active drug substance A221-CA 
and GRAS excipients (mannitol and magnesium stearate). The intended route of 
administration is oral delivery. APR003 is designed using medicinal chemistry principles 
derived from an analysis of liver-targeting compounds (Tu 2013). Additionally, APR003 is 
designed to have a short half-life and low volume-of-distribution, which minimizes 
undesired systemic TLR7 activation. The purpose of designing a TLR7 agonist with these 
pharmacokinetic characteristics was maximize the ability to counteract the 
immunosuppressive effects of the GI tract and liver microenvironments (GI tract and liver) 
on a patients’ overall anti-tumor immunity while minimizing the potential “TLR tolerance” 
that can be associated with systemic TLR7 agonism.  
Importantly, despite local drug concentration in the liver, GI, and kidneys robust 
pharmacodynamic (PDx) response can be measured by the induction of serum IP10 and 
blood ISG15, two sensitive interferon-response markers. These markers will be utilized to 
evaluate on-target immune activation. 
 


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5.4.1 Non-clinical Experience 
Safety Pharmacology (IB Section 2.4.3.3) 
The results of the safety pharmacology cardiovascular testing indicate little-to-no potential 
for QT prolongation. In an in vitro human ether-a-go-go related gene (hERG) potassium 
channel screening assay, using manual-patch clamp technique, the IC50 was shown to be 
>30 μM A221. This concentration was the highest tested, corresponds to 11,175 ng/mL, and 
is a 210-fold margin over 59.4 ng/mL, the highest maximum concentration (Cmax) plasma 
level achieved in the pivotal toxicology studies after conservatively correcting for an 
unbound plasma level of 15% (monkey Cmax of 396 ng/mL × 0.15 = 59.4 ng/mL). 
Therefore, at the concentrations tested, A221-CL-3 had no significant inhibition on the 
potassium currents passing through cloned hERG channels stably expressed in Human 
Embryonic Kidney 293 (HEK 293) cells. In support of a lack of effect on QT prolongation, 
no change was observed in QTc interval during the pivotal monkey toxicology study.  
For additional detailed information, please refer to the Investigator’s Brochure. 
5.4.1.1 
Pharmacology 
APR003 is a potent and selective TLR7 agonist, with activity across mouse, monkey, and 
human cells. APR003 has demonstrated anti-tumor efficacy in several syngeneic orthotopic 
models of colorectal and liver cancer, as a single agent and in combination with anti-PD-
1/-L1. Mechanistic studies in these models demonstrated that APR003 induces a greater 
frequency of activated cross-presenting dendritic cells in the liver/GI draining lymph nodes, 
and increased tumor antigen-specific CD8+ T cells within the tumor microenvironment, 
thereby confirming the mechanism of action. IFNα and downstream IP-10/ISG are the key 
pharmacodynamic markers of TLR7 activation that are responsible for the therapeutic effect 
of APR003. In fact, it has previously been demonstrated that type I IFNα is required for 
CD8+ T cell-mediated anti-tumor responses (Fuertes 2011), and that blocking of IFNα 
receptor has been shown to negate the antitumor efficacy of similar innate agonists (Sivick 
2018). The cytokines that were not induced by APR003 in monkeys, such as TNFα and IL-
10, have been attributed to cause poor tolerability and/or reduced efficacy (Sivick 2018). 
TLR7 agonism also induces chemokines such as interferon-γ-inducible protein 10 
(IP-10), which functions to bridge the gap between innate and adaptive immunity by 
attracting monocytes, macrophages, T cells, NK cells, and dendritic cells (Prinz 2003, 
Dufour 2002, Schwabe 2006, Lee 2007). IP-10, as well as interferon-stimulated gene 15 
(ISG15) are sensitive interferon-response markers utilized to confirm pre-systemic target 
engagement.  


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The in vivo pharmacodynamic (PDx) response to APR003 was assessed in mice and 
cynomolgus monkeys. In C57BL/6 mice, a single oral dose of APR003 at 30 mg/kg induced 
type I IFN transcription in the small intestines, liver, and mesenteric lymph nodes, followed 
by upregulation of interferon-stimulated genes (ISGs) in these tissues (Isg15, Mx1, Ip-10). In 
C57BL/6 and ICR mice, oral administration of APR003 induced serum IP-10, TNFα, and 
IL-6 dose-dependently. Serum IP-10 and liver ISGs (Ip-10, Isg15, Mx1) were elevated at 
0.3 mg/kg compared to concurrent vehicle control group and reached a plateau at 30 mg/kg 
and above, while TNFα and IL-6 elevations were not detected until 3 mg/kg and 30 mg/kg, 
respectively. Similar to mouse pharmacology, high levels of IP-10 and ISG15 were induced 
in monkeys after APR003 oral administration. IFNα was induced transiently and was 
consistently detected at high dose. However, in contrast to mice, only low levels of IL-6 
were induced (dose independently), and no TNFα or IL-10 were detected in monkeys.  
In the current study, APR003 target engagement and TLR7 agonism will be evaluated by 
measuring peripheral blood levels of IP-10 and/or ISG15, as well as other pathway-related 
cytokines.  
5.4.1.2 
Non-clinical Pharmacokinetics 
APR003 is designed to concentrate in the GI and liver with low peripheral tissue 
distribution. Plasma half-lives are short and volume of distribution is low across species. 
Tissue PK studies in mice after oral dosing showed approximately 20- to 30-fold liver 
exposure over serum, and 10-fold kidney exposure over serum. Tissue distribution in mice 
showed the highest APR003 concentrations in the stomach, intestines, liver, and kidney. In 
these tissues, APR003 exhibited similar half-lives to plasma (between 5 to 7 hours) and is 
mostly excreted (>99%) by 72 hours, suggesting lack of tissue accumulation. In vitro studies 
demonstrated APR003 to be a substrate of various intestinal transporters (OATP1A2, 
OATP2B1), liver transporter (OATP1B1), and kidney transporters (OAT3, MATE1, 
MATE2-K). Excretion studies showed orally administered APR003 was mostly unabsorbed 
as it passed through the GI tract and excreted through the feces. Taken together, these results 
support a PK profile whereby APR003 concentrates in the GI/liver and has low peripheral 
(non-target) tissue distribution, except for the kidney (2- to 3-fold less than liver). Given the 
intended once-weekly dosing regimen in human, tissue accumulation is unlikely even after 
multiple doses. 
5.4.1.3 
Non-clinical Toxicology 
Mouse and cynomolgus monkey were selected as the species for toxicity testing. Monkeys 
are known to display a TLR7 tissue expression pattern and immunostimulatory cytokine 


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release profile that closely mirrors humans (Junt 2015, Ketloy 2008, Messaoudi 2011, 
Thompson 2017). In humans and monkeys, TLR7 is mainly expressed in plasmacytoid 
dendritic cells (pDCs) and memory B-cells but have been also reported to be expressed in 
monocytes under certain conditions (Thompson 2017, Zarember 2002). In contrast, mice 
have prominent TLR7 expression in monocytes/macrophages, which is believed to be the 
reason for greater sensitivity and exaggerated responses to TLR7 agonism in this species 
compared to monkeys and humans (Clarke 2009, Junt 2015, Huber 2006). 
5.4.1.3.1 Rodent Toxicology Studies 
In a 4-week GLP study in mice, the toxicity and toxicokinetics of APR003 were evaluated at 
doses of 30 mg/kg, 100 mg/kg, or 300 mg/kg, administered once weekly (5 doses). One 
female treated with 100 mg/kg was found dead after the final dose on Day 29. Inflammatory 
cell infiltration in multiple organs was observed on microscopic evaluation and the death 
was considered to be related to exaggerated sensitivity to TLR7 agonism in rodents. No 
other deaths occurred. Clinical observations of loose/watery stool and a reversible decrease 
in mean body weight at 300 mg/kg were noted during the dosing phase of the study. 
Decreases in PLT count occurred at all doses. Non-reversible increases in mean absolute and 
relative liver and spleen weights occurred at all APR003 dose levels and correlated 
microscopically with lymphocytic infiltrates in the liver and increased cellularity of the 
white pulp of the spleen. APR003-related histopathologic observations of lymphocytic 
infiltrates in the kidney, liver, lacrimal gland, submandibular salivary gland, and prostate 
gland were seen at all doses and were consistent with on-target pharmacology and tissue 
distribution of APR003. Lymphocytic infiltrates in the kidney, liver, lacrimal gland, 
submandibular salivary gland, and prostate gland persisted at the end of the recovery period. 
The no-adverse-effect level (NOAEL) in mice, which is considered to be a species that is 
much more sensitive to TLR7 agonism compared to humans, was 30 mg/kg and the severely 
toxic dose in 10% of the mice (STD10) was > 300 mg/kg. 
5.4.1.3.2 Cynomolgus Monkey Toxicology Studies 
In a 4-week GLP study in cynomolgus monkeys, the toxicity and toxicokinetics of APR003 
were assessed at doses 15 mg/kg, 50 mg/kg, or 150 mg/kg, administered once weekly for a 
total of 5 doses. Goblet cell hyperplasia in the jejunum and/or ileum was seen in 3 of the 
10 monkeys treated with 50 mg/kg. Similar findings were not noted at the 150 mg/kg dose. 
Additionally, mild, and transient increases in ALT and bilirubin was observed at the 
150 mg/kg dose; no correlating histopathologic findings were observed in the liver. 


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APR003 and its active metabolite, A329, were detected in liver and kidney samples 
collected at the terminal necropsy (24 hours post last dose), with liver/plasma and 
kidney/plasma ratios of approximately 20-fold and 15-fold, respectively, for both APR003 
and A329, consistent with tissue distribution in mice. 
In cynomolgus monkeys, the NOAEL, which was also the highest non-severely toxic dose 
(HNSTD), of APR003 was 150 mg/kg, the highest dose level administered in the 4-week 
GLP toxicology study. Effects related to pharmacological response were observed at 
≥ 15 mg/kg (i.e., elevated IP-10, ISG15 mRNA, and IL-6), and related transient slight 
decreases in WBC and LYM and transient slight increases in ALT and bilirubin, with no 
histologic correlate, were observed at 150 mg/kg. The No Observed Adverse Effect Level 
(NOAEL) was determined to be 150 mg/kg, where the plasma AUC0-t and Cmax of A221 
on Day 1 were 1110 hr*ng/mL and 396 ng/mL, and the plasma AUC0-t and Cmax of A329 
(metabolite) on Day 1 were 596 hr*ng/mL and 193 ng/mL (male and female values 
combined). 
In this 4-week monkey GLP toxicology study to observe the effects of A221-CA on 
cardiovascular system and respiratory frequency when administered via nasogastric gavage. 
In this study, cynomolgus monkeys were randomized into 4 groups with 10 animals in each 
group (5 males and 5 females), which were dose with vehicle control (0.5% CMC-Na/0.5% 
Tween-80), or test article of 15, 50, 150 mg/kg, respectively ECG parameters (PR interval 
(PR), RR interval(RR), QRS complex duration (QRS), QT interval (QT), corrected QT 
interval (QTcf), heart rate (HR)), blood pressure parameters (systolic blood pressure(SBP), 
diastolic blood pressure(DBP), mean arterial blood pressure(MABP)) and respiratory 
frequency examinations were performed once during the acclimation period (baseline), four 
times at dosing period (2 and 24 hrs post dosing on D1 and D22), and once at the end of 
recovery period. 
Comparing with the vehicle control group, no test article-related abnormality was noted in 
blood pressure parameters (SBP, DBP, MABP), ECG parameters (PR, RR, QRS, QT, QTcF, 
HR), and respiratory frequency in animals of each test article-treated groups. 
In conclusion, no risk was identified in the cardiovascular and respiratory safety 
pharmacology readouts as part of this 4-week monkey GLP study. 
5.4.1.4 
Genotoxicity 
In a mini-Ames assay, APR003 was not mutagenic in S. typhimurium, TA98 and TA100, 
with or without metabolic activation. 


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5.4.2 
Selection of the Starting Dose 
Since APR003 is an immune-activating drug, the starting dose was selected using the 
minimal anticipated biologic effect level (MABEL) approach according to established 
regulatory standards (ICH S9; Saber 2016). APR003 target activation was evaluated in both 
in vitro and in vivo test systems.  
IP-10 was determined to be the most sensitive in vitro cytokine readout in primary cells 
across species.  Furthermore, IP-10 (protein) was determined to be the most sensitive and 
robust in vivo pharmacodynamic (PDx) readout of TLR7 activation across species, 
supported by literature and data obtained with APR003 (Lopatin 2013). Because TLR7 
expression in monkeys is more similar to humans compared to mice, in vivo monkey PDx 
was used to calculate the human starting dose. Results from pharmacology, 
pharmacokinetics and toxicology studies were utilized for determination of the APR003 
starting dose. The approach incorporated data on the PK/PDx relationship, species 
differences between animal models and humans and allometric scaling of data from animals 
to the projected human starting dose.  
A dose of 50 mg APR003 was selected based on the aforementioned algorithm and 
consideration of an additional margin of safety. 
5.4.3 
Clinical Experience 
5.4.3.1 
Toxicity of TLR Therapies 
Multiple TLR agonists have been shown to have systemic inflammatory toxicities including 
Grade 3 and 4 cytokine release syndrome (CRS). Additional common drug related adverse 
events (AEs) are pyrexia, fatigue, chills, decreased lymphocyte count, and nausea. 
Cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity 
syndrome (ICANS) can be fatal if not recognized early. Patients should be hospitalized as 
soon as they develop a symptom or sign of toxicity, and caregivers must be taught to 
recognize symptoms of ICANS. 
The first clinical manifestation of CRS is pyrexia.  It usually starts with fever that can 
exceed 40°C, and includes other symptoms such as malaise, headache, myalgias, and 
tachycardia. Possible manifestations include organ dysfunctions, cytopenias, and 
coagulopathy. In severe cases, patients can develop life-threatening capillary leakage with 
hypoxia and hypotension. 


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The standard of care for CRS is Actemra® (tocilizumab), an anti‑IL‑6 receptor antagonist. If 
the patient does not respond to Actemra® (tocilizumab), corticosteroids can be effective in 
reversing CRS. Some data suggest that the anti‑IL‑6 monoclonal antibody siltuximab or the 
IL‑1 receptor antagonist anakinra may have clinical efficacy. In CRS, patients can require 
vasopressors to correct hypotension and oxygen supply or intubation for hypoxia. 
ICANS may occur as an adoptive cell‑related encephalopathy syndrome. The clinical 
manifestations of ICANS are very wide ranging, as toxicity does not affect a specific region 
of the central nervous system. They include encephalopathy (confusion or delirium), 
expressive aphasia or language disturbance, motor weakness, myoclonus or tremor, 
headache, seizures, and a depressed level of consciousness.  In rare cases patients can 
rapidly develop diffuse cerebral oedema. Expressive aphasia seems to be a typical symptom. 
ICANS can occur almost simultaneously with CRS or even after CRS has resolved. ICANS 
is usually self-limiting, and most symptoms reverse in three to four weeks, with persistent 
abnormalities being uncommon. For ICANS, the American Society for Transplantation and 
Cellular Therapy (ASTCT) consensus grading is based on 5 elements: the 10-point immune 
effector cell-associated encephalopathy (ICE) score, depressed level of consciousness, 
seizure, motor findings, and elevated intracranial pressure/cerebral edema (Appendix 11). 
Severity can range from grade 1 to grade 4, with the grade determined by the most severe 
event. The ICE score is a tool that measures alterations in speech, orientation, handwriting, 
and concentration (Appendix 11). Severe ICANS develops almost only in patients who have 
experienced CRS, with severity being influenced by disease type, disease burden, patient’s 
age, and treatment history. For grading and management, refer to Appendix 10 and 
Appendix 11. 
As of the data cut off of 01 December 2021, 11 subjects with advanced colorectal cancer 
have been treated with APR003, 6 at 25 mg, 4 at 50 mg and 1 at 100 mg, dose levels -1 to 2 
(Table 1). At dose level 2 (100 mg) a subject experienced an SAE (Cytokine Release 
Syndrome). Table 1 identifies enrollment dose levels, Table 2 indicates the frequency of 
adverse events, and Table 3 adverse events by dose level. 


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Table 1. 
 
Enrollment by Dose Level 
Subject Identifier 
Sex 
Age 
Dose Level 
Stage at Entry 
100--1-101 
Male 
64 
DOSE LEVEL -1: 25 MG 
IV 
100--1-102 
Male 
49 
DOSE LEVEL -1: 25 MG 
IVC 
100--1-104 
Male 
47 
DOSE LEVEL -1: 25 MG 
IV 
100-01-101 
Male 
51 
DOSE LEVEL 1: 50 MG 
IVB 
100-01-104 
Male 
64 
DOSE LEVEL 1: 50 MG 
IVB 
101--1-105 
Female 
47 
DOSE LEVEL -1: 25 MG 
IVC 
101-01-103 
Male 
60 
DOSE LEVEL 1: 50 MG 
IVB 
101-02-101 
Female 
52 
DOSE LEVEL 2: 100 MG 
IV 
102--1-103 
Male 
52 
DOSE LEVEL -1: 25 MG 
IVB 
102-01-102 
Male 
52 
DOSE LEVEL 1: 50 MG 
IVB 
103--1-106 
Female 
74 
DOSE LEVEL -1: 25 MG 
IVB 


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Table 2. 
 
Frequency of All Adverse Events Regardless of Causality 
AE Preferred 
Term 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Life-Threatening 
Grade 5 
Death 
Subjects 
Chills 
5 (45.5%) 
5 (45.5%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
9 (81.8%) 
Pyrexia 
8 (72.7%) 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
8 (72.7%) 
Nausea 
7 (63.6%) 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
8 (72.7%) 
Vomiting 
6 (54.5%) 
3 (27.3%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
8 (72.7%) 
Lymphopenia 
1 (9.1%) 
1 (9.1%) 
4 (36.4%) 
0 (0.0%) 
0 (0.0%) 
5 (45.5%) 
Fatigue 
4 (36.4%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
4 (36.4%) 
Cytokine release 
syndrome 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
3 (27.3%) 
Tumour pain 
3 (27.3%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
3 (27.3%) 
Neutropenia 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Pain 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Abdominal pain 
upper 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Blood creatinine 
increased 
2 (18.2%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Headache 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Flushing 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Hydronephrosis 
2 (18.2%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Urinary tract 
infection 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%)* 
Cough 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Flank pain 
2 (18.2%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Abdominal pain 
2 (18.2%) 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Diarrhoea 
2 (18.2%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Back pain 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Dyspnoea 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Anaemia 
0 (0.0%) 
2 (18.2%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Dizziness 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
COVID-19 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Flatulence 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Chest discomfort 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Haematuria 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 


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AE Preferred 
Term 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Life-Threatening 
Grade 5 
Death 
Subjects 
Blood pressure 
increased 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Blood alkaline 
phosphatase 
increased 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypotension 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Aspartate 
aminotransferase 
increased 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Myalgia 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Nail pigmentation 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Nasal congestion 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Alanine 
aminotransferase 
increased 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Neuropathy 
peripheral 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%)* 
Night sweats 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Oral herpes 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Iron deficiency 
anaemia 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%)* 
Platelet count 
decreased 
1 (9.1%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Proteinuria 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypokalaemia 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%)* 
Renal colic 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Seasonal allergy 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Taste disorder 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Thirst 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Tinea infection 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Tumour flare 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypocalcaemia 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%)* 
Type 2 diabetes 
mellitus 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Ureteral disorder 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Dysuria 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 


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AE Preferred 
Term 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4 
Life-Threatening 
Grade 5 
Death 
Subjects 
Weight decreased 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Constipation 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%)* 
Blood creatine 
increased 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Cellulitis 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Cystitis 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hyperhidrosis 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypertension 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Oedema peripheral 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pain in extremity 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pancreatitis 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pleural effusion 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Procedural pain 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pyelonephritis 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Sinusitis bacterial 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Blood bilirubin 
increased 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Colon cancer 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypoglycaemia 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypoxia 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Lipase increased 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Oral candidiasis 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Disease progression 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
1 (9.1%) 
*One instance of each is in the adverse event database without an associated grade: urinary tract infection, 
neuropathy peripheral, iron deficiency anaemia, hypokalaemia, hypocalcaemia, constipation 
 


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Table 3. 
 
Adverse Events by Dose Level 
AE Preferred  
Term 
DOSE LEVEL -1: 
25 MG 
DOSE LEVEL 1:  
50 MG 
DOSE LEVEL 2: 
100 MG 
Total Subjects 
N=6 
N=4 
N=1 
N=11 
Chills 
5 (83.3%) 
3 (75.0%) 
1 (100.0%) 
9 (81.8%) 
Vomiting 
5 (83.3%) 
2 (50.0%) 
1 (100.0%) 
8 (72.7%) 
Pyrexia 
5 (83.3%) 
2 (50.0%) 
1 (100.0%) 
8 (72.7%) 
Nausea 
4 (66.7%) 
3 (75.0%) 
1 (100.0%) 
8 (72.7%) 
Lymphopenia 
3 (50.0%) 
2 (50.0%) 
0 (0.0%) 
5 (45.5%) 
Fatigue 
3 (50.0%) 
1 (25.0%) 
0 (0.0%) 
4 (36.4%) 
Cytokine release 
syndrome 
1 (16.7%) 
1 (25.0%) 
1 (100.0%) 
3 (27.3%) 
Tumour pain 
1 (16.7%) 
2 (50.0%) 
0 (0.0%) 
3 (27.3%) 
Blood creatinine 
increased 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Anaemia 
1 (16.7%) 
1 (25.0%) 
0 (0.0%) 
2 (18.2%) 
Neutropenia 
1 (16.7%) 
1 (25.0%) 
0 (0.0%) 
2 (18.2%) 
Urinary tract 
infection 
1 (16.7%) 
0 (0.0%) 
1 (100.0%) 
2 (18.2%) 
Abdominal pain 
upper 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Abdominal pain 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Cough 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Hydronephrosis 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Headache 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Diarrhoea 
0 (0.0%) 
1 (25.0%) 
1 (100.0%) 
2 (18.2%) 
Flushing 
1 (16.7%) 
1 (25.0%) 
0 (0.0%) 
2 (18.2%) 
Dyspnoea 
1 (16.7%) 
1 (25.0%) 
0 (0.0%) 
2 (18.2%) 
Flank pain 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Back pain 
2 (33.3%) 
0 (0.0%) 
0 (0.0%) 
2 (18.2%) 
Pain 
0 (0.0%) 
2 (50.0%) 
0 (0.0%) 
2 (18.2%) 
Flatulence 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Dizziness 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Haematuria 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Cystitis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
COVID-19 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 


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AE Preferred  
Term 
DOSE LEVEL -1: 
25 MG 
DOSE LEVEL 1:  
50 MG 
DOSE LEVEL 2: 
100 MG 
Total Subjects 
N=6 
N=4 
N=1 
N=11 
Hyperhidrosis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Lipase increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Colon cancer 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Malignant neoplasm 
progression 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Myalgia 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Nasal congestion 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Chest discomfort 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Cellulitis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Night sweats 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Oedema peripheral 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pain in extremity 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pancreatitis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pleural effusion 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Procedural pain 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Pyelonephritis 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Blood pressure 
increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Renal colic 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Sinusitis bacterial 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Taste disorder 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Thirst 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Tinea infection 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Blood bilirubin 
increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Type 2 diabetes 
mellitus 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Ureteral disorder 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Blood alkaline 
phosphatase 
increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Aspartate 
aminotransferase 
increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 


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AE Preferred  
Term 
DOSE LEVEL -1: 
25 MG 
DOSE LEVEL 1:  
50 MG 
DOSE LEVEL 2: 
100 MG 
Total Subjects 
N=6 
N=4 
N=1 
N=11 
Weight decreased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Alanine 
aminotransferase 
increased 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Hypotension 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Nail pigmentation 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Oral herpes 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Dysuria 
1 (16.7%) 
0 (0.0%) 
0 (0.0%) 
1 (9.1%) 
Proteinuria 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Seasonal allergy 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Tumour flare 
0 (0.0%) 
1 (25.0%) 
0 (0.0%) 
1 (9.1%) 
Blood creatine 
increased 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Constipation 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Hypertension 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Hypocalcaemia 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Hypoglycaemia 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Hypokalaemia 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Hypoxia 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Iron deficiency 
anaemia 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Neuropathy 
peripheral 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Oral candidiasis 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
Platelet count 
decreased 
0 (0.0%) 
0 (0.0%) 
1 (100.0%) 
1 (9.1%) 
 




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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Infections and febrile 
neutropenia 
The occurrence of infections and 
febrile neutropenia is common 
following infusion with the use of 
lymphodepletion and adoptive cell 
therapies. 
Subjects will be monitored for signs 
and symptoms of infection and treated 
appropriately.  Subjects, at the 
discretion of the Investigator, will be 
given anti‑infective agents and G‑CSF 
as needed. 
Infection prophylaxis: 
Subjects, at the discretion of the 
Investigator, will be given 
anti‑infective agents as needed Section 
10.1.4. 
Fungal infection: 
 Antifungal agents can be initiated and 
given either orally or as an IV dose 
(Section 10.1.4).  
Neurologic adverse events 
(AEs) and immune effector 
cell associated neurologic 
syndrome (ICANS) 
Neurologic AEs may occur with high 
grade CRS. 
Subjects will receive aggressive 
treatment including corticosteroids. 
Actemra® (tocilizumab) may be 
administered if neurotoxicity is 
accompanied by CRS (Sections 10.1.7  
and 10.1.9). 
Prolonged cytopenia 
Thrombocytopenia, neutropenia, and 
anemia, and should be carefully 
monitored. 
Blood counts should be monitored as 
prolonged neutropenia is associated 
with increased risk of infection. 
Tumor lysis syndrome 
(TLS) 
TLS occurs when tumor cells release 
their contents into the blood stream, 
either spontaneously or due to 
treatment, leading to metabolic 
disturbances including hyperuricemia, 
hyperkalemia, hypophosphatemia, and 
hypocalcemia. 
Management of cardiac and 
neuromuscular abnormalities and 
preservation of kidney function are 
most important. Allopurinol can be 
used to reduce the hyperuricemia and 
rasburicase can be used to preserve or 
improve renal function Section 10.1.10.  
Viral reactivation 
Viral infections are very commonly 
associated with lymphodepletion and 
adoptive cell therapy infusion. 
Herpes or Epstein Barr virus: 
Subjects can receive valacyclovir orally 
or acyclovir intravenously if the patient 
cannot take oral antiviral medications 
after lymphodepletion Section 10.1.4. 
Nausea and diarrhea 
A general risk with cell therapies. 
Prophylactic medication can be used at 
the Investigator’s discretion with 
Sponsor approval (Section 10.1) 
 


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5.5 
Program Development 
Biologically, APR003 has the potential to impact any cancer type with metastases to the liver. 
The intended initial evaluation of and planned first indication is for the treatment of advanced 
CRC with metastases to the liver. 
Following determination of the monotherapy RP2D, the anti-tumor activity of APR003 as a 
single agent will be evaluated. In addition, the safety and anti-tumor activity of APR003 in 
combination with PD1/PD-L1 checkpoint inhibition may also be considered. 


