Conditions: Pancreatic Cancer Non-resectable Pancreatic Cancer Metastatic
Keywords: Antibody Anti-PD-1 Human monoclonal immunoglobulin antibody Immunotherapy INCMGA00012 (anti-PD-1 antibody) Anti-PD-1 antibody (MGA012) Metastatic adenosquamous pancreatic cancer Unresectable adenosquamous pancreatic cancer Adenosquamous pancreatic cancer Programmed cell death protein 1 (PD-1) Programmed death-ligand 1 (PD-L1)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 25
Healthy volunteers: no

Brief summary:
Phase 2 study to evaluate the clinical activity of INCMGA00012 in patients with Unresectable or metastatic Adenosquamous Pancreatic or Ampullary Cancer.

Detailed description:

Arms:
arm 1: All participants received the interventional study drug; INCMGA00012.

Interventions: intervention 1: INCMGA00012 (PD-1 antibody)
Intervention descriptions: intervention 1: INCMGA00012 (PD-1 antibody): 500 mg, 30 min IV infusion on Day 1 of each cycle (every 28 days)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
TITLE: A Phase II trial of retifanlimab (INCMGA00012) in patients with previously treated 
unresectable or metastatic adenosquamous pancreatic or ampullary cancer 
 
Johns Hopkins Protocol #:  
 
J19106/IRB00224849 
 
Incyte Protocol #: 
I-0012-19-07 
 
Principal Investigator 
Nilofer Azad, MD (Protocol Chair)
(JHU): 
 
 
Principal Investigator: 
Arsen Osipov, MD  
 
(Cedars) 
 
IND Sponsor: 
Nilofer Azad, MD 
 
IND #: 
 
 
 
  
 
 
 
146050 
 
ClinicalTrials.gov ID: 
 
NCT04116073 
 
Incyte Supplied Agent: 
 
Retifanlimab (INCMGA00012, MGA012; anti-PD-1 mAb) 
 
Date of Issue:                                     Original/Version 1/ September 18, 2019 
Version 2 / October 9, 2019 
Version 3 / April 9, 2020 
Version 4 / August 10, 2020 
Version 5 / September 2, 2020 
Version 6/ January 28, 2021 
Version 7/ February 8, 2021 
Version 8/ May 26, 2022 
Version 9/ July 20, 2022 
 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................4 
1.1 
Primary Objectives ...................................................................................................4 
1.2 
Secondary Objectives ...............................................................................................4 
1.3 
Exploratory Objectives ............................................................................................4 
1.4 
Study Design ............................................................................................................4 
2. 
BACKGROUND .................................................................................................................6 
2.1 
Study Disease ...........................................................................................................6 
2.2 
Rationale ..................................................................................................................6 
3. 
PATIENT SELECTION ......................................................................................................8 
3.1 
Inclusion Criteria .....................................................................................................8 
3.2 
Exclusion Criteria ....................................................................................................9 
3.3 
Inclusion of Women and Minorities ......................................................................11 
4.  
REGISTRATION ..............................................................................................................12 
4.1 
General Guidelines .................................................................................................12 
4.2 
Registration Process ...............................................................................................12 
5. 
TREATMENT PLAN ........................................................................................................12 
5.1 
Retifanlimab Administration .................................................................................12 
5.2 
General Concomitant Medication and Supportive Care Guidelines ......................13 
5.3 
Prohibited and/or Restricted Medications and Devices .........................................15 
5.4 
Other Restrictions and Precautions ........................................................................16 
5.5 
Definition of an Overdose for this Protocol ...........................................................16 
5.6 
Unacceptable Toxicity ...........................................................................................16 
5.7 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing ................................17 
5.8 
Duration of Therapy ...............................................................................................21 
5.9 
Criteria for Removal from Treatment ....................................................................21 
5.10 
End of Treatment (EOT) Visit ...............................................................................23 
5.11 
Duration of Follow-Up ..........................................................................................24 
6. 
DOSE MODIFICATION, DELAYS AND TOXICITY MANAGEMENT 
GUIDELINES FOR IMMUNE-RELATED AES .............................................................24 
6.1  
Dose Modifications ................................................................................................24 
6.2  
Dose Delays and Discontinuation ..........................................................................24 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................28 
7.1 
Definitions..............................................................................................................28 
7.2 
Assessment of Causality ........................................................................................29 
7.3 
Expectedness ..........................................................................................................30 
7.4  
Handling of Expedited Safety Reports ..................................................................30 
7.5 
Reporting................................................................................................................31 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................35 
8.1  
Retifanlimab ...........................................................................................................35 


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9. 
CORRELATIVE/SPECIAL STUDIES .............................................................................37 
9.1 
Tumor Tissue Studies ............................................................................................38 
9.2 
Peripheral Blood Mononuclear Cells (PBMCs) ....................................................38 
9.3 
Serum and Plasma Marker and Liquid biopsy/ctDNA Studies .............................38 
9.4 
Diagnostic Tissue Samples ....................................................................................38 
10. 
STUDY CALENDAR .......................................................................................................39 
11.  
STUDY ENDPOINTS .......................................................................................................42 
11.1 
Primary Endpoint ...................................................................................................42 
11.2 
Secondary Endpoints .............................................................................................42 
11.3 
Exploratory Endpoints ...........................................................................................43 
12. 
 DATA REPORTING / REGULATORY REQUIREMENTS ..........................................43 
12.1 
Data Collection and Processing .............................................................................43 
12.2 
Safety Meetings .....................................................................................................44 
12.3 
Monitoring .............................................................................................................45 
12.4 
Study Documentation.............................................................................................45 
13. 
STATISTICAL CONSIDERATIONS...............................................................................47 
13.1 
Study Design/Endpoints.........................................................................................47 
13.2 
Data and Analysis Plan ..........................................................................................48 
13.3 
Safety Analysis ......................................................................................................49 
REFERENCES ..............................................................................................................................51 
APPENDIX A: Performance Status Criteria .................................................................................52 
APPENDIX B: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ...............................................................................53 
APPENDIX C: Description of the iRECIST Process For Assessment of Disease 
Progression .........................................................................................................................56 
APPENDIX D: SAE Reporting Form ...........................................................................................61 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To determine the disease control rate (DCR) at 4 months using Response Evaluation 
Criteria for Solid Tumors (RECIST 1.1) in subjects with previously treated unresectable or 
metastatic adenosquamous pancreatic or ampullary cancer (ASQ) treated with 
retifanlimab. 
 
