Clinical trial NCT05239182
Conditions: Pancreatic Adenocarcinoma
Keywords: glycogen biosynthesis Glycogen synthase kinase-3 (GSK-3) NF-κB pathway
Sponsor: Anwaar Saeed
Start date: 2022-01-26; Completion date: 2024-02-04
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial examines how Pancreatic Adenocarcinoma reacts to the addition of 9-ING-41 and retifanlimab to the standard of care chemotherapy treatment, to see if using this combination will help and is able to effect disease progression.

Detailed description:
Given the role of GSK-3β in immune regulation, the combination of GSK-3β inhibition with PD 1 inhibition may be expected to provide synergistic anti-tumor efficacy. The excellent safety profile of 9-ING-41, along with preclinical and clinical evidence of anti-tumor activity in pancreatic cancer, provides a strong rationale to evaluate the efficacy of 9-ING-41 in combination with a PD 1 inhibitor plus standard chemotherapy (gemcitabine/nab-paclitaxel) as frontline therapy for patients with advanced PDAC.

The combination of 9-ING-41 and retifanlimab with gemcitabine/nab-paclitaxel has not previously been administered to human subjects. In the 1801 study, 9-ING- 41 has been administered in combination with various chemotherapy regimens including gemcitabine/nab-paclitaxel, with one 9-ING-41-related SAE (transient visual change) documented to date. Retifanlimab alone has been well-tolerated when administered for up to 2 years in patients with anal cancer. Overall, based on previous nonclinical and clinical experience, both of these agents appear to have an acceptable safety profile and do not appear to have significant overlapping toxicities. However, it is possible that when they are administered together and in combination with gemcitabine/nab-paclitaxel, more frequent or severe AEs, or new AEs not previously observed with any of these agents administered alone, may occur.

It is not known if administration of 9-ING-41 and retifanlimab will act synergistically to provide increased anti-tumor activity compared to gemcitabine/nab-paclitaxel alone. Subjects in this study should not expect to benefit directly by their participation in the study. The data collected in this study may benefit future cancer patients.

Arms: arm 1: * intravenous (IV) infusion of nab-paclitaxel at a dose of 125 mg per square meter, followed by an infusion of gemcitabine according to the gemcitabine label at a dose of 1000 mg per square meter, on days 1, 8, 15 of a 28-day cycle.
* Retifanlimab 500 mg IV on day 1 of a 28-day cycle. (Retifanlimab will be administered following gemcitabine/nab-paclitaxel.)
* 9-ING-41 administered at a dose of 9.3 mg/kg by IV infusion twice weekly on Days 1 and 4 of each week of a 28-day cycle. (9-ING-41 will be administered following retifanlimab.)
Interventions: intervention 1: 9-ING-41 intervention 2: Retifanlimab intervention 3: Gemcitabine intervention 4: Abraxane
Intervention descriptions: intervention 1: 9-ING-41 is a small molecule potent selective GSK-3β inhibitor intervention 2: Humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1. intervention 3: cytotoxic chemotherapy agent intervention 4: cytotoxic chemotherapy agent

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Investigator Initiated Trial 
 
HCC 22-194: A Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3-beta (GSK-3β) inhibitor, combined with 
Retifanlimab, a PD-1 inhibitor, plus Gemcitabine/Nab-Paclitaxel as frontline therapy for patients with advanced 
Pancreatic Adenocarcinoma (RiLEY) 
 
 
SPONSOR – INVESTIGATOR 
Anwaar 
Saeed, 
MD 
Associate Professor of Medicine 
Chief – Gastrointestinal Medical Oncology 
UPMC Hillman Cancer Center. 
UPMC Cancer Pavilion, 5th Floor Room 556 
5150 Centre Avenue, Pittsburgh, PA 15232 
P: 412-623-2091 | E: saeeda3@upmc.edu 
 
 
 
Protocol Number: 
HCC 22-194 (formely IIT-2021-RiLEY) 
 
 
NCT Number: 
NCT05239182 
 
IND Number: 
IND 157852 
 
 
Study Drug(s): 
9-ING-41 – Provided by Actuate Therapeutics 
Retifanlimab (INCMGA00012, MGA012) – Provided by Incyte Corporation 
Gemcitabine / Nab-Paclitaxel – Commercially Available 
 
 
Initial Version: 
1.1 dated 09-27-2021 (University of Kansas Cancer) 
 
Amendments: 
2.0 dated 02-04-2023 (UPMC Hillman Cancer Center) 


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LIST OF COLLABORATORS 


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The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical Practice 
(ICH GCP) and the following: 
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 
CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
The Principal Investigator will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the Investigational New Drug (IND) sponsor, funding agency and documented approval 
from the Institutional Review Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial 
participants. All personnel involved in the conduct of this study have completed Human Subjects Protection and 
ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the Institutional Review Board (IRB) for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study. In addition, all changes to the consent 
form will be IRB-approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
 
Protocol Number IIT-2021-RiLEY 
Protocol Title 
A Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3-beta (GSK- 
3β) inhibitor, combined with Retifanlimab, a PD-1 inhibitor, plus 
Gemcitabine/Nab-Paclitaxel as frontline therapy for patients with 
advanced Pancreatic Adenocarcinoma (RiLEY) 
Sponsor/Investigator Anwaar Saeed, MD 
Protocol Version and Date: 
Version 2.0, dated 02-04-2023 
 
Anwaar Saeed 
Electronically signed by: Anwaar 
Saeed 
Reason: I approve this agreement. 
10/24/2023 
Sponsor-Investigator Signature 
 
Date: Oct 24, 2023 11:13 EDT 
 
 
 
Date 
Print Name: 
Anwaar Saeed, MD 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT 


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LIST OF COLLABORATORS ...................................................................................................... 2 
STATEMENT OF COMPLIANCE / PROTOCOL AGREEMENT ................................................... 3 
TABLE OF CONTENTS .................................................................... Error! Bookmark not defined. 
SCHEMATIC OF STUDY DESIGN .............................................................................................. 8 
PROTOCOL SUMMARY ............................................................................................................. 9 
1 
INTRODUCTION ............................................................................................................. 12 
1.1 
Pancreatic Adenocarcinoma ................................................................................... 12 
1.2 
Glycogen Synthase Kinase-3 (GSK-3) .................................................................... 12 
Effect of GSK-3β Inhibition in Cancer Cells ................................................... 12 
Role of GSK-3β in Immune Regulation .......................................................... 14 
1.3 
9-ING-41 ................................................................................................................ 14 
Preclinical Experience with 9-ING-41 in Pancreatic Tumor Cells ............. 14 
Role of 9-ING-41 as an Immune Modulator ............................................. 18 
Human Pharmacokinetics of 9-ING-41 .................................................... 18 
Phase 1 Trial of 9 ING-41 (EudraCT# 2018-003739-32 and NCT03678883) 
20 
1.4 
Retifanlimab ........................................................................................................... 22 
Overview ................................................................................................ 22 
Justification for retifanlimab dose ............................................................ 22 
1.5 
Rationale for Study ................................................................................................. 23 
1.6 
Risk/Benefit Assessment ........................................................................................ 23 
Known Potential Risks ............................................................................ 24 
Known Potential Benefits ........................................................................ 24 
Assessment of Potential Risks and Benefits ........................................... 24 
1.7 
Measures to Minimize Bias: Randomization and Blinding ...................................... 24 
2 
HYPOTHESIS ................................................................................................................. 24 
3 
OBJECTIVES AND ENDPOINTS .................................................................................... 25 
3.1 
Primary Objective ................................................................................................... 25 
3.2 
Secondary Objectives ............................................................................................. 25 
3.3 
Exploratory Objectives ............................................................................................ 25 
3.4 
Primary Endpoints .................................................................................................. 25 
3.5 
Secondary Endpoints ............................................................................................. 25 
3.6 
Exploratory Endpoints ............................................................................................ 26 
4 
STUDY DESIGN ............................................................................................................. 26 
4.1 
Overall Design ........................................................................................................ 26 
4.2 
Justification for Dose .............................................................................................. 26 
4.3 
End of Study Definition ........................................................................................... 26 
5 
PARTICIPANT SELECTION ........................................................................................... 27 
5.1 
Inclusion Criteria ..................................................................................................... 27 
5.2 
Exclusion Criteria .................................................................................................... 28 
5.3 
Ineligible Patients ................................................................................................... 29 
5.4 
Participant Replacement ......................................................................................... 29 
6 
CHILD-BEARING POTENTIAL / PREGNANCY .............................................................. 30 
7 
PARTICIPANT REGISTRATION PROCEDURES ........................................................... 30 
7.1 
General Guidelines ................................................................................................. 30 
7.2 
Registration Process .............................................................................................. 31 
TABLE OF CONTENTS 


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8 
PHARMACEUTICAL INFORMATION .............................................................................. 31 
8.1 
9-ING-41 ................................................................................................................ 31 
Overview ................................................................................................ 31 
Pharmacokinetics and Metabolism .......................................................... 31 
Adverse Effects ...................................................................................... 31 
Pregnancy and Lactation ........................................................................ 31 
Drug Interactions .................................................................................... 32 
Packaging and Labeling Information ....................................................... 32 
Drug Storage and Stability ...................................................................... 32 
Preparation/Mixing Instructions ............................................................... 33 
Administration ......................................................................................... 33 
Acquisition and Accountability ................................................................. 33 
8.2 
Retifanlimab (INCMGA00012) ................................................................................ 34 
Overview ................................................................................................ 34 
Pharmacokinetics and Metabolism .......................................................... 34 
Adverse Effects ...................................................................................... 34 
Pregnancy and Lactation ........................................................................ 34 
Drug Interactions .................................................................................... 35 
Packaging and Labeling Information ....................................................... 35 
Drug Storage and Stability ...................................................................... 35 
Preparation/Mixing Instructions ............................................................... 36 
Administration ......................................................................................... 37 
Acquisition and Accountability ................................................................. 37 
8.3 
Gemcitabine/Nab-paclitaxel .................................................................................... 37 
Overview ................................................................................................ 37 
Pharmacokinetics and metabolism .......................................................... 38 
Adverse Effects ...................................................................................... 38 
Pregnancy and Lactation ........................................................................ 38 
Drug Interactions .................................................................................... 38 
Packaging and Labeling Information ....................................................... 38 
Drug Storage and Stability ...................................................................... 38 
Preparation/Mixing Instructions ............................................................... 38 
Administration ......................................................................................... 38 
Acquisition and Accountability ................................................................. 38 
9 
TREATMENT PLAN ........................................................................................................ 39 
9.1 
Treatment Regimen ................................................................................................ 39 
Safety Lead-in AND Phase II Treatment Regimen .................................. 39 
Safety Rules Trigger for Enrollment Pause ............................................. 40 
9.2 
Treatment Duration ................................................................................................. 40 
10 
STUDY PROCEDURES AND SCHEDULE ..................................................................... 41 
10.1 
Screening/Enrollment/Baseline ............................................................................... 41 
10.2 
Procedures During Treatment ................................................................................. 41 
History, Physical Exam, Vital Signs, Height and Weight .......................... 42 
Tumor Biopsies ....................................................................................... 43 
Laboratory Assessments ........................................................................ 43 
10.3 
End of Treatment / Safety follow up Visit .............................................................................. 44 
10.4 
Post-Treatment Follow-Up ...................................................................................... 44 
10.5 
Pregnancy Follow-Up ............................................................................................. 44 


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10.6 
Progression Free Survival Follow Up (PFS-FU) ...................................................... 44 
Overall Survival Follow Up (OS-FU) ........................................................ 45 
10.7 
Lost to Follow Up .................................................................................................... 45 
10.8 
SCHEDULE OF EVENTS ....................................................................................... 46 
10.9 
Concomitant Medication and Supportive Care Guidelines ....................................... 50 
Supportive Care ...................................................................................... 50 
Prohibited or Restricted Concomitant Medications ............................................. 50 
Vaccines ................................................................................................. 50 
DIET ....................................................................................................... 50 
11 
DOSING DELAYS/DOSE MODIFICATIONS ................................................................... 51 
11.1 
9-ING-41 ................................................................................................................ 53 
9-ING-41 Dose Reduction Steps ............................................................. 53 
9-ING-41Dose Modification Guidelines ................................................... 53 
9-ING-41 Dose Reduction Criteria .......................................................... 53 
9-ING-41 Treatment Discontinuation Criteria........................................... 53 
11.2 
9-ING-41 Guidelines for Restarting 9-ING-41.......................................................... 54 
11.3 
Retifanlimab ........................................................................................................... 55 
Management of Suspected Infusion Reactions ....................................... 55 
Procedures for Participants Exhibiting Immune-Related Adverse Events57 
Treatment Discontinuation Criteria For Retifanlimab ............................... 60 
Participant Access To Study Agent At Study Closure .............................. 60 
11.4 
Participant Discontinuation/Withdrawal from the Study ............................................ 60 
12 
EXPLORATORY STUDIES ............................................................................................. 61 
12.1 
Exploratory Objectives ............................................................................................ 61 
12.2 
Sample Preparation, Handling, Storage and Shipment ........................................... 62 
13 
SAFETY ASSESSMENT, DOCUMENTATION AND REPORTING .................................. 62 
13.1 
Definitions .............................................................................................................. 62 
13.2 
Eliciting Adverse Event Information ......................................................................... 63 
Recording Requirements ........................................................................ 63 
Abnormal Test Findings .......................................................................... 64 
13.3 
Adverse Event Evaluation ....................................................................................... 64 
Grading / Severity ................................................................................... 65 
Expectedness ......................................................................................... 65 
Attribution ............................................................................................... 66 
Classification of Outcome ....................................................................... 66 
Action Taken due to AE .......................................................................... 66 
13.4 
Serious Adverse Event Reporting ........................................................................... 67 
Follow-up Reports................................................................................... 67 
Pregnancy Reporting .............................................................................. 68 
13.5 
Review of Safety Information: Sponsor-Investigator Responsibilities ....................... 68 
13.6 
IND Safety Report .................................................................................................. 68 
Serious and Unexpected Suspected Adverse Reaction........................... 68 
Findings from Other Studies ................................................................... 69 
Findings from Animal or In Vitro Testing ................................................. 69 
Increased Rate of Occurrence of Serious Suspected Adverse Reactions69 
13.7 
Submission of IND Safety Reports .......................................................................... 69 
Unexpected Fatal or Life-threatening Suspected Adverse Reaction Reports 
70 


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Reporting Format or Frequency .............................................................. 70 
Investigations of Marketed Drugs ............................................................ 70 
Reporting Study Endpoints ..................................................................... 70 
13.8 
Follow-up ................................................................................................................ 70 
13.9 
Disclaimer .............................................................................................................. 71 
13.10 
Reporting Adverse Events to the Responsible IRB ................................................. 71 
14 
MEASUREMENT OF EFFECT ........................................................................................ 71 
14.1 
Antitumor Effect ...................................................................................................... 71 
15 
STATISTICAL CONSIDERATIONS ................................................................................. 72 
15.1 
Sample Size Justification ........................................................................................ 73 
15.2 
Description of Statistical Methods ........................................................................... 73 
Populations for Analysis.......................................................................... 73 
Disposition .............................................................................................. 74 
Demographics and Baseline Characteristics ........................................... 74 
Exposure ................................................................................................ 74 
Safety Analyses ...................................................................................... 74 
Efficacy Analyses ................................................................................... 75 
15.3 
Interim Analysis ...................................................................................................... 76 
15.4 
Study Stopping Rules ............................................................................................. 76 
16 
REGULATORY REQUIREMENTS AND DATA REPORTING .......................................... 76 
16.1 
Institutional Review Board/Ethics Committee Approval ........................................... 76 
16.2 
Investigators Protocol Agreement ........................................................................... 77 
16.3 
Remaining Samples ............................................................................................... 77 
16.4 
Confidentiality ......................................................................................................... 77 
16.5 
Publication .............................................................................................................. 77 
16.6 
Compliance with Trial Registration and Results Posting Requirements ................... 77 
16.7 
Data Management .................................................................................................. 78 
16.8 
Data Monitoring ...................................................................................................... 78 
17 
DATA SAFETY MONITORING PLAN .............................................................................. 79 
17.1 
Serious Adverse Events ......................................................................................... 80 
17.2 
Review of Serious Adverse Event Rates ................................................................. 80 
17.3 
Study Safety and Progress ..................................................................................... 80 
18 
DATA HANDLING AND RECORD KEEPING .................................................................. 80 
18.1 
Data Collection and Management Responsibilities .................................................. 80 
18.2 
Protocol Deviations ................................................................................................. 80 
18.3 
Study Closure ......................................................................................................... 81 
18.4 
Study Records Retention ........................................................................................ 81 
19 
APPENDICES ................................................................................................................. 81 
Appendix A: ECOG Performance Status ............................................................................... 81 
Appendix B: Mode of Action and Common Side Effects of Gemcitabine and Nab-paclitaxel. 82 
Appendix C: Protocol Criteria for imRECIST .......................................................................... 85 
20 
LITERATURE REFERENCES ......................................................................................... 86 


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Patients with advanced pancreatic 
adenocarcinoma meeting study 
eligibility criteria 
Complete or Partial 
Response 
Progressive Disease 
Stable Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1- Metastatic tissue preferred to primary tissue. (Archival tissue if available and adequate could be used for testing). 
2- Standard biopsy at progression will be used for longitudinal evaluation of exploratory biomarkers and exploration of 
mechanism of resistance to the drug combination is no longer required. 
SCHEMATIC OF STUDY DESIGN 
Baseline archival or fresh biopsy of tumor tissue1 
Treatment regimen 
1. Chemotherapy: Nab-paclitaxel IV at 125mg/m2 & gemzar IV 
at 1000mg/m2, on days 1,8,15 
2. Retifanlimab: IV at 500mg on day 1 
3. 9-ING-41: IV at 9.3mg/kg twice weekly on days 1 and 4 
Cycle duration: 28 days 
Continue study therapy AND 
biopsy at time of 
progression2 
Discontinue study 
therapy (No biopsy at 
time of progression) 
Continue study therapy 
AND biopsy at time of 
progression2 


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Title 
A Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3-beta (GSK-3β) 
inhibitor, combined with Retifanlimab, a PD-1 inhibitor, plus 
Gemcitabine/Nab-Paclitaxel as frontline therapy for patients with 
advanced Pancreatic Adenocarcinoma (RiLEY) 
Protocol Number 
IIT-2021-RiLEY 
Phase 
2, preceded by a safety lead-in 
Design 
Open label, single-arm, Simon 2-stage, Phase 2 design 
Study Duration 
Study treatment will continue until disease progression and/or 
unacceptable toxicity for a maximum duration of 2 years. Patients will be 
followed for survival for up to 18 months after the last day of study drug. 
Study Center(s) 
UPMC Hillman Cancer Center 
Objectives 
Primary: 
• 
To determine the rate of disease control of the combination of 9-ING- 
41 and retifanlimab plus gemcitabine/nab-paclitaxel in patients with 
pancreatic cancer without prior systemic therapy for advanced 
disease. 
Secondary: 
• 
To further assess the efficacy (Overall response rate (ORR), median 
Progression Free Survival (PFS) and median Overall Survival (OS)) of 
the combination of 9-ING-41 and retifanlimab plus gemcitabine/nab- 
paclitaxel in patients with advanced pancreatic cancer. 
• 
To assess the safety and tolerability of the combination of 9-ING-41 
and retifanlimab plus gemcitabine/nab-paclitaxel in patients with 
advanced pancreatic cancer. 
Correlative/Exploratory 
studies 
• 
Correlation of disease control rate with specific molecular and 
immunologic tumor profiles. 
• 
Correlation of disease control rate with cancer antigen (CA) 19-9 
levels. 
Number of Participants 
32 patients (including 6-9 patient safety lead-in) 
Diagnosis and Main 
Inclusion Criteria 
• 
Patients ≥ 18 years of age with pathologically confirmed advanced, 
recurrent, or metastatic pancreatic cancer previously untreated with 
systemic agents in the advanced/metastatic setting. 
• 
At least one measurable lesion per RECIST v1.1 
• 
Available archived tumor tissue at study entry or willing to provide a 
fresh tumor biopsy prior to start of study treatment. 
PROTOCOL SUMMARY 


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Study Product(s), Dose, 
Route, Regimen 
• 
30- to- 40–minute intravenous (IV) infusion of nab-paclitaxel at a dose 
of 125 mg per square meter, followed by an infusion of gemcitabine 
according to the gemcitabine label at a dose of 1000 mg per square 
meter, on days 1, 8, 15 of a 28-day cycle. 
• 
Retifanlimab 500 mg IV on day 1 of a 28-day cycle. (Retifanlimab will 
be administered following gemcitabine/nab-paclitaxel.) 
• 
9-ING-41 administered at a dose of 9.3 mg/kg by IV infusion twice 
weekly on Days 1 and 4 of each week of a 28-day cycle. (9-ING-41 will 
be administered following retifanlimab.) 
Duration of 
Administration 
Study treatment will continue until disease progression and/or 
unacceptable toxicity for a maximum duration of 2 years. 
Interim Monitoring 
Investigator/sub-investigators, regulatory, CRS management, clinical 
research coordinators, clinical research associates, data managers, and 
clinic staff meet regularly in disease center Data Safety Monitoring 
Boards (DSMB) to review and discuss study data to include, but not 
limited to, serious adverse events (SAEs), subject safety issues, 
recruitment issues, accrual, protocol deviations, unanticipated problems, 
breaches of confidentiality. 
Minutes of the disease center DSMB meetings are available to those who 
are unable to attend in person. 
Statistical Methodology 
The primary objective of the study is to assess the disease control rate of 
9-ING-41 administered in combination with retifanlimab plus 
gemcitabine/nab-paclitaxel. Secondary objectives include the assessment 
of other efficacy variables as well as evaluation of toxicities. 
A Simon 2-stage design will be employed as follows: 
Endpoint: 
The primary endpoint for the study is DCR defined as: stable disease for 
≥ 16 weeks, confirmed CR, or confirmed PR. 
Sample Size: 
The minimum number of responders needed to continue to the next 
stage, is determined based on the Simon’s 2-stage design, with 80% 
power and one-sided significance level of 0.10. A disease control rate of 
70% is hypothesized. A disease control rate of 50% is considered the 
lower threshold activity (null hypothesis), based on historical data.1 Based 
on the design elements specified above, up to 12 patients will be enrolled 
during Stage 1. If >6 patients achieve disease control, 20 additional 
patients will be enrolled during Stage 2. Otherwise, enrollment will be 
terminated. Upon completion of Stage 2, if ≥20 of 32 patients achieve 
disease control, further evaluation may be pursued. If the DCR is 50% or 
less, the probability of terminating enrollment after Stage 1 is 61%. 