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6.0 
Study Objectives 
6.1 
Primary Objectives and Endpoints 
The primary objective(s) of the study include the following: 
Phase 1 Dose Escalation 
• To evaluate the safety and tolerability of single-agent APR003 and to establish the 
Recommended Phase 2 Dose (RP2D). The corresponding endpoints include:  
• Incidence and nature of Dose Limiting Toxicities (DLTs) 
• Incidence, nature, and severity of adverse events graded according to National 
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v5. ASTCT Grading will be utilized for CRS (Appendix 10) and 
ICANS (Appendix 11).  
• To characterize the PK of APR003. Corresponding endpoints may include, but are not 
limited to, the following PK parameters:  
• Area under the curve (AUC) from time zero to time t (AUC0-t)  
• AUC from time zero to time infinity (AUC0-ꝏ)  
• AUC over the dosing interval (AUCtau)  
• Maximum concentration (Cmax)  
• Time-to-maximum concentration (Tmax)  
• Elimination half-life (T1/2)  
• Apparent volume of distribution at steady state after administration (Vss/F)  
• Apparent total plasma clearance (CL/F)  
 
 
 
 
 
 
 
 
 


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• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
7.0 
Study Design & Plan 
This is a Phase 1 study designed to evaluate the safety, tolerability, and PK of APR003 
monotherapy in patients with advanced, unresectable CRC with metastases to the liver. In 
addition, PDx, and antitumor activity will be explored. It is anticipated that approximately 
12-36 patients will be enrolled; however, the actual number of patients enrolled will depend 
upon multiple factors, including but not limited to, safety/occurrence of DLTs. 


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7.1 
Phase 1 (Dose escalation) 
The Dose Escalation is designed as a classical 3+3 to determine the RP2D. 
Table 5 shows the dose levels planned for evaluation. Intermediate and/or higher dose levels 
may be added based upon safety, anti-tumor activity, PK and PDx observations. 
Table 5. 
 
Planned Dose Levels 
Dose Level 
Dosage 
Incremental Increase 
[-1] 
25 mg 
[1/2x] 
1 (starting dose) 
50 mg 
N/A 
2 
100 mg 
2x 
3 
175 mg 
1.75x 
4 
250 mg 
~1.4x 
5 
350 mg 
1.4x 
6 
500 mg 
~1.4x 
A minimum of 3 patients will be enrolled at each dose level. If 1 of 3 patients experiences a 
DLT during the first 3 weeks (i.e., Cycle 1), an additional 3 patients will be enrolled and 
treated at that dose level. If 0 of 3 or ≤ 1 of 6 patients experience a DLT during Cycle 1, 
escalation to the next higher dose level will occur. If ≥2 of 3 or 6 patients experience a DLT 
during Cycle 1, dose escalation will be discontinued and either intermediate dose level will be 
evaluated or the prior dose level, if at least 6 patients had been evaluated, will be considered 
the maximum tolerated dose (MTD). It is anticipated that approximately 6 dose levels of 
APR003 will be evaluated, although additional dose levels may be considered based upon the 
observed safety profile, anti-tumor activity and/or PDx observations. 
Treatment of the first 3 patients in each dose level cohort will be staggered such that 
consecutive patients will initiate treatment at least 2 days apart.  
Patients will be monitored for CRS with vital signs performed every 2 hours for a minimum of 
6 hours post-dose for the first cycle.  If CRS is not observed during the first cycle, monitoring 
is not necessary on Day 1 of subsequent cycles 
7.1.1 
Dose-Limiting Toxicities (DLTs) 
The following definition of DLTs will be applied. A DLT is defined as any AE that is not 
clearly due to progression of the patient’s malignancy, which occurs within the first 21 days of 


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treatment initiation (i.e., Cycle 1) and that meets at least one of the non-hematologic or 
hematologic criteria below: 
Non-Hematologic DLT: 
• Any ≥ Grade 3 non-hematologic toxicity according to the CTCAE v5 or ASTCT ≥ 
Grade 3 Grade for CRS and ICANS except for the following: 
• Grade 3 nausea, vomiting, or diarrhea lasting ≤ 72 hrs will not be considered a 
DLT 
• Grade 3 fatigue lasting ≤ 7 days 
• Grade 3 chills lasting ≤ 72 hrs 
• Grade 3 allergic or hypersensitivity reactions lasting ≤ 24 hrs 
• Grade 3 increases in total bilirubin of any duration in patients with Gilbert’s 
Syndrome. (Note: Grade 4 increases in bilirubin of any duration and in any patient 
regardless of Gilbert’s Syndrome, will constitute a DLT) 
• Grade 3 increases in liver transaminases lasting < 7 days (Note: Grade 3 increases 
in liver transaminases with concurrent Grade 2 increases in bilirubin of any 
duration, consistent with Hy’s Law, will constitute a DLT)  
• Any Grade 4 increase in liver transaminases  
• Grade 3 or 4 clinical laboratory abnormalities that are reversible to ≤ Grade 1 or 
baseline status within 72 hrs, that do not require continuous monitoring, or that are 
considered not clinically significant by the Principal Investigator 
Hematologic DLT: 
• Grade 4 neutropenia (absolute neutrophil count [ANC] < 0.5 x 109/L) 
• Grade 3 neutropenia (ANC < 1.0 x 109/L) lasting > 14 days 
• ≥ Grade 3 febrile neutropenia (ANC < 1.0 x 109/L with a fever ≥ 38.3ºC) 
• Grade 4 thrombocytopenia (< 25.0 x 109/L)  
• ≥ Grade 3 thrombocytopenia associated with clinically significant bleeding 
• Any hematologic toxicity resulting in death (i.e., Grade 5) 
In addition, any other AE that is felt to be treatment-limiting in the medical opinion of the 
Principal Investigator and the Sponsor’s Medical Monitor may be considered a DLT. 


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7.2 
Patient Replacement 
In general, patients will not be replaced on study. However, if a patient is considered as non-
evaluable for the DLT evaluation, enrollment of a new patient to the current cohort will be 
considered if there are less than the required number of evaluable patients. In order to be 
considered DLT-evaluable, patients must receive at least 3 doses of APR003 in Cycle 1, unless 
they experience a DLT (see Section 15.2.2.2) Enrollment of new patients may be considered 
until at least the minimum number (3) or at most the maximum number (6) of evaluable 
patients is achieved within the DLT cohort. 
All reasons for patient replacement in DLT and efficacy analyses will be described. 
7.3 
Evaluation Committees 
Safety will be reviewed on an ongoing basis. The Safety Review Committee (SRC), comprised 
of the Sponsor Medical Monitor and Principal Investigator (or designee) from each 
participating site, will review and evaluate the safety of APR003 throughout the study. The 
SRC will review and discuss all key safety data and determine whether enrollment into the next 
higher dose level cohort may proceed. 


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7.4 
Study Design Rationale 
The proposed first-in-human (FIH) trial is a Phase 1 study consisting of a dose escalation of 
single-agent APR003 to identify the RP2D. The purpose of this study is to evaluate the safety 
and tolerability profile of APR003 monotherapy and to identify the single-agent recommended 
Phase 2 dose (RP2D), as well as to characterize the pharmacokinetic profile of APR003. This is 
the first time APR003 will be administered to humans. Thus, the dose escalation part of this 
study is required to characterize the safety and tolerability of APR003.  
The traditional “3 + 3” design was selected because it is the prevailing method for conducting 
Phase 1 cancer clinical trials (Storer 1989) and supports the identification of a dose of APR003 
for which the rate of DLTs is less than 33%. Based on the mechanism-of-action and 
distribution of APR003, it is reasonable to make the classical assumption that toxicity will 
increase with increasing dose.  
7.5 
Early Study Termination 
The study can be terminated at any time for any reason by the Sponsor. Reasons for study 
termination include, but are not limited to: 
• occurrence of > 10% deaths in Phase 1a that are not due to progression of the patient’s 
primarily malignancy 
• occurrence of >1 DLT at Dose Level -1 
In addition, the Safety Review Committee may decide to terminate the study for reasons such 
as an overall Phase 1 APR003 toxicity profile.  
Should study termination be necessary, all patients on study treatment should be seen as soon 
as possible for the End of Treatment (EOT) visit and the assessments for EOT should be 
performed as described in the Schedule of Evaluations (Appendix 1). The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing institutional review boards (IRBs) and/or independent ethics committees (IECs) of 
the early termination of the trial. 
 


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8.0 
Patient Population and Study Eligibility Criteria 
8.1 
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for inclusion in the study:  
1. Histopathological diagnosis of advanced, unresectable CRC with malignant liver lesions.  
2. Age ≥ 18 years at the time of consent. 
3. Patient must have disease that is considered non-surgically resectable. 
4. Patient must have disease that is relapsed or persistent/refractory to at least two prior 
systemic treatment regimens for locally advanced or metastatic disease considered to be 
standard-of-care (SOC). Patients who were previously not considered candidates for 
intensive treatment, who have not received SOC agents due to contraindications, and/or 
who have had <2 lines of therapy may be eligible with clear documentation and approval 
from the Sponsor Medical Monitor. Specific requirements are outlined below: 
a. Patients must have previously received an irinotecan or oxaliplatin-based therapy, as 
well as a targeted antibody therapy for metastatic disease 
b. Patients whose tumors are MSI-H/dMMR must have previously received checkpoint 
inhibitor therapy 
5. Has at least 1 malignant lesion that is considered to be measurable according to RECIST 
v1.1 criteria. The lesion site must be measured accurately in at least one dimension (longest 
diameter in the plane of measurement to be recorded) with a minimum size of 
a. 10 mm by CT scan  
b. 10 mm by caliper measurement 
c. 20 mm by chest X-ray 
d. Malignant lymph nodes must be ≥ 15 mm in short axis when assessed by CT scan 
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.  
7. Life expectancy of > 3 months. 
8. Adequate organ and marrow function within 14 days of planned treatment initiation on 
Day 1, Cycle1 (C1D1), as defined below: 
a. Absolute neutrophil count (ANC) ≥ 1,500 cells/μL. Patients must not have received 
growth factors (e.g., G-CSF) within 14 days of Screening. 


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b. Platelet count ≥ 100,000/μL. Patients must not have received platelet transfusions 
within 14 days of Screening. 
c. Hemoglobin ≥ 8 g/dL. Patients must not have received pRBC transfusions within 28 
days of Screening. 
d. Total serum bilirubin ≤ 1.5x upper limit of normal (ULN). For patients with Gilbert’s 
Syndrome, total serum bilirubin must be ≤ 3x ULN. 
e. AST and ALT ≤ 3x ULN 
f. Serum albumin >3 g/dL 
g. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) ≤ 1.5x 
ULN. This applies only to patients who are not receiving therapeutic 
anticoagulation. Patients receiving therapeutic anticoagulation (e.g., low molecular 
weight heparin or warfarin) should be on a stable dose. 
h. Serum creatinine ≤ 1.5x ULN, or creatinine clearance (CrCl) ≥ 60 mL/min based on 
the Cockcroft-Gault formula.  
9. Resolution of all treatment-related toxicities, except alopecia, anemia, and peripheral 
neuropathy, from any previous cancer therapy to ≤ Grade 1 at Screening. Patients with 
ongoing Grade 2 alopecia, anemia and/or peripheral neuropathy are eligible. 
10. Female patients must have a negative serum or urine pregnancy test within 72 hours of 
Cycle 1 Day 1. Post-menopausal females (> 45 years old and without menses for > 1 year) 
and surgically sterilized females are exempt from these requirements. 
11. Patients must agree to use adequate birth control methods from the time of informed 
consent and for up to 6 months following treatment discontinuation. 
a. Sexually active females of child-bearing potential must agree to use two methods of 
birth control that includes as least one barrier.  
b. Sexually active males must agree to use an acceptable barrier method of birth 
control.  
c. For patients who are not sexually active: at the discretion of the Principal 
Investigator, sexual abstinence may be considered to be an acceptable method of 
contraception. The Principal Investigator should consider the reliability of sexual 
abstinence in relation to the patient’s usual lifestyle. Periodic abstinence (e.g., 
calendar, post-ovulation symptothermal methods, etc.) is not considered to be an 
acceptable method of contraception. 


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12. Willing and able to provide informed consent and to comply with the study protocol, in the 
Investigator’s judgement. 
8.2 
Exclusion Criteria 
Patients who meet one of the following criteria will be excluded from the study:  
1. Chemotherapy, or other systemic small molecule therapy for the treatment of the primary 
malignancy, within 5 half-lives of Cycle 1 Day 1. 
2. Radiation therapy, immunotherapy, or other biological therapy (e.g., monoclonal 
antibodies) within 28 days prior to Cycle 1 Day 1. 
3. Treatment with an unapproved investigational agent or device within 28 days (or 5 half-
lives for small molecule agents) prior to Cycle 1 Day 1. 
4. Presence of clinically significant malignant ascites 
5. Has a primary immunodeficiency diagnosis (e.g., X-linked agammaglobulinemia, common 
variable immunodeficiency, severe combined immunodeficiency, acquired immune 
deficiency syndrome, etc.). 
6. Is receiving systemic steroid therapy or any other form of immunosuppressive therapy 
within 28 days prior Screening. Intranasal and inhaled corticosteroids, or systemic 
corticosteroids at physiological doses (≤ 10 mg/day of prednisone, or an equivalent 
corticosteroid) are permitted. 
7. Known hypersensitivity to APR003 excipients.  
8. Any other current or previous malignancy within the past three years EXCEPT 
a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the 
cervix, c) prostate cancer with stable prostate specific antigen (PSA) levels for 3 years, 
d) or other neoplasm that, in the opinion of the Principal Investigator and with the 
agreement of the Sponsor’s Medical Monitor, will not interfere with study-specific 
endpoints. 
9. Current or history of central nervous system (CNS) metastases. 
10.  Patients with malignant lesions within the immediate proximity of the biliary tract and 
who, in the opinion of the Principal Investigator, are at risk of biliary obstruction. 
11. Active autoimmune disease requiring systemic steroid treatment (e.g., disease modifying 
anti-rheumatic agent, corticosteroids, or other immunosuppressive drugs). Physiologic 


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hormone/steroid replacement therapy (e.g., thyroxine, glucocorticoids for treatment of 
adrenal insufficiency) is permitted with approval of the Sponsor Medical Monitor. 
12. Patients who are unable to receive medication per os (po), or who have refractory nausea 
and/or vomiting, uncontrolled diarrhea, malabsorption (e.g., Crohn’s disease, ulcerative 
colitis, etc.), significant small bowl resection or gastric bypass surgery, or other situation 
that may preclude adequate absorption. 
13. Major surgery within 28 days prior to Cycle 1 Day 1. 
14. Active infection requiring parenteral antibiotics, antivirals, or antifungals within 14 days of 
Cycle 1 Day 1 Patients with infections requiring only oral antibiotics may be considered 
following approval by the Sponsor Medical Monitor.  
15. Cardiac abnormalities including: 
a. Symptomatic ischemia 
b. Uncontrolled or clinically significant conduction abnormalities (e.g., ventricular 
tachycardia on antiarrhythmics, unstable atrial fibrillation) are excluded from 
enrollment. 1st degree AV block or asymptomatic LAFB/RBBB may be eligible for 
enrollment. 
c. Corrected QT/QTc interval using Fridericia’s method (QTcF) > 480 ms, family 
history of Long QT syndrome, heart failure, hypokalemia, or other risk factor for 
Torsades de pointes. 
d. Myocardial infarction in the previous six months 
e. Congestive heart failure (New York Heart Association class III to IV) 
16. Patients who are pregnant, lactating or breastfeeding. 
17. Patients who are known to have HIV infection/ seropositivity. 
18. Patients with active Hepatitis virus infection (include Hepatitis A, B and/or C). Patients 
with positive Hepatitis B surface antigen (HBsAg) with detected Hepatitis B virus (HBV) 
DNA or positive Hepatitis C antibody with detected Hepatitis C virus (HCV) RNA are 
excluded. 
19. Patients with active CMV infection/reactivation. 
20. Prior liver or other organ transplantation 


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21. Patients who are receiving treatment with medications that are prohibited on study that 
cannot be discontinued prior to study entry and that are considered to be any of the 
following: 
a. Other antineoplastic agents 
22. Patients receiving concomitant medications that prolong the QT/QTc interval (Appendix 8 
in the protocol) are excluded unless such agents can be discontinued prior to the initiation 
of study therapy. Allergy to meat products or gelatin. 
23. Known psychiatric disorders, substance abuse, or other medical conditions that would 
interfere study compliance or interpretation of study results, or that would make the patient 
inappropriate for entry into the study. 
8.3 
Patient Numbering and Treatment Assignment 
8.3.1 
Method of Assigning Patients to Treatment Groups 
The enrollment and treatment assignment will be centrally managed by the Sponsor (or 
designee). When a treatment cohort is open for enrollment, sites will complete and submit a 
Patient Registration Form along with patient eligibility supporting documents for each potential 
patient to the Sponsor (or designee). The Sponsor (or designee) will assign a patient number 
and treatment cohort for each patient that is accepted into the study. Sites cannot enroll or start 
dosing the patient without receiving the assigned patient number and treatment cohort from the 
Sponsor (or designee). 
8.3.2 
Treatment Assignment 
All patients will receive APR003 monotherapy. The starting dose of APR003 will be 
determined by the dose escalation cohort to which the patient is enrolled. Patients who remain 
on study treatment at the time of RP2D selection may have the option of dose modification to 
the RP2D following discussion and approval of the Sponsor Medical Monitor.


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9.0 
Study Treatments 
9.1 
Treatments Administered 
All patients will receive APR003, an orally bioavailable agonist of TLR7. In the absence of 
unacceptable treatment-related toxicity or disease progression, patients may receive the 
assigned study treatment for up to 1 year at the discretion of the Investigator and beyond 1 year 
with the agreement of the Investigator and the Sponsor.  
9.1.1 
APR003 Description 
APR003 is a small molecule TLR7 agonist that is orally administered and is in development for 
the treatment of CRC with malignant liver lesions. 
APR003 will be supplied as 25 mg and 100 mg opaque off-white hard gelatin capsules (Sizes 3 
and 00, respectively) by the Sponsor. For additional details, please refer to the Pharmacy 
Manual. The pharmacist or study staff will supply the appropriate dose for each dose cohort. 
9.1.2 
Storage and Labeling 
At a minimum, each bottle label shipped to the sites will provide the following information: lot 
number, study identification, required storage conditions, directions for use, and region-specific 
caution statements (including “Caution: New Drug – Limited by United States law to 
investigational use” language). 
APR003 accountability records will be maintained by the pharmacy or designated drug 
preparation area at the study site. Upon receipt of APR003 supplies, the pharmacist or 
designated drug handler will inventory APR003 and complete the designated section of the 
shipping form. The shipping/inventory form must be sent to Sponsor (or designee), as 
instructed. 
APR003 should be stored at controlled room temperature 15°C to 25°C (59°F to 77°F). All 
study supplies must be kept in a restricted access area. 
A complete dispensing log must be maintained for all APR003 dispensed and all capsules of 
APR003 must be accounted for. 
9.1.3 
Directions for APR003 Administration 
Planned Phase 1 dose levels are described in Section 7.1. Patients will be asked to keep a diary 
to record APR003 administration. 


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The following applies to APR003 dosing: 
• Prior to each dose of APR003, premedication may be used (as specified in 
Section 9.1.3.1). 
• APR003 will be administered orally, once weekly, in 21-day cycles. APR003 will be 
taken on the Days 1, 8 and 15 of each treatment cycle. Patients will be monitored for 
CRS with vital signs performed every 2 hours for a minimum of 6 hours post-dose for 
the first cycle.  If CRS is not observed during the first cycle, monitoring is not 
necessary on Day 1 of subsequent cycles 
• APR003 should be taken on an empty stomach (patients must not eat for at least 2 hours 
before and 1 hour after APR003 administration). Patients should be instructed to record 
both the date and time of the dosing. It is recommended that patients take APR003 first 
thing in the morning on scheduled dosing days (except for PK sampling days). Note: on 
PK sampling days, patients should be instructed not to take their APR003 dose until 
instructed to do so in the clinic. 
• On days when blood for PK samples will be collected and study drug administered, 
APR003 must be administered in the clinic.  
• On each clinic day, the site will administer APR003 after all required procedures are 
complete. The patient should be counseled not to take their APR003 dose at home on 
the day of the clinic visit. APR003 will then be dispensed to the patient. 
• Each dose should be taken with a glass of water (at least 8 oz) and consumed over as 
short a time as possible unless otherwise instructed. Patients should be instructed to 
swallow the capsules whole and not to chew, crush or open them. If the patient is 
assigned to a dose level where multiple capsules are to be taken, the capsules should be 
taken consecutively, within as short an interval as possible.  
• If a patient misses to take their dose of study drug on the scheduled day, they should 
take APR003 within 72 hours after the missed dose but remain on the original dosing 
schedule. If more than 72 hours have elapsed, the patient should omit the dose and 
inform the site as soon as possible.  
• The date and time of actual APR003 dosing should be reported in the drug diary and 
eCRFs. 
If emerging clinical data (e.g., safety, tolerability, and/or PK relationships to PDx, and/or 
activity) suggest that a different regimen (e.g., frequency of administration) may be appropriate 
for APR003, the dosage of study drug will be determined and implemented by the Sponsor and 
may include a protocol amendment. 