1.2 
Secondary Objectives 
 
1.2.1 To determine the objective response rate (ORR) using RECIST 1.1. 
1.2.2 To assess progression-free survival (PFS). 
1.2.3 To characterize the treatment-related adverse events attributable to retifanlimab. 
 
1.3 
Exploratory Objectives 
 
1.3.1 To assess overall survival (OS). 
1.3.2 To assess duration of response (DOR) and time to progression (TTP). 
1.3.3  To assess the DCR, ORR, PFS, and DOR by immune RECIST (iRECIST).  
1.3.4 To identify potential biomarker predictors of response versus resistance to 
retifanlimab and autoimmune toxicity in plasma samples. 
1.3.5 To test for predictors of response and resistance and explore changes in the tumor 
microenvironment (TME) following retifanlimab treatment in collected archived 
tissue and pre- and post-treatment biopsies via immunohistochemical studies. 
1.3.6 Measure tumor marker kinetics (CA 19-9) in subjects receiving treatment and 
correlate with OS, PFS, and best overall response. 
1.3.7 Measure tumor mutation burden, microsatellite instability, and profile genetic 
abnormalities in treated patients and correlate with response and resistance to 
therapy. 
 
1.4 
Study Design 
 
This is multi-center two stage phase 2 study to evaluate the clinical activity of retifanlimab in 
patients with unresectable or metastatic ASQ. This study will enroll subjects who have progressed 
after at least 1 prior chemotherapy regimen, have been deemed unfit for cytotoxic chemotherapy 
or who have refused cytotoxic chemotherapy. The primary endpoint of this study will be disease 
control rate (DCR) at 4 months following the start of treatment using RECIST 1.1. Up to 25 
subjects will be enrolled to target 21 evaluable patients. 
 
The study will consist of a screening period (within 21 days of first dose), a treatment period per 
the table below (Section 10), and a follow-up period. Subjects will receive a baseline biopsy and 
then be treated with the anti-PD1 antibody retifanlimab every 4 weeks. After 2 doses (8 weeks), 
subjects will be assessed for response with imaging and laboratory tests and receive another 
research biopsy. For patients with stable disease or tumor response and clinical benefit, 
retifanlimab will be continued until disease progression or unacceptable toxicity. Patients will be 
evaluated radiographically after every 2 doses of retifanlimab (every 8 weeks). Subjects will come 


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to the clinic for dosing and assessments on Day 1 of each cycle. Assessment will consist of 1) 
physician evaluation to assess symptoms of tumor response or progression and potential drug 
related toxicity, 2) cross sectional imaging (CT scans), 3) CA19-9 blood levels. Additional visits 
for safety and immune monitoring follow-up will occur per the study calendar in Section 10. 
 
No dose escalations or reductions are allowed. Enrollment will continue until 21 subjects have 
received at least one dose of retifanlimab and completed one cycle of therapy. The null hypothesis 
that the DCR 4 months following the start of treatment is 5% will be tested against a one-sided 
alternative (DCR of 30%).  
 
Complete unacceptable toxicity criteria can be found in Section 5.7. At the investigator’s 
discretion, subjects may receive additional cycles of treatment if they are clinically stable and meet 
dosing eligibility criteria. All subjects may continue in the treatment period until the criteria in 
Section 5.9 are met. Subjects may continue on treatment with radiographic disease progression if 
clinically stable and investigator believes the treatment is providing benefit. Subjects will be 
considered in the treatment period until 28 days after the last dose of study drug. 
 
Patients who have a confirmed complete response by two scans ≥ 4 weeks apart and who have 
been on retifanlimab treatment for at least 6 months may discontinue retifanlimab treatment at the 
discretion of the investigator after receiving at least two doses beyond the initial determination of 
CR.  Patients with SD, PR or CR that received at least 24 months of retifanlimab may also 
discontinue retifanlimab at the discretion of the investigator. Retifanlimab may be resumed upon 
disease recurrence or progression in these patients. Criteria and procedures for retreatment are 
described in Sections 5.9.2 and 10.0.  
 
After completion of treatment and end of treatment (EOT) visit assessments, all subjects, including 
those who did not receive treatment, will continue to be followed every three months (± 2 weeks) 
by telephone, e-mail, or optional clinic visit until death, withdrawal of consent, or closure of study.  
Subjects will also be contacted at 90 days (+14 day reporting window) from the last dose of 
therapy. Information on survival and new cancer therapies will be collected. All subjects who 
discontinue study treatment should continue to be monitored for disease status by radiologic 
imaging every two months (± 2 weeks) until: 1) the start of a new antineoplastic therapy 
(information of the new cancer therapy will be collected), 2) disease progression, 3) death, 4) 
withdrawal of consent, or 5) the close of the study, whichever occurs first.  All subjects will be 
followed after their last dose of study drug for the development of adverse events (AEs) and serious 
adverse events (SAEs) as described in Section 7.5.  
 
The primary analysis will be conducted 4 months after the last enrolled subject begins treatment, 
or all patients have either come off study or have completed 4 months on study. Information on 
survival may continue to be gathered for supplementary analyses after the completion of the 
primary analysis.  
 