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The phase 2 trial will be preceded by a safety lead-in of 6-9 patients. 
Stopping Rules 
Safety lead-in part of the trial has safety stopping rules built within the 
design and as highlighted here: 
If ≥ 5/6 participants do not experience Dose limiting toxicities (DLTs) 
within the DLT window of 28 days, the study will proceed to the phase 2 
part. If > 1/6 participants experience DLTs, de-escalation to a lower dose 
level will follow. Participants enrolled to this lower dose level will receive 
the drug doses per the dose de-escalation scheme described in section 15 
under statistical consideration. Three participants will be enrolled to this 
dose level. If 0/3 participants do not experience DLTS, the study will 
proceed to the phase 2 part. The study will be terminated if ≥ 1/3 patients 
experience DLTs at this lower dose level. 
Efficacy related stopping rules for Phase 2 is as detailed per the Simon’s 2 
stage design described in the statistical methodology. 
Additionally, we will also follow the following safety stopping rules: 
Taking into account participant safety considerations, study will be 
stopped if 30% or greater of the currently enrolled and registered 
participants experience Grade 3 or greater 9-ING-41 or Retifanlimab 
related AEs. Thus, based on a Binomial calculator: P (toxicity > 30% data 
from the trial) > 0.95, the following stopping rules will be implemented: 
• 
> 4 of the first 10 participants experiencing Grade 3 or greater 
investigational agents related AEs 
• 
> 7 of the first 15 participants experiencing Grade 3 or greater 
investigational agents related AEs 
• 
> 8 of the first 20 participants experiencing Grade 3 or greater 
investigational agents related AEs (if more than 20 participants are 
recruited in the study) 


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1.1 
Pancreatic Adenocarcinoma 
1.2 
Glycogen Synthase Kinase-3 (GSK-3) 
 
Effect of GSK-3β Inhibition in Cancer Cells 
 
 
 
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor arising from the ductal and acinar epithelium of 
the exocrine pancreas which accounts for 95% of malignant neoplasms of the pancreas. In the United States, 
PDAC accounts for ~60,000 newly diagnosed cases per-year and ~48,000 deaths per-year which make up 3% of all 
cancers and 7% of all cancer deaths, respectively.2 PDAC has an abysmal prognosis including a 5-year survival rate 
of 10% in all stages combined. In metastatic disease, the 5-year survival is 3% and median survival is ~6 months.3 
Furthermore, only 20% of newly diagnosed patients are eligible for curative resection and the rest must be 
treated with palliative systemic chemotherapy.4 
 
The standard of care systemic therapy for advanced, metastatic disease is limited to combination cytotoxic 
chemotherapy including gemcitabine plus nab-paclitaxel or FOLFIRINOX.5 In the pivotal Phase 3 trial, FOLFIRINOX 
treatment was associated with a median overall survival (OS) of 11.1 months compared with 6.8 months in 
gemcitabine alone (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P < 0.001).6 However, 
due to the toxicities of this regimen, it is not appropriate for all patients with newly diagnosed pancreatic cancers. 
Gemcitabine/nab-paclitaxel was approved in the first-line setting in metastatic disease based on a median OS of 
8.5 months, as compared with 6.7 months in patients receiving gemcitabine alone (hazard ratio for death, 0.72; 
95% CI, 0.62 to 0.83; P < 0.001).7 The rate of disease control (confirmed response or stable disease for ≥ 16 weeks) 
was 48% (95% CI, 43 to 53) in the nab-paclitaxel–gemcitabine group and 33% (95% CI, 28 to 37) in the gemcitabine 
group (rate ratio for disease control, 1.46; 95% CI, 1.23 to 1.72; P < 0.001). Therefore, there is a great unmet need 
for finding novel treatment options and improving survival outcomes. 
 
Glycogen synthase kinase-3 (GSK-3) is a serine (S)/threonine (T)(ST) kinase initially described as a key regulator of 
metabolism, specifically glycogen biosynthesis.8 It has since been shown to play a role in several disease processes 
including cancer. GSK-3 has two ubiquitously expressed and highly conserved isoforms, glycogen synthase kinase- 
3 alpha (GSK-3α) and glycogen synthase kinase-3 beta (GSK-3β), with both shared and distinct substrates and 
functional effects. 
In cancer, much focus has been placed on the role of GSK-3β in tumor progression and its modulation of 
oncogenes (beta-catenin, cyclin D1 and c-Myc), cell cycle regulators (e.g., p27Kip1) and mediators of epithelial- 
mesenchymal transition (e.g., Zinc finger protein SNAI1, Snail) have been extensively described .9,10,11,12,13 More 
recently, aberrant overexpression of GSK-3β has been shown to promote tumor growth and chemotherapy 
resistance in various solid tumors including pancreatic, ovarian, colon cancer and glioblastoma14,15,16,17,18 through 
differential effects on pro-survival nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c- 
Myc pathways as well on tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and p53-mediated 
apoptotic mechanisms.19,20 GSK-3β is thus a potentially very important therapeutic target in human malignancies. 
 
NF-κB is regarded as one of the most important transcription factors and its activation plays an essential role in 
promoting human cancer progression, metastasis, and chemoresistance.21,22 GSK-3β has been demonstrated to 
have opposing roles in this context, repressing Wnt/beta-catenin signaling on the one hand but maintaining cell 
1 
INTRODUCTION 


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survival and proliferation through the NF-κB pathway on the other.23 Recent data suggests that GSK-3β positively 
regulates human cancer cell survival in part through regulation of NF-κB-mediated expression of anti-apoptotic 
molecules.24 Disruption of the GSK-3β gene in mice leads to embryonic lethality due to hepatocyte apoptosis and 
massive liver degeneration, a phenotype that is similar to the disruption of the NF-κB p65 or inhibitor of nuclear 
factor kappa-B kinase subunit beta (IKKβ) genes.25 These findings suggest a link between GSK-3β and the 
activation of the NF-κB pathway and support GSK-3β as a candidate therapeutic target in human cancer. 
 
Using GSK-3β-deficient mouse embryonic fibroblasts, it was shown that the early steps leading to NF-κB activation 
following tumor necrosis factor alpha (TNF-α) treatment (degradation of nuclear factor of kappa light polypeptide 
gene enhancer in B-cells inhibitor, alpha (IκBα) and translocation of NF-κB to the nucleus) were unaffected by the 
loss of GSK-3β, suggesting that NF-κB is regulated by GSK-3β at the level of the transcriptional complex in the 
nucleus.26 Furthermore, nuclear accumulation of GSK-3β was identified selectively in pancreatic, bladder and renal 
cancer cells, and malignant B-cells but not in normal human cells).27,28,29,30 Studies demonstrated that only the 
active form of GSK-3β accumulates in the nucleus of pancreatic cancer cells and that inhibition of GSK-3β activity 
depletes its nuclear accumulation via proteasome degradation (0).31 
 
These studies also revealed an important role of GSK-3β in the regulation of histone modifications, which may 
contribute to NF-κB p65/p50 binding to promoters and activation of target genes in cancer cells that would lead 
to increased cancer cell survival.32 Nuclear GSK-3β may well be the primary effector target for GSK-3 inhibition in 
cancer cells, leading to depletion of GSK-3β from the nucleus and subsequent inhibition of NF-κB mediated 
transcription and decreased cancer cell survival (Figure 1). 
Figure 1. 
The Role of GSK-3β in Cancer Cells 
 
Source Ref: 33 
 
Nuclear GSK-3β positively regulates NF-κB binding to its target gene promoters and NF-κB transcriptional activity 
in cancer cells. Preclinical results suggest that GSK-3β inhibits hypermethylation of histones and thereby GSK-3β 
contributes to maintenance of active chromatin at NF-κB target gene promoters, allowing p65 binding and 
transcriptional activation.34 Inhibition of GSK-3β resulted in rapid ubiquitin-proteasome degradation of its nuclear 
pool in cancer cells.35 
In the clinical setting, the safety and potential efficacy of GSK-3β inhibition was demonstrated in a Phase I dose 
escalation study of LY2090314, an intravenous competitive inhibitor of GSK-3β, in combination with 
chemotherapy in various advanced tumors.36 


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1.3 
9-ING-41 
 
Preclinical Experience with 9 -ING-41 in Pancreatic Tumor Cells 
 
 
The role of GSK-3β in immune regulation has been extensively studied with consequent implications in anti-tumor 
therapy. Emerging evidence shows that GSK-3β is a central upstream regulator of major co-inhibitory receptors on 
T cells. First, GSK-3β was found to regulate the transcriptional activation of programmed death-1 (PD-1) on 
T cells.37 Subsequent studies showed that pharmacological GSK-3β inhibition leads to reduction of PD-1 
expression and increased function of CD8+ cytotoxic T cells in vitro and in vivo.38,39 Second, GSK-3β was also found 
to regulate the expression of the coinhibitory receptor Lymphocyte Activation Gene-3 (LAG-3) on CD4+ and CD8+ 
T cells. Furthermore, small molecule GSK-3β inhibitors were found to downregulate LAG-3 on CD4+ and CD8+ T 
cells and enhance tumor clearance. Taken together, these studies highlight the multi-pronged immune regulatory 
effects of GSK-3β.40 
 
9-ING-41 is a small molecule potent selective GSK-3β inhibitor, which has shown broad anti-tumor activity in cell 
lines and in various patient derived xenografts (PDX) including breast cancer, lymphoma, neuroblastoma, 
glioblastoma, ovarian cancer, bladder cancer, and pancreatic cancer .41,42,43,44,45It acts through downregulation of 
NF-κB and decreases the expression NF-κB target genes cyclin D1, Bcl-2, anti-apoptotic protein (XIAP) and B-cell 
lymphoma-extra-large (Bcl-XL) leading to inhibition of tumor growth in multiple solid tumor cell and lymphoma 
lines and PDX models. NF-κB is constitutively active in cancer cells and promotes anti-apoptotic molecule 
expression. NF-κB activation is particularly important in cancer cells that have become chemo- and radioresistant, 
therefore it is believed that inhibition of GSK-3β may overcome NF-kB-mediated chemoresistance in human 
cancers. 
 
GSK-3β has been established as a novel therapeutic target in human pancreatic cancer.46,47,48 Aberrant nuclear 
GSK-3β accumulation in pancreatic cancer cell lines and in 62 of 122 (51%) human pancreatic adenocarcinomas 
(0), with nuclear GSK-3β accumulation significantly correlated to higher grade pancreatic carcinomas.49 In 
pancreatic carcinomas, aberrant nuclear GSK-3β is a specific marker of pancreatic cancer cells whereas nuclear 
GSK-3β was not detectable in acinar or epithelial pancreatic cells and in pancreatic intraepithelial neoplasia 
(PanIN) lesions (Figure 2). 
 
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Figure 2. 
GSK-3β is Overexpressed and Accumulated in the Nucleus of Pancreatic Cancer Cells 
 
(A) Immunohistochemical analysis of GSK-3β expression and localization in human pancreatic adenocarcinoma. Arrows 
indicate cancer cells. (B) Nuclear accumulation of GSK-3β is associated with the loss of pancreatic cancer differentiation. 
Figure represents the distribution of GSK-3β staining patterns in PanIN lesions and pancreatic carcinomas. 
Source Ref: 50 
 
Only the active form of GSK-3β accumulates in the nucleus of pancreatic cancer cells and the inhibition of GSK-3β 
activity depletes its nuclear accumulation via proteasome degradation, whereas the expression level of 
cytoplasmic GSK-3β is not changed. In vivo studies show that treatment with a commercially available toolkit GSK- 
3 inhibitor (AR-A014418) suppresses growth of CAPAN2 (Caucasian pancreas adenocarcinoma cell line) pancreatic 
xenograft tumors in mice. 51 Another in vivo study demonstrated that treatment with AR-A014418 suppresses 
growth of PANC1 (Caucasian pancreatic carcinoma cell line) pancreatic xenograft tumors. Moreover, inhibition of 
GSK-3β and thus, NF-κB activity, could make pancreatic cancer cells more sensitive to chemotherapeutic agents 
such as gemcitabine. It has been demonstrated in vitro and in vivo that inhibition of GSK-3β sensitizes pancreatic 
cancer cells to gemcitabine . 52 
 
Unlike the commercially available toolkit GSK-3β inhibitors, which are not amenable for clinical development, 
9-ING-41 is potent and possesses attractive drug-like properties that make it a clinical candidate. 9-ING-41 inhibits 
GSK-3β, as shown by downregulation of phospho-glycogen synthase expression, leading to a decreased 
expression of B-cell lymphoma-2 (BCL-2) and XIAP, and significant apoptosis in pancreatic cancer cells in vitro 
(Figure 3). 


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Figure 3. 
9-ING-41 Induces Apoptosis in Pancreatic Cancer Cells 
 
(A) Representative Hoechst staining pictures of BXPC3 and HupT3 pancreatic cancer cells treated with 9-ING-41 (5μM) for 36 
hours. Fragmented nuclei represent apoptotic cells (B) BXPC3 pancreatic cancer cells were treated with 9-ING-41 (5μM) for 6, 
12, 24, and 36 hours as indicated. Whole cell lysates were prepared, separated by SDS-PAGE (50 μg/well), transferred to 
PVDF membrane, and probed with indicated antibodies. pGS, phosphorylated Glycogen Synthase; GS, Glycogen Synthase. 
Source Ref: 53 
 
In the tetrazolium (MTS) proliferation assay, the GI50 (50% growth inhibition) of 9-ING-41 was 1 μM and 0.6 μM 
for BXPC3 and HupT3 pancreatic cancer cell lines, respectively. With short- term treatment (12 hours), 9-ING-41 
significantly enhanced the effect of gemcitabine, cisplatin, docetaxel or doxorubicin in the inhibition of L3.6pl 
pancreatic cancer cell growth in vitro (Figure 4). 
 
Figure 4. 
9-ING-41 Potentiates the Antitumor Effect of Standard Agents in Pancreatic Cancer Cells 
 
Source Ref: 54 
Pancreatic L3.6pl cancer cells were treated with 9-ING-41 (1 μM), standard cytotoxic agent, or combination of 
both drugs for 12 hours. After the treatment, drugs were replaced with fresh media and relative cell growth was 
measured by MTS assay after 96 hours. 
 
Based on these results, it was hypothesized that inhibition of GSK-3β by 9-ING-41 may overcome NF-κB-mediated 
chemoresistance to conventional chemotherapeutic drugs in vivo representing a novel therapeutic strategy for 
the targeted treatment of human pancreatic cancer. For in vivo experiments, subcutaneous and orthotopic 
pancreatic PDX tumor models by transplantation of freshly resected pancreatic cancer specimens from the patient 
to immunodeficient mice were developed (Figure 5). 


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Figure 5. 
9-ING-41 Enhances the Antitumor Effect of Gemcitabine in Pancreatic PDX Tumor In Vivo 
 
 
Upper left panel: Points, mean tumor volume; bars, standard error (SE). 
Upper right panel: Columns, mean tumor weight; bars, SE. 
Source Ref: 55 
 
Pancreatic PDX tumors were size matched and mice were randomized into four treatment groups: control (30 μL 
DMSO (dimethyl sulfoxide), daily, Mon-Fri), 9-ING-41 (60 mg/kg dissolved in 30 μL of DMSO, daily, Mon-Fri), 
gemcitabine (50 mg/kg, twice a week) or a combination of gemcitabine and 9-ING-41 were injected 
intraperitoneally (i.p.) for 3 weeks as shown in upper left panel of Figure 5. Mice were sacrificed when tumors 
grew to more than 5 times the original starting volume and the weight of resected tumors was measured as 
shown in upper right panel (Figure 5). Treatment with 9-ING-41 slowed the growth of pancreatic PDX tumors and 
led to partial regression of PDX tumors when 9-ING-41 was combined with gemcitabine. 56 
In subsequent work by the Billadeau group, pancreatic cancer cell lines and PDX were treated with 9-ING-41 alone 
or in combination with chemotherapy. Activation of the DNA damage response pathway and S-phase arrest 
induced by gemcitabine were assessed in pancreatic tumor cells with pharmacologic inhibition or siRNA depletion 
of GSK-3 kinases by immunoblotting, flow cytometry and immunofluorescence.57 9-ING-41 treatment significantly 
increased pancreatic tumor cell killing when combined with chemotherapy. 9-ING-41 prevented gemcitabine- 
induced S-phase arrest suggesting an impact on the ATR-mediated DNA damage response. Both 9-ING-41 and 
siRNA depletion of GSK-3 kinases impaired the activation of ATR leading to the phosphorylation and activation of 
Chk1. Mechanistically, depletion or knockdown of GSK-3 kinases resulted in the degradation of the ATR- 
interacting protein TopBP1, thus limiting the activation of ATR in response to single-strand DNA damage. These 
data identify a previously unknown role for GSK-3 kinases in the regulation of the TopBP1/ATR/Chk1 DNA damage 
response pathway and provide a compelling rationale for the inclusion of patients with PDAC in clinical studies of 
9-ING-41 alone and in combination with gemcitabine or irinotecan. 


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Human Pharmacokinetics of 9-ING-41 
 
 
Recent pre-clinical data supports the role of 9-ING-41 as an immune modulator in both in vivo and in vitro tumor 
models. Melanoma mouse models reveal 9-ING-41 downregulates PD-1 and LAG-3 expression, leading to a 
synergistic effect when given sequentially or in combination with immune checkpoint inhibitors (Taylor et al. 
Communication). In both MYC-N amplified and non-amplified cell lines of neuroblastoma, exposure to 9-ING-41 
leads to a boost in MHC-1 expression when stimulated with IFNy; and in MYC-N non-amplified lines, a notable 
increase in PD L1 expression is seen, supporting a combination approach with immune checkpoint blockade 
(Boes et al. Communication). Moreover, in colorectal cells, 9 ING-41 boosts NK and effector T-cell mediated killing 
of tumor cells.58 
 
 
The pharmacokinetics (PK) of 9-ING-41 have been evaluated in cohorts (n=4-7) of patients given 9-ING-41 as IV 
infusions. Concentrations increased rapidly at all the tested doses, reaching near steady-state levels by 0.25 to 
0.5 h into the infusion (Figure 6). Following the end of the infusion, concentrations declined rapidly, decreasing by 
approximately 30% over the next hour, and approximately 70% by 3 hours post-infusion. The rate of decline in the 
concentrations slowed after 3 hours post-infusion, dropping just an additional 10% to approximately 20% of the 
peak concentrations by 7 hours post-infusion. The mean terminal half-lives (over the time interval from 5 to 
23 hours post-infusion) ranged from 12 to 20 hours, with no systematic dependence on dose. The systemic 
exposures, both peak exposure (Cmax) and total exposure (AUC0-72), were dose proportional (Figure 7), indicating 
linear pharmacokinetics over the studied dose range. Repeated dosing of 9-ING-41 at 3 to 4 day intervals resulted 
in similar PK profiles as were observed with the first dose. Based on these data, a sparse sampling protocol has 
been specified that identifies the minimum and maximum concentrations associated with a dose of 9-ING-41, and 
obtains an estimate of total exposure (AUC0-72) by taking advantage of the good correlation (R2 = 0.60,Figure 7) 
observed between the AUC0-72 and the plasma concentration 1 hour after the end of the infusion. This sampling 
protocol is also anticipated to be able to identify poor metabolizers of 9-ING-41 from the measured pre-dose 
concentrations in samples collected at the time of the second (and subsequent) dose(s). 
 
Role of 9-ING-41 as an Immune Modulator 


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Figure 6. 
9-ING-41: Human Dose-proportional Plasma Pharmacokinetics 
1.0 mg/kg 9-ING-41 
10000 
 
 
1000 
 
 
100 
 
 
10 
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Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 
Plasma 9-ING-41 (ng/mL) 


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Phase 1 Trial of 9 ING-41 (EudraCT# 2018-003739-32 and NCT03678883) 
 
Figure 7. 
9-ING-41: Human Dose-proportional Plasma Pharmacokinetics – AUC versus Concentration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
On the 1801 study Part 1 (monotherapy dose escalation), 65 patients with both advanced solid and hematologic 
malignancies have received 9-ING-41 on a twice weekly IV schedule at eight dose levels: 1.0, 2.0, 3.3, 5, 7, 9.3, 
12.4 and 15 mg/kg. No 9-ING-41-attributable SAEs have been observed. The dose of 15 mg/kg has been deemed 
the RP2D based on the volume of fluid given with this dose. 
 