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All dosages prescribed and dispensed to the patient and all dose changes during the study must 
be reported in the eCRF.  
9.1.3.1 
Premedications 
The following premedications may be used prior to each dose of APR003. This should be done 
in accordance with clinical site policy and best judgement of the Principal Investigator. 
• Oral acetaminophen, 1000 mg, to be taken 20 minutes prior to APR003 
• Oral diphenhydramine, 25 mg, to be taken 20 minutes prior to APR003 
The dose of acetaminophen and diphenhydramine listed above are provided as suggestions 
only. Any and all premedication should be consistent with institutional policy and the best 
judgement of the treating physician. We requested that steroids not be used prophylactically 
prior to APR003 dosing. 
After APR003 dosing, additional medications may be used according to the discretion of the 
Principal Investigator. These include but are not limited to use of tocilizumab, prednisone, 
additional acetaminophen and diphenhydramine, and nonsteroidal anti-inflammatory drugs. 
Additional guidance can be obtained from the Apros Medical Monitor. 
9.1.4 
APR003 Dose Modifications and Interruptions 
For patients who do not tolerate the protocol-specified dosing schedule, including during Cycle 
1 of Phase 1, dose adjustments are permitted in order to allow the patient to continue study 
drug. Dose adjustments must be made following discussion with and approval from the 
Sponsor Medical Monitor. All dose modifications should be based on the worst preceding 
toxicity (NCI CTCAE version 5.0) and follow the guidelines provided in Table 6. 
Given the potential that a patient who undergoes a prolonged APR003 treatment interruption 
may experience CRS upon retreatment with study drug, patients experiencing an APR003 dose 
interruption of greater than or equal to 21 consecutive days for any reason, should have their 
safety monitoring follow that of Cycle 1 Day 1 schedule upon retreatment with APR003. Thus, 
as is the case in Cycle 1 for new enrollment, patients who missed 21 or more consecutive days 
of APR003 treatment will be monitored for CRS with vital signs performed every 2 hours for a 
minimum of 6 hours post-dose for the first resumed cycle.  If CRS is not observed during this 
resumed dosing cycle, prolonged monitoring is not necessary on Day 1 of subsequent cycles.  
 


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If, however, a patient requires an APR003 dose interruption of > 21 consecutive days due to 
treatment-related toxicities, then the patient should be discontinued from treatment unless 
otherwise specified based on specific toxicities as defined in Table 6. 
In exceptional situations, study drug may continue even if the patient experienced one of the 
treatment stopping rules (Table 6) or has required a dose interruption of > 21 days. The 
decision to allow continuation of treatment will be made on a case-by-case basis following 
documented discussion between Sponsor Medical Monitor and the Investigator. If a patient 
remains on study despite a dose interruption of > 21 days, i.e., patient has evidence of clinical 
benefit and in the opinion of the investigator it is in the best interest of the patient to remain on 
study, then the rationale for remaining on study and the decision and documentation of the 
discussion with the sponsor must be available in the source documentation and described as an 
investigator comment in the eCRF.






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Worst toxicity CTCAEa 
Grade (v5.0) 
Recommended dose modifications for APR003 
Other Management Recommendations 
Formula) 
Correct any electrolyte abnormalities, or hypoxia  
Continue at the same dose level 
 
Grade 2 Assess electrolytes and concomitant medications 
Correct any electrolyte abnormalities, or hypoxia  
Continue at the same dose level 
 
Grade 3 Withhold dose  
Assess electrolytes and concomitant medications 
Correct any electrolyte abnormalities, or hypoxia.  
Upon recovery to Grade ≤1 resume treatment at one dose level lower 
500 msec 
Grade 4 QTc prolongation 
(Fridericia Formula) 
Discontinue treatment 
Infections and Infestations 
Grade 3 or 4 infection 
Hold APR003 until resolution to ≤ Grade 1 and clinically stable, and restart 
one dose level lower 
Supportive care and  
antibiotic/antifungal/antiviral intervention 
as appropriate 




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Worst toxicity CTCAEa 
Grade (v5.0) 
Recommended dose modifications for APR003 
Other Management Recommendations 
Nephritis 
Grade 3 Hyper- or 
Hypothyroidism 
Hold APR003 until resolution to ≤ Grade 1 and clinically stable, and restart 
one dose level lower 
If findings recur again, discontinue treatment 
Supportive care as clinically indicated 
Grade 4 Hyper- or 
Hypothyroidism 
Discontinue treatment 
Other Grade 3 immune-related, 
non-hematologic toxicity 
Hold APR003 until resolution to ≤ Grade 1 and completion of 
corticosteroid taper (if administered) and restart one dose level lower 
If findings recur again, discontinue treatment 
Supportive care, including corticosteroids, 
as clinically indicated 
Other Grade 4 immune-related, 
non-hematologic toxicity 
Discontinue treatment 
a 
Common Toxicity Criteria for Adverse Events (CTCAE Version 5.0) 
b 
The hepatic dose modification guidelines should be followed for deranged liver transaminases and bilirubin as defined in the above table if not 
definitively due to progressive disease in the view of the treating physician. 
c 
Determine whether hyperbilirubinemia is direct vs. indirect; if indirect, rule out hemolysis. If Grade 3 or 4 hyper-bilirubinemia is due to the indirect 
(non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear 
and haptoglobin determination), then restart one dose level lower and continue treatment at the discretion of the investigator and in consultation with the 
Sponsor Medical Monitor.  
d 
Given the potential that a patient who undergoes a prolonged APR003 treatment interruption may experience CRS upon retreatment with study drug, 
patients experiencing an APR003 dose interruption of greater than or equal to 21 consecutive days for any reason, should have their safety monitoring 
follow that of Cycle 1 Day 1 schedule upon retreatment of APR003. Thus, as is the case in Cycle 1 for new enrollment, patients who missed 21 or more 
consecutive days of APR003 treatment will be monitored for CRS with vital signs performed every 2 hours for a minimum of 6 hours post-dose for the 
first resumed cycle.  If CRS is not observed during this resumed dosing cycle, prolonged monitoring is not necessary on Day 1 of subsequent cycles.  If, 
however, a patient requires an APR003 dose interruption of > 21 consecutive days due to treatment-related toxicities, then the patient should be 
discontinued from treatment unless otherwise specified based on specific toxicities as defined in Table 6. 


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9.1.5 
APR003 Treatment Compliance 
The importance of treatment compliance should be emphasized to the patient. Patients 
will be given take-home kits and detailed instructions on how to take medications at 
home. Patients will be instructed to return all used and unused study drug containers at 
each study visit. Patient compliance with the dosing regimen will be assessed by 
reconciliation of the used and unused study drug at each clinic visit. The quantity 
dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided for 
the study. Compliance will be monitored and documented by site personnel on the 
appropriate form. The site personnel will question the patient regarding adherence to the 
dosing regimen by reviewing dosing dates and times on the used bottles, recording the 
number of capsules and strengths returned, the date returned, and determining treatment 
compliance before dispensing new medication to the study patient. 
9.1.6 
Investigational Product Accountability 
The investigator or designee must maintain an accurate record of the study drug received, 
patients to whom study drug is dispensed, study drug lost or accidentally or deliberately 
destroyed. The investigator or designee must retain all unused or expired study supplies 
until the monitor has confirmed the accountability data. Drug accountability will be noted 
by the monitor during site visits and at the completion of the study. Patients will be asked 
to return all unused study drug and packaging on a regular basis and at the end of the 
study or at the time of study drug discontinuation. 
9.1.7 
APR003 Disposal and Destruction 
The Sponsor will provide written notification to each study site regarding the destruction 
of the study drug supply, which can be destroyed by a third party. 
Drug supply may be destroyed at the study site only if permitted by local regulations and 
authorized by the Sponsor in a prior agreement. 
9.2 
Warnings and Precautions 
Based on the mechanism of action of APR003 (i.e., immune activation via TLR7 
agonism) and drug distribution, there is a potential for immune-related adverse reactions, 
in particular, immune-related hepatitis, colitis and nephritis. Investigators should closely 
follow liver transaminases and bilirubin, serum BUN and creatinine, and results of 


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urinalyses, as well as evaluate patients with diarrhea, blood in the stool, abdominal pain, 
and weight loss. 
9.2.1 
Elevations in Transaminases and/or Bilirubin 
All patients should be followed closely for treatment-emergent jaundice; nausea and/or 
vomiting; right-sided abdominal pain; bilirubinuria; coagulopathies, thrombocytopenia, or 
easy bruising; anorexia; and increased AST, ALT and/or bilirubin. Patients with 
treatment-emergent elevated liver transaminases and/or bilirubin ≥ 2x ULN or baseline 
should receive a complete work-up for hepatotoxicity, including hepatology consult. 
Concomitant medications, including alternative and herbal treatments, should be 
evaluated for potential contribution to hepatotoxicity and discontinued whenever possible. 
Imaging (ultrasound, CT, or MRI) should be performed to rule out biliary obstruction and 
tumor progression in the liver. Anti-nuclear antibodies (ANA), anti-smooth muscle 
antibodies (SMA), Epstein Barr virus (EBV) IgM, and cytomegalovirus (CMV) PCR 
should be performed as clinically indicated. A liver biopsy should be considered in 
patients with persistent ≥ 2x AST/ALT elevation above ULN or baseline, or in patients 
with ≥ Grade 3 elevations (Sanjeevaiah 2018). 
9.2.2 
Gastrointestinal Adverse Reactions 
All patients should be followed closely for the occurrence of or worsening of diarrhea 
and/or blood in the stool. Intravenous fluids should be considered and corticosteroids 
administered for colitis as clinically indicated. A lower GI endoscopy should be 
considered for patients with ≥ Grade 3 colitis. 
9.2.3 
Nephritis and Renal Dysfunction 
All patients should be followed closely for signs and symptoms of nephritis and/or renal 
dysfunction, such as increase serum creatinine, reduced urine output or oliguria, 
hematuria and/or edema. Increased frequency of monitoring (every 3 days) should be 
considered for patients with Grade 2 increased creatinine (>1.5x to 3x ULN or baseline). 
Nephrology consultation and corticosteroids should be considered for patients with ≥ 
Grade 3 increased serum creatinine. 


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9.3 
Follow-up for Toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value, must be followed-up per Table 7 below or 
more frequently as clinically indicated until resolution or stabilization of the event. 
All patients must be followed up for adverse events and serious adverse events for at least 
30 days following the last dose of study drug or until new anticancer therapy has been 
initiated, whichever occurs first.  
Suggested recommendations for follow-up of patients experiencing selected toxicities are 
described in Table 7. 
Table 7. 
 
Follow-up Evaluations for Selected Toxicities 
Toxicity 
Follow-up evaluation 
Hematologic 
If ≥ CTCAE grade 3 – 4 neutropenia or febrile neutropenia or thrombocytopenia 
has been demonstrated, these parameters should be repeated at least once a week 
(or more frequently per institutional practices, or if clinically indicated) for 4 
weeks, and subsequently at approximately 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. 
Renal 
If serum creatinine ≥ CTCAE grade 3 has been demonstrated, this parameter 
should be repeated at least twice a week until resolution to ≤ CTCAE grade 1 or 
baseline. 
Hepatic 
If direct bilirubin ≥ 3 x ULN, and ALT is ≥ CTCAE grade 3, these parameters 
should be repeated at least twice a week until resolution to ≤ CTCAE grade 1 or 
baseline. 
Cardiac 
If a QTcF > 500 msec has been demonstrated and no contraindicated medicines 
have been identified: 
• 
the ECG should be repeated, ensuring the patient is rested 
• 
draw a blood sample for APR003 PK analysis 
• 
Evaluate serum potassium and magnesium, and consider other potential 
confounding clinical factors (e.g., oxygenation, cardiac ischemia) 
• 
monitored the patient with serial ECGs until the QTcF is ≤ 500 msec. 
Prolonged QTc 
interval 
Grade 1  
• 
Assess electrolytes and concomitant medications 
• 
Correct any electrolyte abnormalities, or hypoxia  
• 
Continue at the same dose level 
 
Grade 2  
• 
Assess electrolytes and concomitant medications 


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Toxicity 
Follow-up evaluation 
• 
Correct any electrolyte abnormalities, or hypoxia  
• 
Continue at the same dose level 
 
Grade 3  
• 
Withhold dose  
• 
Assess electrolytes and concomitant medications 
• 
Correct any electrolyte abnormalities, or hypoxia.  
• 
Upon recovery to Grade ≤1 resume treatment at one dose level lower 
 
Grade 4  
• 
Discontinue 
Other Toxicities 
Patients who experience treatment-limiting toxicities must be evaluated at least 
once a week following demonstration of the toxicity until resolution to grade 1 or 
to the patient’s baseline. 
Given the potential that a patient who undergoes a prolonged APR003 treatment 
interruption may experience CRS upon retreatment with study drug, patients 
experiencing an APR003 dose interruption of greater than or equal to 21 consecutive 
days for any reason, should have their safety monitoring follow that of Cycle 1 Day 1 
schedule upon retreatment with APR003. Thus, as is the case in Cycle 1 for new 
enrollment, patients who missed 21 or more consecutive days of APR003 treatment 
will be monitored for CRS with vital signs performed every 2 hours for a minimum of 
6 hours post-dose for the first resumed cycle.  If CRS is not observed during this 
resumed dosing cycle, prolonged monitoring is not necessary on Day 1 of subsequent 
cycles.   
 
If, however, a patient requires an APR003 dose interruption of > 21 consecutive days 
due to treatment-related toxicities, then the patient should be discontinued from 
treatment unless otherwise specified based on specific toxicities as defined in Table 6. 
 


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10.0 Concomitant Medications 
The patient must be told to notify the study site about all medications he/she takes, 
including ongoing medications during the Screening period and any new medications 
taken after the start of the study drug. All prescription, over-the-counter, and herbal 
medications, in addition to supplements, should be reported until 30 days after last 
administration of the study drug. 
Participating sites that enroll into APR003-001 must have on-site, immediate access to 
tocilizumab, and ensure tocilizumab is available for each patient for administration within 
2 hours after APR003 is administered, if needed for treatment of CRS. If there is a local 
shortage of tocilizumab, 1 dose of tocilizumab must be available on-site for each patient 
for immediate administration (within 2 hours). There should also be access to an 
additional dose of tocilizumab within 8 hours after each previous dose of tocilizumab 
administered to each patient, if needed. 
Therefore, sites who do not have adequate supplies of tocilizumab should not be allowed 
to enroll patients into APR003-001. 
10.1 
Permitted Concomitant Therapy 
In general, the use of any concomitant non-cancer medication/therapy, including over-the- 
counter (OTC) medications deemed necessary for the care of the patient or to treat AEs is 
permitted during the study except for those specified as prohibited in Section 10.3. 
Medications required to treat AEs, manage cancer symptoms, concurrent stable diseases, 
and supportive care agents, such as packed red blood cell transfusions (PRBCs) (with the 
exception of the DLT evaluation period, see below), pain medications, anti-emetics, and 
anti-diarrheal agents are allowed. The use of any other potential new concomitant 
medications may be discussed between the investigator and the Sponsor Medical Monitor 
on a case-by-case basis. 
Patients taking permitted concomitant medication chronically should be maintained on the 
same dose and dose schedule throughout the study period, as medically feasible. The days 
of full pharmacokinetic blood sampling should be representative of the other study days 
with regard to the use of the chronically administered concomitant medications. However, 
if a concomitant medication is used intermittently during the study, this medication should 
be avoided on the days of full PK sampling, if medically feasible. 


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10.1.1 
Anti-diarrheal Treatment 
Anti-diarrheal treatment is recommended at the first sign of diarrhea. As a 
recommendation, initial management of diarrhea should include dietary modifications, 
extra fluid, and loperamide. 
10.1.2 
Hematopoietic Growth Factors and Transfusions 
Transfusions or growth factor support should not be used prophylactically during the DLT 
window unless clinically indicated by institutional and/or ASCO guidelines (Smith 
2006).  
If during the DLT evaluation period, growth factors are used within 7 days from the onset 
of neutropenia grade ≥ 3, the event will be considered a DLT. Patients treated with 
growth factors targeting the myeloid lineage (e.g., G-CSF, GM-CSF, M-CSF) 
≤ 2 weeks prior to Screening are not eligible for study enrollment.  
Similarly, if during the DLT evaluation period, platelet transfusions are required for 
supportive management of the patient, the event will be considered a DLT. Patients 
requiring platelet transfusions within 14 days of Screening are not eligible for study 
enrollment.  
Patients who receive RBC transfusions within 28 days of Screening are not eligible for 
study enrollment. However, after study enrollment, RBC transfusions and growth factors 
targeting the erythroid lineage (e.g., erythropoietin and darbepoetin) are allowed at any 
time. 
10.1.3 
Anti-Coagulation 
Anti-coagulation is permitted if the patients are already at stable doses of warfarin or 
stable doses of low molecular weight heparin for > 2 weeks at the time of first dose of 
study treatment. INR should be monitored as clinically indicated per investigator’s 
discretion. However, ongoing anti- coagulant therapy should be temporarily discontinued 
to allow tumor biopsy according to the institutional guidelines. 
10.1.4 
Infection Prophylaxis 
Subjects should receive preventive and anti-infection medications for fungal infections, 
pneumocystis pneumonia, herpes virus, and varicella-zoster virus according to 
institutional guidelines. In the absence of institutional guidelines, refer to the Infection 


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Prophylaxis Considerations for IEC Therapies (IEC MDACC 2020) for recommendations 
on the following medications: 
Filgrastim (Granulocyte Colony-Stimulating Factor, G-CSF, Filgrastim, Neupogen): 
Filgrastim may recommended to be administered subcutaneously at a dose of 300ug/day 
per institutional practice to reduce the duration of neutropenia and incidence of infection. 
Dose and route of administration may be altered as clinically indicated. 
Pentamidine and sulfamethoxazole/trimethoprim (SMZ/TMP): As clinically indicated 
pentamidine inhaled or IV within one week prior to C1D1 and then transition to 
sulfamethoxazole/trimethoprim (SMZ/TMP) by 3-4 weeks if counts have recovered is 
recommended per institutional standard of care to prevent Pneumocystis Jirovecii 
Pneumonia. SMZ/TMP should continue for at least one year and until CD4 > 200 cells/μL 
for two consecutive measurements Dapsone (in G6PD deficient patients), or atovaquone 
may be substituted for SMZ/TMP. 
Valacyclovir: Subjects with positive HSV or VZV serology should be given valacyclovir 
orally per institutional standard of care. Acyclovir may be substituted for Valacyclovir to 
prevent the occurrence of herpes virus infections in patients who cannot take oral 
medications. 
Entecavir: Subjects who are positive for HBsAg or HBcAb should receive entecavir per 
institutional standard. Tenofovir alafenamide or Tenofovir disopoxil fumarate may be 
substituted. Infectious Disease and/or Hepatology should be consulted if not already 
following. Subjects should be monitored for HBV DNA PCR once a month while on 
prophylaxis and for a year after stopping.  
Anti-fungal 
• Fluconazole: It is recommended that low-risk patients receive fluconazole for 
fungal prophylaxis in accordance with institutional guidelines until ANC 
> 0.5 K/μL for 3 consecutive days without growth factor support. The drug may be 
given via IV in patients unable to take it orally. 
• Posaconazole: It is recommended that high-risk patients with leukemia, recent 
allogenic transplant, prior history of mold infection, neutropenia lasting ≥ 14 days, 
Grade 3 or 4 CRS/ICANS, those who receive ≥ 3 days of corticosteroids, or those 
who develop hemophagocytic lymphohistiocytosis (HLH). If corticosteroids are 
given, continue Posaconazole for at least 1 month after completion of 
corticosteroids. Posaconazole should continue until clinically indicated. Do not 
stop posaconazole prophylaxis if ANC < 1K/μL. Voriconazole or isavuconazole 


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may be used if the patient had previously been taking them. In the event 
Posaconazole, voriconazaole, isavuconazole, or echinocandin are contraindicated 
or pose affordability/access issues, then use fluconazole for prophylaxis and 
consider aspergillus antigen testing at least once a week during corticosteroids and 
for at least a month after completion of corticosteroids. Patients not meeting high 
risk definitions will be considered to be at low risk for fungal infections and 
should receive prophylaxis as detailed above. 
NOTE: Other anti-infective agents may be substituted at the discretion of the treating 
physician. 
10.1.5 
Empiric Antibiotics 
Subjects should be started on broad-spectrum antibiotics in accordance with current 
institutional guidelines or at a minimum, a fever of 38.3°C once or two temperatures 
≥ 38.0°C at least one hour apart, and an ANC <500/mm3. Treatment with antibiotics 
should continue until ANC>500/mm3 for 3 consecutive days without growth factor 
support. Infectious disease consultation should be obtained for all subjects with 
unexplained fever or any infectious complications and if the patient is allergic to 
quinolones and cephalosporins. Antibiotic coverage for central venous catheters may be 
provided at the discretion of the investigator. 
10.1.6 
Blood Product Support 
Using daily CBCs as a guide, the subject will receive platelets and packed red blood cells 
as needed. All blood products will be irradiated and transfused per institutional guidelines 
and/or standard of care.  
10.1.7 
Medication for Cytokine Release Syndrome (CRS) 
CRS is commonly observed following immune-based biotherapeutics. Subjects can 
present with fever, rigor, malaise, headache, nausea/vomiting, or more severe, 
life-threatening symptoms of hypoxia, pulmonary edema, tachycardia, hypotension, 
aphasia, confusion, or seizures.  Early recognition of CRS is important (e.g., monitoring 
of symptoms, cytokines, CRP, and ferritin); however, diagnosis is difficult due to the 
non-specific symptoms that are observed. Recommendations for treatment and the grading 
system is based on Lee et al., 2019 and is shown in Appendices 10 and 11. 


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Premedication for CRS prophylaxis in all patients per institutional guidelines will be 
administered after discussion and review of data between Sponsor, Apros Medical 
Monitor or designee and Investigator(s). 
10.1.8 
Fever (≥ 38.3°C; ≥ 101°F) Antipyretic Therapy 
If grade 1 fever dose not respond to antipyretics/analgesics as needed after 24 hours 
initiate Actemra® (tocilizumab) therapy 8 mg/kg to be repeated every 4 to 6 hours as 
needed if no improvement in fever after 3 days. Dexamethasone 10 mg therapy may be 
administered concurrently. 
Total acetaminophen (APAP) utilization is not to exceed 2 g/day. 
10.1.9 
Medication for Immune Effector Cell-Associated Neurologic Syndrome 
(ICANS) 
ICANS occurs frequently following immune-based biotherapeutics and like CRS, is 
associated with rapid cytokine increases and high tumor burden as well as other factors. 
Severe ICANS is associated with increased CSF protein levels, encephalopathy, and other 
signs of neurotoxicity. Aggressive treatment is suggested and includes administering 
corticosteroids. Actemra® (tocilizumab) may be administered if neurotoxicity is 
accompanied by CRS (Appendices 10 and 11). 
10.1.10 
Medication for Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage 
Activation Syndrome (MAS) 
Clinical and laboratory features of MAS include fever, increased ferritin levels, 
pancytopenia, hemophagocytosis in bone marrow or lymph nodes, fibrinolytic 
coagulopathy, and liver dysfunction. Specific treatment includes administration of 
Actemra® (tocilizumab) and corticosteroids given intravenously. Canakinumab may also 
be used. Refer to (Center, 2020) for medication for Tumor Lysis Syndrome (TLS). 
TLS occurs when tumor cells release their content in the blood stream, either 
spontaneously or due to treatment, leading to metabolic disturbances including 
hyperuricemia, hyperkalemia, hypophosphatemia, and hypocalcemia. The incidence and 
severity of TLS depends on tumor volume, potential for the tumor to lyse and patient 
characteristics. Management of cardiac and neuromuscular abnormalities and preservation 
of kidney function are most important. 
Allopurinol can be used to reduce hyperuricemia and rasburicase can be used to preserve 
or improve renal function. 


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Because hyperkalemia can cause sudden death due to cardiac arrhythmias, patients should 
limit potassium and phosphorus intake during the TLS risk period (0 to 3 months). 
Frequent measurements of serum electrolytes, continuous cardiac monitoring and the 
administration of oral sodium polystyrene are recommended. Symptomatic hypocalcemia 
should be treated with calcium supplementation; non-symptomatic hypocalcemia does not 
require treatment. 
10.1.11 
Surgery 
Caution is advised on theoretical grounds for any surgical procedures during the study. 
The appropriate interval of time between surgery and the dose of APR003 required to 
minimize the risk of impaired wound healing and bleeding has not been determined. 
10.1.12 
Other Concomitant Medications to Control Side Effects 
Concomitant medications to control side effects of therapy may be given per institutional 
standard of care. 
10.2 
Permitted Concomitant Therapy to be Used with Caution 
Organic anion transporting polypeptides 1A2 and 1B1 (OATP1A2 and OATP1B1, 
respectively) are believed to play a central role in the absorption and liver-directed 
distribution of APR003. In addition, APR003 is a substrate of CYP3A4. Therefore, the 
concomitant use of drugs that are inhibitors of OATP1A2 and OATP1B1, or that affect 
CYP3A4 (inducers or inhibitors) may impact the pharmacokinetic profile of APR003. 
Whenever possible, such agents should be avoided during study participation and 
discontinued fourteen (14) days prior to first drug administration. If such agents cannot be 
avoided, site must collect the information per the eCRF guidelines for concomitant 
medications, including the drug name, dosage, duration, and duration of administration. In 
addition, unscheduled PK evaluations should be obtained in the event of AEs considered 
related to the use of these agents concurrently with APR003. 
Drugs that impact gastric pH should not be administered during study participation 
whenever possible. In particular, proton pump inhibitors or H2-blockers should be 
avoided. Patients must discontinue these agents at least 7 days prior to Cycle 1 Day 1. If 
gastric acid management is necessary, antacids such as such as milk of magnesia, Tums®, 
Pepto-Bismol®, etc., is preferred and should not be administered within 24 hours of 
APR003 administration. Please contact the Sponsor Medical Monitor for additional 
guidance. 