 
 
 
 


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2. BACKGROUND 
 
2.1 
Study Disease 
 
Pancreatic cancer is estimated to be the second leading cause of cancer-related death in the US by 
20301. It is one of the deadliest cancers – it has the lowest 5 year survival rate of all cancer types 
with most patients being diagnosed with advanced disease with a median survival less than 1 year2. 
In unresectable and metastatic patients standard regimens only include cytotoxic chemotherapy. 
As far as single agents – gemcitabine reports a median survival of 5.65 to 6.8 months and overall 
tumor response rates are 5.4 to 9.4% 3. To achieve reasonable response rates multiagent regimens 
are utilized. The FOLFIRINOX regimen utilizes a combination of oxaliplatin, irinotecan, 
fluorouracil, and leucovorin. Response rates are 31.6% and estimated median OS is 11.1 months4. 
Another established combination regimen is nab-paclitaxel combined with gemcitabine with ORR 
of 23% and median OS of 8.5 months5. As expected these multiagent cytotoxic regimens cause 
significant toxicity and are often reserved for the fittest patients. This trial involves a targeted 
approach to treating a subtype of pancreatic adenocarcinoma with the goal to establish 
immunotherapy in this deadly disease. 
 
ASQ of the pancreas constitutes 1 to 5% of all pancreatic cancers and compared to pancreatic 
adenocarcinoma has a worse survival. ASQs have glandular and squamous histologic components 
(>30% squamous component for the diagnosis) and are considered a variant of pancreatic ductal 
adenocarcinomas. Given its rarity and aggressiveness, systemic therapy has not been well studied 
in ASQ and in practice a cytotoxic chemotherapy treatment paradigm is pursued in advanced 
disease with overall poor outcomes6. In addition, there is no data regarding the efficacy of immune 
checkpoint inhibition in ASQ pancreatic cancer, and most clinical trials have excluded them from 
eligibility. 
 
2.2 
Rationale 
 
Immunotherapies in Pancreatic Cancer 
 
Pancreatic ductal adenocarcinoma (PDAC) is considered an immune quiescent tumor and single 
agent checkpoint blockade has had an overall disappointing impact on survival (including targeting 
PD-1, PD-L1 and CTLA-4)7–9. Immunotherapeutic approaches have shown some ability to 
“reprogram” the immune tumor microenvironment (TME) within pancreatic tumors10–12. Several 
studies have also described the clinical and prognostic significance of PD-L1 expression in 
pancreatic cancer including higher expression levels predicting a poor prognosis further suggesting 
the immune TME influences pancreatic tumor behavior13–15. In an effort to identify patient 
subgroups most likely to respond to immunotherapy, the immune TME in the rare pancreas cancer 
histological subtype - adenosquamous carcinoma (ASQ) was evaluated by our team. Indeed a 
recent article reported high PD-L1 expression in a series of ASQ cases (5 of 6 surgical cases)16. 
 
Tumor microenvironment of adenosquamous pancreatic cancer subtype 


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Retifanlimab and its dose selection 


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Hypothesis 
 
Retifanlimab treatment will have clinical activity in patients with ASQ, a subtype of pancreatic 
and ampullary cancer that has a dynamic tumor microenvironment. 
 
 
3. PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
3.1.1 Age ≥18 years.   
 
3.1.2 Have histologically- or cytologically-proven adenosquamous carcinoma of the 
pancreas or ampulla by pathologic review.  Patients must have squamous 
component to be included. All pathology will be reviewed by Johns Hopkins or 
Cedars-Sinai Department of Pathology. 
 
3.1.3 Have unresectable or metastatic disease. 
 
3.1.4 Must have received (or been intolerant to, ineligible for, or refused) at least 1 prior 
line of cytotoxic chemotherapy and received no more than 2 prior systemic 
treatments. 
 
3.1.5 Presence of at least one lesion with measurable disease as defined by 10 mm in 
longest diameter for a soft tissue lesions or 15 mm in short axis for a lymph node 
by RECIST 1.1. 
 
3.1.6 Patient’s acceptance to have a tumor biopsy of an accessible lesion at baseline and 
on treatment if the lesion can be biopsied with acceptable clinical risk (as judged 
by the investigator). 
 
 
 
3.1.7 
ECOG performance status 0 or 1 (Appendix A). 
 
 
 
3.1.8 If HIV-positive, then all of the following criteria must also be met: CD4+ count ≥ 
350/μL, undetectable viral load, and receiving highly active antiretroviral therapy. 
 
 
 
3.1.9 
Life expectancy of greater than 3 months. 
 
 
 
3.1.10 Adequate organ and marrow function as defined below: 
 
 


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− 
Leukocytes 
  
 
 
 
≥ 3,000/mcL 
− 
Absolute neutrophil count 
≥ 1,500/mcL 
− 
Platelets 
 
  
 
 
 
≥ 75 × 103/uL 
− 
Hemoglobin    
 
 
 
≥ 8.0 g/dL 
− 
Total bilirubin   
 
 
 
≤ upper limit of normal (ULN) except subjects with 
Gilbert Syndrome, who can have total bilirubin < 
3.0 mg/dL 
− 
AST(SGOT) and ALT(SGPT)≤2.5 × ULN 
− 
Alkaline phosphatase  
 
≤5.0 × ULN  
− 
Creatinine  
  
 
 
 
≤1.5 × ULN or creatinine clearance (CrCl) 
≥ 40 mL/min (if using the Cockcroft-Gault formula 
below): 
 
Female CrCl = (140 - age in years) x weight in kg x 0.85 
                              72 x serum creatinine in mg/dL 
 
    Male CrCl = (140 - age in years) x weight in kg x 1.00  
                    
 
 
 
 
72 x serum creatinine in mg/dL 
 
− 
Albumin  
 
  
 
 
≥2.5 g/dL 
 
3.1.11 Women of childbearing potential (WOCBP) must have a negative serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of human chorionic 
gonadotropin [HCG]).  WOCBP is defined in Section 5.7. NOTE: If a patient has 
a positive or indeterminate serum or urine pregnancy test, then an ultrasound must 
be done to rule out pregnancy to enroll on trial. 
 