Over 50% of patients receiving 9-ING-41 have experienced transient visual symptoms, assessed as Grade 1 in 54% 
and Grade 2 in 3% of patients, respectively. These usually begin approximately one hour into the infusion. 
Patients report that lights seem brighter and skin tones darker. These symptoms last for approximately one to two 
hours in most patients but can last for longer. There are no associated, preceding, or delayed visual symptoms. 
There are no associated vital sign or biochemical abnormalities. No attendant abnormalities have been 
demonstrable on retinal or general ocular examinations. These episodes tend to attenuate over time and are 
always completely transient. Some investigators chose to slow the rate of the 9-ING-41 infusion when these visual 
symptoms occurred, but it is not clear if this had any impact on symptom duration. No specific additional tests or 
precautions are required if these symptoms occur. 
There were also Grades 1 and 2 infusion reactions associated with 9-ING-41 in 8.9% (grade 1) and 3% (grade 2) of 
patients. Symptoms included but were not limited to: flushing, rash, pruritus, painful chest spasms, nausea, 
vomiting, dyspnea, tachycardia, dizziness and hypotension. These resolved upon rapid institution of local infusion 
reaction protocols, usually involving administration of Tylenol, anti-histamines, intravenous fluids and occasionally 
steroids. Patients who presented with infusion reactions were required to pre-medicate with the same 
medications upon subsequent infusions. 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
  
  
  
 
AUC∞ (ng•h/mL) 


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Two patients currently remain on Part 1 of the study, including one patient with refractory BRAF V600K mutated 
melanoma with CNS disease in CR after a year, and another patient with ATLL with sustained PR over 15 months. 
On the 1801 study Part 2 (8 chemotherapy combination regimens), 171 patients with advanced solid tumors have 
received 9-ING-41 on a twice weekly schedule at doses of 3.3, 5, 7, 9.3, 12.4 and 15 mg/kg combined with 
carboplatin, doxorubicin, gemcitabine, irinotecan, lomustine, carboplatin plus paclitaxel, carboplatin plus 
pemetrexed or gemcitabine plus nab-paclitaxel. Patients initially needed to have been previously exposed to that 
same chemotherapy agent to qualify for study entry, but this was later amended to allow first-line doxorubicin 
patients. One 9-ING-41 attributable Grade 3 SAE of visual disturbance was observed, but no other clinically 
significant AEs attributable to the investigational product have been noted in this cohort. The RP2D for all 
combinations was determined to be 15mg/kg IV. Seven patients still remain on Part 2 of the study, and clinical 
responses include sustained PRs in PDAC, endometrial cancer and undifferentiated pleomorphic sarcoma, as well 
as prolonged disease stability in several histologies, including PDAC, appendiceal cancer and mesothelioma. 
 
The data generated on safety and activity on the 1801 study supported its expansion into a Phase 2 signal-seeking 
gemcitabine/nab-paclitaxel + 9-ING-41 study for first-line advanced PDAC patients. This study is currently in 
Stage I of a Simon 2-Stage design with disease control rate (CR, PR, or SD for ≥16 weeks) as the primary endpoint. 
 
Of 24 patients enrolled, there are early signs of efficacy in this population, with one confirmed CR (non-centrally 
reviewed) in a patient with local recurrence after surgical resection and adjuvant gemcitabine-based 
chemotherapy, one confirmed CR after 4 cycles of SD, 4 PRs and 2 SD ≥16 weeks in an initial cohort of 12 
evaluable patients. 
 


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Overview 
 
Justification for retifanlimab dose 
 
 
 
Retifanlimab (also known as INCMGA00012) is a humanized, hinge-stabilized, IgG4κ monoclonal antibody that 
recognizes human PD-1. Retifanlimab contains a human IgG4 Fc domain to limit effector function while retaining 
neonatal Fc receptor binding to extend circulating half-life. Retifanlimab is designed to target PD-1–expressing 
cells, including T cells, and to sustain/restore their effector function by blocking checkpoint inhibitory interactions 
between PD-1 and its 2 ligands, PD-L1 and PD-L2. 
 
In vitro studies with retifanlimab have demonstrated high affinity binding to both recombinant human and 
cynomolgus monkey PD-1 as well as to PD-1 that is naturally expressed on the cell surface, including on T cells. 
Consistent with its intended mechanism of action and functional properties, retifanlimab has been shown to 
inhibit the binding of PD L1 and PD L2 to PD-1, to disrupt the PD-1/PD-L1 inhibitory axis, and to enhance IFN γ 
secretion in SEB-stimulated human PBMCs with activity comparable to pembrolizumab and nivolumab replicas 
(generated by MacroGenics, Inc. based on the published sequences of these antibodies). Retifanlimab does not 
induce ADCC or CDC, mitogenic activity, hemolysis, or cytokine release. 
Retifanlimab is currently under development as a therapeutic candidate for the treatment of multiple solid 
tumors, both as a monotherapy and in combination with other agents. 
 
As of the data cutoff date of 23 SEP 2020, 578 unique participants have been exposed to retifanlimab as 
monotherapy at doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, 10 mg/kg Q4W, 375 mg 
Q3W, 500 mg Q4W, and 750 mg Q4W. An additional 96 participants have been exposed to retifanlimab in 
combination with other anticancer agents (53 participants in combination with epacadostat [INCB024360], 22 
participants in combination with parsaclisib [INCB050465], 15 participants in combination with pemigatinib 
[INCB054828], and 6 participants in combination with INCB001158). The most frequently TEAEs reported for 
monotherapy studies were fatigue (16.6%), asthenia (15.7%), and diarrhea (14.4%). The most frequently reported 
immune-related AEs were hypothyroidism (8.1%) and rash (2.4%). The overall safety profile of retifanlimab is as 
expected for a PD-(L)1 inhibitor. 
 
Retifanlimab has shown meaningful efficacy in platinum-refractory SCAC59 along with preliminary evidence of 
clinical activity in multiple other tumor types.60,61,62 
 
 
Information for 500 mg Q4W(every 28 days) Fixed Dose 
Retifanlimab will be administered at 500 mg every 28 days. The selection of this dose was based on modeling of 
clinical PK data from the first-in-human monotherapy study, INCMGA 0012-101 (NCT03059823), in which 219 
participants were treated at doses of 1 mg/kg Q2W, 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, and 10 mg/kg 
Q4W, 375 mg Q3W, 500 mg Q4W and 750 mg Q4W. 
A simulation was conducted to investigate the use of weight-based and fixed doses for retifanlimab with the aim 
of targeting a steady-state trough concentration of approximately 21 μg/mL, which is the median trough 
1.4 
Retifanlimab 


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1.5 
Rationale for Study 
1.6 
Risk/Benefit Assessment 
 
concentration for pembrolizumab 200 mg Q3W.63 In addition, full PD-1 receptor occupancy was observed on PD 1 
expressing CD4+ and CD8+ cells with effects on circulating cytokines that are typical for a PD 1 inhibitor in all dose 
regimens of Study INCMGA 0012-101. Therefore, the 500 mg Q4W doses was selected as a dose for further 
development in monotherapy treatments. 
Noncompartmental analysis of PK data from 40 participants who received 500 mg Q4W in Study INCMGA 0012- 
101 demonstrated a Ctrough value at steady state was 58.7 ± 26.8 mg/L. First dose clearance was 0.302 ± 0.132 
L/day. Distribution of retifanlimab was generally limited to the systemic circulation, with a volume of distribution 
of 6.34 ± 2.49 L. Retifanlimab Cmax and AUC0–∞ were 168 ± 51.6 mg/L and 1940 ± 795 mg·day/L, respectively after 
the first dose. Trough serum concentrations of retifanlimab appeared to reach steady state at or before Cycle 6. 
The accumulation ratio was approximately 1.3 for the Q4W dose regimen. Taken together, retifanlimab showed a 
PK profile typical of a monoclonal antibody.64 
 
Given the role of GSK-3β in immune regulation, the combination of GSK-3β inhibition with PD-1 inhibition may be 
expected to provide synergistic anti-tumor efficacy. The excellent safety profile of 9-ING-41, along with preclinical 
and clinical evidence of anti-tumor activity in pancreatic cancer, provides a strong rationale to evaluate the 
efficacy of 9-ING-41 in combination with a PD-1 inhibitor plus standard chemotherapy (gemcitabine/nab- 
paclitaxel) as frontline therapy for patients with advanced PDAC. 
 
The PD-1 inhibitor to be used in the present study is retifanlimab, a humanized, hinge-stabilized immunoglobulin 
G4 (IgG4) monoclonal antibody. Retifanlimab has shown positive results for the treatment of patients with 
squamous carcinoma of the anal canal (SCAC) who have progressed after first-line chemotherapy treatment. In the 
Phase 2 PODIUM-202 trial, retifanlimab was well-tolerated at a dose of 500 mg administered via IV infusion every 
4 weeks (28-day cycle) for up to 2 years.65 Immune-related AEs of grade 3 or higher occurred in 6.4% of patients 
and treatment discontinuation due to immune-related AEs occurred in 2.1% of patients. No grade 3 or higher 
infusion reactions were reported. The most common AEs observed (incidence ≥20%) were fatigue and diarrhea. 
 
The combination of 9-ING-41 and retifanlimab with gemcitabine/nab-paclitaxel has not previously been 
administered to human subjects. In the 1801 study, 9-ING- 41 has been administered in combination with various 
chemotherapy regimens including gemcitabine/nab-paclitaxel, with one 9-ING-41-related SAE (transient visual 
change) documented to date. Retifanlimab alone has been well-tolerated when administered for up to 2 years in 
patients with anal cancer. Overall, based on previous nonclinical and clinical experience, both of these agents 
appear to have an acceptable safety profile and do not appear to have significant overlapping toxicities. However, 
it is possible that when they are administered together and in combination with gemcitabine/nab-paclitaxel, more 
frequent or severe AEs, or new AEs not previously observed with any of these agents administered alone, may 
occur. 
 
It is not known if administration of 9-ING-41 and retifanlimab will act synergistically to provide increased anti- 
tumor activity compared to gemcitabine/nab-paclitaxel alone. Subjects in this study should not expect to benefit 
directly by their participation in the study. The data collected in this study may benefit future cancer patients. 


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Known Potential Benefits 
 
Assessment of Potential Risks and Benefits 
1.7 
Measures to Minimize Bias: Randomization and Blinding 
2 
HYPOTHESIS 
 
 
 
 
 
 
 
Immediate Risks 
More severe or more frequent AEs than expected with gemcitabine/nab-paclitaxel 
alone, including SAEs or discontinuation due to AEs. 
Immediate risks also include immunotherapy (retifanlimab) related adverse events 
including but not limited to immune related hepatitis, pneumonitis, 
endocrinopathies, colitis, enteritis, mucositis, dermatitis, and nephropathy. 
Long-range Risks 
Potential long term sequelae of immune related adverse events including but not 
limited to endocrinopathies, liver dysfunction, respiratory and renal dysfunction. 
 
 
Immediate Potential Benefits 
Improved response to treatment/disease control. 
Long-Range Potential Benefits 
Increased PFS and/or OS. 
 
 
Rationale for necessity of 
exposing participants to risks 
The prognosis for patients with advanced PDAC is poor. The rate of disease 
control with standard chemotherapy is approximately 50%. New treatment 
options are needed. 
Summary of ways risks were 
minimized in study design 
Participants are monitored closely for adverse events/drug reactions. Dose 
modification and discontinuation guidelines are provided. Supportive care 
for mitigation of adverse events is described. [Study stopping rules are 
provided.] 
Justification why benefits 
outweigh risks 
The combination of 9-ING-41 and retifanlimab has the potential to increase 
the anti-tumor response to standard chemotherapy and prolong survival. 
 
Therefore, the potential benefit of this study is judged to outweigh risk and the risk/benefit ratio is in favor of 
benefit. 
 
This is a single-arm, open-label study; therefore, no randomization or blinding procedures will be performed. 
 
Patients with advanced pancreatic cancer previously untreated with systemic agents will have greater responses 
to standard cytotoxic agents (gemcitabine/nab-paclitaxel) administered in combination with the GSK-3β inhibitor 
9-ING-41 plus a PD-1 inhibitor (retifanlimab) compared to historical response rates observed with 
 
Known Potential Risks 


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CONFIDENTIAL 
 
 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objective 
3.2 
Secondary Objectives 
3.3 
Exploratory Objectives 
3.5 
Secondary Endpoints 
 
gemcitabine/nab-paclitaxel alone because of the potential of GSK-3β inhibition with PD-1 inhibition to provide 
synergistic anti-tumor efficacy. 
 
 
 
To determine the rate of disease control of the combination of 9-ING-41 and retifanlimab plus gemcitabine/nab- 
paclitaxel in patients with pancreatic cancer without prior systemic therapy for advanced disease. 
 
 
To further assess the efficacy (Overall Response Rate (ORR), median Progression Free Survival (PFS) and median 
Overall Survival (OS)) of the combination of 9-ING-41 and retifanlimab plus gemcitabine/nab-paclitaxel in patients 
with advanced pancreatic cancer. 
 
To assess the safety and tolerability of the combination of 9-ING-41 and retifanlimab plus gemcitabine/nab- 
paclitaxel in patients with advanced pancreatic cancer. 
 
To correlate disease control rate with specific molecular and immunologic tumor profile(s). 
To correlate disease control rate with cancer antigen (CA) 19-9 levels. 
 
 
What is being measured 
Measurement/ time frame 
Measurement Tool 
Disease control rate (DCR) 
Stable disease for ≥ 16 weeks, 
confirmed complete response (CR), 
or confirmed partial response (PR) 
during study treatment 
Immune-Modified Response 
Evaluation Criteria in Solid Tumors 
(imRECIST66) 
 
 
What is being measured 
Measurement/ time frame 
Measurement Tool 
Objective response rate (ORR) 
Percent of patients with CR or PR 
imRECIST 
Duration of response (DOR) 
Time from documentation of tumor 
response to disease progression 
imRECIST 
Progression-free survival (PFS) 
Time from study entry until objective 
tumor progression or death 
Survival curve 
Overall survival (OS) 
Time from study entry to death from 
any cause 
Survival curve 
3.4 
Primary Endpoints 


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3.6 
Exploratory Endpoints 
4 
STUDY DESIGN 
4.1 
Overall Design 
4.2 
Justification for Dose 
4.3 
End of Study Definition 
 
Time to treatment failure (TTF) 
Time from study entry to disease 
progression, or death, whichever 
occurs first. 
Survival curve 
 
 
What is being measured 
Measurement/ time frame 
Measurement Tool 
Correlation of DCR with specific 
molecular tumor profiles 
Enrollment to EOT 
Baseline pre treatment tumor 
molecular NGS reports through a 
CLIA certified commercially 
approved vendors (e.g. UPMC 
local oncomine panel, Foundation 
One, Caris, or Tempus) 
Correlation of DCR with CA 19-9 
levels 
Enrollment to EOT 
Per standard of care 
 
 
This is an open label, single-arm, Simon 2-stage, Phase 2 study of the combination of 9-ING-41 and retifanlimab 
plus gemcitabine/nab-paclitaxel in patients with pancreatic cancer without prior systemic therapy for advanced 
disease. The phase 2 trial will be preceded by a safety lead-in of 6-9 patients to determine the recommended 
phase 2 dose (RP2D). 
 
Based on the results obtained in the 1801 study, 9-ING-41 will be administered at the dose of 9.3 mg/kg twice 
weekly. 
 
Retifanlimab will be administered at a dose of 500 mg every 4 weeks, which is the dose used for the treatment of 
patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have 
progressed on, or who are refractory to, platinum-based chemotherapy. 
 
Gemcitabine/nab-paclitaxel will be administered at the dose regimen approved for the treatment of patients with 
advanced pancreatic cancer. 
 
The study will continue until the planned number of patients have been enrolled and treated and all patients have 
been followed for at least 3 months after the last dose of study drug or until disease progression or death, 
whichever occurs first, unless the study is stopped due to futility after Stage 1. Patients who discontinue 
treatment for reasons other than disease progression will be followed for PFS or until patient starts a new anti- 
cancer treatment, whichever occurs first. 


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CONFIDENTIAL 
 
 
5.1 
Inclusion Criteria 
 
 
 
Patients with pancreatic cancer without prior systemic therapy for advanced disease may be eligible for this trial if 
they meet all entry criteria. 
 
Each potential patient must satisfy all of the following criteria to be enrolled in the study: 
• 
Is able to understand and voluntarily sign a written informed consent and is willing and able to comply 
with the protocol requirements including scheduled visits, treatment plan, laboratory tests and other 
study procedures. 
• 
Is aged ≥ 18 years. 
• 
Has pathologically confirmed advanced, recurrent, or metastatic pancreatic cancer AND is previously 
untreated with systemic agents in the advanced/metastatic setting. 
• 
Must have at least 1 measurable lesion per RECIST v1.1. Lesions that are radiated should not count as 
target lesions unless there is evidence of growth post radiation on a subsequent scan prior to trial 
enrollment. 
• 
Must have available archived tumor tissue at study entry; paraffin-embedded tissue block preferred or 
10 unstained slides (metastatic tissue preferred to primary tissue) OR if archived tissue is not available, 
willing to provide a fresh tumor biopsy prior to start of study treatment for tumor comprehensive NGS 
molecular testing through one of the following vendors: local UPMC oncomine panel (preferred), 
Foundation One, Caris, or Tempus. Confirmation that archival tissue or fresh tumor tissue is adequate 
for molecular testing through one of those vendors is needed prior to trial enrolment. 
• 
Has laboratory function within specified parameters (may be 
repeated): 
• 
Adequate bone marrow function: absolute neutrophil 
count (ANC) ≥ 1000/mL; hemoglobin ≥ 8.5 g/dL, platelets 
≥ 100,000/mL 
• 
Adequate liver function: transaminases (aspartate 
aminotransferase/ alanine aminotransferase, AST/ALT) 
and alkaline phosphatase ≤ 2.5 x ULN (≤ 5 X the upper 
limit of normal (ULN) in the setting of liver metastasis or 
infiltration with malignant cells); bilirubin ≤ 1.5 x ULN 
• 
Adequate renal function: creatinine clearance 
• 
CrCl > 60 mL/min measured or calculated by Cockcroft- 
Gault (C-G) equation (estimated glomerular filtration rate 
[eGFR] can also be used in place of CrCl) 
• 
Serum amylase and lipase ≤ 1.5 x ULN 
• 
Eastern Co-operative Oncology Group (ECOG) performance status 
(PS) 0 – 1 (Appendix A) 
• 
Has received the final dose of any of the following treatments/ procedures 
within the specified minimum intervals before first dose of study drug: 
• 
Focal radiation therapy – 7 days 
• 
Surgery with general anesthesia – 7 days 
5 
PARTICIPANT SELECTION 


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CONFIDENTIAL 
 
 
5.2 
Exclusion Criteria 
 
• 
Surgery with local anesthesia – 7 days 
 
• 
May have received treatment with fluorouracil or gemcitabine as a radiation sensitizer in the 
adjuvant setting if the treatment was received at least 6 months before study enrollment. 
• 
May have received neoadjuvant chemotherapy with FOLFIRINOX if given at least 6 months 
before study enrollment. 
• 
May have received prior cytotoxic doses of systemic chemotherapy in the adjuvant setting if 
given at least 6 months before study enrollment. 
• 
Women of childbearing potential must have a negative baseline blood or urine pregnancy test within 72 
hours of first study therapy. Women may be neither breastfeeding nor intending to become pregnant 
during study participation and must agree to use effective contraceptive methods (hormonal or barrier 
method of birth control, or true abstinence) for the duration of study participation and in the following 
6 months after discontinuation of study treatment. 
• 
Male patients with partners of childbearing potential must take appropriate precautions to avoid 
fathering a child from screening until 6 months after discontinuation of study treatment and use 
appropriate barrier contraception or true abstinence. 
• 
Must not be receiving any other investigational medicinal product. 
 
Participants meeting any of the exclusion criteria listed below at screening will be excluded from study 
participation. 
 
• 
Is pregnant or lactating. 
• 
Is known to be hypersensitive to any of the components or metabolites of 9-ING-41 or to the 
excipients used in its formulation, or known sensitivity to one of the chemotherapeutic agents or to 
the PD-1 inhibitor. 
• 
History of receiving prior treatment with any anti-PD-1, PD-L1 or PD-L2 agent. 
• 
Has endocrine or acinar pancreatic carcinoma. 
• 
Has not recovered from clinically significant toxicities as a result of prior anticancer therapy, except 
alopecia, anemia not requiring transfusion support and infertility. Recovery is defined as ≤ Grade 1 or 
baseline severity per Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0). 
• 
Has significant cardiovascular impairment: history of congestive heart failure greater than New York 
Heart Association (NYHA) Class II, unstable angina, or stroke within 6 months of the first dose of 9-ING- 
41, or cardiac arrhythmia requiring medical treatment detected at screening. 
• 
Has had a myocardial infarction within 12 weeks of the first dose of 9-ING-41 or has electrocardiogram 
(ECG) abnormalities that are deemed medically relevant by the investigator or study medical 
coordinator. 
• 
Has symptomatic rapidly progressive brain metastases or leptomeningeal involvement as assessed by 
computed tomography (CT) scan or magnetic resonance imaging (MRI). Patients with stable brain 
metastases or leptomeningeal disease or slowly progressive disease are eligible provided that they 
have not required new treatments for this disease in a 28-day period before the first dose of study 
drug, and anticonvulsants and steroids are at a stable dose for a period of 14 days prior to the first 
dose of study drug. 