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A list of these agents that are inhibitors of OATP1A2 and OATP1B1, inducers/inhibitors 
of CYP3A4, and PPIs/H2-antagonists is provided in Appendix 8. The Sponsor will 
monitor for potential increased adverse events in patients concurrently administered 
sensitive CYP450 substrates or substrates with a narrow therapeutic range, as APR003 is 
a cytokine modulator. 
10.3 
Prohibited Concomitant Therapy 
Anti-cancer therapies and investigational agents other than those specified in this protocol 
are prohibited during the study. Similarly, systemic corticosteroids or other form of 
immunosuppressive therapy (other than inhaled or intranasal, or physiological steroid 
replacement) are also prohibited during the study unless requirement for the management 
of a toxicity. In addition, the medications agents that are known or possible risk of QT 
prolongation prohibited. Please refer to Appendix 9.


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11.0 Visit Schedule and Assessments 
11.1 
Study Flow and Visit Schedule 
The detailed schedule of evaluations is provided in Appendix 1. 
11.1.1 
Screening 
A written informed consent form (ICF) approved by the Sponsor. and by the appropriate 
IRB or IEC will be obtained by the study site before any study specific procedures are 
initiated. After a patient signs the study ICF, the investigator or study site personnel 
should determine patient eligibility.  
The clinical screening period starts once a patient has provided written informed consent 
to participate in the study. Patients will be evaluated against study inclusion and exclusion 
criteria and safety assessments. 
Data will be collected on patient characteristics including demographic information, 
relevant medical history and current medical conditions, diagnosis and extent of cancer, 
prior anticancer therapies, prior medication/significant non-drug therapies, and any other 
assessments that are done for the purpose of determining eligibility for inclusion in the 
study. 
Most screening assessments must be completed within 28 days prior to the first dose of 
study medication. Screening safety laboratory tests (e.g., hematology, serum chemistry 
panel, coagulation tests, urinalysis) must be performed within 14 days of C1D1. For 
females of child-bearing potential, a serum or urine pregnancy test must be performed 
within 72 hrs of the first dose of study drug. Radiologic tumor evaluation should be 
conducted within 14 days of C1D1; however, tumor assessments up to 28 days prior to the 
first dose will be acceptable. The Screening tumor assessment will provide the baseline 
tumor measurements, which will be used to determine future responses and/or 
progression. 
Any procedure collected as part of patients’ standard of care can be referenced to meet 
screening criteria even if performed before the ICF for this study has been signed, as long 
as the evaluation was performed within the required window period prior to the planned 
first dose, data are entered into the appropriate eCRF page, and source documents are 
available at the site for verification during monitoring visits. Acceptable procedures 
include hematology, serum chemistry, thyroid function (TSH, T3 and T4, 12-lead ECG, 
tumor imaging, urinalysis, hepatitis B and C serologies, and HIV serology. 


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Please refer to Appendix 1 for a detailed description of all Screening procedures. 
11.1.1.1 
Screen Failures 
A patient who signed an ICF but did not satisfy inclusion/exclusion criteria will be 
considered a screen failure. Demographic information, informed consent, and 
Inclusion/Exclusion pages, as well as the reason for screen failure must be reported for all 
screen failure patients. No other data will be entered into the clinical database for patients 
who are screen failures. For patients who fail screening, AEs related to study procedures 
will be reported in the database up to the screen failure date. 
Rescreening is permitted in this study. If a patient fails any of the inclusion or exclusion 
criteria, at the agreement of the Sponsor Medical Monitor and the investigator, the patient 
may be rescreened after a suitable period of time (the exact length is dependent upon the 
reason for the screen failure). Any patient who is rescreened will be issued a new patient 
number that will be linked to the original patient number. A patient may only fail 
screening once. 
11.1.2 
Treatment Period 
During the treatment period, the patient must follow the Investigator’s instructions with 
regards to contraception, concomitant medications, and dosing regimen. A treatment cycle 
is defined as 21 days (3 calendar weeks) for the purposes of scheduling procedures and 
evaluations. Patients may continue study treatment for up to 1 year or until the patient 
experiences unacceptable toxicity that precludes any further treatment, disease 
progression, and/or treatment is discontinued at the discretion of the investigator or by 
patient request. 
For details of assessments during the treatment period, refer to Appendix 1. 
11.1.3 
Treatment Discontinuation 
All patients will be permitted to continue on treatment for up to 1 year, or until an early 
discontinuation event, whichever occurs first. Reasons for early discontinuation include, 
but are not limited to: 
1. Progressive disease (PD).* 
2. Unacceptable toxicity. 
3. Request by the patient to withdraw. 


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4. Administration of medications that are prohibited while on study, including but 
not limited to, non-protocol chemotherapy, immunotherapy, or anti-tumor 
hormonal therapy, other experimental drugs, systemic corticosteroids or other 
form of immunosuppressive treatment, or other agents listed in Appendix 9. 
5. Patients whose treatment is delayed due to treatment-related toxicities for more 
than 21 days. 
6. Death 
7. Pregnancy 
8. Investigator decision 
9. Significant protocol violation 
10. Patient noncompliance 
11. Study termination by the Sponsor.  
*Due to the potential for pseudoprogression and/or delayed response, patients with an 
initial assessment of PD by RECIST v1.1., should, whenever possible, continue on study 
treatment until disease progression is radiologically confirmed. Confirmation of PD is 
defined as radiographic demonstration of progressive disease in two consecutive imaging 
evaluations performed 4-8 weeks apart. 
At the time a patient permanently discontinues study drug, the End of Treatment (EOT) 
visit should be scheduled as soon as possible (within 30 days), at which time all of the 
assessments listed for the EOT visit will be performed (Appendix 1). An End of 
Treatment Disposition eCRF page should be completed, giving the date and reason for 
stopping the study drug. If the decision to withdraw the patient occurs at a regularly 
scheduled visit, that visit may become the EOT visit rather than having the patient return 
for an additional visit. Treatment discontinuation is not considered as the end of the study. 
Upon treatment discontinuation, patients will enter the Long-Term Follow Up period. 
11.1.4 
Long-term Follow-up 
Long-term follow-up information, including survival status and the first subsequent 
anticancer therapy, will be obtained for all surviving subjects who discontinue study 
therapy. Information will be collected at approximately 3- to 6-month intervals at the 
Sponsor’s discretion through 2 years. This information will be gathered via telephone or 
e-mail with the subjects/caregivers or referring physician offices. Data will be collected in 
the source documents (e.g., subject medical record) and transcribed into the eCRF. 


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11.1.5 
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want 
any further study related contact.  
The Sponsor will continue to retain and use all research results that have already been 
collected for the study evaluation. All biological samples that have already been collected 
may be retained for up to 25 years or longer if required under local law and analyzed at a 
later date. Other analyses may include other potentially relevant biomarkers and/or safety. 
This may also include the development of ways to detect, monitor or treat cancer. 
If a patient withdraws consent, the investigator or designee must make every effort (e.g., 
telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information. Study drug must be discontinued, and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.


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12.0 Assessment Types 
12.1 
Safety & Tolerability Assessments 
Safety endpoints include the following: 
• Incidence and nature of DLTs. 
• Incidence, nature, and severity of adverse events, including clinically significant 
laboratory values, graded according to NCI CTCAE v5. 
12.1.1 
Physical Examination 
Physical examinations will take place at the visits specified in Appendix 1. Complete physical 
exams are required at Screening, C1D1 and EOT. More frequent or complete physical 
examinations may be performed at the discretion of the investigator and if clinically indicated. 
An abbreviated and symptom-directed physical exam will occur at all other visits as indicated 
in Appendix 1 unless the investigator considers a complete physical examination necessary. 
Significant findings that were present prior to the signing of ICF must be included in the 
Medical History eCRF page. 
12.1.2 
Vital Signs 
Vital signs (body temperature, heart rate, blood pressure and respiratory rate) and oxygen 
saturation must be performed before dosing and as indicated in Appendix 1, and according to 
the standards at each institution. Patients will be monitored for CRS with vital signs performed 
every 2 hours for a minimum of 6 hours post-dose for the first cycle.  If CRS is not observed 
during the first cycle, monitoring is not necessary on Day 1 of subsequent cycles. 
Vital signs will be assessed on the scheduled day, even if study drug is being withheld. More 
frequent examinations may be performed at the discretion of the investigator and as clinically 
indicated. Abnormal findings that are considered to be clinically significant must be reported as 
an AE on the AE eCRF. 
As clinically indicated, vital signs will be measured as an out-patient and recorded in the 
patient diary and reported to the investigative site. 


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12.1.3 
Height and Weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor 
clothing, but without shoes) will be measured as indicated in Appendix 1. Height will be 
measured only at Screening/baseline. 
12.1.4 
Performance Status 
The ECOG performance status (Table 8) will be assessed as indicated in Appendix 1, 
irrespective of the time of dosing. 
Table 8. 
 
Eastern Cooperative Oncology Groups Performance Status (ECOG) 
Grade 
ECOG Status 
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 
12.1.5 
Laboratory Evaluations 
Each site’s local, CLIA-certified laboratories will be used for the analysis of all safety 
laboratory evaluations. Refer to Appendix 4 for a list of all the safety laboratory parameters 
that should be measured. Samples will be collected at the specified time points as indicated in 
Appendix 1. More frequent assessments may be performed if clinically indicated, or at the 
investigator’s discretion; these should be recorded on the Unscheduled Visit eCRFs. 
Abnormal laboratory values that are considered by the investigator to be clinically significant 
(e.g., require an interruption or delay to study drug, lead to clinical symptoms, or require 
therapeutic intervention) must be reported as an AE in the AE eCRF.  
At study start, the Sponsor must be provided with a copy of each site’s local laboratory 
certification and tabulation of the normal ranges for each parameter required. The local 
laboratory normal ranges should be kept up to date on an ongoing basis. In addition, if at any 
time a patient has laboratory parameters obtained from a different outside laboratory, the 
Sponsor must be provided with a copy of the certification and a tabulation of the normal ranges 
for that laboratory. 


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Hematology, chemistry, coagulation, urinalysis, and pregnancy local clinical laboratory 
parameters collection plan and requirements are detailed in Appendix 1 and Appendix 4. 
12.1.6 
Electrocardiogram (ECG) 
Standard 12 lead ECGs will be performed as per the assessment schedule provided in 
Appendix 1. More frequent examinations may be performed at the discretion of the 
investigator and as clinically indicated. 
All ECGs will be performed in triplicate (3 sequential ECGs spaced over a 5-minute period, 
approximately). 
Significant findings must be recorded either as Medical History (if present before the first dose 
of study treatment) or as an AE on the AE eCRF page (if newly occurring or worsening since 
treatment initiation). 
If an abnormal ECG is obtained at any time and is considered clinically significant, the 
patient’s electrolytes must be reviewed and repeat ECG measurements done after correction of 
any electrolyte abnormalities. Whenever an ECG with a QTcF change from baseline > 60 msec 
or a new absolute QTcF ≥ 501 msec result is observed in patients on study drug, an 
unscheduled PK sample to assess concentration APR003 should be obtained; the time of 
sample collection and time of dosing should be noted. 
Generally, baseline and all corresponding time point ECGs should not be collected within 
3 hours after food or beverage consumption and should be performed after the subject has 
rested quietly for at least 10 minutes in a supine position.  
When the timing of these measurements coincides with a blood collection, the ECG should be 
obtained prior to the nominal time of the blood collection, BP, and heart rate. 
When matched with PK sampling, the ECG must be carried out before each PK sample 
drawing such that the PK sample is collected at the nominal time (i.e., the timing of the PK 
collections overrides the timing of the ECG collections).  
At each time point (see the Schedule of Evaluations, Appendix 1), 3 consecutive ECGs will be 
performed at approximately 2 minutes apart to determine the mean QTcF interval; the average 
of the triplicate ECG measurements collected at each pretreatment time point on Day 1 will 
serve as each subject’s time-controlled baseline QTc value. If the mean QTcF is prolonged 
(≥45 msec from the baseline or is ≥500 msec), then the ECGs should be re-evaluated by a 
qualified person at the site for confirmation as soon as the finding is made, including 
verification that the machine reading is accurate. If manual reading verifies a QTcF 
of ≥45 msec from the baseline; or is ≥500 msec, immediate correction for reversible causes 


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(including electrolyte abnormalities, hypoxia, and concomitant medications for drugs with the 
potential to prolong the QTcF interval) should be performed. In addition, repeat ECGs should 
be immediately performed hourly for at least 3 hours until the QTcF interval falls below 
≥45 msec from the baseline; or is ≤500 msec. If QTcF interval reverts to less than 45 msec 
from the baseline; or is ≤500 msec, and in the judgment of the investigator(s) and sponsor is 
determined to be due to cause(s) other than investigational product, treatment may be continued 
with regular ECG monitoring. If in that timeframe the QTcF intervals rise above ≥45 msec 
from the baseline; or is ≥500  msec the investigational product will be held until the QTcF 
interval decreases to ≤45 msec from the baseline; or is ≤500  msec.  
Note: If QTc values remain ≥500 msec (or ≥45 msec from the baseline) for greater than 4 hours 
(or earlier at the discretion of the investigator); or QTc intervals get progressively longer, the 
subject should undergo continuous ECG monitoring. A cardiologist should be consulted if QTc 
intervals do not return to less than 500 msec (or to <45 msec above the baseline) after 8 hours 
of monitoring (or earlier at the discretion of the investigator). 
Once the QTcF interval decreases to ≤45 msec from the baseline or ≤500 msec, patients may 
restart the investigational product at the next lowest dose level. If the QTcF interval has still 
not decreased to ≤45 msec from the baseline or ≤500 msec after 2 weeks, or if at any time a 
patient has a QTcF interval >515 msec or becomes symptomatic, the patient will be removed 
from the study. Additional triplicate ECGs may be performed as clinically indicated.  
Prior to concluding that an episode of QTcF interval prolongation is due to investigational 
product, thorough consideration should be given to potential precipitating factors (e.g., change 
in patient clinical condition, effect of concurrent medication, electrolyte disturbance) and 
possible evaluation by specialist. 
If patient experiences a cardiac or neurologic AE (specifically syncope, dizziness, seizures, or 
stroke), triplicate ECGs should be obtained at the time of the event.  
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a qualified 
physician’s interpretation determines that the QTc values are in the acceptable range. 
ECG values of potential clinical concern are listed below in Table 9. 




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The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the ECG laboratory to the investigator, and not to be considered as all-inclusive of what to 
be reported as AEs/SAEs. 
Clinically significant findings must be discussed and documented with the Sponsor prior to 
enrolling the patient in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor response will be determined locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 (Appendix 5) and the modified RECIST criteria for 
immunotherapeutics (iRECIST) (Appendix 6). The local investigator’s assessment will be used 
for the efficacy endpoint analyses and for treatment decision making. 
12.2.1 
Imaging Requirements 
Imaging assessments (Table 10) will be performed at screening/baseline, preferably within 
14 days of start of treatment (Day -14 to Day -1 prior to C1D1). All CT, MRI or PET/CT scans 
will image the chest/abdomen/pelvis. Assessment modality should stay consistent over the 
course of the study unless precluded by clinical status (e.g., renal insufficiency precludes 
contrast administration). 


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Table 10.  
Imaging Assessments and Collection 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
CT, PET/CT* or MRI 
with contrast enhancement (Chest, 
Abdomen, Pelvis) 
*if PET/CT is the preferred method for 
imaging, the CT portion must be of the 
same resolution as a diagnostic CT 
Required 
Every 3 cycles (± 5days), e.g., 
C4D1, C7D1, C10D1, etc. 
Brain CT or MRI with contrast 
As clinically indicated; required 
if there is clinical evidence of 
brain metastasis 
Not Applicable. Presence of 
CNS metastases is an exclusion 
criterion 
Any imaging assessments already completed within 28 days of the planned C1D1 as part of the 
patient’s standard-of-care, including before signing the main study ICF, can be considered as 
the baseline images for this study. 
Subsequent radiologic tumor assessments will be performed every 3 cycles (e.g., C4D1, C7D1, 
C10D1, etc.) ± 5 days Patients assessed to have either complete response (CR), partial response 
(PR), or progressive disease (PD) will undergo a confirmatory CT scan 4- 8 weeks later.  
Whenever possible, patients with progressive disease should remain on treatment until a 
subsequent radiologic tumor evaluation confirms PD.  
Sites of known or suspected bone disease may be assessed by 18F NaF PET scan, 99Tc bone 
scan, or CT/MRI according to local clinical practice. Bone metastases may only be considered 
as non-target lesions. 
In case of an unscheduled or delayed tumor assessment for any reason, subsequent tumor 
assessments should be performed according to the originally planned schedule unless a scan has 
been performed within 30 days. 
Note: The radiological assessment should be performed prior to any tumor biopsy procedure 
because inflammation and edema caused by the procedure may affect the imaging evaluation. 
12.3 
Pharmacokinetic, Pharmacodynamic and Immunogenicity Assessments 
12.3.1 
Pharmacokinetic (PK) Assessments 
A primary objective of this study is to characterize the PK of APR003 at different dose levels. 
Although APR003 is designed to have limited systemic distribution, with exposure 
concentrated in the liver and GI tract, standard PK evaluations are key to understanding the 
relationship between dose and actual systemic levels. 


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Serial blood samples will be collected from all patients at all dose levels to characterize the PK 
of APR003 according to the schedule provided in Appendix 2. 
On the day of the PK sampling, APR003 must be administered in the clinic on an empty 
stomach (patients should not eat for at least 1 hour before APR003 administration, and for 
2 hours after). The exact dates and times of dosing and sampling must be recorded on a PK 
blood and collection log in a 24-hour format. 
Residual samples from this study may also be used for exploratory analysis to further 
characterize the PK and any metabolite(s), or PDx, as necessary. 
If any of the scheduled sampling times are missed or a sample is not drawn according to this 
schedule, the actual collection date and time will be recorded, and the remaining samples will 
be collected on schedule whenever possible. 
If vomiting occurs within 4 hours following study drug administration on the day of PK blood 
sampling, no additional study medication should be taken in an effort to replace the material 
that has been vomited. Any vomiting during a treatment cycle must be recorded in the Adverse 
Events eCRF and the Sponsor Medical Monitor notified. Because APR003 is only administered 
once weekly, the Sponsor may request that another day of PK sample be scheduled as 
unscheduled visits. 
If any of the following events occurs, an unscheduled PK sample should be collected: 
• If a patient treated with the study drug experiences an AE that results in an unscheduled 
visit or fits the criteria of a SAE or DLT, as determined by the investigator. The date and 
time of last dose should be recorded. 
• Whenever an ECG with a QTcF change from baseline > 60 msec or a new absolute 
QTcF ≥ 501 msec result is known. The exact time of sample collection should be noted 
in the unscheduled eCRF. 
For details on sample handling, please refer to the study the Laboratory Manual. 
12.3.1.1 
Analytical Method 
Plasma APR003 concentrations will be measured using a validated liquid chromatography-
mass spectrometry/mass spectrometry (LC-MS/MS) assay. The lower limit of quantification 
(LLOQ) of APR003 is targeted to be approximately 0.1 ng/mL. 


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13.0 Safety Monitoring and Reporting 
13.1 
Adverse Events 
13.1.1 
Definitions and Reporting 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with the study drug. AEs include any unfavorable and unintended illness, sign, symptom, 
clinically significant laboratory test abnormality, or disease temporally associated with the use 
of a medicinal product that has appeared or worsened during the course of the clinical trial, 
regardless of causal relationship to the study drug(s) under study.  
• The documentation of non- serious AEs and SAEs begins following the patient’s first 
dose.  
• Any medical condition or clinically significant laboratory abnormality with an onset 
date before the dosing on C1D1 is considered to be a pre-existing condition that must 
be listed on the Medical History eCRF and should not be considered an AE unless the 
condition worsens in intensity or frequency after study drug start on Day 1 (e.g., Grade 
2 nausea prior to Cycle 1 Day1 becomes Grade 3 nausea after first dose on Cycle 1 
Day1) 
• Any medical condition or clinically significant laboratory abnormality with an onset 
date before C1D1 and, in the opinion of the investigator, is felt to be secondary to a 
study-related procedure should be reported on the Medical History eCRF and noted as 
“study procedure-related”. 
All Adverse Events (AEs) from the time of first study drug dose through 30 days after the last 
dose of the study drug or until a new anti-cancer therapy is initiated, whichever is shorter, must 
be documented in the medical record and reported on the AE electronic Case Report Form 
(eCRF). AEs considered to be possibly related to study drug should be followed to resolution 
or stabilization. 
The grading of AEs will be done using the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 5.0. In addition, for each AE, the investigator must indicate the 
attribution of the AE to study drug (i.e., related or unrelated), and the attribution of the AE to 
the malignancy. 


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13.1.2 
Laboratory Test and Vital Sign Abnormalities 
13.1.2.1 
Definitions and Reporting 
Laboratory and vital sign abnormalities should only be reported as AEs if they are considered 
to be clinically significant by the investigator (i.e., associated with clinical symptoms and/or 
require treatment). Not every laboratory abnormality or abnormal vital sign qualifies as an 
adverse event. A laboratory test result or vital sign result must be reported as an adverse event 
if it meets any of the following criteria: 
• Accompanied by clinical symptoms. 
• Results in a change in study drug (e.g., treatment interruption or treatment 
discontinuation). 
• Results in a medical intervention (e.g., potassium supplementation for hypokalemia) or 
a change in concomitant therapy. 
• Results in more frequent follow-up assessments or further diagnostic investigation. 
• Clinically significant in the investigator’s judgment. 
13.1.3 
Documenting Adverse Events 
It is the responsibility of the investigator to document all AEs that occur during the course of 
the study. An AE should be documented as a single medical diagnosis whenever possible. 
When this is not possible, the AE should be documented in terms of signs and/or symptoms 
observed by the investigator or reported by the patient at each study visit. 
All AEs occurring after the patient’s first dose through the treatment termination visit must be 
reported, regardless of whether or not the AEs are considered drug-related until 30 days after 
the last dose or until new anticancer therapy is initiated, whichever is shorter. All AEs, whether 
in response to a query, observed by the study site personnel, or reported spontaneously by the 
patient, will be recorded. 
At each visit during the study, the patient will be assessed for the occurrence of new and 
ongoing AEs. The following data will be collected on all AEs and recorded on the appropriate 
eCRF: 
• Event name (diagnosis preferred, if unknown, record the signs/symptoms) 
• Onset date and end date 
• Severity 


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• Seriousness 
• Action taken regarding study drug 
• Corrective treatment, if given 
• Outcome 
• Investigator’s assessment of causality 
13.2 
Serious Adverse Events (SAEs) 
13.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Death 
• Life-threatening (i.e., the patient was, in the opinion of the investigator, at immediate 
risk of death from the event as it occurred. It does not apply to an AE that 
hypothetically might have caused death if it were more severe). 
• Inpatient hospitalization or prolongation of existing hospitalization (i.e., the AE 
required at least a 24-hour in-patient hospitalization or prolonged a hospitalization 
beyond the expected length of stay). Hospitalizations for elective medical/surgical 
procedures, scheduled treatments, or routine check-ups are not SAEs by this criterion). 
• Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly/birth defect (i.e., an adverse outcome in a child or fetus of a patient 
exposed to the molecule or investigational product before conception or during 
pregnancy). 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 


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13.2.2 
SAE Reporting 
SAE collection starts from the time of first study drug dose through 30 days after the last dose 
of the study drug or until a new anti-cancer therapy is initiated, whichever is shorter. 
All SAEs, whether related or unrelated to study drug, must be immediately reported to the 
sponsor or its designees within 24 hours of the investigator’s awareness of the event via EDC. 
In the event that the EDC is not available, paper forms may be used. In the event of questions 
regarding SAE reporting, the site may contact: 
Safety Contact Information: 
Medpace Clinical Safety 
 
Medpace SAE hotline – USA: 
Telephone: +1-800-730-5779, dial “3” or +1-513-579-9911, dial “3” 
Facsimile: +1-866-336-5320 or +1-1-513-570-5196 
E-mail: medpace-safetynotification@medpace.com 
1. Email your SAE form to [Drug safety contact] email address, copying the Sponsor Medical 
Monitor. 
2. Provide the name of the PI, your name, the telephone number where you can be reached 
and the protocol name and title. 
3. Immediately forward the SAE form and any supporting documentation to [drug safety 
contact], copying the Sponsor Medical Monitor. This must be done within 24  hours of 
becoming aware of the event. 
The investigator should take all appropriate measures to ensure the safety of the patients, 
notably he/she should follow a patient with an SAE until the event has resolved or the 
condition has stabilized. This may imply that follow-up will continue after the patient has left 
the study, and that additional investigations may be requested by the sponsor.  
13.3 
Assessment of Severity: AE and SAE Grading 
The severity assigned to an AE (Table 11) should be graded according to NCI CTCAE criteria 
v. 5.0. 