- 
WOCBP must agree to follow instructions for method(s) of contraception from 
the time of screening, through the duration of treatment with study drug plus 6 
months after the last dose of study drug. 
 
- 
Men who are sexually active with WOCBP must agree to follow instructions 
for method(s) of contraception from the time of screening, through the duration 
of treatment with study drug plus 6 months after the last dose of study drug. 
 
- 
At least one barrier method of contraception must be employed by all sexually 
active patients (male and female), regardless of other methods, to prevent the 
transfer of body fluids. 
 
3.1.12 Ability to understand and willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
 
 
3.2.1 Patients with known MSI-H / dMMR adenosquamous pancreatic or ampullary 
cancer 
 


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3.2.2 Patient has a known history or evidence of active brain/CNS metastases. Patients 
with treated brain/CNS metastases by surgery or radiation who are not on steroid 
therapy for this indication and have a stable MRI brain for 3 months are eligible for 
the study. 
 
3.2.3  Patient who has had chemotherapy, radiation, or biological cancer therapy within 
14 days prior to the first dose of study drug. With the following caveats: 28 days 
for pelvic radiotherapy, 6 months for thoracic region radiotherapy that is > 30 Gy. 
Hormonal therapy in the setting of a second, hormone-sensitive malignancy not 
thought to have impact on longevity (i.e. prostate cancer, early stage breast cancer) 
are allowed at the discretion of the principal investigator. 
 
3.2.4 Patient has received an antineoplastic investigational agent or used an 
investigational device within 28 days of the first dose of study drug. 
 
3.2.5  Patient is expected to require any other form of systemic or localized antineoplastic 
therapy while on study. Exceptions are hormonal therapy in the setting of a second, 
hormone-sensitive malignancy not thought to have impact on longevity (i.e. 
prostate cancer, early stage breast cancer) 
 
3.2.6 Patients who have had major surgery within 28 days of dosing of investigational 
agent, excluding minor procedures (dental work, skin biopsy, port placement, etc.), 
celiac plexus block, biliary stent placement, etc. 
 
3.2.7 Patients who have received a live vaccine within 28 days prior to the first dose of 
study drug.  Seasonal influenza vaccines for injection are generally killed virus and 
are allowed; however, intranasal influenza vaccines (e.g. FluMist®) are live 
attenuated vaccines and are not allowed. 
 
3.2.8 Patients with a history of prior treatment with immune checkpoint inhibitor therapy 
including anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA4, anti-OX40, and anti-
LAG-3 antibodies. 
  
3.2.9  Have used any systemic steroids within 14 days of study treatment. 
 
3.2.10  History of severe hypersensitivity reaction to any monoclonal antibody. 
 
3.2.11  Evidence of clinically significant ascites, defined as requiring a paracentesis within 
the last 3 weeks OR clinical symptoms with palpable ascites on exam 
 
3.2.12  Have clinically significant and/or malignant pleural effusion (pleural effusions that 
are not clinically significant are allowed, defined as no more than 25% fluid level 
of the corresponding hemithorax and stable fluid level [non-progressive] over at 
least 6 weeks documented radiographically). 
 
3.2.13 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 


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arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.14 History of autoimmune disease requiring systemic immunosuppression within the 
last 2 years.  
 
3.2.15 Presence of any tissue or organ allograft, regardless of need for 
immunosuppression, including corneal allograft. Patients with a history of 
allogeneic hematopoietic stem cell transplant will be excluded. 
 
3.2.16 All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue 
must have resolved to grade 1 (National Cancer Institute Common Terminology 
Criteria for Adverse Events [CTCAE], version 5.0) or baseline before 
administration of study drug. Subjects with toxicities attributed to prior anti-cancer 
therapy which are not expected to resolve and result in long-lasting sequelae, such 
as neuropathy after chemotherapy, are permitted to enroll. 
 
3.2.17 Known active HAV, HBV, or HCV infection, as defined by elevated transaminases 
with the following serology: positivity for HAV IgM antibody, anti-HCV, anti-HBc 
IgG or IgM, or HBsAg (in the absence of serology suggesting prior immunization 
or achieve immunity). Patients who are hepatitis C antibody positive may be 
enrolled if they are confirmed with negative viral load at screening. 
 
3.2.18 Patient has a pulse oximetry of <92% on room air. 
 
3.2.19 Patient is on supplemental home oxygen. 
 
3.2.20  Patient has an unhealed surgical wound or ulcer, or a bone fracture considered non-
healing. 
 
3.2.21  Patient has clinically significant heart disease (such as uncontrolled angina, 
myocardial infarction within the last 3 months or congestive heart failure of New 
York Heart Association III or IV). 
 
3.2.22 Patient is, at the time of signing informed consent, a regular user (including 
“recreational use”) of any illicit drugs or other substance abuse (including alcohol) 
that could potentially interfere with adherence to study procedures or requirements. 
 
3.2.23  Patient is unwilling or unable to follow the study schedule for any reason. 
 
 
3.2.24 Patient has history of non-infectious pneumonitis. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial.   
 


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4.  REGISTRATION  
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study at the Sidney Kimmel Comprehensive Cancer Center at 
the Johns Hopkins University by the Lead Study Coordinator. All sites should contact the Lead 
Study Coordinator to verify ongoing study enrollment. 
 