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CONFIDENTIAL 
 
 
5.3 
Ineligible Patients 
5.4 
Participant Replacement 
 
• 
Has had major surgery (not including placement of central lines) within 7 days prior to study entry or is 
planned to have major surgery during the course of the study (major surgery may be defined as any 
invasive operative procedure in which an extensive resection is performed, e.g., a body cavity is 
entered, organs are removed, or normal anatomy is altered). In general, if a mesenchymal barrier is 
opened (pleural cavity, peritoneum, meninges), the surgery is considered major. 
• 
Has any medical and/or social condition that, in the opinion of the investigator would preclude study 
participation. 
• 
Has received an investigational anti-cancer drug in the 14-day period before the first dose of study 
drug (or within 5 half-lives if longer) or is currently participating in another interventional clinical trial. 
• 
Has a current malignancy other than pancreatic cancer. 
• 
Known immunodeficiency syndrome or active autoimmune disease or requiring systemic 
immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of 
prednisone or equivalent). 
• 
Physiologic corticosteroid replacement therapy at doses > 10 mg/day of prednisone or 
equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune 
disease is permitted. 
• 
Participants with asthma that requires intermittent use of bronchodilators, inhaled steroids, or 
local steroid injections may participate. 
• 
Participants using topical, ocular, intra-articular, or intranasal steroids (with minimal systemic 
absorption) may participate. 
• 
Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment– 
related standard premedication are permitted. 
• 
Evidence of interstitial lung disease, history of interstitial lung disease, or active, noninfectious 
pneumonitis. 
• 
Palliative radiation therapy administered within 1 week of first dose of study treatment or radiation 
therapy that is > 30 Gy within 6 months of the first dose of study treatment. Note: Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids for this purpose, and 
not have had radiation pneumonitis. 
• 
Has received systemic antibiotics ≤ 7 days prior to the first dose of study drug. 
• 
History of organ transplant, including allogeneic stem cell transplantation. 
• 
Known hypersensitivity to another monoclonal antibody that cannot be controlled with standard 
measures (eg, antihistamines and corticosteroids). 
• 
Known allergy or hypersensitivity to any component of retifanlimab or formulation components. 
• 
Has received a live vaccine within 28 days of the planned start of study drug. 
 
Patients who do not meet the study eligibility requirements will be referred back to their treating physicians for 
additional treatment options. 
 


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CONFIDENTIAL 
 
 
6 
CHILD-BEARING POTENTIAL / PREGNANCY 
7 
PARTICIPANT REGISTRATION PROCEDURES 
7.1 
General Guidelines 
 
Participants will not be replaced once treated. Any participant who signs consent but does not receive study 
treatment may be replaced. 
 
Because the effect of the study treatment is considered possibly teratogenic and has potential risks to the fetus, 
pregnant females will not be included in the study. However, no female of childbearing potential will be excluded 
from the study. 
An effective form of contraception of the woman’s choice will be required during study participation. Participants 
should not get pregnant, breastfeed, donate sperm or father a child while participating in this study and for 6 
months after the last dose of the study medication. 
 
Women of childbearing potential and male participants must agree to use adequate contraception (hormonal 
AND barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. If 
a woman becomes pregnant or suspects she is pregnant while participating in this study or if her male partner is a 
participant in this study, the treating physician should be informed immediately. 
Child-bearing potential is defined as any female (regardless of sexual orientation, having undergone a tubal 
ligation, or remaining celibate by choice) who meets the following criteria: 
• 
Has either not undergone a hysterectomy or bilateral oophorectomy or has not been naturally 
postmenopausal for at least 12 consecutive months. 
 
Participants must agree to use one of the following acceptable forms of birth control. 
• 
Sexual Abstinence 
• 
One barrier method (cervical cap with spermicide plus male condom; diaphragm with spermicide plus 
male condom) PLUS hormonal method (oral contraceptives, implants, or injections) or an intrauterine 
device (e.g., Copper-T). 
 
If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her 
treating physician immediately. 
 
If the partner of a man becomes pregnant or suspects she is pregnant while he is participating in this study, he 
should inform his treating physician immediately. 
Men of child-bearing potential must not father a child or donate sperm while receiving investigational treatment 
and for 6 months after their last study treatment. 
 
 
Eligible participants will be required to be registered through The University of Kansas Cancer Center Clinical 
Research Office central registration process and registration must occur prior to the initiation of therapy 


UPMC Hillman Cancer Center 
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CONFIDENTIAL 
 
 
7.2 
Registration Process 
8 
PHARMACEUTICAL INFORMATION 
8.1 
9-ING-41 
 
Overview 
 
Pharmacokinetics and Metabolism 
 
Adverse Effects 
 
Pregnancy and Lactation 
 
Issues that would cause treatment delays should be discussed with the Sponsor/Investigator. If a participant does 
not receive protocol therapy following registration, notify The University of Kansas Cancer Center Clinical Site 
Management team via email at KUCC-CTO-IIT@kumc.edu and update participant’s status in the CRIS system. 
 
The University of Kansas Cancer Center participant registration is accessible for registration Monday through 
Friday, 8:00 AM to 5:00 PM Central Time. Please allow up to 24 hours for completion of registration. 
The registration procedures are as follows: 
1. Obtain written informed consent prior to the performance of any study related procedures or 
assessments. Tests required at screening and performed as part of customary care prior to signing 
consent, are allowed IF those tests were performed within the timeframe listed in Participant Selection 
section. 
2. Complete appropriate baseline demographic information in CRIS. Print, complete and obtain appropriate 
signatures for the inclusion/exclusion criteria to document eligibility. Maintain completed documents in 
participant’s research record. Participants must meet all eligibility criteria to be eligible for registration. 
3. Use the hyperlink at the bottom of the eligibility criteria or in the CRIS system, complete information and 
submit to initiate the registration process. 
4. Email confirmation of registration will be sent to the person initiating the registration. Registration 
confirmation should be maintained as part of the participant’s research record. 
 
For this study, both 9-ING-41 for injection and retifanlimab are considered investigational products. The 
combination of gemcitabine and nab-paclitaxel (Abraxane) is approved as first-line therapy in patients with 
advanced pancreatic adenocarcinoma. 
 
 
9-ING-41 is a GSK-3β inhibitor, which is being evaluated as potential anti-cancer therapy in various solid tumors 
including pancreatic cancer (See Section with title Introduction / 9-ING-41). 
 
See Section with title, Introduction / 9-ING-41 / Human Pharmacokinetics of 9-ING-41. Additional details are 
provided in the 9-ING-41 Investigator Brochure. 
 
Adverse effects are provided in the 9-ING-41 Investigator Brochure. 
 


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CONFIDENTIAL 
 
 
 
Drug Interactions 
 
Packaging and Labeling Information 
 
Drug Storage and Stability 
 
 
The teratogenic risk of 9-ING-41 is currently unknown. Patients who are pregnant or lactating are excluded from 
participation in this study. 
 
Fertile male patients and female patients who are of childbearing potential must agree to use 2 methods of highly 
effective contraception throughout the study and for at least 90 days after the last dose of investigational product 
as described in with title, CHILD-BEARING POTENTIAL / PREGNANCY. 
 
9-ING-41 has a low potential for interaction with the cytochrome P450 metabolic system within the liver. 
 
For FDA designation of drugs with the potential for strong inhibition of CYP2C19, CYP3A4, and CYP1A2 or strong 
inducers of CYP3A4 please use this URL: https://www.fda.gov/drugs/drug-interactions-labeling/drug- 
development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 
 
9-ING-41 for injection is a light-red to red clear solution of 10 mg/mL 9-ING-41 in an inactive co-solvent mixture of 
polyethylene glycol 400, ethanol and Tween 80 (polysorbate 80) (PEG400:EtOH:Tween80; 75:17:8). 
 
9-ING-41 for injection is provided as a 27-mL fill (i.e., 2 mL overage) in a 30-mL, clear, USP Type I molded glass vial 
with Teflon-lined (FluroTec™) gray butyl rubber stopper. 
 
The route of administration is by IV infusion after diluting 9-ING-41 for injection with 0.9% Sodium Chloride 
Injection. Dilution must be made into a DEHP-free infusion container/bag; please refer to the Pharmacy Manual 
for approved infusion supplies. Administration to the patient must be via a DEHP-free, study-approved, giving set; 
please refer to the Pharmacy Manual for approved giving sets. 
9-ING-41 Sample Composition 
 
Component 
Amount per Vial* 
Function 
Quality Standard 
9-ING-41 
250 mg 
active 
Manufactured using GMP 
Polyethylene Glycol 400 
20.06 g 
solubilizer 
National Formulary (NF) 
Ethanol anhydrous 
4.55 g 
co-solvent 
National Formulary (NF) 
Polysorbate 80 
2.14 g 
co-solvent and detergent United States Pharmacopeia (USP) 
* Label claim; total fill includes a 0.756 g overfill for a fill weight of 27.756 g. The amount per vial in this 
table reflects the expected deliverable dose, and is the label claim of 25 mL containing 250 mg of 
drug. 
 
 


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Page 33 of 93 
CONFIDENTIAL 
 
 
 
Preparation/Mixing Instructions 
 
Administration 
 Acquisition and Accountability 
 
The investigator, or an approved representative (e.g., pharmacist) will ensure that all 9-ING-41, the investigational 
product (IP), is stored in a secured area with controlled access and in accordance with applicable regulatory 
requirements. IP should be stored in original containers and in accordance with the labels. 
 
 
 
9-ING-41 for injection should be prepared and dispensed by an appropriately qualified and experienced member 
of the study staff (e.g., physician, nurse, physician’s assistant, nurse practitioner, pharmacy assistant/technician, 
or pharmacist) as allowed by local, national, state, or institutional guidance. 
 
Only qualified personnel who are familiar with procedures that minimize undue exposure to themselves and to 
the environment should undertake the preparation, handling, and safe disposal of chemotherapeutic agents. 
 
After calculating the dose required for the patient, withdraw the appropriate mL of drug from the vial using sterile 
technique and add to 0.9% Sodium Chloride Injection in the approved infusion container to produce 
concentrations specified in the 9-ING-41 Pharmacy Manual. 
Upon dilution, infusion contents must equilibrate for 0.25 to 1 hour prior to beginning patient administration. 
Administer the entire contents of the diluted solution in the infusion container. Complete administration to the 
patient within 8 hours of making the dilution. 
 
Please reference the recommended infusion rate in the Pharmacy Manual. If the prescribing clinician chooses to 
amend the volume for infusion, this is permitted within recommended concentrations specified in the Pharmacy 
Manual. 
 
9-ING-41 9.3 mg/kg will be administered on Day 1 and 4 of each week of a 28-day cycle. On Day 1 of each cycle, 
patients will receive 9-ING-41 following administration of gemcitabine/nab-paclitaxel and retifanlimab. On Days 8 
and 15 of each cycle, patients will receive 9-ING-41 following administration of gemcitabine/nab-paclitaxel. 
 
The recommended infusion rate is found in the 9-ING-41 Pharmacy Manual. If the prescribing clinician chooses to 
amend the volume for infusion, this is permitted within recommended concentrations found in the Pharmacy 
Manual. Infusion may be as an in-patient or as an out-patient according to local resources and the requirements 
of associated monitoring and concomitant chemotherapy. 
Detailed procedures for 9-ING-41 infusion are provided in the Pharmacy Manual. All patients should be weighed 
within 72 hours prior to dosing for every cycle to ensure they did not experience either a weight loss or gain >10% 
from the prior weight used to calculate the dose of 9-ING-41 and concomitant chemotherapy. The decision to 
recalculate dose(s) according to a change in weight should be in accordance with local practice, however where 
weight has changed by >10%, dose MUST be recalculated using the most recent weight recorded. 
 
9-ING-41 will be supplied for participants by Actuate Therapeutics. 


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8.2 
Retifanlimab (INCMGA00012) 
 
Overview 
 
Pharmacokinetics and Metabolism 
 
Adverse Effects 
 
Pregnancy and Lactation 
 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents according to institutional standard operating procedures and 
policies. 
 
Used drug and remaining unused drug may be destroyed, according to institutional standard operating 
procedures and policies. 
 
 
 
Retifanlimab is a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1. 
Retifanlimab contains a human IgG4 Fc domain to limit effector function while retaining neonatal Fc receptor 
binding to extend circulating half-life. Retifanlimab is designed to target PD-1–expressing cells, including T cells, 
and to sustain/restore their effector function by blocking checkpoint inhibitory interactions between PD-1 and its 
2 ligands, PD-L1 and PD-L2. 
Retifanlimab is an investigational new drug being evaluated for the treatment of patients with solid tumors, both 
as monotherapy and in combination with other agents. 
 
See retifanlimab Investigator Brochure. 
 
Adverse effects are listed in the Invetgiator’s Brochure for retifanlimab. 
 
*Refer to section 11.3.2 to Table B detailing Toxicity Management Guidelines for Immune Related Adverse Events. 
 
See Appendix C for URL to access the following: Management of Immune-Related Adverse Events in Patients 
Treated with Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice 
Guideline 
 
 
Standard fertility and early embryonic development, embryo-fetal development and pre- and postnatal 
development studies have not been conducted with retifanlimab. 
 
Based on its mechanism of action and a literature-based reproductive toxicity assessment, retifanlimab could 
cause fetal harm when administered to a pregnant woman. Animal studies have demonstrated that inhibition of 
the PD-1/PD-L1 pathway can lead to increased risk of immune-mediated rejection of the developing fetus 
resulting in fetal death. Participants must use contraceptive measures as described in the study protocols and in 
accordance with CTFG 2020. 67 


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CONFIDENTIAL 
 
 
 
Drug Interactions 
 
Packaging and Labeling Information 
 
Drug Storage and Stability 
 
NOTE: The CTFG guidance indicates monthly pregnancy testing and use of contraception for 1 to 6 months after 
final dose. 
 
 
 
Retifanlimab belongs to the class of IgG antibodies that are administered parenterally and cleared by protein 
catabolism, extrinsic factors such as food and drug-drug interactions are not anticipated to affect the exposure of 
retifanlimab. Specifically, drugs that affect cytochrome P450 and other metabolizing enzymes are not expected to 
interfere with the catabolism of retifanlimab.68,69 It is unlikely that retifanlimab would be a victim or a perpetrator 
of PK drug-drug interactions.70,71 Dedicated drug-drug interaction studies of retifanlimab have not been 
performed. 
 
Retifanlimab is known to increase some proinflammatory cytokine levels. This is a known class effect of 
checkpoint inhibitory mAbs 72,73 but is unlikely to modulate CYP enzymes or drug transporters, based on clinical 
evidence with other agents of this class.74 It is unlikely that retifanlimab would be a perpetrator of drug-drug 
interactions, and the potential for clinically significant drug-drug interaction is low. 
 
HIV antiretroviral medications, used according to protocols as appropriate by HIV-positive participants in 
retifanlimab studies, may be substrates, inhibitors, or inducers of the P‑glycoprotein and multidrug-resistant 
protein transporters and the cytochrome P450 enzyme system. None of the highly active antiretroviral therapies 
are immunosuppressors.75 Since retifanlimab is not expected to be a victim or perpetrator of drug transporters or 
cytochrome P450 enzymes, the potential of drug-drug interaction between antiretroviral drugs and retifanlimab is 
low.76 No clinically important differences in the CL of retifanlimab were found in HIV-positive participants taking 
antiretroviral medications compared to participants who were not HIV-positive. 
Glucocorticoid co-administration was explored as a time series covariate in the population pharmacokinetics 
model. Results show that glucocorticoid co-administration is not a predictor for retifanlimab clearance in the 
model. 
 
Hormonal contraceptives are metabolized by the cytochrome P450 enzyme system, and retifanlimab is not 
expected to be a victim or perpetrator of cytochrome P450 enzymes. 
 
Therefore, the potential for pharmacokinetic drug interactions between hormonal contraceptives 
and retifanlimab is low.77 
 
25 mg/mL retifanlimab will be provided in a glass vial for single use. Each vial will be labeled as required per 
country requirement. 
 
Store upright under refrigeration at 2°C-8°C (36°F-46°F), protected from light. 
See also retifanlimab pharmacy manual. 


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CONFIDENTIAL 
 
 
 
 
 
 
 
 
 
Prior to Preparation: 
Verify that there were no temperature excursions prior to preparing INCMGA00012 for infusion. Deviations from 
the acceptable temperature range (2°C − 8°C; 36°F − 46°F) since the last documented temperature must be 
reported immediately and the vials should be placed in temporary quarantine until notified by Incyte. 
 
Before dose preparation, each vial should be inspected visually. If solution is cloudy, there is pronounced 
discoloration (solution may have pale-yellow color), or visible particulate matter or discoloration is noted, the vial 
should not be used. If visible particulate matter, pronounced discoloration, or damage is evident, the vial should 
be permanently quarantined The study pharmacist or assigned designee should note the time, date and reason 
for permanently quarantining the vial(s) and a product complaint should be submitted to Incyte as per Section 11. 
INCMGA00012 was observed to be compatible with the following materials: 
• 
Polyvinylchloride (PVC) with DEHP (di-2-ethylhexyl phthalate) 
• 
PVC (without DEHP) 
• 
Polyolefin (Polyethylene and Polypropylene) 
• 
Polyolefin with polyamide coating 
• 
Ethylene Vinyl Acetate (EVA) 
• 
Polyurethane (PUR) 
Study drug administration supplies (ie, IV bags and tubing), should be made only of these materials. The type of 
infusion components (ie, bags and infusion sets) used for administration should be documented as per institution 
guidelines. 
INCMGA00012 will be prepared by adding the drug product directly to a bag containing 0.9% sodium chloride 
(normal saline) injection USP or 5% dextrose in water, USP (D5W). Prepared infusion solution will be delivered 
through an IV administration set including a 0.2 micron low protein binding preferably in-line filter made of 
polyethersulfone (PES). The density of liquid formulation is 1.04 g/ml. The final concentration range for 
INCMGA00012 must be within 0.3 mg/mL to 12 mg/mL in the normal saline IV bag. Institutional guidelines may 
be followed provided that the drug concentration falls within those parameters. It is recommended to use 100 
mL normal saline IV bags for infusion preparation, however, in case of supply constraints, 250 mL normal saline IV 
bags may be used if needed. 
 
Infusion Preparation 
The total time at room temperature (23-27°C) for the prepared infusion solution should not exceed 6 hours inclusive 
of infusion time. 
Note: if necessary, the prepared solution may be stored refrigerated (2-8°C) for up to 24 hours. The refrigerated 
solution should be allowed to come to room temperature for no more than 30 minutes prior to starting the infusion. 
 
The preparation of INCMGA00012 with 0.9% sodium chloride injection USP (normal saline) in IV bag is to be 
performed aseptically by the pharmacy or qualified personnel using the following steps: 
1. Confirm the proper dose to be administered. 
 
Preparation/Mixing Instructions 


UPMC Hillman Cancer Center 
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CONFIDENTIAL 
 
 
 
Administration 
8.3 
Gemcitabine/Nab-paclitaxel 
 
Overview 
 
2. Determine the required drug volume to be administered. 
3. Using aseptic technique, prepare the necessary volume of normal saline in the IV bag and label appropriately. 
The local method for preparing infusion solution is acceptable (ie, gravimetric, volumetric). 
4. The vial should be gently inverted to mix the solution. THE VIAL MUST NOT BE SHAKEN; excessive agitation 
may cause aggregate formation. Before use, parenteral drug products should be inspected visually. If 
particulate matter or discoloration is noted, the vial should not be used and the vial should be placed in 
Permanent Quarantine. Incyte should be notified immediately and a product complaint filed. 
5. Using aseptic technique, withdraw the required volume from the vial(s). If more than one vial is needed, it is 
advisable to deliver the study drug to an appropriate single use syringe using a new needle for each vial. 
6. Transfer the required volume of INCMGA00012 to the normal saline IV bag. The total infusion volume (normal 
saline + INCMGA00012) should be rounded to the nearest mL. 
7. Gently invert normal saline IV bag to mix the content. 
8. THE INFUSION BAG CONTAINING THE DOSE TO BE ADMINISTERED MUST NOT BE SHAKEN; excessive 
agitation may cause aggregate formation. Before administration the parenteral drug product solution 
should be inspected visually. The diluted dose solution may contain small translucent to white 
proteinaceous INCMGA00012 particles. It is acceptable to administer the dose solution with these 
proteinaceous particles using extension sets with the required sterile, non-pyrogenic, low-protein binding 
polyethersulfone (PES) 0.2 micron in-line filter. However, if foreign particulate matter or solution 
discoloration is noted, the final prepared IV solution should not be administered and a product complaint 
should be submitted as described in Section 10. 
See also retifanlimab pharmacy manual. 
 
Retifanlimab 500 mg will be administered IV (30-minute infusion [-5/+ 15 min]) using an in-line filter on Day 1 of 
each 28-day cycle. Refer to the Package Insert for additional details of administration. 
Retifanlimab will be administered after gemcitabine/nab-paclitaxel and prior to administration of 9-ING-41. 
See also retifanlimab pharmacy manual. 
 
Retifanlimab will be obtained for participants from Incyte Corporation. 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents according to institutional standard operating procedures and 
policies. 
 
Used drug and remaining unused drug may be destroyed, according to institutional standard operating 
procedures and policies. 
 
 
 Acquisition and Accountability 


UPMC Hillman Cancer Center 
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Page 38 of 93 
CONFIDENTIAL 
 
 
 
Pharmacokinetics and metabolism 
 
Adverse Effects 
 
Pregnancy and Lactation 
 
Drug Interactions 
 
Packaging and Labeling Information 
 
Drug Storage and Stability 
 
Preparation/Mixing Instructions 
 
Administration 
 Acquisition and Accountability 
 
Gemcitabine plus nab-paclitaxel (Abraxane) is a standard of care systemic therapy for advanced, metastatic PDAC. 
 
 
 
Refer to package inserts. 
 
Common side effects associated with gemcitabine and nab-paclitaxel are indicated in Appendix B. 
 
Refer to package inserts. 
 
Refer to package inserts. 
 