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Table 11.  
Definitions of Adverse Events Severity 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. The AE does not interfere with routine activities. The 
patient may experience slight discomfort. 
Grade 2 (Moderate) 
Moderate; minimal, local, or noninvasive intervention indicated. The AE 
interferes with routine activities. The patient may experience significant 
discomfort. 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated. The patient is unable 
perform routine activities. The patient may experience intolerable discomfort or 
pain. 
Grade 4  
(Life- Threatening) 
Life-threatening consequences: urgent intervention indicated. 
Grade 5 (Fatal) 
Death due to AE 
Based on the NCI Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
13.4 
Assessment of Causality 
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related”. An event is considered related if there is “a reasonable possibility” that the event 
may have been caused by the product under investigation (i.e., there are facts, evidence, or 
arguments to suggest possible causation). 
Categories of Attributions for “related” events: 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the study medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later 
be upgraded to “probably related” or “definitely related”, as appropriate. 


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Categories of Attributions for “unrelated” events: 
• Unlikely related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration 
of the study intervention) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
13.5 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study drug must be 
reported to the Sponsor within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the Sponsor. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the study drug any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported on the SAE Report Form 
within 24 hours of learning of its occurrence. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
drug in this study. Consent to report information regarding these pregnancy outcomes and 
details of the birth should be obtained from the mother.


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14.0 Data Collection and Management 
14.1 
Data Confidentiality 
Information about study patients will be kept confidential and secured in accordance with 
applicable laws and regulations. Those regulations require a signed patient authorization 
informing the patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI 
In the event that a patient revokes authorization to collect or use PHI, all information collected 
prior to the revocation of patient authorization will continue to be used by the Sponsor. For 
patients who have revoked authorization to collect or use PHI, the investigator and study site 
should attempt to obtain permission to collect follow-up safety information (e.g., has the 
patient experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, in order to prevent unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of individually 
assigned user identification codes and passwords, made available only to authorized personnel 
who have completed prerequisite training. 
14.2 
Clinical Monitoring 
Representatives of the Sponsor (or designee) will monitor this study until completion. 
Monitoring will be conducted through personal visits with the Investigator and study site staff 
as well as any appropriate communications by mail, fax, email, or telephone. The monitor is 
responsible for routine review of the eCRFs at regular intervals throughout the study to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The purpose of monitoring is to ensure compliance with the protocol and the 
quality and integrity of the data. 
In accordance with GCP, the study monitor must have direct access to the Investigator’s source 
documentation in order to verify the data recorded in the eCRFs for consistency. The 
Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are resolved. 


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14.3 
Data Collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR 
Part 11 requirements, Investigator site staff will not be given access to the EDC system until 
training. Automatic validation programs check for data discrepancies in the eCRFs and allow 
modification or verification of the entered data by the investigator staff. 
The principal investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Blood and tumor samples for PK and PDx evaluations will be collected by sites and sent to a 
central laboratory for processing. Radiological data will be acquired by the sites and interpreted 
locally.  
14.4 
Database Management and Quality Control 
For studies using eCRFs, Sponsor personnel (or designee) will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
15.0 Statistical Considerations 
15.1 
Sample Size Justification 
It is anticipated that between 12-36 patients will be enrolled into this trial. Patients who 
discontinue prior to receiving at least 3 doses of APR003 in Cycle 1 for reasons other than a 
DLT will not be considered evaluable for DLTs and will be replaced. 


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15.2 
Analysis Populations 
15.2.1 
All Enrolled Population 
The All Enrolled population includes all patients who are enrolled into the study after signing 
an informed consent form. 
15.2.2 
Safety and DLT Evaluable Populations 
15.2.2.1 
Safety Population 
The Safety population includes all patients who received at least one full or partial dose of 
study treatment. Patients will be analyzed according to the treatment they actually received as a 
first dose. Except for the summary of DLTs, the safety population will be used for all safety 
analyses. All tables will be presented for each dose escalation cohort. Listings will include all 
patients’ data regardless of analysis population. 
15.2.2.2 
DLT Evaluable Population 
The DLT-evaluable population includes all patients who either receive at least 3 doses of 
APR003 in Cycle 1, or who experience a DLT. Patients who discontinue prior to receiving the 
requisite amount of study treatment for reasons other than a DLT (for example, withdrawal of 
consent, rapidly progressive disease, protocol violation, etc.) will not be considered evaluable 
for DLTs and will be replaced. 
 
 
 
 
 
 


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15.2.4 
Pharmacokinetic Analysis Population 
The PK analysis population consists of all dosed patients who provide adequate PK samples for 
the characterization of PK parameters. A profile is considered evaluable if all of the following 
conditions are satisfied: 
• Patient receives one of the planned treatments 
• Patient did not vomit within 4 hours after the dosing of APR003 
Note: patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. Specific time points might be 
removed from the analysis set if technical issues with the sample are reported (e.g., sampling 
issues, missing information). These patients and data points will be identified at the time of 
analysis. 
15.3 
Pharmacokinetic and Pharmacodynamic Analyses 
15.3.1 
Pharmacokinetic (PK) Analyses 
Descriptive statistics (mean, SD, CV% or median [range]) will be presented on all parameters 
for each dose level group. All patients treated at the same dose level will be analyzed together.  
Individual and mean plasma concentrations of APR003 and APR003 metabolites by time point 
will be descriptively summarized in tables and graphs by dose level. Summary statistics include 
n, arithmetic mean, median, standard deviation (SD), geometric mean, coefficient of variation 
(CV) (%) and geometric CV (%), minimum and maximum.  
Pharmacokinetic endpoints include, but are not limited to, the following parameters: 
• Area under the curve (AUC)  
• AUC from time zero to time t (AUC0-t)  
• AUC from time zero to time infinity (AUC0-ꝏ)  
• AUC over the dosing interval (AUCtau)  
• Maximum concentration (Cmax)  
• Time-to-maximum concentration (Tmax)  
• Elimination half-life (T1/2)  
• Apparent volume of distribution at steady state after administration (Vss/F)  


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• Apparent total plasma clearance (CL/F) 
The PK of APR003 will be summarized and date presented as appropriate for data collected. 
Additional PK analyses will be conducted as appropriate. 
 
 
 
 
 
 
 
15.4 
Patient Disposition 
Patient disposition will be summarized, including of patients who enrolled in the study, of 
patients in various analysis populations, of patients who completed the treatment, discontinued 
treatment early, and the reasons for treatment discontinuation, as well as summary for those 
patients who completed the study, terminated study early, and the reasons for early study 
termination. 
Patient disposition information and patients excluded from various analysis populations will be 
listed. 
15.5 
Demographics 
The demographic characteristics (e.g., age, race, ethnicity, sex, baseline height, and baseline 
body weight) will be summarized and listed. Categorical baseline characteristics (e.g., sex, 
ethnicity, and race) will be summarized by frequency and percentage. 
A listing for all demographic characteristics will be provided. 
15.6 
Baseline Characteristics 
Baseline characteristics summary will include the following: 
• Disease history, such as time since cancer diagnosis, site of disease involvement, and 
time since metastases; 


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• Prior therapies, such as prior systemic therapy, number of prior chemotherapy, and 
Prior surgery; and 
• Baseline disease characteristics, such as ECOG PS and tumor burden. 
15.7 
Prior and Concomitant Medications 
Each medication will be coded to a preferred term and an Anatomic Therapeutic Classification 
(ATC) code using WHODrug dictionary. Prior concomitant medication is defined as any 
medication ended prior to the first day of the study drug. The number and percentage of 
patients taking each prior or concomitant medication will be displayed by medication class, 
preferred term, and dose cohort. 
15.8 
Efficacy Analyses 
Imaging (CT, MRI, PET/CT) assessments will be used for all efficacy assessments of anti-
tumor activity on study. Tumor assessment will be evaluated by investigators per both RECIST 
v1.1 and iRECIST.  
Objective response rate (ORR), disease control rate lasting ≥ 6 months (DCR6) duration of 
response (DOR), and progression-free survival (PFS) will be defined using the rules of both 
RECIST v1.1 (see Appendix 5) and iRECIST (see Appendix 6). The results for DOR and PFS 
using the different evaluation methods will both be reported. The primary ORR endpoint will 
be based upon RECIST v1.1. 
• ORR is defined as the proportion
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




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DLTs will be listed and their incidence summarized by primary system organ class, worst 
grade based on the CTCAE version 5.0, and type of adverse event for each dose escalation 
cohort. DLT-evaluable population will be used for these summaries. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type of 
AE and treatment group for each study part. 
15.9.3 
Vital Signs 
Vital signs and the corresponding change from baseline values will be summarized by dose 
escalation group and scheduled time point. All treatment-emergent abnormal and clinically 
significant findings must be reported as AEs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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15.9.6 
Safety Monitoring 
Safety data will be reviewed by the Safety Review Committee (SRC) at the end of each dose 
escalation cohort (i.e., after 3 or 6 patients have been enrolled and all patients have completed 
the DLT-evaluation period [Cycle 1]). The SRC is comprised of the Sponsor Medical Monitor 
and the Principal Investigator (or designee) from each participating site. Safety data will be 
examined on an ongoing basis by the SRC to ensure safety of the study patients and 
compliance with the trial rules. Ethical, Legal, and Administrative Issues. 
15.10 
Good Clinical Practice 
The procedures described in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigator abide by 
GCP, as described in ICH guideline E6 and in FDA 21 CFR parts 11, 50, 54, 56, and 312. 
Compliance with GCP provides public assurance that the rights, safety, and well-being of trial 
subjects are protected and are consistent with the principles that have their origin in the 
Declaration of Helsinki, and that the clinical trial data are credible. 
15.11 
Subject Information and Informed Consent 
Before being admitted to the clinical study, the subject must consent to participate after the 
nature, scope, and possible consequences of the clinical study have been explained in a form 
understandable to the subject. An informed consent document that includes both information 
about the study and the consent form will be prepared and given to the subject. This document 
will comply with GCP, ICH, and all US federal regulatory requirements. The document must 
be in a language understandable to the subject. 
After reading the informed consent form (ICF), the subject must give consent in writing prior 
to screening. To confirm the subject’s consent, the person obtaining informed consent will sign 
and date the document at the time of consent. A signed consent document must be given to the 
subject, and an original will be retained by the Investigator. The Investigator will not undertake 
any measures specifically required only for the clinical study until valid consent has been 
obtained. 
15.12 
Institutional Review Board/Independent Ethics Committee 
Before the start of the study, the study protocol, ICF, and any other appropriate documents will 
be submitted to the IRB with a cover letter or a form listing the documents submitted, their 


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dates of issue, and the site for which approval is sought. If applicable, the documents will also 
be submitted to the authorities, in accordance with local legal requirement. 
Formal approval by the IRB should preferably mention the study title, protocol number, study 
site, date of site approval, date of ICF approval, and any other documents reviewed. It must 
mention the date on which the decision was made and must be officially signed by a committee 
member. Before the first subject is enrolled in the study, all ethical and legal requirements must 
be met. 
The Investigator will promptly report to the IRB any new information that would adversely 
affect the safety of the subjects or the conduct of the study. The Investigator will obtain 
approval from the IRB for any change(s) in any aspect of the study, such as modification(s) of 
the protocol, ICF, written information to be provided to subjects, and/or other procedures. The 
Investigator will submit periodic reports to the IRB on the progress of the study, as required. 
Upon completion of the study, the Investigator will provide the IRB with a final report of the 
outcome of the study. 
The Investigator or designee must keep a record of all communication with the IRB. This 
record also applies to any communication between the Investigator and the regulatory 
authorities. 
 


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Evaluation 
Screening 
Cycle 1 
Cycle 2 and Cycle 3 
Cycle 4+ 
End of 
Treatment22 
Day 1 
Day 2 
Day 8 
(± 1 day) 
Day 15 
(± 1 day) 
Day 1 
(± 2 days) 
Day 11 
(± 2 days) 
Day 1 
(± 5 days) 
CRS/ICANS 
Evaluation24 
 
X 
 
X 
X 
X 
 
X 
 
Adverse Events21 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. Safety evaluations (e.g., physical exam, vital signs (body temperature, heart rate, blood pressure and respiratory rate) and oxygen saturation, 
hematology, serum chemistry, coagulation, pregnancy test, urinalysis, ECG, etc.) must be performed prior to study drug administration on treatment 
days. Height is collected only at Screening Visit. Weight will be collected at Day 1 of each cycle. Patients will be monitored for CRS with vital signs 
performed every 2 hours for a minimum of 6 hours post-dose for the first cycle.  If CRS is not observed during the first cycle, monitoring is not 
necessary on Day 1 of subsequent cycles 
2. Complete physical exam is required at only at Screening and End of Treatment. Symptom-directed physical exams will be performed at all other visits 
3. Screening hematology must be obtained within 14 days prior to C1D1. Hematological evaluation includes a CBC with differential and platelet count. 
4. Starting on Cycle 2 Day 1, hematological evaluation is only required on Day 1 of each cycle. Interim evaluations should occur as clinically indicated. 
Hematological evaluation is required at EOT. 
5. Complete metabolic panel are required at all timepoints. Screening serum chemistry evaluation must be obtained within 14 days prior to C1D1. Please 
refer to Appendix 4 for additional details. 
6. Starting on Cycle 4 Day 1, serum chemistry evaluation are only required on Day 1 of each cycle. Interim evaluations should occur as clinically 
indicated. Please refer to Appendix 4 for additional details.  
7. Fasting glucose is only required at Screening or pre-dose on Cycle 1 Day 1, and every 3 cycles thereafter (e.g., Cycle 4 Day 1, Cycle 7 Day 1, Cycle 10 
Day 1) and at End of Treatment.  


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8. Thyroid function tests should be obtained approximately every 6 weeks following treatment initiation 
9. Coagulation tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR), thrombin 
time (as clinical indicated) and fibrinogen (as clinically indicated) must be performed prior to all biopsy procedures 
10. A pregnancy test (serum or urine) is required for all females of child-bearing potential (FOCBP) within 72 hrs of the first dose of study treatment. If the 
Screening evaluation is performed within 72 hrs of C1D1, the test does not need to be repeated.  
11. Triplicate ECGs must be completed after the patients has been in a supine position for at least 5 minutes. On Cycle 1 Day 1 and Cycle 2 Day 1 an ECG 
will be performed prior to APR003 dosing and 30 minutes (± 5 minutes) after dosing 
12. PET/CT is required at Screening, at the time of suspected disease progression, at EOT for all patients. A PET/CT scan & tumor evaluation is also 
required at C1D1 if a clinically significant increase in tumor burden from the Screening evaluation is suspected. Beginning at Cycle 1 Day 1, imaging 
and tumor evaluation will occur approximately every 3 cycles (i.e., Cycle 4 Day 1, Cycle 7 Day 1, etc.), or more frequently as clinically indicated. 
Imaging at EOT does not need to be repeated if the reason for treatment discontinuation is due to imaging-documented tumor progression. 
13. Tumor evaluations of initial response, deeper response, or initial disease progression must be confirmed by a subsequent imaging evaluation performed 
within 4-8 weeks in accordance with iRECIST criteria.  
14. Positive Hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) should prompt evaluation of HBV DNA. Patients with an active 
infection are not eligible for study participation. 
15. Positive Hepatitis C antibodies should be followed by HCV RNA levels. Patients with an active infection are not eligible for study participation. 
16. APR003 is administered orally once weekly, on Days 1, 8, and 15 of each treatment cycle. All doses during Cycle 1 (C1D1, C1D8 and C1D15) and at 
Day of 1 of every cycle APR003 will be administered in the clinic, after pre-treatment evaluations have been performed. All other doses will  be self-
administered by the patient at home. Patients should be instructed to take APR003 an empty stomach.  Premedication with acetaminophen and 
diphenhydramine is allowed per discretion of the investigator.  Patients will be monitored for CRS with vital signs performed every 2 hours for a 
minimum of 6 hours post-dose for the first cycle.  If CRS is not observed during the first cycle, monitoring is not necessary on Day 1 of subsequent 
cycles.  Given the potential that a patient who undergoes a prolonged APR003 treatment interruption may experience CRS upon retreatment with study 
drug, patients experiencing an APR003 dose interruption of greater than or equal to 21 consecutive days for any reason, should have their safety 
monitoring follow that of Cycle 1 Day 1 schedule upon retreatment with APR003. Thus, as is the case in Cycle 1 for new enrollment, patients who 


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missed 21 or more consecutive days of APR003 treatment will be monitored for CRS with vital signs performed every 2 hours for a minimum of 6 
hours post-dose for the first resumed cycle.  If CRS is not observed during this resumed dosing cycle, prolonged monitoring is not necessary on Day 1 
of subsequent cycles.  If, however, a patient requires an APR003 dose interruption of > 21 consecutive days due to treatment-related toxicities, then the 
patient should be discontinued from treatment unless otherwise specified based on specific toxicities as defined in Table 6. 
17. Peripheral blood samples for PK evaluation will be obtained. On C1D1, samples will be obtained at pre-dose, and at 0.5, 1, 2, 4, 6, 8 and 24 hrs after 
dosing. On C1D15, samples will be obtained at pre-dose, and at 0.5, 1, 2, 4, 6 and 8 hr after dosing. On C2D1, samples will be obtained at pre-dose, 
and at 0.5, 1, 2, 4, and 6 hrs after dosing. Please refer to, Appendix 2 for more details 
18. Peripheral blood samples for PDx and biomarker evaluations should be obtained at all specified timepoints. On C1D1 and C1D15, a series of samples 
will be obtained. On C2D1, samples will be obtained at pre-dose, and at 0.5, 1, 2, 4, and 6 hrs after dosing. Please refer to Appendix 3 for more details. 
PDx and biomarker evaluations may include, but are not limited to, anti-drug antibodies, cytokine levels (e.g., IL-2, IL-4, IL-6, IL-8, IL-10, IFN-α, 
TNF-α, T and B-cell enumeration.  
19. An archival sample should be submitted whenever adequate samples are available. Please refer to the Laboratory Manual for archival sample 
specifications. 
20. All patients will be required to maintain a diary of study drug self-administration. The diary must be reviewed at each study visit and administration 
deviations reported starting at Cycle 2.  All dosing performed in Cycle 1 are taken at the clinic. 
21. The adverse event reporting period begins at signed Informed Consent and continues until 30 days after the last dose of study treatment, or until 
initiation of subsequent anti-cancer therapy, whichever occurs first. 
22. The EOT visit must occur within 30 days of the last dose of study drug. 
23. Long-term follow-up: Information about survival status and the first subsequent anticancer therapy will be collected at approximately 3- to 6-month 
intervals at the Sponsor’s discretion through 2 years.  This information will be gathered via telephone or email with the subjects/caregivers or referring 
physician offices. 
24. Every 2 hours signs and symptoms will be reviewed of CRS for up to 6 hours post dose for the first three drug administrations after which 6 hours post 
dose then as clinically indicated (e.g., fever, fatigue, nausea, vomiting, chills, hypotension, rash, wheezing). In addition, blood pressure, pulse 


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oximetry, heart rate, respiratory rate and body temperature will be recorded until 2 consecutive cycles have transpired where no symptoms of CRS are 
reported 


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Appendix 2.  
Pharmacokinetics (PK) Detailed Schedule of Events 
Cycle / Day 
Scheduled time relative to dosing 
C1D1 
Pre-dose AM 
30 min post 1st dose ± 5 min 
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
8 hours post 1st dose ± 10 min 
24 hours post 1st dose ± 1 hr (i.e., C1D2)  
C1D15 
Pre-dose AM 
30 min post 1st dose ± 5 min 
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
8 hours post 1st dose ± 10 min 
C2D1 
Pre-dose AM 
30 min post 1st dose ± 5 min 
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
Unscheduled 
In the event of a treatment-related AE, whenever feasible 


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Appendix 3.  
Pharmacodynamics (PDx) Detailed Schedule of Events 
Cycle / Day 
Scheduled time relative to dosing 
C1D1 
Peripheral Blood Sample 
Pre-dose  
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
8 hours post 1st dose ± 10 min 
24 hours post 1st dose ± 1 hr (i.e., C1D2)  
C1D15 
Peripheral Blood Sample 
Pre-dose 
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
8 hours post 1st dose ± 10 min 
C2D1  
Peripheral Blood Sample 
Pre-dose AM 
30 min post 1st dose ± 5 min 
1 hour post 1st dose ± 5 min 
2 hours post 1st dose ± 5 min 
4 hours post 1st dose ± 10 min 
6 hours post 1st dose ± 10 min 
Every 3 Cycles thereafter 
(e.g., C4D1, C7D1, 
C10D1, etc.) 
Peripheral Blood Sample 
Pre-dose AM 
 
 


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Appendix 4.  
Laboratory Evaluations 
Hematology 
(Peripheral Blood 
Sample) 
• 
hemoglobin 
• 
hematocrit 
• 
red blood cell (RBC) count 
• 
RBC Indices: 
o Mean corpuscular volume (MCV) 
o Mean corpuscular hemoglobin (MCH) 
o Mean cell hemoglobin concentration (MCHC) 
o %Reticulocytes* 
• 
white blood cell (WBC) count with differential 
• 
platelet count 
Serum Chemistry 
(Peripheral Blood 
Sample) 
• 
comprehensive metabolic panel, including 
o sodium, potassium, bicarbonate (total CO2) and chloride, 
calcium (total), magnesium (total), phosphorus (inorganic), 
uric acid 
o blood urea nitrogen (BUN) and creatinine (Cr) 
o albumin and total protein 
o alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), total bilirubin, 
direct bilirubin, lactate dehydrogenase (LDH) 
o amylase, lipase 
o Triglycerides 
o glucose. Fasting glucose is required at either Screening or 
C1D1, every 3 cycles thereafter (e.g., C4D1, C7D1, 
C10D1, etc.) and at End of Treatment 
o Creatine kinase as clinically indicated 
Coagulation 
• 
prothrombin time (PT), activated partial thromboplastin time 
(aPTT) and international normalized ration (INR) 
• 
Thrombin time (as clinically indicated) 
• 
Fibrinogen (as clinically indicated) 
Thyroid Function Tests 
• 
thyroid stimulating hormone (TSH), triiodothyronine (T3) and 
thyroxine (T4) 


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Serology 
• 
Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody)  
• 
HIV I and II 
• 
Hepatitis C Virus (qualitative and quantitative) 
• 
HBsAg (hepatitis B surface antigen) 
• 
HBcAb (hepatitis B core antibody) 
• 
HBsAb (hepatitis B surface antibody) 
 
Optional Infectious Disease Screening as clinically indicated 
• 
Herpes virus 6 and 7 
• 
EBV 
• 
T spot to assess for exposure or history of tuberculosis anti-HTLV 
antibody HTLV I II Ab 
• 
RPR syphilis 
• 
CMV IgG and IgM 
• 
Covid 19 antigen and antibody 
Markers of Inflammation  
• 
C-reactive protein (CRP)* 
• 
Ferritin* 
• 
Cytokine panel* 
• 
D-dimer* 
Other 
• 
serum or urine pregnancy test (β-HCG) for females of child-
bearing potential is required; must be negative within 72 hrs of 
C1D1. If Screening evaluation is within 72 hrs of C1D1, the test 
does not need to be repeated 
Other Specialty Tests 
(autoimmune hepatitis 
work-up) 
The following tests should be performed in patients with treatment-
emergent increases in transaminases and/or bilirubin 
• 
anti-nuclear antibody (ANA) 
• 
anti-smooth muscle antibody (ASMA) 
• 
Epstein Barr Virus IgM 
• 
Cytomegalovirus (PCR)  
Other disease specific 
labs as clinical indicated  
• 
Serum iron 
• 
Quantitative test EBV by PCR 
* To be done at screening and then on treatment only if clinically indicated. 