If a patient does not receive protocol therapy following registration, the patient’s registration on 
the study may be canceled.  The Study Coordinator should be notified of cancellations as soon as 
possible. 
 
4.2 
Registration Process 
 
To register a patient, the following de-identified documents should be completed and sent to the 
Lead Study Coordinator
• 
Registration Form 
• 
Signed patient consent form 
• 
Eligibility Checklist 
• 
Copy of required screening tests and scans 
 
To complete the registration process, the Lead Study Coordinator will: 
• 
Assign a patient study number 
• 
Register the patient on the study 
 
 
5. TREATMENT PLAN 
 
 
5.1 
Retifanlimab Administration 
 
Treatment will be administered on an outpatient basis.  Dosing delays are described in Section 6.2. 
No investigational or commercial agents or therapies other than retifanlimab may be administered 
with the intent to treat the subject’s malignancy.   
 
SUMMARY  DESCRIPTION 
Agent 
Premedications; Precautions 
Dose 
Route 
Cycle Length 
Retifanlimab 
No prophylactic 
pre-medication will be given 
unless indicated by previous 
experience in an individual 
subject per Section 5.2. 
500 mg 
IV infusion 
over 30 
minutes* 
28 days 
*Infusion times are approximate (-5/ +15 min) and may need to be adjusted based on subject 
tolerability. 
 


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13
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
Retifanlimab is a fully human monoclonal immunoglobulin (Ig) G44κ antibody. Subjects should 
be closely monitored for potential AEs during antibody infusion and potential AEs throughout the 
study.  
 
5.2.1 Infusion Reactions 
Infusion or hypersensitivity reactions may be observed with administration of any foreign protein.  
Premedication with 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. 
 
Guidelines for management of suspected infusion reactions are provided in Table 1. 


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Table 1: 
Guidelines for Management of Suspected Infusion Reactions 
 
Grade 
Descriptiona) 
Treatment 
Subsequent Infusions 
1 
Mild reaction; infusion interruption not indicated; 
intervention not indicated. 
Monitor vital signs closely until medically stable. 
Premedication with 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 (e.g., antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic medications indicated 
for ≤ 24 hours. 
First occurrence:  Stop infusion and initiate appropriate 
medical measures (e.g., IV fluids, antihistamines 
NSAIDS, acetaminophen/paracetamol, 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 (e.g., diphenhydramine 50 mg PO) and 
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 (i.e., not rapidly responsive to 
symptomatic medication and/or brief interruption of 
infusion); recurrence of symptoms following initial 
improvement; hospitalization indicated for other clinical 
sequelae (e.g., renal impairment, pulmonary infiltrates). 
Grade 4:  Life-threatening; pressor or ventilatory 
support indicated. 
Stop infusion and initiate appropriate medical therapy 
(e.g., IV fluids, antihistamines NSAIDS, acetaminophen/ 
paracetamol, narcotics, oxygen, pressors, epinephrine, 
corticosteroids, per institutional preferences). 
Monitor vital signs frequently until medically stable.  
Hospitalization may be indicated. 
Permanently discontinue study treatment. 
a) 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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15
 
Please refer to Section 6.2 for guidelines to manage treatment delays due to retifanlimab infusion-
related reactions. 
 
5.2.2 Retifanlimab Related Adverse Events  
 
Blocking PD-1 function may permit the emergence of auto-reactive T cells and resultant clinical 
autoimmunity. Rash/pruritus, diarrhea/colitis, pneumonitis, hepatitis, and hypothyroidism were 
drug-related, presumptive autoimmune events noted in previous anti-PD1 studies.  
 
For the purposes of this study, a retifanlimab-related AE is defined as an AE of unknown etiology, 
associated with drug exposure and is consistent with an immune phenomenon. Efforts should be 
made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes. Serological, 
immunological, and histological (biopsy) data should be used to support the diagnosis of an 
immune-mediated toxicity. Suspected retifanlimab-related AEs must be documented on an AE or 
SAE CRF. Identification and treatment of retifanlimab-related AEs can be found in NCCN’s 
guidelines for the management of immunotherapy-related toxicities. Additional guidance can be 
found in the Retifanlimab Investigator’s Brochures (IB). 
 
5.3 
Prohibited and/or Restricted Medications and Devices 
 
The following therapies or devices are not permitted during the treatment period (if administered, 
the subject may be removed from the study): 
 
• 
Immunosuppressive agents unless they are utilized to treat an AE or as specified in 
Sections 5.2 and 5.6. 
• 
Any non-study anticancer chemotherapy or immunotherapy (approved or 
investigational) with the exception of subjects in the survival period of the study, with 
the exception of hormonal therapy in the setting of a second, hormone-sensitive 
malignancy not thought to have impact on longevity (i.e. prostate cancer, early stage 
breast cancer) 
• 
Any major surgery or surgical procedure; if required must be discussed with the IND 
Sponsor to determine if it is appropriate for the subject to continue study treatment 
• 
Another investigational agent 
• 
Live vaccines (examples of live vaccines include, but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid [oral] vaccine). 
Seasonal influenza vaccines for injection are generally killed virus vaccines and are 
allowed. However, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
•  Palliative (limited-field) radiation therapy is permitted, but only for pain control and 
with approval by the IND Sponsor. 
• 
Systemically active steroids can be used but should be reported to the IND Sponsor. 
Steroid treatment should be completed at least 14 days prior to resuming study-related 
treatments. Patients requiring adrenal replacement steroid doses < 10 mg daily 
prednisone equivalent (in the absence of active autoimmune disease) may resume 
treatment if approved by the IND Sponsor.  
• 
Use of growth factors unless prior discussion and agreement with the IND Sponsor. 
• 
Use of allergen hyposensitization therapy 


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5.4 
Other Restrictions and Precautions 
 
Palliative (limited-field) radiation therapy is permitted, but only for pain control to sites present at 
baseline and with approval by the IND Sponsor. 
 