Refer to package inserts. 
 
Refer to package inserts. 
 
Refer to package inserts. 
 
Nab-paclitaxel 125 mg/m2 will be administered according to standard of care, IV over 30-40 minutes immediately 
followed by gemcitabine according to standard of care, 1000 mg/m2 IV over 30-minutes on Days 1, 8 and 15 of 
each 28-day cycle. 1-2 days dose administration window would be acceptable. 
 
Gemcitabine and nab-paclitaxel will be supplied for participants by the study site. 
 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of the 
receipt, dispensing and final disposition of all agents according to institutional standard operating procedures and 
policies. 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 39 of 93 
CONFIDENTIAL 
 
 
9 
TREATMENT PLAN 
9.1 
Treatment Regimen 
 
Safety Lead-in AND Phase II Treatment Regimen 
 
Used drug and remaining unused drug may be destroyed, according to institutional standard operating 
procedures and policies. 
 
The study drugs will be administered within a 28-day cycle. Treatment will be administered on an outpatient 
basis. Reported adverse events and potential risks are described in Adverse Events section. Appropriate dose 
modifications are described in the Dosing Delays/Dose Modifications section. No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to treat the 
participant's malignancy. 
 
 
The study treatment regimen is as follows: (1-2 days window) 
30- to- 40–minute intravenous (IV) infusion of nab-paclitaxel at a dose of 125 mg per square meter, followed by 
an infusion of gemcitabine according to the gemcitabine label at a dose of 1000 mg per square meter, on Days 1, 
8, and 15 of a 28-day cycle. 
• 
30-minute (-5/+ 15 min) IV infusion of retifanlimab 500 mg on Day 1 of a 28-day cycle. (retifanlimab will 
be administered following gemcitabine/nab-paclitaxel.) 
• 
9-ING-41 administered by IV infusion over 30 minutes to one hour twice weekly (Days 1 and 4 of each 
week) at a dose of 9.3mg/kg. (On Day 1 of each cycle, 9-ING-41 will be administered following 
retifanlimab; on Days 8 and 15 of each cycle, 9-ING-41 will be administered following gemcitabine/nab- 
paclitaxel.) 
 
Agent 
Dose 
Route 
Schedule 
Cycle Length 
Nab-paclitaxel 
125 mg/m2 
IV infusion 
Days 1, 8, and 15 
28 days 
Gemcitabine 
1000 mg/m2 
IV infusion 
Days 1, 8, and 15 
28 days 
Retifanlimab 
500 mg 
IV infusion 
Day 1 
28 days 
9-ING-41 
9.3 mg/kg 
IV infusion 
Twice weekly (Days 1 and 4) 
28 days 
 
The safety lead-in will enroll 6-9 patients. The participants enrolled in this study part will receive 9-ING-41 at 
9.3mg/kg IV on days 1 and 4 of each week + Retifanlimab at 500mg IV on Day 1 + (gemcitabine at 1000mg/m2 + 
Nab-paclitaxel at 125mg/m IV on days 1,8, and 15) (28-day cycles). If ≥ 5/6 participants do not experience Dose 
limiting toxicities (DLTs) within the DLT window of 28 days, the study will proceed to the phase 2 part. If > 1/6 
participants experience DLTs, de-escalation to a lower dose level will follow. Participants enrolled to this lower 
dose level will receive the drug doses per the dose de-escalation scheme below. Three participants will be 
enrolled to this dose level. If 0/3 participants do not experience DLTS, the study will proceed to the phase 2 part. 
The study will be terminated if ≥ 1/3 patients experience DLTs at this lower dose level. 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 40 of 93 
CONFIDENTIAL 
 
 
 
Safety Rules Trigger for Enrollment Pause 
9.2 
Treatment Duration 
 
Phase I Dose De-escalation Scheme 
Dose Level 
Dose of 9-ING-41 
(IV) Days 1 & 4 of 
each week 
All Cycles 
(Cycles = 28 days) 
Dose of 
Retifanlimab (IV) 
Day 1 
All Cycles 
Doses of Gemcitabine/Nab- 
Paclitaxel (IV) Days 1, 8, and 
15 
All Cycles 
Number of 
Participants 
Level 0 
9.3 mg/kg 
500 mg 
1000 mg/m2 
125 mg/m2 
6 
Level -1 
7 mg/kg 
500 mg 
1000 mg/m2 
125 mg/m2 
3 
 
 
The PI and study team will review and monitor toxicity and accrual data from this study. Information that raises 
any questions about participant safety will be addressed with the Data Safety & Monitoring Committee. The 
committee is composed of medical oncologists, research nurses, pharmacists and biostatisticians with direct 
experience in cancer clinical research. 
 
If any deaths occur on study that cannot be directly related to disease progression or extraneous causes, we will 
pause enrollment and the DSMC will review and monitor toxicity from this study to provide guidance regarding 
whether to continue enrollment or terminate the study. 
 
Patients should complete a minimum of two cycles of study treatment unless criteria for patient withdrawal or 
discontinuation of treatment are met (see Section with title, Participant Discontinuation / Withdrawal from the 
Study). Study treatment may be continued for as long as the patient does not have progressive disease as defined 
per imRECIST and/or unacceptable toxicity and as long as the investigator deems that the patient is benefiting 
from treatment but for a maximum treatment duration of 2 years. Treatment may also be stopped if the patient 
withdraws consent, or study termination occurs (see Section with title, Participant Discontinuation / Withdrawal 
from the Study). 
Participants who discontinue treatment with any drug in the regimen for any reason may continue treatment with 
the other drugs in the regimen at the investigator’s discretion if in participant’s best interest. 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 41 of 93 
CONFIDENTIAL 
 
 
10.1 Screening/Enrollment/Baseline 
10.2 Procedures During Treatment 
 
 
 
 
If the tests required at screening were performed as part of standard of care prior to signing consent for this 
study, the results from those tests are allowed in this study if the tests were completed within 28 days prior to the 
start of study treatment. 
Within 28 days prior to Day 1 of study treatment the following data will be collected: 
• 
Informed consent 
• 
Complete medical and surgical history, physical examination, including measurement of height, weight, vital 
signs, and assessment of ECOG performance status 
• 
Laboratory studies: complete blood count (CBC) with differential and platelets, comprehensive metabolic 
panel (CMP), pancreatic enzymes (amylase and lipase), TSH (Only measure free T3 or free T4 if TSH is 
abnormal) , and urinalysis 
• 
Electrocardiogram (ECG) 
• 
Routine visual exam at the eye clinic (if not done within the 6 months prior to day 1 of study regimen) 
• 
Pregnancy test (for women of childbearing potential): for female patients of childbearing potential, a blood or 
urine pregnancy test, with sensitivity of at least 25 mIU/mL, will be performed on 2 occasions prior to starting 
administration of study treatment—once at the start of screening and once within 72 hours of starting the 
investigational product. In the case of a positive confirmed pregnancy prior to receipt of 9-ING-41, the patient 
will be withdrawn from study. 
• 
Archived tumor tissue available at study entry: paraffin-embedded tissue block preferred or 10 unstained 
slides (metastatic tissue preferred to primary tissue) OR if archived tissue is not available, a fresh tumor 
biopsy must be obtained prior to start of study treatment. Tumor tissue should be sent as a standard of care 
procedure to one of the CLIA certified lab vendors for comprehensive molecular testing (e.g., UPMC local 
oncomine panel, Foundation One, Caris, or Tempus). Adequate tissue for molecular testing should be 
confirmed prior to trial enrolment. 
• 
If not done within the prior 28 days, a positron emission tomography (PET)/CT scan, MRI, and/or CT scan will 
be performed for radiological evaluation of disease. Bone imaging will be performed as appropriate according 
to the judgment of the investigator. 
• 
CA19-9 level 
 
 
The following evaluations will be performed at the intervals specified. 
• 
Adverse event occurrence at each visit starting with first dose; physical exam and performance status 
score (ECOG), each cycle (±5 days within the relevant cycle) 
• 
Vital signs and weight as per Section below with title History, Physical Exam, Vital Signs, Height and 
Weight. Blood pressure to be taken pre- and post-dose of 9-ING-41; other vital signs (temperature, pulse, 
respiration) to be taken pre-dose and additionally if clinically indicated. 
• 
Complete blood count with differential and platelets prior to Day 1 of every cycle and as clinically 
indicated 
• 
Comprehensive metabolic panel prior to Day 1 of every cycle and also as clinically indicated 
10  STUDY PROCEDURES AND SCHEDULE 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 42 of 93 
CONFIDENTIAL 
 
 
 History, Physical Exam, Vital Signs, Height and Weight 
 
• 
Serum amylase and lipase prior to Day 1 of every cycle and also as clinically indicated 
• 
TSH (Only measure free T3 or free T4 if TSH is abnormal), prior to day 1 of every cycle and as clinically 
indicated 
• 
Concomitant medications should be recorded on the CRF (see Section with title Concomitant Medication 
and Supportive Care Guidelines) 
• 
Restaging scans/radiologic evaluations (positron emission tomography (PET)/computed tomography (CT), 
CT and/or MRI, with or without bone imaging, every 2 cycles. 
• 
CA19-9 levels if elevated at baseline to be followed as per standard of care. 
• 
Pregnancy test (serum) on Day 1 of every cycle if relevant. 
 
History of the patient’s disease under study, including details of the primary diagnosis and treatment history, will 
be collected within 4 weeks before the start of treatment. In addition, a history of disease process other than the 
cancer under study (active or resolved) and concurrent illness will be collected. This will also include prior 
treatments and any current medical treatments for any condition. 
 
Patients will have a physical examination (PE) to include weight, vital signs (blood pressure, pulse, respiratory rate 
and temperature), and assessment of ECOG performance status and height prior to the start of treatment and 
throughout the study as listed in Section with title Schedule of Events. Note: height need only be recorded at 
baseline. 
A complete PE will be performed at Screening and at the End of Treatment visit for each patient and will include 
an assessment of all body systems including neurological examination. (Genitourinary examination is optional). 
Findings of all PEs should be recorded in the source documents, and any change from baseline considered by the 
investigator to be clinically significant should be recorded as an AE in the CRF. 
 
Abbreviated PEs should be performed as appropriate, and on an as needed basis for assessment of AEs. 
Abbreviated exams should be targeted to specific symptoms or complaints and be consistent with local standard 
of care. 
Vital signs will include measurements of blood pressure and pulse rate to be recorded in the supine or seated 
position. On dosing days, blood pressure and pulse rate should be measured prior to administration of the 
investigational product (pre-dose) and at the end of the infusion. 
 
A blood pressure cuff, which has been properly sized and calibrated, should be used to measure blood pressure. 
The use of automated devices with valid quality control for measuring blood pressure is acceptable. 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 43 of 93 
CONFIDENTIAL 
 
 
 Laboratory Assessments 
 
 
A standard tumor biopsy will be recommended (if feasible) from trial patients at the time of confirmed disease 
progression. The purpose of these biopsies is to examine the biologic effect of the trial drugs and for longitudinal 
evaluation of exploratory biomarkers (see Section with title, EXPLORATORY STUDIES). 
 
This tumor biopsy tissue, if obtained, will be sent as a standard of care procedure to one of the commercially 
available CLIA certified vendors (UPMC local oncomine panel, Foundation One, Caris, or Tempus) for 
comprehensive NGS molecular testing. 
 
 
The following hematology and blood chemistry parameters will be assessed on Day 1 of every cycle and also as 
clinically indicated: 
 
Laboratory Tests to be Performed at Local Laboratory* 
 
Hematology 
Chemistry 
Pancreatic Enzymes 
Endocrine 
Hemoglobin 
ALT 
Amylase 
TSH (Only measure free 
T3 or free T4 if TSH is 
abnormal) 
Platelets 
AST 
Lipase 
WBC 
Alk Phos 
% neutrophils 
Sodium 
% lymphocytes 
Potassium 
%monocytes 
Magnesium 
% eosinophils 
Chloride 
% basophils 
Total calcium 
Total bilirubin 
BUN or Urea 
Creatinine 
Glucose (nonfasted) 
Albumin 
Phosphorus or 
Phosphate 
 
*CBC will be monitored per standard of care practice prior to each chemotherapy dose. 
 Tumor Biopsies 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 44 of 93 
CONFIDENTIAL 
 
 
10.4 Post-Treatment Follow-Up 
10.5 Pregnancy Follow-Up 
10.6 Progression Free Survival Follow Up (PFS-FU) 
 
 
All patients should have a documented End of Treatment visit with associated safety follow up visit monitoring 
performed within 28 days of the last dose on 9-ING-41 (±5 days). 
 
The visit should incorporate: 
• 
History including concomitant medication usage 
• 
Physical examination to include assessment of all body systems including neurological examination. 
Genitourinary examination is optional. 
• 
Include weight, vital signs (blood pressure, pulse, respiratory rate and body temperature), and assessment 
of ECOG performance status 
• 
Hematology 
• 
Blood chemistry 
• 
Pancreatic enzymes 
• 
TSH (Only measure free T3 or free T4 if TSH is abnormal) 
• 
Pregnancy test if clinically indicated as per standard of care 
• 
PET/CT scan if clinically indicated as per standard of care 
• 
MRI and or CT if clinically indicated as per standard of care 
• 
Bone imaging if clinically indicated as per standard of care 
• 
CA19-9 levels as per standard of care 
• 
Safety reporting as per standard CRF (SAEs, non-serious SAEs, exposure to IP whilst pregnant or breast 
feeding) 
 
Progression free follow up (PFS-FU) and Overall survival follow (OS-FU) up assessments should be completed on 
all participants unless due to death, lost to follow-up, or the participant specifically has withdrawn consent for 
follow-up. Discontinuation from treatment does not preclude the need to complete follow-up assessments. 
 
Telephone call to check pregnancy status - 6 months after EOT 
 
 
For patients who discontinue study treatment prior to objective disease progression, PFS follow-up is to be 
performed, in person, every 6-8 weeks for up to 18 months after the last day of study drug, or until objective 
disease progression or death, whichever occurs first. 
 
The date and regimen of the first subsequent therapy should be recorded in the eCRF if it occurs during PFS-FU. 
10.3 End of Treatment & Safety follow up Visit 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 45 of 93 
CONFIDENTIAL 
 
 
10.7 Lost to Follow Up 
 
 
 
For patient who go off treatment due to disease progression, survival follow-up is to be performed every 3 
months for up to 18 months after the last day of study drug. 
 
OS-FU may be completed by phone contact. Death information from public sources (e.g. death registry, obituary 
listing, etc.) can also be used when it is available and verifiable. The date and regimen of the first subsequent 
therapy should be recorded in the eCRF if it occurs during OS-FU. 
 
 
Institution policy will be followed for participants considered lost to follow up. 
 Overall Survival Follow Up (OS-FU) 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 46 of 93 
CONFIDENTIAL 
 
 
 
 
 
28-day Cycles 
Week 
Within 28 
days prior 
to Day 1 of 
treatment 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
End of 
Treat 
ment c 
Safety 
follow 
-up c 
(± 5 
days) 
Preg- 
nancy 
Follow- 
up 
(± 7 
days) 
Survival 
follow- 
up 
Screening 
Period 
Cycle 1 
(± 2 days) 
Cycle 2 
(± 2 days) 
Cycle 3 
(± 2 days) 
Cycles ≥ 4 
(± 2 days) 
6 
months 
after 
EOT 
Informed consent 
X 
Nab-paclitaxel plus gemcitabine: 
Day 1, 8, and 15 of each 28-day cycle 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing of retifanlimab: 
Day 1 of each 28-day cycle 
X 
X 
X 
X 
Dosing of 9-ING-41: 
Day 1 and Day 4 of each week 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
History (complete history prior to Day 
1) 
X 
X 
X 
Concomitant medications (all visits) & 
adverse events (only visits after dosing) 
X 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
XX 
X 
X 
ECOG 
X 
X 
X 
X 
X 
X 
X 
Vital signs: BP (pre- and post-dose), HR, 
temp, resp (pre-dose and as clinically 
indicated) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height (baseline only) & weight (within 
72 hours prior to dosing) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination to be performed 
as timetabled each cycle (±5 days); 
collect vitals pre- and post-dose 9-ING- 
41 and as clinically indicated. 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
10.8 SCHEDULE OF EVENTS 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 47 of 93 
CONFIDENTIAL 
 
 
 
28-day Cycles 
Week 
Within 28 
days prior 
to Day 1 of 
treatment 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
End of 
Treat 
ment c 
Safety 
follow 
-up c 
(± 5 
days) 
Preg- 
nancy 
Follow- 
up 
(± 7 
days) 
Survival 
follow- 
up 
Screening 
Period 
Cycle 1 
(± 2 days) 
Cycle 2 
(± 2 days) 
Cycle 3 
(± 2 days) 
Cycles ≥ 4 
(± 2 days) 
6 
months 
after 
EOT 
ECG: if abnormal at Screening, follow- 
up as per standard of care 
X 
Routine visual exam @ eye clinic (if not 
done within 6 months prior to trial 
enrollment). 
X 
Complete blood count with differential 
and platelets on Day 1 of every cycle 
and also as clinically indicatedb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive metabolic panel, 
including magnesium and phosphorus 
on Day 1 of every cycle and also as 
clinically indicatedb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pancreatic enzymes (amylase and 
lipase) on Day 1 of every cycleb 
X 
X 
X 
X 
X 
X 
X 
TSH (only measure free T3 and free T4 if 
TSH is abnormal) on Day 1 of every 
cycleb 
X 
X 
X 
X 
X 
X 
X 
Urinalysis: dipstick is acceptable; if 
abnormal at Screening, repeat per 
standard of care 
X 
Pregnancy test of women of child- 
bearing potential (at start of Screening 
AND with 72 hours of starting study 
drug) 
X 
Day 1 of every cycle 
X 
X 
Standard of care Tumor biopsy or 
archive tissue sample at Screening 
X 
X 
At time of disease progression 


UPMC Hillman Cancer Center 
HCC 22-194 
Sponsor/Investigator: Anwaar Saeed, MD 
Page 48 of 93 
CONFIDENTIAL 
 
 
 
28-day Cycles 
Week 
Within 28 
days prior 
to Day 1 of 
treatment 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
End of 
Treat 
ment c 
Safety 
follow 
-up c 
(± 5 
days) 
Preg- 
nancy 
Follow- 
up 
(± 7 
days) 
Survival 
follow- 
up 
Screening 
Period 
Cycle 1 
(± 2 days) 
Cycle 2 
(± 2 days) 
Cycle 3 
(± 2 days) 
Cycles ≥ 4 
(± 2 days) 
6 
months 
after 
EOT 
PET/CT scan, MRI and/or CT scan (if not 
done within 4 weeks prior to Day 1) and 
thereafter every 2 cycles 
X 
X 
X 
X 
X 
Bone imaging at the discretion of the 
Investigator (at baseline if not done 
within 4 weeks prior to Day 1) and 
thereafter per standard of care 
X 
X 
X 
CA19-9 if elevated at baseline; follow 
on day 1 of every cycle 
X 
X 
X 
X 
X 
X 
X 
End of Treatment visit, procedures 
performed as appropriate 
X 
X 
X 
Safety Follow-up within 4 weeks of last 
dose of 9-ING-41 (±5 days) 
X 
Patients who discontinue prior to 
disease progression: PFS follow-up 
every 6-8 weeks for up to 18 months 
after last dose or until objective disease 
progression or death, whichever occurs 
first 
X 
Telephone call to check pregnancy 
status 
X 
Survival follow-up every 3 months for 
up to 18 months after last dose 
Phone call or medical record review 
X 


UPMC Hillman Cancer Center 
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Sponsor/Investigator: Anwaar Saeed, MD 
Page 49 of 93 
CONFIDENTIAL 
 
 
a If archived tissue is not available, tumor biopsy tissue, if obtained, will be sent as a standard of care procedure to one of the commercially available CLIA certified vendors (UPMC local 
oncomine panel, Foundation One, Caris, or Tempus) for comprehensive NGS molecular testing. 
b Approximately 1 tablespoon of blood will be collected each time during the study. 
c The End of Treatment visit procedures are performed as clinically indicated and per standard of care: pregnancy test, PET/CT scan, MRI and/or CT scan, bone imaging, CA19-9 
levels, safety reporting. 


UPMC Hillman Cancer Center 
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Page 50 of 93 
CONFIDENTIAL 
 
 
 Supportive Care 
 Prohibited or Restricted Concomitant Medications 
 Vaccines 
 DIET 
 
 
All concomitant treatments, blood products, as well as nondrug interventions received by patients from 
screening until the end of study visit will be recorded on the CRF. 
 
Concomitant palliative and supportive treatment(s) considered necessary for the patient’s wellbeing 
may be given at discretion of the investigator or her/his designee assuming there is no known or 
expected drug-drug interaction. 
Anti-emetics 
Anti-emetics should be prescribed prophylactically with gemcitabine/nab-paclitaxel according to local 
recommendations. 
 
Haematopoeitic Growth Factors 
Primary prophylactic use of granulocyte colony stimulating factors is permitted during Cycle 1, and they 
may be used to treat treatment emergent neutropenia as indicated by local guidelines. Erythropoietin 
may be used at the investigator’s discretion for the supportive treatment of anemia. 
 
Prohibited concomitant medications: 
1. Anti-platelet agents and anticoagulants that require INR monitoring, such as warfarin 
(treatments that do not require INR monitoring, such as low molecular weight heparin and 
certain factor X inhibitors are permitted) 
2. Any other investigational product(s) apart from 9-ING-41 and retifanlimab 
 
COVID-19 
COVID-19 vaccination is allowed during the study without restriction. 
 