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Appendix 5.  
RECIST v1.1 Response Assessment 
Source: Eisenhauer et al, 2009 
Sponsor’s Note: Confirmatory scans are required approximately 4 weeks after any scan that 
indicates either an objective response or disease progression 
MEASURABILITY OF TUMOR AT BASELINE 
A. DEFINITIONS 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows. 
1. Measurable tumor lesions 
Tumor lesions must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:  
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
• 10 mm by caliper measurement (lesions which cannot be accurately measured with 
calipers should be recorded as non-measurable) 
• 20 mm by chest X-ray 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. See also section below on ‘Baseline documentation of target 
and non-target lesions’ for information on lymph node measurement. 
2. Non-measurable tumor lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable 
lesions. Lesions considered truly non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin 
or lung, peritoneal spread, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques. 


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3. Special considerations regarding lesion measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment:  
a. Bone lesions: 
• Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions. However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or MRI can be considered as measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• Blastic bone lesions are non-measurable. 
b. Cystic lesions: 
• Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since 
they are, by definition, simple cysts. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
c. Lesions with prior local treatment:  
• Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there has 
been demonstrated progression in the lesion.  


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B. SPECIFICATIONS BY METHODS OF MEASUREMENTS 
1. Measurement of lesions 
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. 
2. Method of assessment 
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: 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 lesion 
is suggested. As noted above, when lesions can be evaluated by both clinical exam and 
imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less. When CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice 
the slice thickness. MRI is also acceptable in certain situations (e.g., for body scans). 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast 
due to allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with 
or without IV contrast) will be used to evaluate the subject at baseline and follow-up, should be 
guided by the tumor type under investigation and the anatomic location of the disease. For 
patients who develop contraindications to contrast after baseline contrast CT is done, the 
decision as to whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed, 
should also be based on the tumor type, anatomic location of the disease and should be 
optimized to allow for comparison to the prior studies if possible. Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. 


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FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible ‘new’ disease). New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive* FDG-PET at follow-up is a sign of PD 
based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not 
PD. 
*A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
C. TUMOR RESPONSE EVALUATION 
1. Assessment of overall tumor burden and measurable disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients 
with measurable disease at baseline will be enrolled into this study.  
Measurable disease is defined by the presence of at least one measurable lesion.  
2. Baseline documentation of ‘target’ and ‘non-target’ lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five 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. 
This means in instances where patients have only one or two organ sites involved a maximum 
of two (one site) and four lesions (two sites), respectively, will be recorded. Other lesions in 
that organ will be recorded as non-measurable lesions (even if size is greater than 10 mm by 
CT scan). 


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Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement in which circumstance the next largest lesion 
which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the 
plane of acquisition may be axial, sagital, or coronal). The smaller of these measures is the 
short axis. For example, an abdominal node which is reported as being 20 mm x 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. All other pathological nodes (those with short 
axis ≥ 10 mm but < 15 mm) should be considered non-target lesions. Nodes that have a short 
axis < 10 mm are considered non-pathological and should not be recorded or followed. 
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, then as noted above, only the short axis is added into the sum. The 
baseline sum diameters will be used as reference to further characterize any objective tumor 
regression in 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’, ‘absent’, or in rare cases ‘unequivocal 
progression.’ In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (e.g., ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
D. RESPONSE CRITERIA 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 


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1. Evaluation of Target Lesions 
• Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to < 10 mm. 
• Partial Response (PR): At least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum diameters.  
• Progressive Disease (PD): At least a 20% increase in the sum of diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum 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 5 mm. (Note: the appearance of one or 
more new lesions is also considered progression). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study.  
Special notes on the assessment of target lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short 
axis measurement recorded (measured in the same anatomical plane as the baseline 
examination), even if the nodes regress to below 10 mm on study. This means that when lymph 
nodes are included as target lesions, the ‘sum’ of lesions may not be zero even if complete 
response criteria are met, since a normal lymph node is defined as having a short axis of 
<  10  mm. Case report forms or other data collection methods may therefore be designed to 
have target nodal lesions recorded in a separate section where, in order to qualify for CR, each 
node must achieve a short axis < 10 mm. For PR, SD, and PD, the actual short axis 
measurement of the nodes is to be included in the sum of target lesions.  
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and non-
nodal) recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scan that the radiologist 
may not feel comfortable assigning an exact measure and may report them as being ‘too small 
to measure’. When this occurs it is important that a value be recorded on the case report form: 
• If it is the opinion of the radiologist that the lesion has likely disappeared, the 
measurement should be recorded as 0 mm. If the lesion is believed to be present and is 
faintly seen but too small to measure, a default value of 5 mm should be assigned and 
BML (below measurable limit) should be ticked (Note: It is less likely that this rule will 


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be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node 
is believed to be present and is faintly seen but too small to measure, a default value of 
5 mm should be assigned in this circumstance as well and BML should also be ticked). 
This default value is derived from the 5 mm CT slice thickness (but should not be changed with 
varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, 
therefore providing this default value will prevent false responses or progressions based upon 
measurement error. 
To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm and in that case BML should not be ticked. (BML is 
equivalent to a less than sign <) 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion 
sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
2. Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol.  
• Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm short 
axis). 
• Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
• Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
(Note: the appearance of one or more new lesions is also considered progression).  
Special notes on assessment of progression of non-target disease 
The concept of progression of non-target disease requires additional explanation as follows:  


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• When the patient also has measurable disease: In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of 
substantial worsening in non-target disease in a magnitude that, even in presence of SD 
or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
• When the patient has only non-measurable disease: This circumstance arises in some 
phase III trials when it is not a criterion of study entry to have measurable disease. The 
same general concepts apply here as noted above; however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in non-
measurable disease burden. Because worsening in non-target disease cannot be easily 
quantified (by definition: if all lesions are truly non-measurable) a useful test that can 
be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease: i.e., an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an 
increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ 
is seen, the patient should be considered to have had overall PD at that point. While it 
would be ideal to have objective criteria to apply to non-measurable disease, the very 
nature of that disease makes it impossible to do so; therefore the increase must be 
substantial. 
3. New lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: i.e., not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions). This is particularly 
important when the patient’s baseline lesions show partial or complete response. For example, 


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necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it 
is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
the patient who has visceral disease at baseline and while on study has a brain CT or MRI 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
4. Time point response 
It is assumed that at each protocol specified time point (i.e., radiographic evaluation of tumor 
burden), a response assessment occurs. Table 12 and Table 13 provides a summary of the 
timepoint response status calculation at each time point for patients who have measurable 
disease at baseline.  
Table 12.  
Time Point Response: Patients with Target (± Non-target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = not evaluable 
Abstracted from Eisenhauer et al, 2009 
 


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Table 13.  
Time Point Response: Patients with Non-target Disease Only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease and NE = not evaluable 
A ‘Non-CR/non-PD is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised. 
5. Missing assessments and not-evaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not 
change the assigned time point response. This would be most likely to happen in the case of 
PD. 
For example, if a patient had a baseline sum of 50 mm with three measured lesions and at 
follow-up only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done or could 
not be assessed because of poor image quality or obstructed view, the Response for Target 
Lesions should be “Unable to Assess” since the patient is not evaluable. Similarly, if one or 
more non-target lesions are indicated as ‘not assessed’, the response for non-target lesions 
should be “Unable to Assess” (except where there is clear progression). Overall response 
would be “Unable to Assess” if either the target response or the non-target response is “Unable 
to Assess” (except where this is clear evidence of progression) as this equates with the case 
being not evaluable at that time point. 


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Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (< 10 mm), they may still have a measurement reported on scans. This measurement 
should be recorded even though the nodes are normal in order not to overstate progression 
should it be based on increase in size of the nodes. As noted earlier, this means that patients 
with CR may not have a total sum of ‘zero’ on the electronic case report form (eCRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
‘symptomatic deterioration’. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response: it is a reason for stopping study therapy. The objective response status of 
such patients is to be determined by evaluation of target and non-target disease. 
Conditions that define ‘early progression, early death, and non-evaluability are study specific 
and should be clearly described in each protocol (depending on treatment duration, treatment 
periodicity). 
6. Evaluation of best overall response 
The best overall response is the best response recorded from the start of the study treatment 
until the end of treatment taking into account any requirement for confirmation. The patient’s 
best overall response assignment will depend on the findings of both target and non-target 
disease, will also take into consideration the appearance of new lesions and will depend upon 
confirmatory scans. For this study, determinations of either CR, PR or PD require a 
confirmatory scan at least 4 weeks later. This is described further in Table 14 below. 


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Table 14.  
Best Overall Response 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Response for this Category 
Also Requires 
CR 
CR 
No 
CR 
≥4 weeks confirmation 
CR 
Non-CR/ 
Non-PD 
No 
PR 
≥4 weeks confirmation 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
documented at least once ≥4 weeks 
from baseline 
PD 
Any 
Yes or No 
PD 
no prior SD, PR, or CR 
Any 
PD* 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of 
complete response. FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis 
or scarring. The use of FDG-PET in this circumstance should be prospectively described in the 
protocol and supported by disease specific medical literature for the indication. However, it 
must be acknowledged that both approaches may lead to false positive CR due to limitations of 
FDG-PET and biopsy resolution/sensitivity. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment. If at the next scheduled assessment, progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
 
 




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Confirmation of CR and PR and 
when applicable 
Definition of progression in Target 
and Non-Target lesions 
First RECIST v1.1 PD is considered unconfirmed for 
iRECIST, termed i-Unconfirmed Progression (iUPD) 
Management of new lesions 
Assessed using RECIST 1.1 principles: 
• 
Classified as measurable or non-measurable 
• 
Up to 5 (2 per site) measured (but not included 
in the SOM of target lesions identified at 
baseline) and recorded as new lesions target 
(NL-T) with an i-sum of measurements (iSOM) 
• 
Other new lesions (measurable/non-measurable) 
are recorded as new lesions non-target (NL-NT) 
• 
New lesions do not have to resolve for 
subsequent iSD or iPR providing that the next 
assessment did not confirm progression 
Time point response after RECIST 
1.1 progression 
There can be iSD, iPR or iCR after RECIST 1.1 PD 
• 
First RECIST 1.1 PD is “unconfirmed” for 
iRECIST – termed iUPD  
• 
iUPD must be confirmed at the next assessment 
(4-8 weeks)  
• 
If confirmed, termed iCPD 
Time point response is dynamic and based on 
• 
Change from baseline (for iCR, iPR, iSD) or 
change from nadir (for PD) 
• 
The last i-response 
Confirmation of progression 
required 
First RECIST 1.1 PD is “unconfirmed” for iRECIST; 
disease progression must be confirmed at the next 
assessment (4-8 weeks later  
Treatment past RECIST 1.1 PD is permitted if patient 
clinically stable 
• 
No worsening of performance status 
• 
No clinically relevant ↑in disease related 
symptoms 


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• 
No requirement for intensified management of 
disease related symptoms (analgesics, 
radiation, palliative care) 
Collection of reason why 
progression cannot be confirmed 
Record the reason iUPD not confirmed 
• 
Not stable 
• 
Treatment stopped but patient not 
reassessed/imaging not performed  
• 
iCPD never occurs 
• 
Patient has died 
 
Secondary efficacy endpoints based on iRECIST criteria will include the following adaptations 
(Seymour et al, 2017): 
• If radiologic imaging shows initial PD, tumor assessment should be repeated 4-8 weeks 
later in order to confirm PD. At the discretion of the investigator, patients may continue 
on study treatment awaiting radiologic confirmation of progression. 
• If repeat imaging does not show objective PD (i.e., less than 20% increase in the sum of 
longest diameters [SLD] compared to nadir), stable or improved previous new lesion (if 
identified as cause for initial PD), or stable/improved non-target disease (if identified as 
cause for initial PD), treatment may be continued / resumed.   
• If repeat imaging confirms PD due to any of the scenarios listed below, patients will be 
discontinued from study therapy. 
• In determining whether or not the tumor burden has increased or decreased, the site 
study team should consider all target lesions as well as non-target lesions. 
Scenarios where PD is confirmed at repeat imaging: 
• SLD of target lesions remains ≥ 20% and at least 5 mm absolute increase compared to 
nadir 
• Non-target disease resulting in initial PD is qualitatively worse 
• New lesion resulting in initial PD is qualitatively worse 
• Additional new lesion(s) since last evaluation 
In subjects who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a subject on study treatment until repeat imaging is obtained. 


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This clinical judgment decision should be based on the subject’s overall clinical condition, 
including performance status, clinical symptoms, and laboratory data. Subjects may continue to 
receive study treatment while waiting for confirmation of PD if they are clinically stable as 
defined by the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response. Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease. 
 


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Appendix 7.  QTcF Calculation 
QT correction formula Fridericia: 
QTcF = QT ÷ 3√RR 
Luo S, Michler K, Johnston P, et al. (2004) A comparison of commonly used QT correction 
formulae: the effect of heart rate on the QTc of normal ECGs. Journal of Electrocardiology. 
37:81-90. 
 


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Appendix 8.  
Concomitant Medications to be Used with Caution 
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study. Combination administration of the study drug with agents that are 
strong inhibitors of OATP1A2 and OATP1B1 could result in drug-drug interactions (DDI) or 
food-drug interactions (FDI) that could potentially lead to altered levels of APR003. 
The list of medications and foods in the table below is meant to provide guidance only and it is 
not a comprehensive list. If a patient is required to take an agent that is not in the list, but there 
may be a risk of DDI or FDI, please contact the Sponsor clinical study team for further advice. 
If an agent appears in Table 16, caution should be exercised when the agent is administered 
during the study. 
Please contact the Sponsor Medical Monitor with any questions. 
Table 16.  
Drugs and Foods to be used with Caution while on Study 
Category 
Drug Names 
Strong inhibitors of 
CYP3A4/5 
• 
boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, 
itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
sequinavir/ritonavir, telaprevir, telithromycin, voriconazole, 
indinavir/ritonavir, tipranoavir/ritonavir, cobicistat, troleandomycin, 
danoprevir/ritonavir, eltegravir/ritonavir 
Strong inducers of 
CYP3A4/5 
• 
avasimibe, carbamazepine, phenytoin, rifampin, St. John’s wort, 
rifabutin, phenobarbital, mitotane, enzalutamide 
Known substrates of 
CYP3A4 with a narrow 
therapeutic index 
• 
quinidine, astemizole, terfanadine, cyclosporine, sirolimus, 
tacrolimus, diergotamine, cisapride, ergotamine, pimozide, 
alfentanil, fentanyl, thioridazine, diergotamine, dihydroergotamine, 
ergotamine 
Drugs classified as 
inhibitors of OATP1B1 
• 
atazanavir, clarithromycin, cobicistat, cyclosporine, daclatasvir 
eltrombopag, erythromycin, gemfibrozil, glecaprevir, 
lopinavir/Ritonavir, letermovir, paritaprevir, pibrentasvir, sacubitril, 
saquinavir, simeprevir, telithromycin, teriflunomide, tipranavir, 
rifampin, velpatasvir, voxilaprevir,  
Agents classified as 
inhibitors of OATP1A2 
• 
fruit juices (apple, grapefruit, orange, pomelo), hesperidins, 
naringin, rifampicin, rifamycin, verapamil 


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Category 
Drug Names 
Drugs which modify 
gastric pH (antacid, H2 
receptors antagonists, and 
PPIs) 
• 
Antacids (e.g., TUMS®, Maalox®), H2 receptors antagonists: 
cimetidine, famotidine, nizatidine, ranitidine, proton pump 
inhibitors (PPI): esomeprazole, lansoprazole, omeprazole, 
pantoprazole, rabeprazole 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine 
(2007). "https://drug-interactions.medicine.iu.edu" Accessed 29 Jan 2019. 
Tsai HH, Lin HW, Pickard AS, et al. Evaluation of documented drug interactions and contraindications associated with 
herbs and dietary supplements: a systemic literature review. Int J Clin Pract (2012); 62(11):1056-1078. 
Yu J, Zhou Z, Tay-Sontheimer J et al. Intestinal Drug Interactions Mediated b OATPs: A Systematic Review of Preclinical 
and Clinical Findings. J Pharm Sci (2017); 2312-2325. 
 
 


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Appendix 9.  
QT prolonging Medications to be used with Caution 
In general, the use of any concomitant medication deemed necessary for the care of the patient is 
permitted in this study, medications  below are to be used with caution and drugs classified with 
a known risk of QT prolongation should be substituted when clinically feasible .  
The list of medications in the table below is meant to provide guidance only and it is not a 
comprehensive list. If a patient is required to take a medication that is not in the list, but there 
may be a risk of DDI, please contact the Sponsor clinical study team for further advice. 
If a drug appears in Table 17, the drug should be considered as prohibited. 
Please contact the Sponsor Medical Monitor with any questions. 
Table 17.  
QT Prolonging Medications to be used with Caution while on Study 
Category 
Drug Names 
Drugs classified as known 
risk of QT prolongation 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US mkt), 
azithromycin, bepridil (off US mkt), chloroquine, chlorpromazine, 
cisapride (off US mkt), citalopram, clarithromycin, cocaine, 
disopyramide, dofetilide, domperidone (not on US mkt), dronedarone, 
droperidol, erythromycin, escitalopram, flecainide, grepafloxacin (off 
market worldwide), halofantrine, haloperidol, ibutilide, levofloxacin, 
levomethadyl (off US mkt), mesoridazine (off US mkt), methadone, 
moxifloxacin, ondansetron, pentamidine, pimozide, probucol (off US 
mkt), procainamide (oral off US mkt), quinidine, sevoflurane, sotalol, 
sparfloxacin (off US mkt), sulpiride (not on US mkt), terfenadine (off 
US mkt), thioridazine, vandetanib 
Drugs classified as 
possible risk of QT 
prolongation 
alfuzosin, apomorphine, aripiprazole, atazanavir, bedaquiline, 
bortezomib, bosutinib, clozapine, crizotinib, dabrafenib, dasatinib, 
dexmedetomidine, dihydroartemisinin+piperaquine, dolasetron, eribulin, 
famotidine, felbamate, fingolimod, foscarnet, fosphenytoin, gatifloxacin 
(off US mkt), gemifloxacin, granisetron, iloperidone, isradipine, 
lapatinib, lithium, mifepristone, mirabegron, mirtazapine, 
moexipril/hctz, nicardipine, nilotinib, norfloxacin, ofloxacin, 
olanzapine, oxytocin, paliperidone, pasireotide, pazopanib, perflutren 
lipid microspheres, pipamperone (not on US mkt), promethazine, 
quetiapine, ranolazine, rilpivirine, risperidone, roxithromycin (on non 
US mkt), saquinavir, sertindole (on non US mkt), sorafenib, sunitinib, 


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Category 
Drug Names 
tacrolimus, tamoxifen, telavancin, telithromycin, tetrabenazine (orphan 
drug in US), tizanidine, tolterodine, toremifene, vardenafil, 
vemurafenib, venlafaxine, vorinostat, ziprasidone 
FDA Guidance for Industry, Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations. Accessed 29 Jan 2019. 
http://fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm29236 2.pdf. 
FDA Guidance for Industry, Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, and 
Labeling Recommendations. Accessed 29 Jan 2019. 
http://fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm29236 2.pdf. 
Tsai HH, Lin HW, Pickard AS, et al. Evaluation of documented drug interactions and contraindications associated with 
herbs and dietary supplements: a systemic literature review. Int J Clin Pract (2012); 62(11):1056-1078. 
Woosley, RL, Heise, CW and Romero, KA, www.Crediblemeds.org, QTdrugs List, Accession Date 29 Jan 2019, 
AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755 
 
 


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Appendix 10.  ASTCT Grading for Cytokine Release Syndrome1 
(Note: CRS grade should be determined at least twice daily and any time there is a change in 
patient’s status) 
CRS parameter 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fever2 
Yes 
Yes 
Yes 
Yes 
 
 
With 
Hypotension3 
None 
Requiring IV fluids 
but not requiring 
vasopressors 
Requiring a 
vasopressor with or 
without 
vasopressin 
Requiring 
multiple 
vasopressors 
(excluding 
vasopressin) 
 
 
And/Or 
Hypoxia3 
None 
Requiring low-flow O2 via 
nasal cannula4 or blow-by 
Requiring O2 via high-
flow nasal cannula4, 
facemask, 
nonrebreather mask, or 
Venturi mask 
Requiring O2 via 
positive pressure 
(e.g., CPAP, BiPAP, 
and mechanical 
ventilation) 
Adapted from (Lee et al., 2019) 
CPAP=continuous positive airway pressure 
BiPAP=bilevel positive airway pressure 
1Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS grading. 
2 Fever is defined as temperature ≥ 38 °C not attributable to any other cause. In patients who have CRS then receive 
antipyretics or anti-cytokine therapy such as tocilizumab or steroids, fever is no longer required to grade subsequent CRS 
severity. In this case, CRS grading is driven by hypotension and/or hypoxia. 
3 CRS grade is determined by more severe event: hypotension or hypoxia not attributable to any other cause. For example, a 
patient with temperature of 39.5 °C, hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal cannula is 
classified as grade 3 CRS. 
4 Low-flow nasal cannula is defined as oxygen delivered at ≤ 6 L/min. Low flow also includes blow-by oxygen delivery, 
sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at > 6 L/min. 
 
 


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Appendix 11.  ASTCT GRADING OF ICANS1 
Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
ICE score2 
7-9 
3-6 
03-2 
03 (patient is 
unarousable and unable 
to perform ICE) 
Depressed levels of 
consciousness4 
Awakens 
spontaneously 
Awakens to voice 
Awakens only to 
tactile stimulus 
Patient is unarousable 
or requires vigorous or 
repetitive tactile stimuli 
to arouse. Stupor or 
coma 
Seizure 
N/A 
N/A 
Any clinical seizure 
focal or generalized 
that resolves rapidly or 
nonconvulsive 
seizures on EEG that 
resolve with 
intervention 
Life-threatening 
prolonged seizure (>  5 
min); or repetitive 
clinical or electrical 
seizures without return 
to baseline in between 
Motor findings5 
N/A 
N/A 
N/A 
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis 
Elevated 
intracranial 
pressure 
(ICP)6/cerebral 
edema 
N/A 
N/A 
Focal/local edema on 
neuroimaging7 
Diffuse cerebral edema 
on neuroimaging; 
Decerebrate or 
decorticate posturing; 
or cranial nerve VI 
palsy; or papilledema; 
or Cushing’s triad 


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Neurotoxicity 
Domain 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Adapted from (Lee et al., 2019) 
1 ICANS grading is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, raised 
ICP/cerebral edema) not attributable to any other cause; for example, a patient with an ICE score of 3 who has a generalized 
seizure is classified as grade 3 ICANS.  
N/A indicates not applicable. 
2 Refer to ICE Assessment below for ICE Score.  
3 A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global aphasia or 
Grade 4 ICANS if the patient is unarousable  
4 Depressed level of consciousness should not be attributable to any other cause (e.g., sedating medication) 
5 Tremors and myoclonus associated with immune effector cell therapies may be graded according to CTCAE v5.0, but they 
do not influence ICANS grading. 
6 Opthamology may be consulted to assess for papilledema if concern for elevated ICP, but otherwise not needed for all 
patients 
7 Intracranial hemorrhage with or without associated edema is not considered a neurotoxicity feature and is excluded from 
ICANS grading. It may be graded according to CTCAE v5.0. 
ICE Assessment 
Orientation: orientation to year, month, city, hospital: 4 points (1 point each) 
Naming: ability to name 3 objects (e.g., clock, pen, button): 3 points (1 point each) 
Following commands: ability to follow simple commands (e.g., “Show me 2 fingers” or “Close your 
eyes and stick out your tongue”): 1 point 
Writing: ability to write a standard sentence (e.g., “Our national bird is the bald eagle”): 1 point 
Attention: ability to count backwards from 100 by 10: 1 point 
Score 10: No Impairment 
Score 7-9: Grade 1 ICANS 
Score 3-6: Grade 2 ICANS 
Score 0-2: Grade 31 ICANS  
Score 0 due to patient unarousable or unable to perform ICE assessment: Grade 4 ICANS 
1A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake with global aphasia or 
may be classified as having Grade 4 ICANS if the patient is unarousable 
 


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Appendix 12.  Immune-Effector Cell Toxicity Assessment and Management 
Immune-effector cell toxicity assessment and management should be performed per the 
CARTOX criteria (https://www.mdanderson.org/documents/for-physicians/algorithms/clinical-
management/clin-management-cytokine-release-web-algorithm.pdf). 
 