Medical marijuana for pain or symptom control will be permitted. 
 
5.5 
Definition of an Overdose for this Protocol 
 
Overdose of retifanlimab is defined as: 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as SAEs (see Section 7.5.1 for reporting details). Appropriate supportive treatment should 
be provided if clinically indicated. 
 
All reports of overdose with and without an AE must be reported within 24 hours to the IND 
Sponsor and Incyte. Incyte contact information can be found in Section 7.5.1. 
5.6 
Unacceptable Toxicity 
 
Toxicities are defined in the Investigator’s Brochure and Table 4. Unacceptable toxicities for 
this protocol that will trigger additional review described below are defined as: 
 
1. Any treatment-related > grade 3 AEs.  Exceptions include: 
 
• Asymptomatic laboratory abnormalities (AST, ALT, and bilirubin abnormalities requiring 
discontinuation as per Table 4 will be considered unacceptable toxicity) 
• Grade 3 fatigue 
• Grade 3 dermatologic AEs that are considered mild in severity but only considered grade 
3 because of >30% body surface involvement including pruritus   
• Diarrhea, nausea, or vomiting that resolves to < grade 3 within 48 hours of maximal 
intervention 
• Grade 3-4 hyperglycemia or grade 3 endocrinopathies where symptoms are controlled on 
hormone replacement therapy 
 
2. Treatment related blood bilirubin > 5 x ULN or concurrent blood bilirubin > 2 x ULN and AST 
or ALT > 3 x ULN 
 
3. Treatment related eye pain ≥ grade 2 or reduction of visual acuity that does not respond to 
topical therapy and does not improve to ≤ grade 1 severity within 2 weeks of starting therapy, 
or requires systemic therapy is an unacceptable toxicity. 
 
Unexpected Grade 3 or greater laboratory abnormalities should be repeated within 24-72 hours if 
clinically indicated and monitored as necessary to determine if event meets toxicity criteria.  
 


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The proportion of treated subjects with unacceptable toxicity will be monitored using a Bayesian 
stopping guideline.  A Beta (1.5, 5.5) prior, representing a toxicity rate of 21%, a slightly 
conservative estimate, was used in the development of our guidelines.  We will halt the accrual 
and re-evaluate the safety if the posterior probability that the toxicity rate exceeds the 33% 
boundary is greater than 60%.  Toxicity will be monitored continuously. Table 2 summarizes the 
stopping boundaries for unacceptable toxicities. 
 
Table 2.  The number of unacceptable toxicities needed to trigger stopping guidelines throughout 
the course of the study.   
 
Number of Subjects 
Number of unacceptable toxicities 
needed to trigger  re-evaluation 
2 
2 
3-5 
3 
6-7 
4 
5-10 
5 
11-13 
6 
14-16 
7 
17-19 
8 
20-22 
9 
23-25 
10 
 
Table 3.  Probability of triggering a re-evaluation based upon the proportion with an unacceptable 
toxicity for a range of true toxicity probabilities. 
 
True probability of 
unacceptable toxicity 
Probability of triggering 
stopping guidelines 
5% 
0.4% 
10% 
1.8% 
15% 
6% 
20% 
14% 
25% 
27.5% 
30% 
44.9% 
35% 
62.3% 
40% 
78% 
45% 
89.2% 
 
5.7 
WOCBP, Contraception, Use in Pregnancy, Use in Nursing 
 
A WOCBP is defined as any female who has experienced menarche and who has not undergone 
surgical sterilization (hysterectomy or bilateral oophorectomy) and is not postmenopausal. 
Menopause is defined clinically as 12 months of amenorrhea in a woman over age 45 years in the 
absence of other biological or physiological causes. In addition, women under the age of 62 years 
must have a documented serum follicle stimulating hormone (FSH) level > 40mIU/mL to confirm 
menopause. 
 


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Women treated with hormone replacement therapy (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The 
duration of the washout period is a function of the type of HRT used. The duration of the washout 
period below are suggested guidelines and the investigators should use their judgment in checking 
serum FSH levels. If the serum FSH level is >40 mIU/ml at any time during the washout period, 
the woman can be considered postmenopausal: 
 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
 
5.7.1 Contraception 
 
One of the highly effective methods of contraception listed below is required during study 
duration and until the end of relevant systemic exposure, defined as 6 months after the end 
of study treatment.* 
 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a  
• Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
− oral  
− intravaginal  
− transdermal  
• Progestogen-only hormonal contraception associated with inhibition of ovulationb  
− oral  
− injectable  
Highly Effective Methods That Are User Independent  
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
• Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c 
• Intrauterine device (IUD)c 
• Bilateral tubal occlusion 
• Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  


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• Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant. 
• It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
• WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 10.  
• Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be 
consistent with local regulations regarding the use of contraceptive methods for participants 
participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is 
sufficient evidence that the IMP and other study medications will not alter hormonal exposures such 
that contraception would be ineffective or result in increased exposures that could be potentially 
hazardous.  In this case, alternative methods of contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of 
contraception in the absence of definitive drug interaction studies when hormone exposures from 
intrauterine devices do not alter contraception effectiveness 
 
Unacceptable Methods of Contraception* 
• Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal Sponge with spermicide 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
• Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
• Withdrawal (coitus interruptus). 
• Spermicide only 
• Lactation amenorrhea method (LAM) 
 
* Local laws and regulations may require use of alternative and/or additional 
contraception methods. 