Influenza 
The inactivated seasonal influenza vaccine can be given to participants while on therapy without 
restriction. Influenza vaccines containing live virus or other clinically indicated vaccinations for infectious 
diseases (i.e., pneumovax, varicella, etc.) may be permitted, but must be discussed with the 
Sponsor/Investigator and may require a study drug washout period prior to and after administration of 
the vaccine. 
 
Participants should maintain a normal diet unless modifications are required to manage adverse events 
such as diarrhea, nausea or vomiting. 
10.9 Concomitant Medication and Supportive Care Guidelines 


UPMC Hillman Cancer Center 
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Page 51 of 93 
CONFIDENTIAL 
 
 
 
 
Toxicity will be assessed according to National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v.5.0 (November 27, 2017) U.S. DEPARTMENT OF HEALTH AND HUMAN 
SERVICES National Institutes of Health National Cancer Institute). 
 
Every effort should be made to administer study treatment at the planned dose and schedule. In the 
event of significant toxicity, dosing may be interrupted and/or reduced as described below. In the event 
of multiple toxicities, dose modification should be based on the worst toxicity observed. Patients are to 
be instructed to notify investigators at the first occurrence of any adverse symptom or event. 
 
Dose modifications may occur in one of three ways: 
• 
Within a cycle: dosing interruption until adequate recovery and dose reduction, if required, 
during a given treatment cycle 
• 
Between cycles: next cycle administration may be delayed due to persisting toxicity when a new 
cycle is due to start 
• 
In the next cycle: dose reduction may be required in a subsequent cycle based on toxicity 
experienced in the previous cycle 
Since 9-ING-41 will be given in combination with retifanlimab plus gemcitabine/nab-paclitaxel, it will 
be difficult to know with certainty which drug causes which adverse event. On this study, 
investigators should follow the 3 sets of guidelines; Dosing Modification and Toxicity Management 
Guidelines for 9-ING-41 and retifanlimab and the standard guidelines for gemcitabine/nab-paclitaxel. 
 
Safety lead-in (Phase I) part of the trial will enroll 6-9 participants per the dose scheme and description 
detailed in section 15: statistical consideration. Those 6-9 patients will be evaluated for DLT during the 
first cycle (28 days). Participants who do not complete cycle 1, but did not meet criteria for a DLT will be 
considered unevaluable and will be replaced. (The safety lead-in phase has been completed.) 
Dose Limiting Toxicity Definitions: 
Toxicity that is clearly and directly related to the primary disease or to another etiology is excluded from 
this definition. 
 
Adverse events at least possibly attributable to 9-ING-41, retifanlimab, or gemcitabine/nab-paclitaxel or 
the combination of 9-ING-41, retifanlimab, and gemcitabine/nab-paclitaxel will be used to constitute 
DLT. 
11  DOSING DELAYS/DOSE MODIFICATIONS 


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CONFIDENTIAL 
 
 
A DLT will be defined as any: 
• 
Any Grade 4AE 
• 
Any ≥ Grade 3 colitis 
• 
Any Grade 3 or 4 noninfectious pneumonitis irrespective of duration 
• 
Any Grade 2 pneumonitis that does not resolve to ≤ Grade 1 within 3 days of the initiation of 
maximal supportive care 
• 
Any Grade 3 irAE, excluding colitis or pneumonitis, that does not downgrade to Grade 2 within 3 
days after onset of the event despite optimal medical management including systemic 
corticosteroids or does not downgrade to ≤ Grade 1 or baseline within 14 days 
• 
Liver transaminase elevation > 8 × ULN or total bilirubin > 5 × ULN 
• 
Any related ≥ Grade 3 non-irAE which is unexpected in severity and/or duration compared to 
the known safety profiles of 9-ING-41 or retifanlimab or gemcitabine/nab-paclitaxel when used 
as single agents, and that cannot be managed by dose modification (reduction or interruption) 
and adequate supportive care, and requires permanent discontinuation of 9-ING-41 and/ or 
Retifanlimab and/ or gemcitabine/nab-paclitaxel, except for the exclusions listed below. 
The definition excludes the following conditions: 
• Grade 3 fatigue lasting ≤ 7 days 
• Grade 3 endocrine disorder (thyroid, pituitary, and/or adrenal insufficiency) that is managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy and the participant is 
asymptomatic 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., inflammatory reaction at 
sites of metastatic disease, lymph nodes, etc.) 
• Concurrent vitiligo or alopecia of any AE grade 
• Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that 
resolves within 6 hours with appropriate clinical management 
• Grade 3 or 4 neutropenia that is not associated with fever or systemic infection that improves by at 
least 1 grade within 3 days. Grade 3 or Grade 4 febrile neutropenia will be a DLT regardless of duration 
or reversibility 
• Grade 3 or 4 lymphopenia 
• Grade 3 thrombocytopenia that is not associated with clinically significant bleeding that requires 
medical intervention, and improves by at least 1 grade within 3 days 
• Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or symptoms and 
are reversed with appropriate maximal medical intervention within 3 days 
 
Note: Tumor efficacy (RECIST) assessment dates are not affected by dose delays and remain as originally 
scheduled, as they are based on the date of enrollment (not the date of therapy). 
 
All other scheduled assessments must be performed relative to the start of the dosing cycle such that all 
laboratory procedures, etc required for dosing should be performed within 3 days prior to dosing. 


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CONFIDENTIAL 
 
 
11.1 9-ING-41 
 9-ING-41 Dose Reduction Steps 
 9-ING-41Dose Modification Guidelines 
 9-ING-41 Dose Reduction Criteria 
 9-ING-41 Treatment Discontinuation Criteria 
Dose modification guidelines for 9-ING-41 are described in the following sections. 
Dose delay or discontinuation of retifanlimab are described in the following sections. 
Dose modifications of gemcitabine/nab-paclitaxel should be according to prescribing information or site 
standard of care. 
 
 
Dose reduction steps for 9-ING-41 are shown in the table below. 
9-ING-41 Dose Reduction Levels 
 
Dose level 
9-ING-41 dose 
Starting 
9.3 mg/kg 
-1 
7 mg/kg 
-2 
5 mg/kg 
 
Each Adverse Event should be attributed to a specific study drug so that dose modifications can be made 
accordingly. Further clarification can be obtained in consultation with the Sponsor/Investigator. If 
multiple toxicities are noted, the dose adjustment should be made according to the most severe toxicity 
guidelines. 
 
Patients who experience Grade 3/4 9-ING-41-attributable adverse events / toxicity, should have the 
9-ING-41 dose reduced by one dose level as described in table above with title 9-ING-41 Dose Reduction 
Levels. 
For Grade 1/2 9-ING-41-attributable adverse events, dose reduction should be made at the 
Investigator’s discretion. 
 
9-ING-41 alone, or 9-ING-41 in combination with retifanlimab and chemotherapy should be 
discontinued permanently for the following: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding (aside from minor bleeds ≤ 
Grade 1) requires discontinuation 


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CONFIDENTIAL 
 
 
11.2 9-ING-41 Guidelines for Restarting 9-ING-41 
Any drug-related liver function test (LFT) abnormality that meets the following criteria requires 
discontinuation: 
o AST or ALT > 5-10 x ULN for > 2 weeks 
o AST or ALT > 10 x ULN 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
Any Grade 4 drug-related adverse event or laboratory abnormality, except for the following events 
which do not require discontinuation: 
o Grade 4 neutropenia < 7 days 
o Grade 4 lymphopenia or leukopenia 
o Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with 
clinical sequelae and are corrected with supplementation/appropriate management 
within 72 hours of their onset 
 
Any treatment-related event that leads to interruption in dosing lasting > 6 weeks from the previous 
dose requires patient discontinuation, with the following exceptions: 
o Dosing interruptions lasting > 6 weeks (e.g. minor surgery) from the previous dose that 
occur for non-drug- related reasons may be allowed if approved by the Investigator, the 
Sponsor, and the Data Safety Monitoring Committee (DSMC). Prior to re-initiating 
treatment in a patient with a dose interruption lasting > 6 weeks, the investigator and 
the Sponsor must agree to do so. Tumor assessments should continue as per protocol 
even if dosing is interrupted. Periodic study visits to assess safety and laboratory studies 
should also continue every 4 weeks or more frequently if clinically indicated during such 
dosing interruption. 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator or Sponsor, presents a substantial clinical risk to the patient with continued treatment 
dosing. 
 
After Cycle 1 is completed, if a treatment interruption continues beyond Day 28 of the current cycle, 
then the day when treatment is restarted will be counted as Day 1 of the next cycle. Re-treatment 
following treatment interruption for treatment related toxicity or at the start of any new cycle may not 
occur until all of the following parameters have been met: 
ANC ≥500/mm3; 
Platelets count ≥50,000/mm3; 
Non-hematologic toxicities have returned to baseline or Grade ≤1 severity (or, at the investigator 
discretion, Grade ≤2 if not considered a safety risk for the patient). 
 
If a treatment delay results from worsening of hematologic or biochemical parameters, the frequency of 
relevant blood tests should be increased as clinically indicated. 


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CONFIDENTIAL 
 
 
11.3 Retifanlimab 
 Management of Suspected Infusion Reactions 
9-ING-41 should be delayed for clinically significant CTCAE v5.0 Grade 3/4 toxicity thought to be 
possibly, probably, or definitely related to study drug; in patients where Grade 2 toxicity is intolerable 
despite supportive care, treatment may also be delayed or interrupted. Delays to dosing up to and 
including 28 days beyond planned dosing are at the investigator’s discretion. 
After resolution to less than or equal to CTCAE v5.0 Grade 2, 9-ING-41 can be restarted at a reduced 
dose as indicated in table above with title 9-ING-41 Dose Reduction Levels.. If 9-ING-41 is delayed for 
more than 28 days, it may be restarted only after discussion between the investigator and the Sponsor. 
 
 
The incidence of infusion reactions to retifanlimab in company-sponsored studies is low (2.2%). Infusion 
or hypersensitivity reactions may be observed with administration of any foreign protein. 
Premedication with an antipyretic (eg, acetaminophen/paracetamol) and a histamine blocker (eg, 
diphenhydramine) should be considered for participants who have had previous systemic reactions to 
protein product infusions or when recommended by institutional policy. Routine prophylaxis is not 
required. 
 
Guidelines for management of suspected infusion reactions are provided in the table below. 


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CONFIDENTIAL 
 
 
 
 
Guidelines for management of suspected infusion reactions (Table - A) 
 
Grade 
Description(1) 
Treatment 
Subsequent Infusions 
1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated. 
Monitor vital signs closely until medically stable. 
Premedication with an antipyretic (eg, 
acetaminophen/paracetamol) and a histamine 
blocker should be considered for participants who 
have had previous systemic reactions to protein 
product infusions or when recommended by 
institutional policy. 
2 
Requires infusion interruption but responds promptly 
to symptomatic treatment (eg, antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 hours. 
First occurrence: Stop infusion and initiate 
appropriate medical measures (eg, IV fluids, 
antihistamines, NSAIDS, antipyretics, narcotics, per 
institutional preferences). 
Monitor vital signs until medically stable. 
If symptoms resolve within 1 hour, infusion may be 
resumed at 50% of the original infusion rate. 
Subsequent occurrences (after recommended 
prophylaxis): Permanently discontinue study 
treatment. 
Premedicate at least 30 minutes before infusion with 
antihistamines (eg, diphenhydramine 50 mg PO) and 
an antipyretic (eg, acetaminophen/paracetamol 
[500-1000 mg PO]). 
Additional supportive measures may be acceptable 
(per institutional preference) but should be discussed 
with medical monitor. 
Next infusion should start at 50% of the original 
infusion rate. If no reaction, rate of infusion can be 
increase by 25% every 15 minutes until a rate of 
100% has been reached. Subsequent infusions can 
begin at 100%. 
3 or 4 
Grade 3: Prolonged (ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for other 
clinical sequelae (eg, renal impairment, pulmonary 
infiltrates). 
Grade 4: Life-threatening; pressor or ventilatory 
support indicated. 
Stop infusion and initiate appropriate medical 
therapy (eg, IV fluids, antihistamines NSAIDS, 
antipyretics, narcotics, oxygen, pressors, 
epinephrine, corticosteroids, per institutional 
preferences). 
Monitor vital signs frequently until medically stable. 
Hospitalization may be indicated. 
Permanently discontinue study treatment. 
(1) Per NCI CTCAE v5.0, appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period 
of study treatment administration. 


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CONFIDENTIAL 
 
 
 
 
Adverse events of a potential immunologic etiology, or irAEs, may be defined as AEs of unknown etiology, associated with drug exposure and 
consistent with an immune phenomenon. Immune-related AEs may be predicted based on the nature of the compounds, their mechanism of 
action, and reported experience with immunotherapies that have a similar mechanism of action. Special attention should be paid to AEs that 
may be suggestive of potential irAEs. An irAE can occur shortly after the first dose or several months after the last dose of treatment. 
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes before labeling an AE 
as an irAE. 
 
Recommendations for management of specific immune-mediated AEs known to be associated with other PD-1 inhibitors (eg, pembrolizumab, 
nivolumab) are detailed in the table below. Algorithms for evaluation of selected immune toxicities that have previously been attributed to PD-1 
inhibitors and management guidelines for irAEs not detailed elsewhere in the Protocol should follow the ASCO or ESMO Clinical Practice 
Guidelines.78,79 
Toxicity Management Guidelines for Immune-Related AEs (Table - B) 
 
Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With retifanlimab 
AE Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Pneumonitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
• Administer systemic corticosteroids per local practice followed by taper. 
• Evaluate participants with suspected pneumonitis with radiographic 
imaging and initiate corticosteroid treatment. 
• Add prophylactic antibiotics for opportunistic infections. 
Grades 3 or 4, or recurrent 
Grade 2 
Permanently discontinue. 
Diarrhea/colitis 
Grade 1 
No action. 
None. 
Grades 2 or 3 
Withhold until ≤ Grade 1. 
• Consider prompt initiation of standard anti-diarrheal agents. 
• Administer systemic corticosteroids per local practice followed by taper. 
• Consider prophylactic antibiotics per local practice. 
• Consider gastrointestinal consultation and performing endoscopy to rule 
out colitis. 
Grade 4 or recurrent 
Grade 3 
Permanently discontinue. 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
 Procedures for Participants Exhibiting Immune -Related Adverse Events 


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CONFIDENTIAL 
 
 
 
Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With retifanlimab 
AE Management With Corticosteroid and/or 
Other Supportive Care Therapies 
AST/ALT elevation 
and/or increased 
bilirubin/hepatitis 
Grade 3 or 4, 
or in participants with liver 
metastasis with baseline 
Grade 2 elevation of AST or 
ALT, hepatitis with AST or 
ALT increases ≥ 50% and 
lasts ≥ 1 week 
Permanently discontinue. 
• Administer systemic corticosteroids per local practice followed by taper. 
• Consider monitoring liver enzymes weekly (or more frequently) until 
liver enzyme value returns to baseline or is stable. 
Endocrinopathies 
Type 1 diabetes 
mellitus 
Hyperglycemia 
Hyperthyroidism 
Hypothyroidism 
Hypophysitis 
Adrenal insufficiency 
Grades 1 and 2 
No action. 
None. 
Grades 3 and 4 
hypothyroidism 
No action. 
For hypothyroidism, initiate thyroid replacement hormones (eg, 
levothyroxine or liothyronine) per standard of care. 
Grades 3 or 4 
Withhold until ≤ Grade 1. 
May restart retifanlimab if 
endocrinopathy has improved to ≤ Grade 
2 and is controlled with hormone 
replacement, if indicated, and steroid 
taper is complete. 
• For Type 1 diabetes mellitus, initiate insulin replacement therapy. 
• For hyperglycemia, administer antihyperglycemic. 
• For hyperthyroidism, treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as appropriate. 
• For hypophysitis or adrenal insufficiency, administer corticosteroids and 
initiate hormonal replacements as clinically indicated. 
Nephritis and renal 
dysfunction 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 3 or 4 
Permanently discontinue. 
Rash 
Grade 1 
No action. 
None. 
Grade 2 
No action. 
Manage with topical steroids with or without drug interruption. 
Grade 3(1) or persistent 
Grade 2 (≥ 2 weeks) or 
suspected Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 4 or confirmed 
Stevens-Johnson syndrome 
or toxic epidermal 
necrolysis 
Permanently discontinue. 


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CONFIDENTIAL 
 
 
 
Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With retifanlimab 
AE Management With Corticosteroid and/or 
Other Supportive Care Therapies 
Myocarditis 
Grade 2 
Withhold until ≤ Grade 1. 
• Treatment with systemic corticosteroids should be initiated (initial dose 
of 1-2 mg/kg per day of prednisone or equivalent). Taper as appropriate. 
• Manage cardiac symptoms according to standard of care and with 
guidance from cardiology. Consider cardiac MRI and myocardial biopsy 
for diagnosis. 
Grades 3 or 4 
Permanently discontinue. 
Important nervous 
system events (eg, 
Guillain-Barre syndrome, 
autoimmune 
encephalitis, myasthenia 
gravis, autonomic 
neuropathy, or 
transverse myelitis) 
Grade 2 
Withhold until ≤ Grade 1. 
• Neurology consultation is recommended for all neurologic irAEs 
≥ Grade 2. 
• Treatment with systemic corticosteroids should be initiated (initial dose 
of 1-2 mg/kg per day of prednisone or equivalent). Taper as appropriate. 
• For Grade 2 transverse myelitis consider permanent discontinuation. 
• Permanently discontinue for any grade Guillain-Barre Syndrome 
• Manage symptoms according to standard of care and with guidance 
from neurology. 
Grades 3 or 4 
Permanently discontinue. 
All other irAEs 
Grade 3 or intolerable/ 
persistent Grade 2 
Withhold until ≤ Grade 1. 
Based on severity of AE, administer corticosteroids. 
Recurrent Grade 3 
Consider discontinuation. 
Grade 4 
Permanently discontinue. 
(1) Participants with Grade 3 rash in the absence of desquamation, with no mucosal involvement, not requiring systemic steroids, and resolving or improving to ≤ Grade 1 within 
14 days do not have to interrupt retifanlimab. 


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CONFIDENTIAL 
 
 
 Participant Access To Study Agent At Study Closure 
11.4 Participant Discontinuation/Withdrawal from the Study 
 
 
 
Participants unable to restart study drug treatment ≤ 12 weeks from the start of the treatment delay 
due to toxicity will be permanently discontinued from study treatment. Treatment breaks of greater 
than 12 weeks for reasons other than toxicity will be considered on a case by case basis by the study 
investigator/ sponsor. 
Treatment with study drug may continue up to 2 years in the absence of disease progression, intolerable 
toxicity, death, withdrawal of consent, lost to follow-up, or premature discontinuation for any other 
reason. 
 
Participant management should follow imRECIST80, with the decision to treat beyond conventional 
RECIST progression documented in the study file. 
Participants will be evaluated for immune-related AEs for 90 days after the last dose of study drug or 
until the start of new anticancer therapy whichever comes first. 
 
 
Treatment with study drugs may continue for a maximum duration of to 2 years in the absence of 
disease progression, intolerable toxicity, death, withdrawal of consent, lost to follow-up, or premature 
discontinuation for any other reason. 
 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. 
Participants may be withdrawn from the treatment if any of the following occur: 
• 
Disease progression per imRECIST criteria. 
• 
Intercurrent illness that prevents further administration of treatment. 
• 
Unacceptable adverse event(s). 
• 
Participant decides to withdraw from the protocol therapy (follow-up permitted). 
• 
Patient withdraws consent (no follow-up permitted). 
• 
General or specific changes in the participant's condition render the participant unacceptable for 
further treatment in the judgment of the treating investigator. 
• 
Major violation of the study protocol (i.e., unable to adhere to study schedule) that in the 
opinion of the treating investigator, puts the participant at undue risk. 
• 
Discontinuation of the study by UPMC Hillman Cancer Center. 
• 
Confirmed pregnancy. 
• 
Completed overall survival (OS) follow up as per protocol 
• 
Lost to follow-up. 
• 
Death 
Participants will be removed from the protocol therapy when any of these criteria apply. The reason for 
removal from protocol therapy, and the date the participant was removed, must be documented in the 
 Treatment Discontinuation Criteria For Retifanlimab 


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CONFIDENTIAL 
 
 
12  EXPLORATORY STUDIES 
12.1 Exploratory Objectives 
 
 
electronic case report form (eCRF). Alternative care options will be discussed with the participant. 
Safety monitoring and follow-up assessments should continue as appropriate according to the study 
schedule, unless the participant has withdrawn consent for study participation. Participants removed 
from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization 
of the adverse event. 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off- 
Treatment/Off-Study information will be updated in CRIS. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately notify 
the Sponsor/Investigator. 
 
 
If tumor archival tissue is not available, standard of care fresh tumor biopsy (preferably of an 
accessible metastatic site) should be obtained: 
-Tumor core tissue biopsies are required per institutional standard of care for NGS sequencing (ideally 5 
cores). 
-Tumor tissue biopsies will be collected using standard biopsy needle (core needle of 18 gauge or larger) 
or be collected by an incisional or excisional tumor biopsy. 
 
**Collected tumor tissue or the available archival tissue will be sent to a CLIA certified commercially 
available vendors (e.g., UPMC local oncomine panel, Foundation One, Caris, or Tempus) for 
comprehensive NGS molecular testing as part of standard of care approaches. 
Objectives and Type of studies: 
 
1. To explore the genomic alterations correlating with treatment response to the study drug regimen: 
➢ Comparative analysis of baseline molecular markers between responders and non-responders 
➢ Exploratory Markers: PDL-1 (CPS score), MSI status, tumor mutation burden (TMB), a broad HRD 
gene panel: ARID1A, ATM, ATRX, BAP1, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, FANCC, MRE11A, 
NBN, PALB2, RAD51C, RAD51D. 
2. To explore mechanisms of resistance to the drug combination 
➢ Comparative analysis of tumor molecular derangements at baseline and at time of disease 
progression 
➢ Exploratory Markers: molecular alterations per tumor DNA NGS results. 