ICF_001.pdf: 
 
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Page 1 of 1 
Subject Informed Consent Form 
 
 
Protocol Title: 
A Phase 1 Dose Escalation Study to Evaluate Safety, Tolerability, 
and Pharmacokinetics/Pharmacodynamics of APR003 in patients 
with Advanced Colorectal Cancer (CRC) with Malignant Liver 
Lesions 
Sponsor: 
Apros Therapeutics, Inc.  
Protocol Number: 
APR003-001 
Investigator: 
<Insert Principal Investigator name> 
Investigator Telephone: 
<Insert Principal Investigator telephone number> 
Subject Identification: 
 
 
INTRODUCTION 
You are being invited to take part in a clinical research study because you have been treated for advanced, 
unresectable colorectal cancer and have not responded to conventional therapy or the cancer has come back.  
This study involves research and is being conducted to determine the safety, efficacy of the study drug, how 
your body process the study drug, APR003.  
  
Taking part in this clinical research study is strictly voluntary meaning that you may or may not choose to take 
part.  Before you give your consent to be in this study, we ask you to read the following information.  It is also 
important that you ask as many questions as you need to understand what is involved in this study.  You will 
be given as much time as needed to decide whether you want to take part in this study.  
 
This document is called an informed consent form.  This form explains the purpose of the study and describes 
what is expected of you during the study. It also explains the possible risks and discomforts of taking part in 
this study and how being in the study may help you or others. Medical information will be collected about each 
person who participates in this study.  This form will explain how your medical information will be used and 
provides information about your rights while you are taking part in this study.  If you do not sign the consent 
form, you will be unable to take part in this study. 
 
The study drug, APR003, is made by the pharmaceutical company, Apros Therapeutics, Incorporated (Inc.).  
As the sponsor of the study, Apros Therapeutics is supporting the research study and providing money for 
some of the costs of performing the study.  Your study doctor’s institution is being paid by the study sponsor 
to perform this research study. 
 
PURPOSE OF THE STUDY 
The study drug, APR003, used in this study is experimental.  That means the United States Food and Drug 
Administration (FDA) has not approved it for the treatment of cancer.   
 
APR003 might stop tumor cells (cancers) from growing and living and is being studied as a possible treatment 
for cancer. This is the first study in which APR003 will be given to humans.  APR003 is a drug that changes 
the immune system within the liver. The hope is that by changing the immune system in the liver, the immune 
system will be better able to find and kill the cancer, both in the liver and in other places of the body.  
The people who take part in research studies are called “subjects”.   
 


 
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The purpose of this study is to: 
 
• 
Determine the highest dose that can safely be given without unacceptable (intolerable) side effects to 
subjects who have cancer. 
• 
Determine the amount of APR003 in the blood of subjects who have cancer and have been given 
APR003. 
• 
Determine if APR003 might work to kill cancer or stop cancer from growing and, thus be used in the 
treatment of cancer.  
 
NUMBER OF STUDY SUBJECTS 
Approximately 36 subjects from about (4) study centers (US) will participate in the study to find the highest 
dose of study drug that can safely be given to advanced colorectal cancer patients with metastases to the liver 
without unacceptable side effects.  This is called the dose escalation phase.  <Approximately <XX> Subjects 
will be enrolled at <Insert Institution Name>. 
 
STUDY OVERVIEW 
This study will evaluate the safety, levels of drug in the blood and antitumor activity of APR003. Laboratory, 
imaging and safety assessments will be performed throughout the study to understand how APR003 moves 
through your body and how your body and your cancer respond to APR003. 
  
On the study, you will receive APR003 in 3-week (21 days) treatment cycles.  Your study doctor will inform 
you of which dose group you are assigned to. APR003 is a capsule that is taken by mouth once a week in the 
morning, at approximately the same time of day, and with an empty stomach (2 hours before or 1 hour after 
breakfast).  
 
How long you stay on the study drug depends on how well you tolerate the study drug and how your cancer 
responds. You can continue on the study drug as long as your study doctor feels that you are benefitting. If 
your cancer progresses (gets worse), you may not be able to continue to receive the study drug, but you will 
take part in the follow-up period of the study. 
 
The study is divided into the following periods: 
• 
A 28-day screening period  
• 
A study treatment period, which may last up to 1 year  
• 
A follow-up period, during which you will be contacted by telephone or e-mail every 3 months, which 
may last up to 2 years 
 
SUBJECT RESPONSIBILITIES 
If you are enrolled in this study, you will have the following responsibilities: 
• 
Go to all scheduled clinic visits 
• 
Take the study drug as directed 
• 
Record the date and time of when you take the study drug into a dosing diary 
• 
Bring your dosing diary to all of your clinic visits  
• 
Tell your study doctor of all medications that you are currently taking, and before taking any new 
medications 
• 
Follow the study staff’s directions about the study 
• 
Tell the study doctor about any illnesses or injuries 
• 
Tell the study doctor about any side effects or problems that occur during the study 
• 
Tell the study doctor if you plan to have any surgery or any other medical treatment or procedure 


 
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Page 1 of 1 
 
It is important for your safety that you are completely honest with your study doctor throughout the duration 
of the study. 
 
 
Diet: You will be asked to follow instructions to fast (with the exception of clear liquids) for 2 hours before 
and at least 1 hour after each APR003 dose. No other specific dietary restrictions are required. 
Medications: During the study, you will not be allowed to take certain medications.  You need to tell your 
study doctor what drugs you are taking and let your doctor know you are participating in this study. You may 
need to adjust the dose of some prescription medications or use an alternative medication while participating 
in this study. Medications such as antacids may decrease the drug’s absorption into your body. For this reason, 
you should not take antacids within 7 days of your first dose of study drug.  If antacids medication is necessary, 
some examples of preferred antacids include Pepto Bismol®, Milk of Magnesia, or Tums ® but these must not 
be used within 24 hours of taking the study drug. The study staff will let you know which medications you 
cannot take during the study. If a doctor other than your study doctor prescribes a drug for you to take during 
the course of the study, please inform the study doctor so that we may determine if it can be taken with the 
study drug.  
Therapies: While you are participating in the study, you will not be allowed to receive certain therapies. This 
includes chemotherapy, surgery tumor control, radiation therapy for tumor control, investigational products 
other than APR003 or other prescribed drug that is part of this protocol therapy. The study staff will let you 
know which therapies you cannot receive during the study. 
If, for any reason, the study drug is stopped before your last treatment visit, you will be asked to come into the 
clinic. You will be asked to have all end-of-treatment testing done for your safety. 
STUDY PROCEDURES 
Before any study-related tests and procedures are performed, you will be asked to read, sign and date this 
consent form. If you decide you want to participate in the study, the study staff will need to perform screening 
tests and procedures to find out if you qualify for the study and to determine the current status of your cancer.  
 
These tests and procedures are often used as regular care for colon cancer patients and might be done even if 
you do not take part in the research study. If you have had some of these tests done within the last few weeks, 
they might or might not need to be repeated. Screening tests and procedures may be done over a period of 
approximately 28 days (4 weeks) and include the following: 
 
Screening within 28 days before Day 1 (first Day of study medication) 
 
• 
Health and Medical Questions:  You will be asked about your overall health, medical history, previous 
medical procedures and treatments. You will also be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently taking. 
• 
Demographic questions:  You will be asked to give personal information about yourself, such as your 
date of birth, sex and race.  
• 
Physical Examination:  You will have a physical exam and your height and weight will be recorded.  
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate body temperature, 
oxygen saturation and respiration rate. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your heart. 


 
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• 
Blood Tests:  A small needle will be placed into a vein in your arm to draw blood for testing, unless you 
have a central venous catheter where blood will be drawn. The blood samples will be used for the following 
tests: 
o 
Clinical chemistry:  To evaluate your general health, liver and kidney function   
o 
Complete blood count (CBC) with platelets and differential:  To evaluate white blood cells, red 
blood cells and other blood components that give an indication of your general health and safety  
o 
Coagulation function:  To measure your body’s blood clotting function. 
o 
Virology: To test for the presence of hepatitis B (HBV), hepatitis C (HCV), or human 
immunodeficiency virus (HIV). 
o 
Thyroid function: To measure how much of this hormone is in your blood. 
o 
Pregnancy test: Blood or urine will be collected from women of children bearing potential.  
• 
Urinalysis: A urine sample will be collected to test for problems with your kidneys or urinary tract. 
• 
Radiography Examination:  You will be asked to have a radiology examination using computed 
tomography (CT), positron emission tomography (PET) /CT or magnetic resonance imaging (MRI) scans.  
The scans take pictures of the inside of your body and provide important information about the status of 
the cancer. Your study doctor will explain which type of scan will be best for you. 
 
Study Procedures during Treatment Period (3-week Cycles) 
 
The following tests and procedures will be performed at every visit or as indicated: 
 
Cycle 1 Day 1: 
• 
Physical Examination:  You will have a physical exam and your weight will be recorded.  
• 
Health and Medical Questions:  You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart. 
• 
Blood Tests:  Blood samples will be collected before your morning dose (pre-dose) of APR003. 
Samples collected after your morning dose (post-dose) are indicated as follows.  
o Clinical chemistry and hematology 
o Coagulation function: as deemed necessary by your investigator 
o Pregnancy test:  A blood or urine sample will be collected pre-dose. 
o PK testing for APR003:  Pharmacokinetic (PK) test: PK measures the amount of study drug in 
your blood to understand how the drug is absorbed and removed from your body. Blood samples 
will be collected pre-dose and 30 mins, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose.  
o PD/biomarkers for APR003:  Pharmacodynamic (PD) test: Blood samples will be taken to 
measure the effect of study drug on tumor materials that may be in your blood. These samples will 
be collected pre-dose, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post dose. 
o Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract. 
o Study Medication:  
o You will take your first dose of APR003 in the clinic.  


 
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o After receiving the study drug, you will need to remain in the clinic for a minimum of 6  
hours post-dose for observation or you may be admitted to a hospital for overnight 
observation. During this time, the study team will take your vital signs every 2 hours and 
perform other health checks to ensure your safety.  
Cycle 1 Day 2: 
• 
Physical Examination:  To be performed as deemed necessary by your investigator; your weight will 
be recorded.  
• 
Health and Medical Questions:  You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate and respiration 
rate. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart as deemed necessary by your investigator. 
• 
Blood Tests:  Blood samples will be collected before your morning dose (pre-dose) of APR003. 
Samples collected after your morning dose (post-dose) are indicated as follows.  
o Clinical chemistry and hematology 
o Coagulation function: as deemed necessary by your investigator 
o PK testing for APR003:  Blood sample to be collected at 24 hours post-dose.  
o PD/biomarkers for APR003:  Pharmacodynamic (PD) test: Blood sample will be taken at 24 
hours post dose 
o Other specialty tests: as deemed necessary by your investigator  
• 
Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract 
 
Cycle 1 Day 8: 
• 
Physical Examination:  To be performed as deemed necessary by your investigator; your weight will 
be recorded  
• 
Health and Medical Questions:  You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart as deemed necessary by your investigator. 
• 
Blood Tests: Blood samples will be collected before your morning dose.  
o Clinical chemistry and hematology 
o Other specialty tests: as deemed necessary by your investigator  
• 
Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract 
• 
Study Medication:  
o You will take your dose of APR003 in the clinic. 


 
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o After receiving the study drug, you will need to remain in the clinic for a minimum of 6  
hours post-dose for observation or you may be admitted to a hospital for overnight 
observation. During this time, the study team will  take your vital signs every 2 hours and  
perform other health checks to ensure your safety.  
 
Cycle 1 Day 15: 
• 
Physical Examination:  To be performed as deemed necessary by your investigator, your weight will 
be recorded.  
• 
Health and Medical Questions:  You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart as deemed necessary by your investigator. 
• 
Blood Tests: Blood samples will be collected before your morning dose.  
o 
Clinical chemistry and hematology 
o 
PK testing for APR003:  Blood samples will be collected pre-dose, 30 min, 1 hour, 2 hours, 
4 hours, 6 hours, and 8 hours post dose.  
o 
PD/biomarkers for APR003:  Pharmacodynamic (PD) test: Blood sample will be taken at 
collected pre-dose, 1 hour, 2 hours, 4 hours, 6 hours, and 8 hours post-dose.  
o 
Other specialty tests: as deemed necessary by your investigator  
• 
Study Medication:  You will take your dose of APR003 in the clinic.  
o After receiving the study drug, you will need to remain in the clinic for a minimum of 6  
hours post-dose for observation or you may be admitted to a hospital for overnight 
observation. During this time, the study team will  take your vital signs every 2 hours and  
perform other health checks to ensure your safety.  
• 
Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract 
 
 
Cycle 2 and Cycle 3 Day 1: 
 
• 
Physical Examination:  To be performed as deemed necessary by your investigator, your weight will 
be recorded  
• 
Health and Medical Questions:  You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Medication History:  You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart. 
• 
Blood Tests: Blood samples will be collected before your morning dose (pre-dose) of APR003. 
Samples collected after your morning dose (post-dose) are indicated as follows. 
o Clinical chemistry and hematology 


 
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o Coagulation: To measure your body’s blood clotting function 
o Cycle 2 only: PD/biomarkers for APR003:  Blood samples will be collected pre-dose and 30 
mins, 1 hour, 2 hours, 4 hours, and 6 hours post-dose 
o Cycle 2 only: PK testing for APR003:  Blood samples will be collected pre-dose and 30 mins, 1 
hour, 2 hours, 4 hours, and 6 hours post-dose 
o Other specialty tests: as deemed necessary by your investigator  
 
• Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract 
• Study Medication:  You will take your dose of APR003 in the clinic.  At every visit, you will be 
asked to return the empty, partially used or full drug bottles of APR003 and bring your dosing diary at 
each of your clinic visits 
o After review how you tolerated APR003 during the first 3 doses and if deemed necessary 
by your investigator you may need to continue taking APR003 in clinic and after receiving 
the study drug, you will need to remain in the clinic for a minimum of 6  hours post-dose 
for observation or you may be admitted to a hospital for overnight observation. During 
this time, the study team will  take your vital signs every 2 hours and  perform other health 
checks to ensure your safety or: 
o When taking APR003 at home, it is important you immediately report any side effects, 
such as fever, weakness, dizziness, chills, headache, rash, difficulty breathing and/or 
wheezing, or seizure to your study team. If you experience side effects, the study team 
may request you return to the clinic for further observation and testing.   
o NOTE:  If there is a dose interruption of greater than or equal to 21 consecutive days, the 
monitoring as described above will be restarted as if it was your first day of dosing.   
 
Cycle 2 and Cycle 3 Day 11: 
• 
Health and Medical Questions: You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs:  Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Electrocardiogram (ECG): An ECG will be performed to measure the electrical activity of your heart 
as deemed necessary by your investigator. 
• 
Medication History: You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Blood Tests: Blood sample will be collected pre-dose. 
o Clinical chemistry  
o Other specialty tests: as deemed necessary by your investigator  
• 
Study Medication:  At every visit, you will be asked to return the empty, partially used or full bottles 
of APR003 and bring your Dosing Diary at each of your clinic visits. 
o After review how you tolerated APR003 during the first 3 doses and If deemed necessary by 
your investigator you may need to continue taking APR003 in clinic and after receiving the 
study drug, you will need to remain in the clinic for a minimum of 6  hours post-dose for 
observation or you may be admitted to a hospital for overnight observation. During this time, 
the study team will  take your vital signs every 2 hours and  perform other health checks to 
ensure your safety or: 
o When taking APR003 at home, it is important you immediately report any side effects, such 
as fever, weakness, dizziness, chills, headache, rash, difficulty breathing and/or wheezing, or 
seizure to your study team. If you experience side effects, the study team may request you 
return to the clinic for further observation and testing.   


 
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o NOTE:  If there is a dose interruption of greater than or equal to 21 consecutive days, the 
monitoring as described above will be restarted as if it was your first day of dosing.  .   
 
Cycle 4 Day 1 (and all remaining cycles): Study procedures and assessment to be performed on Day 1 of 
Cycle 4 and for the remainder of time you stay on the study. 
 
• 
Physical Examination: To be performed as deemed necessary by your investigator.  
• 
Health and Medical Questions: You will be asked about your current health and how well you are 
able to perform your daily activities. 
• 
Vital signs: Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract. 
• 
Electrocardiogram (ECG): An ECG will be performed to measure the electrical activity of your heart 
as deemed necessary by your investigator. 
• 
Medication History: You will be asked to list all the medication you have taken and are currently 
taking. 
 
• 
Blood Tests: The blood samples will be used for the following tests: 
o Clinical chemistry: To evaluate your general health, liver and kidney function   
o Complete blood count (CBC) with platelets and differential:  To evaluate white blood cells, 
red blood cells and other blood components that give an indication of your general health and 
safety  
o Coagulation function: To measure your body’s blood clotting function as deemed necessary 
by your investigator. 
o Thyroid function: To measure how much of this hormone is in your blood. 
o Cycle 4 (every 3 cycles thereafter) PD biomarkers for APR003: Blood samples will be 
collected pre-dose.  
o Other specialty tests: as deemed necessary by your investigator  
• 
Radiography Examinations/Tumor Measurement: Imaging studies, such as a CT, CT/PET or MRI 
scan will be performed at Cycle 4 and then every 3 cycles thereafter. 
• 
Study Medication: You will take your dose of APR003 in the clinic.  At every visit, you will be asked 
to return the empty, partially used or full bottles of APR003 and bring your Dosing Diary at each of 
your clinic visits 
o After review how you tolerated APR003 during the first 3 doses and If deemed necessary by 
your investigator you may need to continue taking APR003 in clinic and after receiving the 
study drug, you will need to remain in the clinic for a minimum of 6  hours post-dose for 
observation or you may be admitted to a hospital for overnight observation. During this time, 
the study team will  take your vital signs every 2 hours and  perform other health checks to 
ensure your safety or: 
o When taking APR003 at home, it is important you immediately report any side effects, such 
as fever, weakness, dizziness, chills, headache, rash, difficulty breathing and/or wheezing, or 
seizure to your study team. If you experience side effects, the study team may request you 
return to the clinic for further observation and testing.   
NOTE:  If there is a dose interruption of greater than or equal to 21 consecutive days, the monitoring 
as described above will be restarted as if it was your first day of dosing.   
Study Procedures at the End of Treatment visit 
 
• 
Health and Medical Questions: You will be asked about your current health and how well you are 
able to perform your daily activities. 


 
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• 
Medication History: You will be asked to list all the medication you have taken and are currently 
taking. 
• 
Physical Examination. 
• 
Vital signs: Your vital signs will be measured, including blood pressure, heart rate, body temperature, 
oxygen saturation and respiration rate. 
• 
Urinalysis: A urine sample will be collected to detect problems with your kidneys or urinary tract 
• 
Electrocardiogram (ECG):  An ECG will be performed to measure the electrical activity of your 
heart. 
• 
Blood Tests 
o Clinical chemistry and hematology  
o Coagulation 
o Thyroid 
o Pregnancy test 
o PD/Biomarkers for APR003 
o Other specialty tests 
• 
Radiography Examination: A CT, CT/PET or MRI scan may be performed. 
• 
Study Medication will be collected. The study staff will ask you to return all bottles of used, partially 
used, or unused APR003 to the clinic and bring your Dosing Diary.  
 
Study Procedures during the Follow-Up Period 
 
Long-Term Safety Follow-Up 
You will continue to be followed after you have taken the last dose of study drug on this study. Follow-up will 
occur approximately every 3 months for 2 years. Information on treatments you receive after being on the 
study and on your general well-being will be collected via telephone or email with your caregiver or your 
referring doctor. 
BLOOD DRAWS   
The total amount of blood taken during the study will depend on how long you remain on the study. For the 
initial 3 cycles including Screening, a total of approximately 140 mL or 28 teaspoons will be drawn.  If you 
stay on the study for 6 months, the approximate total amount of blood drawn will be 221.5 mL or 45 teaspoons. 
For comparison, the standard blood donation is about 480 mL (two cups). 
 
KNOWN SIDE EFFECTS 
 
Related adverse events include: 
• 
Shivering and chills 
• 
Feeling sick to the stomach 
• 
Feeling tired, tiredness, weakness. 
• 
Decreased number of a type of white blood cells. This is associated with an increased risk of 
infection. 
• 
Fever 
• 
Pain at the tumor site 
• 
Vomiting 


 
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• 
Cytokine release syndrome: A group of symptoms caused by release of chemicals from cells during 
the infusion. This can include nausea, headache, rapid heartbeat, shortness of breath, kidney damage, 
and rash. It can be-life threatening and may be reversible. 
• 
Sudden reddening of the face and/or neck 
• 
Pain in the head 
• 
Abdominal pain 
• 
Dizziness 
• 
Sweating  
• 
abnormal digestive blood test 
• 
Muscle spasms, body aches 
• 
Condition in which the number of white bloods cells called neutrophils is abnormally low. This 
increases the risk of infection, which may be serious or life-threatening. Symptoms of infection may 
include fever, pain, redness, and/or difficulty breathing. 
• 
Inflammation of the pancreas causing pain in the upper abdomen. This could become severe and 
cause nausea and vomiting, fever and rapid heart rate. This could require hospitalization and may be 
life threatening. 
• 
Sudden growth in tumor or worsening of tumor related problems. 
• 
Weight decrease 


 
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After you receive your dose of APR003, you’ll be watched closely for side effects. Cytokine release syndrome 
(CRS) has occurred and neurological changes are possible side effects of APR003 administration. CRS is a 
group of symptoms that happen when T cells attack cancer cells. T cells help your immune system tell which 
antigens don’t belong in your body. T cells are a type of white blood cell (lymphocyte). T cells have receptors 
that attach to certain antigens. Antigens are substances that activate (turn on) your immune system. Antigens 
are found on the surface of some things made inside your body, such as cells. They’re also found on the surface 
of some things from outside your body, such as bacteria and viruses. Once a T cell attaches to an antigen, it 
sends messages to other cells in your immune system. These cells help kill the thing with the antigen and get 
it out of your body. 
 
Common symptoms of CRS include: 
• 
A fever of 100.4 °F (38 °C) or higher 
• 
Flu-like symptoms, such as: 
• 
Muscle aches 
• 
Headaches 
• 
Chills 
• 
Feeling unusually tired 
• 
Nausea or vomiting 
• 
A faster heart rate than usual 
• 
Feeling dizzy or lightheaded 
 
Common neurologic changes include: 
• 
Confusion 
• 
Trouble finding words 
• 
Tremors 
• 
Seizures 
• 
Sleeping more than usual 
• 
Feeling very drowsy and responding more slowly than usual 
 
Not everyone gets the same symptoms, and everyone responds differently to each dose of APR003. 
 
These side effects aren’t permanent. Your care team will watch you carefully for side effects. They’ll manage 
any side effects you have. It’s very important for you or your caregiver to tell a member of your healthcare 
team if you think you’re having any of these side effects. 
 
If the symptoms become serious, your doctors will use medications (such as tocilizumab, prednisone, Benadryl, 
Tylenol, and NSAIDS) to try to reverse the immune reaction. There is a small possibility that CRS can be so 
severe that it leads to death. 
 
 
 
POSSIBLE SIDE EFFECTS AND RISKS/DISCOMFORT OF THE STUDY DRUG 
 
Participating in a research study can be an inconvenience to your daily life.  Please consider the study time 
commitments and responsibilities as a research subject when you are deciding if you will participate.  It is 
important that you disclose all relevant medical history and medications to the study staff.  You must carefully 
follow any instructions given to you concerning the study. 
 
All drugs can cause side effects in some people. Since the study drug is experimental there may be other risks 
that are unknown. All patients in the study will be monitored for side effects.  The study staff may give you 
medications to help lessen some of the side effects.     
 
There may be rare and unknown side effects, some of which may be irreversible and/or life-threatening.  
 


 
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You must tell the study doctor or study staff about all side effects that you have.  If you are not honest about your 
side effects, it may not be safe for you to stay in the study. 
 