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CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH 
PARTNER(S) OF CHILD BEARING POTENTIAL. 
 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to the following during the treatment and until the end of relevant systemic 
exposure. 
• Inform any and all partner(s) of their participation in a clinical drug study and the need 
to comply with contraception instructions as directed by the investigator. 
• Male participants are required to use a condom for study duration and until end of 
relevant systemic exposure defined as 6 months after the end of study treatment. 
• Female partners of males participating in the study to consider use of effective methods 
of contraception until the end of relevant systemic exposure, defined as 6 months after 
the end of treatment in the male participant. 
• Male participants with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile vaginal intercourse or use a male condom during each episode of 
penile penetration during the treatment and until 6 months after the end of study 
treatment.  
• Refrain from donating sperm for the duration of the study treatment and until 6 months 
after the end of study treatment. 
 
5.7.2 Use in Pregnancy 
 
The investigational agents used in this protocol may have adverse effects on a fetus; 
therefore, women with a positive pregnancy test at screening will not be eligible for 
enrollment.  If a subject inadvertently becomes pregnant while on treatment, the subject 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.   
 
Pregnancy in female subjects or in partners of male subjects throughout the study or within 
6 months of completing treatment should be reported initially as a serious adverse event 
(see reporting procedures in Section 7.5.6) by the investigator within 24 hours of learning 
of its occurrence. Pregnancy information must be reported on the Pregnancy Form. 
 
Protocol required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated.  
 
Follow-up information regarding the course of the pregnancy, including any voluntary or 
spontaneous termination, perinatal and neonatal outcome and where applicable, offspring 
information must be reported on the Pregnancy Follow-up Form. Pregnancy outcomes 
must also be collected for the female partners of any males in this trial. Consent to report 
information regarding these pregnancy outcomes should be obtained from the female 
partner.  
 
 


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5.7.3 Use in Nursing Women 
 
Since many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for 
enrollment. 
 
5.7.4 All Subjects (Male and Female) 
 
All sexually active patients must use at least a barrier method (i.e., condom) to prevent 
transmission of body fluids.  
 
5.8 
Duration of Therapy 
 
Subjects who are clinically stable and meet dosing requirements (per Section 6.2) may continue 
to receive treatment until the criteria in Section 5.9 are met.  
 
5.9 
Criteria for Removal from Treatment 
 
The reason for study removal and the date the subject was removed will be documented in the 
CRF.  
A subject will be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for participation in the study. 
 
A subject must be discontinued from treatment (but may continue to be monitored in the post-
treatment follow-up portion of the trial) for any of the following reasons: 
 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment, 
•  Intercurrent illness that prevents further administration of treatment, 
•  Unacceptable toxicity (see Section 5.6). Exceptions for treatment discontinuation are 
listed in Section 5.6, 
•  Disease progression as defined in Section 5.9.1, 
•  Severe or life-threatening retifanlimab-related AE(s) (see Section 6.2), 
•  Need for >2 dose delays due to the same drug-related toxicity as per the dose delay 
guidelines (see Section 6.2), 
•  If, in the opinion of the Investigator, a change or temporal or permanent discontinuation 
of therapy would be in the best interest of the subject, 
•  Noncompliance with trial treatment or procedure requirements, 
•  Subject is lost to follow-up, or 
• Subject becomes pregnant. 
 
 
 


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A subject may, at the discretion of the Investigator, be discontinued from treatment (but may 
continue to be monitored in the post-treatment follow-up portion of the trial) if they have: 
 
• Completed 6 months of treatment with retifanlimab and has a complete response (CR) 
by at least two scans ≥ 4 weeks apart AND have received at least two doses of 
retifanlimab beyond the initial determination of CR. 
• Completed 24 months of treatment with retifanlimab and has a response of stable 
disease, partial response, or complete response at the time of discontinuation 
 
Note: time on treatment is calculated from the date of first dose. 
 
5.9.1 Disease Progression 
 
Retifanlimab is expected to trigger immune-mediated responses, which require activation 
of the immune system prior to the observation of clinical responses. Such immune 
activation may take weeks to months to be evident. Some subjects may have objective 
volume increase of tumor lesions or other disease parameters within weeks following the 
start of immunotherapy. Such subjects may not have had sufficient time to develop the 
required immune activation or, in some subjects, tumor volume or other disease parameter 
increases may represent infiltration of lymphocytes into the original tumor. In conventional 
studies, such tumor volume or relevant laboratory parameter increases during the first 2-4 
months of the study would constitute disease progression and lead to discontinuation of 
imaging to detect response, thus disregarding the potential for subsequent immune-
mediated clinical response. 
 
Subjects will be permitted to continue with treatment beyond initial RECIST 1.1 defined 
PD as long as they meet the following criteria: 
• 
Investigator-assesses that the patient is not clinically deteriorating, and 
• 
Subject is tolerating study drug. 
 
The assessment of lack of deterioration should take into account whether the subject is 
clinically stable or if they unlikely to receive further benefit from continued treatment. The 
following criteria need to be taken into consideration: 
• 
No significant decline in ECOG performance status. 
• 
Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
 
All decisions to continue treatment beyond PD must be discussed with the IND Sponsor 
and documented in the study records. 
 
Tumor assessments will be made using RECIST 1.1 (Appendix B) and iRECIST 
(Appendix C).  
 
5.9.2 Retreatment with Retifanlimab  
 
Patients who stop retifanlimab with SD or better may be eligible for resume therapy if they 
progress after stopping retifanlimab and they meet the following criteria: 


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EITHER 
• 
Stopped initial treatment with retifanlimab after attaining an investigator 
determined confirmed CR according to RECIST 1.1, was treated for at least 6 
months with retifanlimab, and received at least two doses of retifanlimab beyond 
the date when the initial CR was declared. 
 