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CONFIDENTIAL 
 
 
13  SAFETY ASSESSMENT, DOCUMENTATION AND REPORTING 
13.1 Definitions 
 
 
 
No research samples will be obtained at baseline or throughout this trial. 
The comprehensive tumor molecular testing through commercially available vendors will be done as 
part of standard of care approaches. 
 
Any adverse events or sserious adverse events experienced by a participant will be collected, 
documented and reported as outlined throughout this section. 
 
The following definitions of terms apply to this section: 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an 
adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
Serious adverse event or serious suspected adverse reaction: An adverse event or suspected adverse 
reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes: 
• 
Death 
• 
Life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization. The following 
hospitalizations are NOT considered to be SAEs: 
1. Medical conditions present at the initial trial visit that do not worsen in severity or 
frequency during the treatment plan are defined as baseline medical conditions and 
NOT to be considered AEs/SAEs 
2. Visits to the emergency room or other hospital department < 24 hours, that do not 
result in admission (unless considered an important medical or life-threatening 
event) 
3. Elective surgery, planned prior to signing consent, and admissions for a planned 
medical/surgical procedure 
4. Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason) 
5. Admission for administration of anticancer therapy in the absence of any other 
12.2 Sample Preparation, Handling, Storage and Shipment 


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CONFIDENTIAL 
 
 
13.2 Eliciting Adverse Event Information 
 Recording Requirements 
 
 
SAEs. 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
Congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject 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. 
 
Suspected adverse reaction: Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event. For the purposes of IND safety reporting, "reasonable possibility" means 
there is evidence to suggest a causal relationship between the drug and the adverse event. Suspected 
adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
Adverse reaction: any adverse event caused by a drug. Adverse reactions are a subset of all suspected 
adverse reactions where there is reason to conclude that the drug caused the event. 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or suspected 
adverse reaction is considered "unexpected" if it is not listed in the investigator brochure or is not listed 
at the specificity or severity that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. For example, under this definition, hepatic necrosis 
would be unexpected (by virtue of greater severity) if the investigator brochure referred only to 
elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral vasculitis 
would be unexpected (by virtue of greater specificity) if the investigator brochure listed only cerebral 
vascular accidents. "Unexpected," as used in this definition, also refers to adverse events or suspected 
adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or 
as anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation 
 
 
 
Research subjects will be routinely questioned about AEs at study visits. 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) will be recorded in the 
subjects’ case histories. For all adverse events, sufficient information will be pursued and/or obtained so 
as to permit 1) an adequate determination of the outcome of the event (i.e., whether the event should 


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CONFIDENTIAL 
 
 
 Abnormal Test Findings 
13.3 Adverse Event Evaluation 
 
 
be classified as a serious adverse event) and; 2) an assessment of the casual relationship between the 
adverse event and the study drug(s). 
 
Adverse events will be followed until resolution while the subject remains on-study. Once the subject is 
removed from study, events thought to be related to the study medication will be followed until 
resolution or stabilization of the adverse event, or until the patient starts a new treatment regimen, or 
death, whichever comes first. Subjects will be followed for AEs/SAEs for 90 days after their last dose of 
study drug(s). 
AEs or abnormal test findings felt to be associated with the investigational drug or study treatment(s) 
will be followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the Sponsor-Investigator. 
 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria are 
met: 
• 
The test finding is accompanied by clinical symptoms. 
• 
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical intervention; 
including significant additional concomitant drug treatment or other therapy. 
Note: simply repeating a test finding, in the absence of any of the other listed criteria, does not 
constitute an AE. 
• 
The test finding leads to a change in study dosing or discontinuation of subject participation in 
the clinical study. 
• 
The test finding is considered an AE by the Sponsor-Investigator of the IND application. 
 
The investigator or designee is responsible for ensuring that all AEs (both serious and non-serious) 
observed by the clinical team or reported by the subject which occur after the first dose of study 
treatment are fully recorded in the subject’s medical records. Source documentation must be available 
to support all AEs. 
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to withdraw from 
the study, requiring treatment or causing apparent clinical manifestations, result in a delay or dose 
modification of study treatment, or judged relevant by the investigator), should be reported as an AE. 
The investigator or sub-investigator (treating physician if applicable) will provide the following for all AEs 
(both serious and non-serious): 
• 
Event term (as per CTCAE version 5) 
• 
Description of the event 
• 
Date of onset and resolution 
• 
Expectedness of the toxicity 
• 
Grade of toxicity 
• 
Attribution of relatedness to the investigational agent- (this must be assigned by an investigator, 
sub-investigator, or treating physician) 


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CONFIDENTIAL 
 
 
 Grading / Severity 
 Expectedness 
 
 
• 
Action taken as a result of the event, including but not limited to; no changes, dose interrupted, 
reduced, discontinued, etc. or action taken with regard to the event, i.e. no action, received 
concomitant med or other intervention, etc. 
• 
Outcome of event 
 
Descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting. The following grading scale should be used to assess 
AE/SAE severity for events not specifically listed in CTCAE version 5.0. 
 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note: Based on the most recent version of NCI CTCAE (v5.0), which can be found at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding 
oneself, using the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse 
event 
d. 
Grade 4 and 5 events must be reported as serious adverse events (SAEs) 
 
 
An expected AE is an event previously known or anticipated to result from participation in the research 
study or any underlying disease, disorder, or condition of the subject. The event is usually listed in the 
Investigator Brochure, consent form or research protocol. 
 
An unexpected AE is an AE not previously known or anticipated to result from the research study or any 
underlying disease, disorder, or condition of the subject. 


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 Classification of Outcome 
 Action Taken due to AE 
 
 
 
Attribution is the relationship between an AE or serious AE and the study drugs. Attributions are 
required for each drug administered as part of the treatment regimen. Attribution will be assigned as 
follows: 
• 
Definitely Related – The AE is clearly related to the study drug. There is a reasonable causal 
relationship between study treatment and the AE. The event responds to withdrawal of study 
treatment (dechallenge) and recurs with rechallenge when clinically feasible. 
• 
Probably Related – The AE is likely related to the study drug. There is a reasonable causal 
relationship between study treatment and the AE. The event responds to dechallenge. 
• 
Possibly Related – The AE may be related to the study drug. There is a reasonable possibility that 
study treatment caused the adverse event. The investigator can provide a rationale or evidence 
to suggest a causal relationship between study treatment and the AE other than just a temporal 
relationship. 
• 
Unlikely Related– The AE is doubtfully related to the study drug. There is only a temporal 
relationship to study treatment, but not a reasonable causal relationship between study 
treatment and the AE. 
• 
Unrelated – The AE is clearly NOT related to the study drug. There is no temporal relationship to 
study treatment. There is a reasonable causal relationship to another drug product, concurrent 
disease, or circumstance. 
 
AE outcome describes the status of the AE at the last observation. The Investigator will document the 
outcome of each AE or SAE using the categories provided below. 
 
Classification 
Definition 
Fatal 
Termination of life because of an AE. 
Not recovered/not resolved 
Participant has not recuperated, or the AE has not improved. 
Recovering/resolving 
Participant is recuperating or the AE is improving. 
Recovered/resolved 
Participant has recuperated, the AE resolved, or returned to baseline 
status / stabilized. 
Recovered/resolved with 
sequelae 
AE has resolved, but the participant has been left with symptoms or 
pathology 
Unknown 
Not known, not observed, not recorded, or refused. 
 
The Investigator will provide the action taken regarding study drug in response to the AE. Classifications 
for each of the potential actions taken are provided below. More than one option may apply to a single 
 Attribution 


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13.4 Serious Adverse Event Reporting 
 Follow-up Reports 
 
 
AE/SAE. For example, study drug may be delayed, and the dose reduced in response to an AE. Action 
related to pembrolizumab and/or VS-6766 will be assessed and recorded separately in the EDC. 
 
Classification 
Definition 
Dose not changed 
No change in administration of study drug 
Study drug interrupted 
Temporary interruption (termination) in administration of the 
study drug 
Study drug withdrawn 
Administration of the study drug terminated (no further dosing) 
Not applicable 
Determination of a value is not relevant in the current context 
Unknown 
Not known, not observed, not recorded, or refused 
 
 
All events meeting the definition of a serious adverse event, which occur after the date of first dose of 
study treatment and within 90 days of the last dose of study treatment, should be reported according to 
the departmental SAE checklist and SAE form. The initial SAE form should be sent to the following within 
24 hours of the Principal Investigator becoming aware of the event: 
1. Anwaar Saeed, MD; at saeeda3@upmc.edu 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board when reporting requirements are met, per CRS Safety process. 
4. Incyte: email – SafetyReporting@Incyte.com or fax – (+) 1-866-981-2057 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report 
within the departmental SAE form: 
• 
CTCAE term(s) and grade(s) 
• 
current status of study drug 
• 
all interventions to address the AE (testing and result, treatment and response) 
• 
hospitalization and/or discharge dates 
• 
event relationship to study drug 
 
All SAEs should be followed to resolution or stabilization. Additional information may be added to a 
previously submitted report by adding to the original departmental SAE form and submitting it as 
follow-up or creating supplemental summary information and submitting it as follow-up with the 
original departmental SAE form. All follow-up forms must include the date the form is revised and 
should be submitted to the contacts listed above within 24 hours of the Principal Investigator becoming 
aware of the new information. 


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13.5 Review of Safety Information: Sponsor-Investigator Responsibilities 
13.6 IND Safety Report 
 Serious and Unexpected Suspected Adverse Reaction 
 
 
 
If a woman becomes pregnant or suspects that she is pregnant while participating in this study or within 
6 months after the last dose, she must inform the investigator immediately and permanently 
discontinue study treatment. Reporting requirements are the same as for an SAE in above. The 
pregnancy must be followed for the final pregnancy outcome. 
If a female partner of a male participant becomes pregnant during the male participants participation, or 
within 6 months of discontinuing treatment in this study, he must inform the investigator immediately. 
Reporting requirements are the same as for an SAE above. Every effort should be made to follow the 
pregnancy for the final pregnancy outcome. 
PER INCYTE 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 24 hours of discovery of a pregnancy 
of a subject who has taken the Incyte product or the pregnancy of a partner for a subject who has taken 
the Incyte product. The “Follow-up Pregnancy Report Form” or equivalent must be completed and 
emailed to SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 30 days after delivery, so 
that Incyte is provided with information regarding the outcome of the pregnancy. If the pregnancy 
results in any events which meet the serious criteria (i.e., miscarriage or termination), the SAE reporting 
process needs to be followed and the timelines associated with a SAE should be followed. 
 
The sponsor-investigator must promptly review all information relevant to the safety of the drug 
obtained or otherwise received by the sponsor from foreign or domestic sources, including information 
derived from any clinical or epidemiological investigations, animal or in vitro studies, reports in the 
scientific literature, and unpublished scientific papers, as well as reports from foreign regulatory 
authorities and reports of foreign commercial marketing experience for drugs that are not marketed in 
the United States. 
 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting under 
Sections 13.6.1 to 13.6.4 below. In each IND safety report, the sponsor must identify all IND safety 
reports previously submitted to FDA concerning a similar suspected adverse reaction, and must analyze 
the significance of the suspected adverse reaction in light of previous, similar reports or any other 
relevant information. 
 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
 Pregnancy Reporting 


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 Findings from Other Studies 
 Findings from Animal or In Vitro Testing 
 Increased Rate of Occurrence of Serious Suspected Adverse Reactions 
13.7  Submission of IND Safety Reports 
 
 
suggest a causal relationship between the drug and the adverse event, such as: 
 
• 
A single occurrence of an event that is uncommon and known to be strongly associated with 
drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); 
• 
One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
• 
An aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly occur 
in the study population independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical control group. 
 
 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple studies, 
or clinical studies (other than those reported under section 13.6.1), whether or not conducted under an 
IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to 
the drug. Ordinarily, such a finding would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or other aspects of the 
overall conduct of the clinical investigation. 
 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of mutagenicity, 
teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the expected human 
exposure. Ordinarily, any such findings would result in a safety-related change in the protocol, informed 
consent, investigator brochure (excluding routine updates of these documents), or other aspects of the 
overall conduct of the clinical investigation. 
 
The sponsor must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
 
The sponsor must submit each IND safety report in a narrative format or on Form FDA 3500A or in an 
electronic format that FDA can process, review, and archive. FDA will periodically issue guidance on how 
to provide the electronic submission (e.g., method of transmission, media, file formats, preparation and 
organization of files). The sponsor may submit foreign suspected adverse reactions on a Council for 
International Organizations of Medical Sciences (CIOMS) I Form instead of a Form FDA 3500A. Reports of 
overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or 
clinical studies must be submitted in a narrative format. Each notification to FDA must bear prominent 
identification of its contents, i.e., "IND Safety Report," and must be transmitted to the review division in 


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CONFIDENTIAL 
 
 
 Unexpected Fatal or Life-threatening Suspected Adverse Reaction Reports 
 Reporting Format or Frequency 
 Investigations of Marketed Drugs 
 Reporting Study Endpoints 
13.8 Follow-up 
 
 
the Center for Drug Evaluation and Research or in the Center for Biologics Evaluation and Research that 
has responsibility for review of the IND. Upon request from FDA, the sponsor must submit to FDA any 
additional data or information that the agency deems necessary, as soon as possible, but in no case later 
than 15 calendar days after receiving the request. 
 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse reaction 
as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt of the 
information. 
 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than that 
required under this paragraph. The sponsor may also propose and adopt a different reporting format or 
frequency if the change is agreed to in advance by the director of the FDA review division that has 
responsibility for review of the IND. 
 
A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected adverse reactions that are observed 
in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety information 
from the clinical study as prescribed by the post marketing safety reporting requirements. 
 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under Section 13.8 third bullet of this 
section. However, if a serious and unexpected adverse event occurs for which there is evidence 
suggesting a causal relationship between the drug and the event (e.g., death from anaphylaxis), the 
event must be reported under Serious and unexpected suspected adverse reaction as a serious and 
unexpected suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause 
mortality). 
 
• 
The sponsor must promptly investigate all safety information it receives. 
• 
Relevant follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., "Follow-up IND Safety Report." 
• 
If the results of a sponsor's investigation show that an adverse event not initially determined to 
be reportable under section IND safety reports of this section is so reportable, the sponsor must 
report such suspected adverse reaction in an IND safety report as soon as possible, but in no 
case later than 15 calendar days after the determination is made. 


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13.10  Reporting Adverse Events to the Responsible IRB 
14  MEASUREMENT OF EFFECT 
14.1 Antitumor Effect 
 
 
 
A safety report or other information submitted by a sponsor under this part (and any release by FDA of 
that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the 
report or information constitutes an admission that the drug caused or contributed to an adverse event. 
A sponsor need not admit, and may deny, that the report or information submitted by the sponsor 
constitutes an admission that the drug caused or contributed to an adverse event. 
The principal investigator must promptly review all information relevant to the safety of the drug 
obtained or otherwise received from foreign or domestic sources, including information derived from 
any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and 
reports of foreign commercial marketing experience for drugs that are not marketed in the United 
States. The study sponsor must notify all participating investigators of potential serious risks, from 
clinical trials or any other source, as soon as possible. 
 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board (IRB), 
the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse event that is 
determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; and 3) 
unexpected. Adverse event reports will be submitted to the IRB in accordance with the respective IRB 
procedures. 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 10 
calendar days following the sponsor-investigator’s receipt of the respective information. Adverse events 
which are 1) associated with the investigational drug or study treatment(s); 2) fatal or life-threatening; 
and 3) unexpected will be reported to the IRB within 24 hours of the Sponsor-Investigator’s receipt of 
the respective information. 
 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the relevant 
information is available. If the results of the Sponsor-Investigator’s follow-up investigation show that an 
adverse event that was initially determined to not require reporting to the IRB does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will report the adverse event to the IRB as soon as 
possible, but in no event later than 10 calendar days, after the determination was made. 
 
 
Tumor assessments may include all known or suspected disease sites as per standard of care. Imaging 
may include chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan for patients with or 
known/suspected brain metastases; bone scan and/or bone X-rays for patients with known or suspected 
bone metastases. 
13.9 Disclaimer 


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Measurements will be obtained at baseline and every 2 cycles thereafter. 
Response will be defined as per imRECIST.81 See Appendix C. 
 
This is an open label, single-arm, Simon 2-stage, Phase 2 study of the combination of 9-ING-41, a GSK-3β 
inhibitor, and retifanlimab, a PD-1 inhibitor, plus gemcitabine/nab-paclitaxel in patients with pancreatic 
cancer with no prior systemic therapy for advanced disease. 
 
To better define the Recommended phase 2 dose (RP2D) of the trial drug regimen, the phase II trial will 
be preceded by a safety lead-in of 6-9 patients. Given that published prior trials have already 
established the safety of the combination of PD-1 inhibitors plus gemcitabine/nab-paclitaxel, and also 
the safety of the combination of 9-ING-41 plus gemcitabine/nab-paclitaxel, and given the favorable 
safety profile of 9-ING-41 with no significant overlapping toxicities with either PD-1 inhibitors or 
chemotherapy, a safety lead-in phase with a dose de-escalation scheme was adopted as an alternative 
to the classic 3+3 dose escalation design. 
 
The participants enrolled in this study part will receive 9-ING-41 at 9.3mg/kg IV on days 1 and 4 of each 
week + Retifanlimab at 500mg IV on Day 1 + (gemcitabine at 1000mg/m2 + Nab-paclitaxel at 125mg/m IV 
on days 1,8, and 15) (28-day cycles). If ≥ 5/6 participants do not experience Dose limiting toxicities 
(DLTs) within the DLT window of 28 days, the study will proceed to the phase 2 part. If > 1/6 
participants experience DLTs, de-escalation to a lower dose level will follow. Participants enrolled to this 
lower dose level will receive the drug doses per the dose de-escalation scheme below. Three 
participants will be enrolled to this dose level. If 0/3 participants do not experience DLTS, the study will 
proceed to the phase 2 part. The study will be terminated if ≥ 1/3 patients experience DLTs at this lower 
dose level. The DLTs definition is detailed in section 11 under dose delays/modifications. 
 
 
Phase I Dose De-escalation Scheme 
Dose Level 
Dose of 9-ING-41 
(IV) Days 1 & 4 of 
each week 
All Cycles 
(Cycles = 28 days) 
Dose of 
Retifanlimab (IV) 
Day 1 
All Cycles 
Doses of Gemcitabine/Nab- 
Paclitaxel (IV) Days 1, 8, and 
15 
All Cycles 
Number of 
Participants 
Level 0 
9.3 mg/kg 
500 mg 
1000 mg/m2 
125 mg/m2 
6 
Level -1 
7 mg/kg 
500 mg 
1000 mg/m2 
125 mg/m2 
3 
The safety lead-in phase will be followed by a single arm phase II study to identify whether the regimen 
of 9-ING-41 plus retifanlimab plus gemcitabine/nab-paclitaxel has a better disease control rate than 
historic results with gemcitabine/nab-paclitaxel. 
15  STATISTICAL CONSIDERATIONS 


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15.1 Sample Size Justification 
15.2 Description of Statistical Methods 
 Populations for Analysis 
 
 
The safety lead-in (phase I) patients will be included into the phase 2 size calculation below. 
 
The primary endpoint is DCR, defined as: stable disease for ≥16 weeks, confirmed CR, or confirmed 
PR. 
 
A total of 32 patients are planned to be enrolled, with up to 12 patients initially enrolled in 
Stage 1, and 20 additional patients enrolled in Stage 2 based on outcomes in Stage 1. 
 
The minimum number of responders needed to continue to the next stage, is determined based on 
the Simon’s 2-stage design,82 with 80% power and one-sided significance level of 0.10. A disease 
control rate of 70% is hypothesized. A disease control rate of 50% is considered the lower 
threshold activity (null hypothesis), based on historical data.83 Based on the design elements 
specified above, up to 12 patients will be enrolled during Stage 1. If >6 patients achieve disease 
control, 20 additional patients will be enrolled during Stage 2. Otherwise, enrollment will be 
terminated. Upon completion of Stage 2, if ≥ 20 of 32 patients achieve disease control, further 
evaluation may be pursued. If the DCR is 50% or less, the probability of terminating enrollment 
after Stage 1 is 61%. 
 
As this is an open-label Phase 2 oncology study, descriptive statistics will be utilized for all safety and 
efficacy parameters. Detailed methodology for summary and statistical analyses of the data collected in 
this study will be documented in a statistical analysis plan (SAP). The SAP will be finalized before 
database lock and will describe the analysis populations to be included in the analyses, and procedures 
for accounting for missing, unused, and spurious data. This section is a summary of the planned 
statistical analyses of the study endpoints. 
In general, categorical variables will be summarized by frequency distributions (number and percentage 
of patients), continuous variables will be summarized by mean, standard deviation, median, minimum, 
maximum, and time-to-event variables will be summarized using Kaplan-Meier methods and figures for 
the estimated median time. 
All analyses, summaries, and listings will be performed using SAS software (Version 9.4 or higher). 
 
Safety Population 
The Safety Analysis Population will include all patients who receive at least one dose of 9-ING-41. The 
Safety Analysis Population will be the primary population for evaluating treatment administration, 
compliance, and safety in the study. 