 
Potential Risk Related to APR003 
 
• 
Gastritis (inflammation of the stomach), that may lead to nausea, upset stomach, abdominal bloating, 
vomiting, indigestion or hiccups  
• 
Hepatitis (liver inflammation) and/or liver failure that may lead to fatigue, flu-like symptoms dark 
urine, abdominal pain, loss of appetite/weight loss, or jaundice (yellowing of the eyes and skin) 
• 
Enteritis (inflammation of the small intestine) that may lead to abdominal pain/cramps, diarrhea, 
nausea, vomiting, loss of appetite, bleeding or mucus in the stool 
• 
Colitis (inflammation of the colon) that may lead to diarrhea, abdominal pain/cramps, pain in the 
rectum, blood in the stool, weight loss, fatigue 
• 
Diabetes that may lead to increased thirst, frequent urination, unexplained weight loss, fatigue, blurry 
vision 
• 
Nephritis (inflammation of the kidneys) that may lead to pain in the pelvis, burning sensation while 
urinating, increased need to urinate or frequency or urination, pain in the kidney area or abdomen, 
vomiting, blood in the urine, swelling of the face, hands, legs and/or feet, or increase blood pressure 
• 
Increased risk of bleeding 
• 
 
 
 
These are not all the possible side effects of APR003. Your study doctor can provide you with more information 
about APR003.  
 
Unforeseen Risks 
 
Sometimes people have allergic reactions to drugs. A serious allergic reaction can be life threatening. Some 
signs that you may be having an allergic reaction are: 
 
• 
Rash or hives 
• 
Having a hard time breathing 
• 
Wheezing when you breathe 
• 
Sudden change in blood pressure (making you feel dizzy or lightheaded) 
• 
Swelling around the mouth, throat or eyes 
• 
Fast pulse 
• 
Sweating 
 
You should get medical help and contact the study doctor or staff if you have any of these or any other side 
effects during the study. 
 
 
Potential Risks of Additional Study Procedures 
 
Blood Draw Risks 
 
Blood samples will be taken during the study.  Using a needle to remove blood from a vein is called “a blood 
draw”. Side effects associated with routine blood draws can include pain, bruising, bleeding, swelling, or 
scarring of the skin where the blood is drawn. You may also feel light-headed, faint, or dizzy when the blood 
is taken. 
 
Electrocardiogram Risks 
 


 
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During an ECG, electrode patches/sensors are applied to the chest area, as well as your arms and legs. You 
may experience temporary discomfort (pulling on the skin/skin hair) during removal of the sensors.  You may 
also develop some minor skin irritation from the ECG patch adhesive. 
 
CT, PET/CT or MRI Scan Risks  
 
Computed tomography (CT), positron emission tomography (PET) /CT or magnetic resonance imaging (MRI) 
MRI scanners use special equipment to take pictures of the inside of your body. The scanner is usually a large 
machine shaped like a doughnut and has a bed in the middle of the circle that you lie on. The bed can slide 
backwards and forwards through the hole of the doughnut. Pictures of your internal organs are taken as you 
move through the machine.  
 
The most accurate method for following your cancer and how you respond to the study drug, is CT scanning. 
If the study doctor uses these scans, you will have some radiation exposure. Generally, the amount of radiation 
received during this procedure is the same as a normal person gets from exposure to natural sources of radiation 
in the environment in a 2- to 3-year period. The potential long-term risks from this radiation are uncertain, but 
have not been associated with any definite change in overall medical condition.  
 
A contrast drug or radioactive tracer is commonly injected in a vein before a CT scan to make the organs, 
tumors and the inside of your bones easier to see. One form of contrast dye contains iodine and if you are 
allergic to iodine or shellfish you should notify your study doctor and radiology lab prior to having the CT 
scan. Rarely, some people have allergic reactions (such as hives or itching) due to the contrast agent. Severe 
reactions (for example, drop in blood pressure, difficulty in breathing, or kidney problems) are rare. You should 
inform your study doctor if you have had an allergic reaction in the past. Your doctor will then be able to make 
sure that you are protected during the scan.  
 
Some doctors may use MRI scans, rather than CT scans, to measure your cancer and your response to the study 
drug. If the study doctor uses MRI scans, you will be exposed to powerful magnetic fields. There are no known 
risks resulting directly from exposure to these magnetic fields. However, it possible to feel muscle twitches 
and tingling sensations or a slight increase in body temperature during the test.  
 
The MRI scanner produces tapping sounds that can reach very loud levels. To avoid any discomfort from this 
noise, you can wear earplugs or headphones that are available in the MRI scanning room. 
 
A contrast agent is commonly injected in a vein before the MRI scan. The contrast agent usually used in MRI 
is associated with a low risk of mild problems like headache, nausea, or a tingling sensation around the mouth. 
Allergic reactions are possible but very rare. Subjects who have reduced kidney function may have severe 
scarring reactions that can cause permanent disability or death. The contrast agent should not be given to 
pregnant subjects, so if there is a possibility that you could be pregnant, you should ask to undergo a pregnancy 
test before having the MRI.  
 
Some people have reported feeling anxious or claustrophobic (like being trapped) during the CT or MRI scans 
because they are performed in a narrow, enclosed space. You can ask for the scan to be stopped at any time if 
you cannot stand being in the scanner. Medicine can also be provided to relieve anxiety during these scans.  
 
 
Incidental Findings 
It is possible that the study procedures could detect a medical problem that was previously unknown to you 
and that is unrelated to the purpose of this study.  If the research procedures uncover findings that may be 
important for you to know about, such as the possibility of a previously unknown medical condition, you will 
be informed by a member of the study staff. Or, you may authorize the release and communication of the 
findings to your primary physician. These findings may require additional testing or treatment. The cost of 
any additional tests or related treatment will be your responsibility.  
 
Pregnancy Risks 


 
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The effects of APR003 on pregnancy, an unborn baby, or a nursing child is not known at this time. Therefore, 
if you are pregnant, planning to become pregnant or are breastfeeding a child, you cannot participate in this 
study. You must confirm that, to the best of your knowledge, you are not pregnant, and that you do not intend 
to become pregnant during the study. 
 
If you are a woman of childbearing potential you must agree to use a recommended method of contraception 
during heterosexual intercourse throughout the study dosing period and for up to 6 months after stopping the 
study drug.  
 
Female subjects are considered to be of childbearing potential in this study unless you meet the following 
criteria: 
o 
Surgical hysterectomy  
o 
Bilateral tubular ligation 
o 
Bilateral oophorectomy  
o 
Menopause > 55 years of age with last menses > 6 months ago  
 
Males who can father a child must use one, or a combination, of the approved forms of birth control, for up to 
6 months following stopping the study dosing. Females of childbearing potential must use of combination of 
two of the following methods. 
• 
Individual methods:  
o 
IUD (Intrauterine device) 
o 
Tubal sterilization 
o 
Vasectomy 
o 
Hysterectomy 
• 
Combined with barrier methods (diaphragm with spermicide and/or male condom with spermicide) 
 
Your study doctor or other personal health care provider can discuss birth control options with you. 
 
Males must also refrain from sperm donation from the start of the study therapy until at least 90 days after the 
last dose of the study drug. 
 
Females who become pregnant or think they may be pregnant while taking study drug or within 30 days after 
the last dose of the study drug, you must stop taking the study drug and notify your study doctor immediately. 
The study doctor will request to track your pregnancy and will report the outcome of the pregnancy to the study 
sponsor. 
 
Males with female partners who become pregnant or suspects that she has become pregnant while you are 
taking study drug or within 30 days after the last dose of study drug, you must notify your study doctor 
immediately. Because the risk to your partner and baby is unknown, it is recommended for your partner to 
agree to medical supervision during her pregnancy and for the baby after it is born. If you agree, your partner 
will be invited to sign a consent document to allow medical supervision. Your study doctor may need to 
disclose to your partner details of this study and your participation in it. The study sponsor, through the study 
doctor, will request your consent and your partner’s consent to collect confidential information about her health 
and that of the baby. Neither the study sponsor nor the study doctor will be responsible for providing routine 
medical care relating to the pregnancy.  
 
Because the effects of the study drug on a nursing child are not known, you may not enroll in this study if you 
are a woman who is breastfeeding a child. You should not nurse a baby while taking study drug because of the 
risk that the baby might be exposed to the study drug that comes out of your body into the breast milk. 
 
 


 
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POTENTIAL BENEFITS 
The study therapy may reduce the amount of cancer in your body or slow the growth of your cancer.  Your 
participation in the study may lead to possible improvements in the symptoms of your cancer, but, there is no 
guarantee that this study will help you. Your disease may improve, stay the same, or get worse due to your 
participation in this study.   
 
Your participation in this study may benefit subjects, scientists, and doctors by providing increased knowledge 
and information about the treatment of cancer. The study sponsor may benefit if it is found that the study drug 
is effective in treating cancer.  
 
TREATMENT ALTERNATIVES 
You should discuss participation in this protocol and other potential treatment options with your doctor.  Other 
treatment options that have been shown to prolong life expectancy in some patients include different 
chemotherapy regimens that include drugs like 5-Flourouracil, Oxaliplatin and Irinotecan or treatments 
directed against new blood vessel formation in the tumor (VEGF).  You do not have to be in the study to get 
treatment for your cancer. You can choose to get treatment from your regular doctor that may include 
supportive care, drugs, or combinations of drugs that are currently approved or are being tested in other clinical 
studies investigating the treatment of advanced colorectal cancer. However, by participating in this study, you 
will not be able to receive those treatment option(s) while on study. Your Study Doctor will discuss with you 
the risks and benefits of other treatments.   
 
NEW FINDINGS 
If Apros Therapeutics, Inc obtains any new information about the study medication that might change your 
decision to be in the study, you or your legally authorized representative will immediately be made aware of 
this information. 
 
If additional procedures or tests are required for this study, you will be notified of these requirements.  Before 
any new procedures or tests are performed, you will be asked to sign a new consent form which details the 
potential additional risks, discomforts and benefits.  
 
CONFIDENTIALITY AND DATA PROTECTION 
During this study, the study doctor and the study staff will record information about you, your health and your 
participation in the study on forms provided by the sponsor. These forms are known as case report forms. You 
will not be able to participate in this study if you do not consent to the collection of this information about you. 
 
Your name and any other information that allows you to be identified directly will not be entered on the case 
report forms or included in any records or samples the study doctor provides to the sponsor or the sponsor’s 
representatives. Instead, you will only be identified by a code. The code is used so that the study doctor can 
identify you if necessary. The study doctor will keep the list connecting that code to your name, but the study 
doctor will not send that list to the sponsor or its representatives. However, the study forms will contain other 
information about you that could be used to identify you even though your name does not appear. Although 
efforts will be made to protect your privacy, absolute confidentiality of your records cannot be guaranteed. 
 
Your coded study information will be entered into and kept in a database by the sponsor. This coded 
information will be used by the sponsor, its affiliates and collaborators to analyse the study results and may be 
used for additional unanticipated medical and/or scientific research projects in the future relating to the 
development of the study drug (but at all times in compliance with applicable law and regulation). 
 


 
Apros Therapeutics Main ICF  v4.0 28Jan2022 
 
Page 1 of 1 
The results of this study may be published and presented to the public, and used for educational purposes. 
Information that could identify you will not be used in any publication or presentation. 
 
Other groups may also need to look at your medical records and study records to make sure that the information 
is correct and to evaluate the conduct of this study. These include the following:  
 
o 
The sponsor, its affiliates and its representatives, including any contract research organization helping 
the Sponsor with the study, and any collaborators of the sponsor working with the sponsor to develop 
the study drug. 
o 
The Institutional Review Board (IRB) responsible for overseeing the study. An IRB is a group of 
qualified people that evaluates the ethical merits of a study and looks out for the rights and welfare of 
research subjects. 
o 
The United States Food and Drug Administration and regulatory agencies in other countries where the 
study is taking place.  
 
Storage of blood and biological samples 
 
During this study, you will be asked to provide blood, urine and tissue samples. These samples will be used 
for checking the safety of the study drug, the amounts of study drug in the blood, the effects of the drug on 
blood cells, and the effects of the drug on proteins that are produced by certain cells of the body. Some of these 
samples will be stored in case the sponsor wishes to examine additional drug breakdown products or effects of 
the drug on cellular function at a later time. In signing this consent form, you voluntarily donate all collected 
and stored blood samples to the study sponsor to perform these types of foreseen or unforeseen tests as part of 
the evaluation of the study drug.   
 
You may change your mind and take back your consent at any time. If you take back this consent, no further 
information will be collected about you. If you withdraw from the study, any sample collected prior to your 
withdrawal may still be analyzed as described in the Informed Consent Form, unless you specifically ask for 
your samples to be destroyed or local laws require destruction of the samples.  However, if samples have been 
tested prior to withdrawal, results from those tests will remain as part of the overall research data.  However, 
the sponsor and those identified above will still be able to use and disclose coded information about you from 
this study that has already been collected.   
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. Law. This 
Web site will not include information that can identify you. At most, the Web site will include a summary of 
the results. You can search this Web site at any time. 
 
COSTS OF PARTICIPATION 
You (and/or your insurance company) will not be expected to pay for any of the procedures that are obtained 
solely for the purposes of this study. Also, you (and/or your insurance company) will not be expected to pay 
for the study medication or tests that are part of this research study. 
 
You will still need to pay for your usual medical care. You (and/or your insurance company) will be responsible 
for costs of care that are associated with usual cancer care.   This could include any non-study procedures 
and/or non-study medication that are needed while you are in the study. You should contact your medical 
insurance company to find out if they will pay for routine medical care while you are in this study.  If you have 
any questions, please ask the study doctor or a member of the study staff.  
 
For more information on insurance coverage for clinical trials, you can visit the National Cancer 
Institute’s Web site at http://www.cancer.gov. You can print a copy of the “Clinical Trials and Insurance 
Coverage” information from this Web site. 
 


 
Apros Therapeutics Main ICF  v4.0 28Jan2022 
 
Page 1 of 1 
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you 
a free copy. 
 
COMPENSATION 
You will not be paid for participating in this study. You will not be paid for expenses like lost wages, disability, 
discomfort due to injury, or meals obtained while waiting at the study clinic. 
 
You may ask to be reimbursed for the reasonable cost of travel required to participate in this study. Discuss 
this with the study clinic staff. To receive payment for travel, you will need to submit the original travel receipts 
to the research study clinic staff at the clinic. 
 
COMPENSATION FOR INJURY 
If you become sick or injured as a direct result of taking the study drug and/or following the study procedures, 
the study doctor will provide you with medical treatment. The study sponsor will reimburse you or your study 
doctor for the reasonable and necessary costs of such medical treatment, provided that you have followed the 
instructions of the study doctor and that these expenses are not paid by medical insurance. No other form of 
reimbursement for study-related injury or illness is offered by the study sponsor. You should immediately 
contact your study doctor if you believe you have experienced any study-related illness or injury. 
 
If you receive Medicare benefits in the United States, the study sponsor is required by law to report payments 
made to you for treatment, complications, and injuries that arise from this study. Information that you are 
taking part in the study, medical treatments received, Medicare claims, and other personal information about 
you such as your name, social security number, and date of birth, will be provided to the Centers of Medicare 
and Medicaid Services and its agents and/or contractors for this purpose. 
 
By signing and dating this form, you have not waived any of the legal rights, which you would have 
otherwise, if you were not a participant in a medication research study. 
 
EMERGENCYAND IRB CONTACT 
You have the right to ask questions about the known and unknown risks of this study at any time. 
 
The study doctor will be available and on call during the whole study.  Please call the study doctor at the phone 
number listed on page 1 if: 
o 
You have any questions about this study 
o 
You experience a study-related injury 
o 
You have a medical emergency 
 
If you are unable to reach anyone at the number(s) listed above and you require immediate (life 
threatening) medical attention, please go to the nearest emergency room. 
 
This study has been reviewed by an IRB and has received a positive opinion, meaning that the study was 
deemed ethically sound to conduct.  
 
If you have any questions about your rights as a research subject, or complaints about this study, you should 
call <INSERT IRB NAME, ADDRESS, and PHONE NUMBER>.  


 
Apros Therapeutics Main ICF  v4.0 28Jan2022 
 
Page 1 of 1 
VOLUNTARY PARTICIPATION/ WITHDRAWAL FROM THE STUDY 
You do not have to be in this study.  Your participation is voluntary. Refusal to participate will involve no 
penalty or loss of benefits. If you decide that you do not want to be in the study anymore, you should tell the 
study staff before you stop taking the study drug.  This is called withdrawal. Withdrawal will not affect your 
future medical care at this clinic nor your ability to participate in future studies. You can withdraw at any time 
without having to give a reason. But, if you withdraw because of side effects, it is important that you tell this 
to the study doctor. 
 
You may be asked to stop being in this study at any time by the study doctor, Apros Therapeutics, Inc or the 
Food and Drug Administration (FDA), without your consent and for any reason. Some of these reasons are:  
• 
You do not follow the study instructions. 
• 
You no longer fulfill the criteria for the remainder of the study.  
• 
You need medicine that is not allowed during the study. 
• 
You develop a medical condition that makes you unqualified for the study.  
• 
The study doctor thinks it is best for you to discontinue your participation in the study. 
• 
You have an injury or side effect that is “serious or severe”.  
• 
The study is cancelled or stopped.   
• 
If you are female and become pregnant 
• 
If the study is stopped by Apros Therapeutics, Inc., you will be given the reason for this decision. 
 
You may also be asked to stop being in the study for other reasons including not taking the study medication 
as directed and not coming to the clinic for your scheduled visits.  
 
If you do not finish the study for any reason, you will be asked to come to the clinic to have all end-of-study 
tests and procedures done. You will be required to return all unused, partially used, and/or used containers of 
study drug.  
FINANCIAL DISCLOSURE 
If a commercial product is developed from the research performed in the Study, Apros Therapeutics, Inc., 
will own all rights to the product.  By participating in the Study, you do not acquire any rights to the 
commercial product. 
 
 


 
Apros Therapeutics Main ICF  v4.0 28Jan2022 
 
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CONSENT   
I have read and understand the information in this informed consent document.  I have had an opportunity to 
ask questions and all of my questions have been answered to my satisfaction. I voluntarily agree to participate 
in this study until I decide otherwise.  I do not waive any of my legal rights by signing this consent document.  
I will receive a copy of this signed consent document. 
 
_____________________________________ 
 
 
 
Subject’s Printed Name  
 
_____________________________________ 
 
 
___________ 
Subject’s Signature 
 
 
 
 
 
Date 
 
 
I certify that under law I am the legally authorized representative of the participant named above and that I am 
authorized by law to sign this consent to his/her participation in the research study described above. 
_____________________________________ 
 
 
 
Printed Name of Legal Representative 
 
_____________________________________ 
 
 
___________ 
Signature of Legal Representative 
 
 
 
Date 
 
 
 
Person Conducting the Consent Discussion: 
 
_____________________________________ 
 
 
 
Printed Name of the Person Conducting the  
 
 
 
Consent Discussion  
 
 
_____________________________________ 
 
 
___________ 
Signature of the Person Conducting the   
 
 
Date 
 
Consent Discussion  
 
 
 
 
 
 
 
 
The study subject has indicated that he/she is unable to read.  The consent document has been read to the 
subject by a member of the study staff, discussed with the subject by a member of the study staff, and the 
subject has been given an opportunity to ask questions of the study staff. 
 
_____________________________________ 
 
Printed Name of Impartial Witness  
 
_____________________________________ 
 
 
___________ 
Signature of Impartial                  
 
 
 
Date 
Witness* 
 
*Impartial Witness:  A person, who is independent of the study, who cannot be unfairly influenced by people involved 
with the study, who attends the informed consent process if the subject or the subject’s legally acceptable representative 
cannot read, and who reads the informed consent and any other written information supplied to the subject.  Guidance for 
Industry E6 Good Clinical Practice:  Consolidated Guidance 
 
 
 
 


 
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AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION  
 
During your participation in this research study, the study doctor and study staff will collect or create personal 
health information about you (for example, medical histories and results of any tests, examinations or 
procedures you undergo while in the study) and record it on study documents.  The study doctor will keep this 
personal health information in your study-related records (that we will refer to as "your study records").  In 
addition, the study doctor may obtain, and include in your records, information regarding your past, present 
and/or future physical or mental health and/or condition.  Your study doctor may ask you to sign a separate 
authorization to obtain some or all of your medical records from your doctor. Your study records may include 
other personal information (such as social security number, medical record numbers, date of birth, etc.), which 
could be used to identify you.  Health information that could identify you is called "Protected Health 
Information" (or "PHI").   
 
Under federal law (the "Privacy Rule"), your PHI that is created or obtained during this research study cannot 
be "used" to conduct the research or "disclosed" (given to anyone) for research purposes without your 
permission.  This permission is called an "Authorization."  Therefore, you may not participate in this study 
unless you give your permission to use and disclose your PHI by signing this Authorization.  By signing, you 
are agreeing to allow the study doctor and staff to use your PHI to conduct this study.   
 
By signing this Authorization, you also are agreeing to allow the study doctor to disclose PHI as described 
below: 
 
• 
The sponsor of this study and anyone working on behalf of the sponsor to conduct this study (referred to 
as "the sponsor").  The sponsor will analyze and evaluate the PHI and may use it to develop new tests, 
procedures and commercial products.  The study staff will assign a code number and/or letters to your 
records, which means that you will not ordinarily be identified in the records sent to the sponsor.  The 
sponsor may, however, look at your complete study records that identify you.  In addition, the sponsor 
may visit the study site to oversee the way the study is being conducted and may review your PHI during 
these visits to make sure the information is correct.   
• 
The Institutional Review Board ("IRB") may have access to your PHI in relation to its responsibilities as 
an Institutional Review Board. 
 
The study doctor or sponsor may disclose your PHI to the United States Food and Drug Administration 
(“FDA”) or similar regulatory agencies in the United States and/or foreign countries. 
 
These disclosures also help ensure that the information related to the research is available to all parties who 
may need it for research purposes. 
 
Except for the disclosures described above, your PHI will not be shared with others unless required by law.  If 
your PHI is given to the parties listed above and/or to others who are not required to comply with the federal 
law, your PHI will no longer be protected by this law and could possibly be used or disclosed in ways other 
than those listed here.  
 
You have a right to see, request corrections to errors, and make copies of your PHI.  You are agreeing, however, 
by signing this document, not to see or copy some or all of your PHI until the sponsor has completed all work 
related to this study.  At that time, you may ask to see your records. 
 
This Authorization will expire 50 years from the date you sign it unless you revoke (cancel or withdraw) it 
sooner.   
 
You have a right to revoke your Authorization at any time.  If you revoke it, your PHI will no longer be used 
for this study, except to the extent the parties to the research have already taken action based upon your 
Authorization or need the information to complete analysis and reports for this research.  To revoke your 
Authorization, you must write to the study doctor, stating that you are revoking your Authorization to Use and 


 
Apros Therapeutics Main ICF  v4.0 28Jan2022 
 
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Disclose Protected Health Information.  If you revoke this Authorization, you will not be allowed to continue 
to be in this study.   
 
You will receive a copy of this Authorization after you have signed it. 
 
______________________________________ 
____________ 
Signature of Subject 
 
 
 
 
 
Date 
 
______________________________________ 
Printed Name of Subject 
 
 
I certify that under law I am the legally authorized representative of the participant named above and that I am 
authorized by law to sign this consent to his/her participation in the research study described above.  
 
_____________________________________ 
 
 
 
Printed Name of Legal Representative 
 
_____________________________________ 
 
 
___________ 
Signature of Legal Representative 
 
 
 
Date 
 
 
Person Obtaining the Authorization. 
______________________________________ 
____________ 
Signature of the Person Obtaining the 
 
 
 
Date 
Authorization  
 
______________________________________ 
Printed Name of the Person Obtaining the 
Authorization 
 
The study subject has indicated that he/she is unable to read.  The consent document has been read to the 
subject by a member of the study staff, discussed with the subject by a member of the study staff, and the 
subject has been given an opportunity to ask questions of the study staff. 
 
______________________________________ 
Printed Name of Impartial Witness  
 
______________________________________ 
____________ 
Signature of Impartial                  
 
 
 
Date 
Witness* 
 
*Impartial Witness:  A person, who is independent of the study, who cannot be unfairly influenced by people involved 
with the study, who attends the informed consent process if the subject or the subject’s legally acceptable representative 
cannot read, and who reads the informed consent and any other written information supplied to the subject.  Guidance for 
Industry E6 Good Clinical Practice:  Consolidated Guidance