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 Disposition 
 Demographics and Baseline Characteristics 
 Exposure 
 Safety Analyses 
 
 
Efficacy Population 
All patients who have received at least two cycles of 9-ING-41 therapy will be considered evaluable for 
response unless there is definitive evidence of progression or 9-ING-41 related SAE. 
 
The number of patients included in each analysis set will be summarized, along with the reason for any 
exclusions. Patients discontinuing from study treatment and/or withdrawing from study participation 
the primary reason for discontinuation will be summarized. 
 
 
Descriptive summaries of demographic and baseline characteristics will be tabulated. No statistical tests 
will be performed on these characteristics. 
 
The overall duration of study treatment administration and number of cycles initiated will be 
summarized. For each patient, the cumulative administered doses of 9-ING-41, retifanlimab, 
gemcitabine, and nab-paclitaxel will be calculated. These data will be further summarized by calculating 
the mean, standard deviation, median, and range of these values. The number and proportion of 
patients with 1 or more dose modifications (i.e., dose reduction) of each agent will be tabulated along 
with the reason for modification. 
 
All safety analyses will be performed on the Safety Analysis Population. The safety assessment will be 
based on the frequency of AEs, on the observation of clinically significant abnormalities of laboratory 
values, concomitant medication use, vital signs, ECOG performance status and physical examination 
data in the Safety Analysis Population. 
Concomitant medications will be tabulated and summarized by WHO Drug anatomical therapeutic 
chemical (ATC) and preferred term. 
 
Adverse events will be classified using the standard Medical Dictionary for Regulatory Activities 
(MedDRA) classification system version 20.0 or higher. Adverse events will be graded by the investigator 
according to the CTCAE, version 5.0. 
 
Analyses of AEs will be based on the principle of treatment emergence. Treatment-emergent AEs 
(TEAEs) are defined as having onset after study drug dosing or a sign, symptom, or diagnosis that 
worsens after study drug dosing. All tabulations of AE data will be based on TEAEs. 
TEAEs will be summarized based on the number and percentage of patients experiencing the event by 
system organ class (SOC) and preferred term (PT). The causal relationship between the occurrence of an 
AE and study intervention will be judged by the Investigator on the basis of his or her clinical judgment. 
In the event a patient experiences repeat episodes of the same AE, then the event with the highest 


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 Efficacy Analyses 
 
 
severity grade and strongest causal relationship to study intervention will be used for purposes of 
incidence tabulations. 
 
Tabular summaries will be provided, at a minimum, for: 
All TEAEs. 
TEAEs by relationship to study drug and maximum severity grade. 
TEAEs with action of study drug interrupted or dose reduced. 
TEAEs with action of study drug discontinued. 
SAEs. 
 
Hematology and serum chemistries will be summarized in a descriptive manner by calculating the mean, 
standard deviation, median, and range. Directional shifts in laboratory toxicity grades (comparing 
baseline grade with worst post-baseline grade) will be analyzed using standard shift tables, presenting 
number and proportion of patients and their maximum grade shift. For analytes without a toxicity 
grading scale, the shift table will present directional shifts from baseline to above or below the 
laboratory standard normal range using the maximum increase and/or decrease observed throughout 
the course of treatment. Vital signs will be summarized in a descriptive manner by calculating the mean, 
standard deviation, median, and range in the same manner described for laboratory values. Frequency 
statistics will be presented for ECOG performance status. 
 
Efficacy endpoints are as follows: 
Primary Endpoint: 
• 
DCR, defined as: stable disease for ≥ 16 weeks, confirmed CR, or confirmed PR according to 
imRECIST. 
 
Secondary Endpoints: 
• 
Objective response rate (ORR), defined as the percent of patients with CR or PR according to 
imRECIST. 
• 
Duration of response (DOR), defined as the time from documentation of tumor response to 
disease progression according to imRECIST 
• 
Progression-free survival (PFS), defined as the time from study enrolment until objective tumor 
progression or death 
• 
OS, defined as the time from study entry to death from any cause 
• 
Time to treatment failure (TTF) 
 
Exploratory Endpoints: 
• 
Correlation of DCR with specific molecular tumor profiles 
• 
Correlation of DCR with CA 19-9 levels 
 
The DCR will be summarized along with 95% exact binomial confidence intervals. 
Time-to-event analyses (DOR, PFS, TTF, OS) will be performed using Kaplan-Meier methods, and results 
will be summarized by the 25th, 50th (median), and 75th percentiles with associated 2-sided 95% CIs. 


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15.3 Interim Analysis 
15.4 Study Stopping Rules 
16  REGULATORY REQUIREMENTS AND DATA REPORTING 
16.1 Institutional Review Board/Ethics Committee Approval 
 
 
 
Descriptive statistics for CA19-9 data will be provided, including the number of observations, mean, 
standard deviation, median, 25th percentile (first quartile), 75th percentile (third quartile), minimum, 
and maximum for continuous variables. If this study part proceeds to Stage 2, descriptive analyses will 
be conducted to examine the relationship(s) between the DCR and CA19-9 levels and specific molecular 
tumor profiles. 
 
Data will be assessed after Stage 1 to determine whether enrollment should proceed to Stage 2 per 
rules defined in Section above with title Sample Size Justification. 
 
Taking into account participant safety considerations, study will be stopped if 30% or greater of the 
currently enrolled and registered participants experience Grade 3 or greater 9-ING-41 or Retifanlimab 
related AEs. Thus, based on a Binomial calculator: P (toxicity > 30% data from the trial) > 0.95, the 
following stopping rules will be implemented: 
 
• 
> 4 of the first 10 participants experiencing Grade 3 or greater investigational agents related AEs 
• 
> 7 of the first 15 participants experiencing Grade 3 or greater investigational agents related AEs 
• 
> 8 of the first 20 participants experiencing Grade 3 or greater investigational agents related AEs (if 
more than 20 participants are recruited in the study) 
 
 
Before trial initiation this protocol and informed consent form will be submitted for review and approval 
by the IRB of record for the clinical site. Any form of proposed advertising and advertising text for 
patient recruitment must be reviewed and approved by the IRB. In accordance with FDA 21 CFR 56 of 
the Code of Federal Regulations the Investigator will forward the Sponsor/Investigator a copy of the IRB 
approval letter for the initial approval, amendments, informed consent and any informed consent 
updates. 
 
The Investigator will be responsible for providing the Sponsor/Investigator a list of IRB members 
including profession and affiliation or a United States Department of Health and Human Services 
General Assurance number and expiration date. If neither of these is available, the IRB Chairperson must 
submit a statement indicating the members of the board responsible for the review meet the FDA and 
other appropriate regulatory requirements. The labeling for all approved trial medications should be 
submitted to the IRB for information purposes. 


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16.3 Remaining Samples 
16.4 Confidentiality 
16.5 Publication 
16.6 Compliance with Trial Registration and Results Posting Requirements 
 
 
 
The Investigator must sign the Protocol Agreement before the study is activated. The original will be 
forwarded to the Sponsor/Investigator and the Investigator must retain a copy. The completed 
Investigator’s Protocol Agreement signifies agreement to comply with all procedures outlined by this 
protocol by the Investigator. An Investigator’s Protocol Agreement must be signed when a protocol 
amendment is issued. 
 
Any samples remaining after the trial specified analyses will be stored by the collecting institution. This 
includes the original specimen collected from the participant (blood, tumor tissue) as well as derivatives 
created from the original specimen (DNA, RNA, blocks or slides). 
 
The Investigator and any other personnel involved in the trial shall not disclose or use for any purposes 
other than for the performance of this trial any data, records or other information disclosed to the 
Investigator or other trial personnel. Such information shall remain the confidential and proprietary 
property of the Sponsor/Investigator, the funders, Incyte and Actuate and shall be disclosed only to the 
Investigator or other designated trial personnel. 
 
Participant confidentiality will be ensured by using assigned site-specific participant ID numbers 
throughout the trial. 
 
The Sponsor/Investigator holds the primary responsibility for publication. 
 
Data 
The funders, Incyte and Actuate and their co-development collaborator may use the data generated 
under the Research Agreement for all purposes, subject to Institutions right to publish. 
 
Publication 
The Sponsor/Investigator shall publish the results of the approved study, subject to reasonable delay to 
allow for filing of patent applications on any inventions (as applicable). Sponsor/Investigator will 
provide the funders, Incyte and Actuate with the opportunity to review and comment on any 
publications, prior to submission. 
 
Under the terms of the FDA Modernization Act (FDAMA) and the FDA Amendments Act (FDAA) the 
Sponsor/Investigator of the trial is solely responsible for determining if the trial and results meet the 
requirement for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information 
16.2 Investigators Protocol Agreement 


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16.7 Data Management 
16.8 Data Monitoring 
 
 
posted will allow participants to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate trial 
location and trial site contact information. 
 
Web-based eCRFs will be used to collect participant data. All eCRFs and resulting data will be developed 
and maintained in a manner consistent with currently available regulations and guidance pertinent to 
the use of computerized systems in clinical trials. All users of the eCRF system will be trained prior to the 
use of the system. 
 
A Risk-Based Monitoring (RBM) approach will be used focusing on critical variables and triggered events 
and ensuring the eCRF accurately reflects data recorded in source documents. 
 
Data monitoring procedures will be carried out by UPMC Hillman Cancer Center for all participating sites 
and will be performed on a regular basis to comply with Good Clinical Practice. 
 
The study will be monitored at appropriate intervals, no less than those assigned per The University of 
Kansas Cancer Center Protocol Review and Monitoring Committee (PRMC) risk level designation, to 
assure compliance to GCP and to assess the data quality and study integrity. 
 
Interim monitoring visits (IMV) will occur at regular intervals following enrollment/registration of the 
first study participant with the frequency and duration of each visit depending on recruitment status 
and participant enrollment/registration. 
Review of the case report forms, cross-reference with source documents, review of trial related 
regulatory documents and logs will be monitored on an ongoing basis during monitoring sessions. The 
monitor will ensure that the trial is conducted according to protocol design and regulatory 
requirements. 
 
The monitor will complete a follow-up letter and provide to the Sponsor/Investigator. The letter will 
include a summary of what the site monitor reviewed and the site monitor’s statements concerning the 
significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or 
actions recommended to ensure compliance. The site will be expected to submit any Corrective and 
Preventative Action Plan (CAPA) in writing to the Sponsor/Investigator. A copy of the monitoring forms, 
follow up letter and CAPA will be kept in the site monitor’s trial file and will be followed up at the next 
monitoring session. 
 
The investigator and staff are expected to cooperate and provide all relevant study documentation in 
detail at each site visit on request for review. The study monitor will have direct access to source data 
for data verification. Data verification will be conducted by comparing the data entered into the CRFs 
with source data. 


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Investigators/Sub-investigators, regulatory, CRS management, clinical research coordinators, research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly regularly in 
disease center Data Safety Monitoring Boards (DSMB) to review and discuss study data to include, but 
not limited to, the following: 
• 
Serious adverse events 
• 
Subject safety issues 
• 
Recruitment issues 
• 
Accrual 
• 
Protocol deviations 
• 
Unanticipated problems 
• 
Breaches of confidentiality 
Minutes from the disease center DSMB meetings are available to those who are unable to participate 
during the scheduled meeting time. 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the NCI 
Common Toxicity Criteria version 5.0. All study treatment associated adverse events that are serious, at 
least possibly related, and unexpected will be reported to the IRB and the FDA. Any modifications 
necessary to ensure subject safety and decisions to continue or close the trial to accrual are also 
discussed during these meetings. If any literature becomes available which changes the risk/benefit ratio 
or suggests that conducting the trial is no longer ethical, the IRB will be notified in the form of an 
Unanticipated Problem submission and the study may be terminated. 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem submission. 
The summaries of these meetings are forwarded to the UPMC Hillman Cancer Center DSMC which also 
meets monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC progress 
reports, to include a summary of all serious adverse events and modifications, and approval will be 
submitted to the IRB at the time of renewal. 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly. 
 
Both the UPMC Hillman Cancer Center DSMC as well as the individual disease center DSMB have the 
authority to suspend accrual or further investigate treatment on any trial based on information 
discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
17  DATA SAFETY MONITORING PLAN 


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17.2 Review of Serious Adverse Event Rates 
17.3 Study Safety and Progress 
18  DATA HANDLING AND RECORD KEEPING 
18.1 Data Collection and Management Responsibilities 
18.2 Protocol Deviations 
 
 
 
Serious adverse events that require expedited reporting will be reviewed by the DSMC Chair or designee 
who will determine if immediate action is required. If determined to be necessary by the DSMC, all 
participating sites will be notified of the event and any resulting action within one working day of this 
determination. 
 
Once per month, serious adverse event rates will be monitored by the Cancer Center Quality Assurance 
team. If any study has 2 or more of the same SAE reported within one month, or more than 6 of the 
same SAE in 6 months, the DSMC will review summaries of SAEs, and discuss events in detail with the PI. 
The DSMC chair or designee determines whether further action is required. The Sponsor/Investigator, 
in collaboration with the DSMC Coordinator ensure that collaborating investigators and IRBs for all 
participating sites are notified of any resulting action. 
 
An overall assessment of toxicities as described in the protocol is reviewed at DSMC meetings. This 
review enables DSMC committee members to assess whether significant risks are occurring that would 
warrant study suspension/closure or protocol amendment. 
 
 
Electronic case report forms (eCRFs) will be completed for each participant enrolled and registered on 
this study. All CRFs will be customized per this study, in order to emphasize completeness and accuracy. 
The investigatory and trained study staff will enter and edit the data via a secure network with secure 
identification and password requirements. A complete electronic audit trail will be maintained. 
 
Source documents serve as the evidence of the existence of the participant and the data collected for 
this trial. Source documents will be the responsibility of the Investigator and will be filed at the site and 
available as needed by the Sponsor/Investigator or assigned Clinical Research Manager. 
Data captured in the eCRF is to be transcribed from source documents and must be consistent with any 
discrepancies explained and document. The medical chart and any other clinical worksheets, procedural 
reports, etc. will be the source documentation of data captured into the study database. 
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. All deviations entered into the data reporting 
17.1 Serious Adverse Events 


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18.3 Study Closure 
18.4 Study Records Retention 
Appendix A: ECOG Performance Status 
 
 
system must be reported to the DSMC. All deviations will be reported to the IRB per local reporting 
policy. 
 
Upon study closure, the Sponsor/Investigator and/or Institution will be required to certify that all safety 
reporting obligations were met. 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information 
enables the study to be fully documented and the study data to be subsequently verified. Original 
source documents supporting entries in the case report forms include but are not limited to hospital 
records and clinic charts, laboratory and pharmacy records, ECG, signed ICFs, participant diaries and 
pathology reports. All study-related documents must be retained for the maximum period required by 
applicable federal regulations and guidelines or no less than 7 years, per the University of Pittsburgh’s 
requirements. 
 
 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair.* 
GRADE 
ECOG PERFORMANCE 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 selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair 
5 
Dead 
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649-655. 
19  APPENDICES 


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Cytotoxic 
Chemotherapy 
Class 
(Mode of 
Action) 
Very Common (≥ 1/10) 
Adverse Events 
Common (≥ 1/100 to < 1/10) 
Adverse Events 
Gemcitabine 
Pyrimidine 
antimetabolite 
(inhibition of 
DNA synthesis 
and induction 
of apoptosis) 
• Leucopenia 
• Bone-marrow suppression 
• Thrombocytopenia 
• Anaemia 
• Dyspnoea 
• Vomiting 
• Nausea 
• Elevation of liver transaminases 
(AST and ALT) and alkaline 
phosphatase 
• Allergic skin rash frequently 
associated with pruritus 
• Alopecia 
• Influenza like symptoms 
• Oedema/peripheral oedema 
• Febrile neutropenia 
• Anorexia 
• Headache 
• Insomnia 
• Somnolence 
• Cough 
• Rhinitis 
• Diarrhoea 
• Stomatitis and ulceration of the 
mouth 
• Constipation 
• Increased bilirubin 
• Itching 
• Sweating 
• Back pain 
• Myalgia 
• Fever 
• Asthenia 
• Chills 
Paclitaxel 
protein bound 
(Abraxane) 
Taxane 
(inhibition 
of mitotic 
spindle 
assembly) 
• Neutropenia 
• Anaemia 
• Leukopenia 
• Thrombocytopenia 
• Lymphopenia 
• Bone marrow suppression 
• Anorexia 
• Peripheral neuropathy 
• Neuropathy 
• Hypoaesthesia 
• Paresthesia 
• Nausea 
• Diarrhoea 
• Vomiting 
• Constipation 
• Stomatitis 
• Alopecia 
• Rash 
• Arthralgia 
• Myalgia 
• Fatigue 
• Asthenia 
• Pyrexia 
• Infection 
• Urinary tract infection 
• Folliculitis 
• Upper respiratory tract infection 
• Candidiasis 
• Sinusitis 
• Febrile neutropenia 
• Dehydration 
• Decreased appetite 
• Hypokalaemia 
• Insomnia 
• Depression 
• Anxiety 
• Peripheral sensory neuropathy 
• Headache 
• Dysgeusia 
• Dizziness 
• Peripheral motor neuropathy 
• Ataxia 
• Sensory disturbance 
• Somnolence 
• Increased lacrimation 
• Blurred vision 
• Dry eye 
• Keratoconjunctivitis sicca 
• Madarosis 
• Vertigo 
Appendix B:  Mode of Action and Common Side Effects of Gemcitabine and Nab-paclitaxel 


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Cytotoxic 
Chemotherapy 
Class 
(Mode of 
Action) 
Very Common (≥ 1/10) 
Adverse Events 
Common (≥ 1/100 to < 1/10) 
Adverse Events 
• Tachycardia 
• Arrhythmia 
• Supraventricular tachycardia 
• Flushing 
• Hot flushes 
• Hypertension 
Paclitaxel 
protein bound 
(Abraxane) 
(cont’d) 
• Lymphoedema 
• Interstitial pneumonitis 
• Dyspnoea 
• Epistaxis 
• Pharyngolaryngeal pain 
• Cough 
• Rhinitis 
• Rhinorrhoea 
• Abdominal pain 
• Abdominal distension 
• Upper abdominal pain 
• Dyspepsia 
• Gastrooesophageal reflux disease 
• Oral hypoaesthesia 
• Nail disorder 
• Pruritus 
• Dry skin 
• Erythema 
• Nail pigmentation /discolouration 
• Skin hyperpigmentation 
• Onycholysis 
• Nail changes 
• Pain in extremity 
• Bone pain 
• Back pain 
• Muscle cramps 
• Limb pain 
• Peripheral oedema 
• Mucosal inflammation 
• Pain 
• Rigors 
• Oedema 
• Weakness 
• Decreased performance status 
• Chest pain 
• Influenza-like illness 
• Malaise 
• Lethargy 
• Hyperpyrexia 
• Decreased weight 
• Increased alanine aminotransferase 
• Increased aspartate 
aminotransferase 


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Cytotoxic 
Chemotherapy 
Class 
(Mode of 
Action) 
Very Common (≥ 1/10) 
Adverse Events 
Common (≥ 1/100 to < 1/10) 
Adverse Events 
• Decreased haematocrit 
• Decreased red blood cell count 
• Increased body temperature 
• Increased gamma- 
glutamyltransferase 
• Increased blood alkaline 
phosphatase 
Source of data - accessed March 2020: 
Gemcitabine: Gemcitabine Summary of Product Characteristics https://www.medicines.org.uk/emc/product/3119/smpc 
Abraxane: Abraxane Summary of Product Characteristics https://www.medicines.org.uk/emc/product/6438 


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imRECIST will be used in this study as below:84 
The article to be used can be found at the following URL: 
 
https://ascopubs.org/doi/full/10.1200/JCO.2017.75.1644 
 
imRECIST follows RECIST v1.1 conventions unless otherwise indicated: 
Criterion 
imRECIST 
Tumor burden 
Unidimensional, with other target lesion criteria (number, measurability) 
per RECIST v1.1 
New lesions 
New lesions do not categorically define PD 
Measurable new lesions incorporated into the total tumor burden 
Nonmeasurable new lesions preclude CR 
Nontarget lesions 
Nontarget progression does not define PD 
Can only contribute to defining CR (complete disappearance required) 
Radiographic 
progression 
Determined only on the basis of measurable disease 
≥20% increase in SLD (RECIST) compared with baseline/nadir 
Negated by subsequent non-PD assessment ≥4 weeks from the date first 
documented (lack of confirmation) 
Best response may occur after any number of PD assessments 
CR, complete response; imRECIST, immune-modified RECIST; PD, progression disease; RECIST, Response 
Evaluation Criteria in Solid Tumors; SLD, sum of longest diameters 
Source ref: Hodi 2018 
imRECIST timepoint response definitions: 
% Change in Sum of Diametersa 
Non-target Lesion Response 
Assessment 
Overall imRECIST Timepoint 
Response 
-100% from baselineb 
CR 
CR 
-100% from baselineb 
Non-CR or not all evaluated 
PR 
≤ -30% from baseline 
Any 
PR 
> -30% to < +20% 
Any 
SD 
Not all evaluated 
Any 
NE 
≥ +20% from nadir SLD 
Any 
PD 
CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; RECIST, Response 
Evaluation Criteria in Solid Tumors; SD, stable disease; SLD, sum of the longest diameter. 
a 
Percent change in sum of the diameters (including measurable new lesions when present). 
b 
When lymph nodes are included as target lesions, the % change in the sum of the diameters may not be 
100% even if complete response criteria are met, because a normal lymph node is defined as having a short 
axis of < 10 mm. Any pathological lymph nodes (whether target or non-target) must have reduction in short 
axis to <10 mm in order to meet the definition of CR. 
 
Source Ref: Hodi 2018 
Appendix C:  Protocol Criteria for imRECIST 


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