OR 
• 
Subject had SD, PR or CR and stopped retifanlimab treatment after 24 months of 
study drug for reasons other than disease progression or intolerability 
 
AND 
• 
Experienced an investigator-determined confirmed radiographic or clinical disease 
progression after stopping their initial treatment with retifanlimab 
• 
Did not receive any anti-cancer treatment since the last dose of retifanlimab  
• 
Have an ECOG performance status of 0-2 
• 
Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 3 days prior to receiving retreatment with study medication. 
• 
Female subjects of childbearing potential should be willing to follow instructions 
for method(s) of contraception or abstain from heterosexual activity for the course 
of the study through 6 months after the last dose of study drug. 
• 
Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 6 months after the last dose of study 
therapy. 
• 
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator. 
 
Subjects who restart treatment should resume at the next cycle which they would have 
received prior to discontinuation. Study visit requirements are outlined in the Study 
Calendar (Section 10.0). 
 
5.10 
End of Treatment (EOT) Visit 
 
All subjects will return to the study site 28 days (± 7 days) after the final study treatment for an 
EOT evaluation. Procedures and assessments performed at these visits and beyond should follow 
the respective guidelines described in Sections 5.11 and 10.0 as appropriate.  
 
If the EOT visit occurs early (e.g., 1 week prior to the expected visit as protocol allows) or if the 
patient cannot return due to disease progression, an assessment for AEs should be made by telephone 
or email on day 28 (± 1 day) after last dose of study drug and documented.  
 
For subjects who discontinue study drug after 24 months of SD or better or with a CR after 6 
months (see Section 5.9.2), the EOT visit should be completed as described above.  If a patient 
later restarts study drug, they should have a second EOT visit performed when they eventually 
discontinue study drug for a second time. 
 


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5.11 
Duration of Follow-Up 
 
5.12.1 Safety Follow-up 
 
Subjects who discontinue treatment should be contacted by telephone or email at 90 days 
(+14 day reporting window) from their last dose of study drug or within 7 days before 
initiation of a new antineoplastic treatment (whichever comes first) to assess for treatment 
related toxicities. In addition, all SAEs occurring during this time should be reported as 
well.  
 
Subjects who are discontinued from the study treatment due to an unacceptable drug-
related AE will be monitored for safety until the resolution of the AE to ≤ grade 1 or 
stabilization or until initiation of a new therapy for their cancer, whichever occurs first. 
 
5.12.2 Clinical Follow-up 
 
Subjects who discontinue treatment without disease progression should continue to be 
monitored for disease status by radiologic imaging. Disease monitoring should continue to 
be assessed every two months (± 2 weeks) for the first 2 years and then every 3 months (± 
4 weeks) until: 1) start of a new antineoplastic therapy (information of the new cancer 
therapy will be collected), 2) disease progression, 3) death, 4) withdrawal of consent, or 5) 
study closure, whichever occurs first. 
 
5.12.3 Survival Follow-up  
 
Subjects who discontinue treatment and have disease progression will enter the survival 
follow-up portion of the trial. Subjects should be contacted every 12 weeks (± 2 weeks) to 
monitor overall survival. Information of other cancer therapies after discontinuation from 
the study treatment will be collected as well. 
 
 
 
6. DOSE MODIFICATION, DELAYS AND TOXICITY MANAGEMENT GUIDELINES 
FOR IMMUNE-RELATED AES 
 
6.1  
Dose Modifications 
 
Subjects will be monitored continuously for AEs while on study drug. Subjects will be instructed 
to notify their physician immediately for any and all AEs. Dose escalations or reductions of 
retifanlimab will not be allowed.  
 
6.2  
Dose Delays and Discontinuation 
 
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, 


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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 (e.g., pembrolizumab, nivolumab) are detailed in Table 4 (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 (Brahmer et al 2018, Haanen et al 
2017). 
 
 


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7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
This study will use the descriptions and grading scales found in the revised CTCAE version 5.0 
for AE reporting that can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
Information about all AEs, whether volunteered by the subject, discovered by investigator 
questioning, or detected through physical examination, laboratory test or other means, will be 
collected, recorded, and followed as appropriate.  
 
7.1 
Definitions 
 
7.1.1 Adverse Event  
 
An AE is defined as any undesirable sign, symptom or medical condition occurring after 
starting the study drug (or therapy) even if the event is not considered to be related to the 
study. An undesirable medical condition can be symptoms (e.g., nausea, chest pain), signs 
(e.g., tachycardia, enlarged liver) or the abnormal results of an investigation (e.g., 
laboratory findings, electrocardiogram). Medical conditions/diseases present before 
starting the study treatment are only considered AEs if they worsen after starting the study 
treatment (any procedures specified in the protocol). New medical conditions / diseases 
occurring before starting the study treatment but after signing the informed consent form 
will not be recorded as AEs. Additionally, expected progression of the disease being 
studied will not be recorded as an adverse event.  
 
Laboratory abnormalities: Laboratory abnormalities present at the screening visit will 
be recorded as pre-treatment signs and symptoms. After study treatment administration, all 
grade 3 and 4 clinical laboratory results that represent an increase in severity from baseline 
will be reported as AEs. A grade 1 or 2 clinical laboratory abnormality should be reported 
as an AE only if it is considered clinically significant by the investigator (induce clinical 
signs or symptoms or require therapy), meets the definition of an SAE, or requires the 
participant to have study drug discontinued or interrupted.. 
 
7.1.2 Serious Adverse Event  
 
A SAE is an undesirable sign, symptom or medical condition which:  
• 
Results in death  
• 
Is life threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• 
Requires inpatient hospitalization or causes prolongation of existing hospitalization 
(see note below for exceptions) for >24 hours 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect (note: reports of congenital anomalies/birth 
defects must also be reported on the Pregnancy Form)  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 


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29
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 
• 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
• 
Is a new cancer (that is not a condition of the study) 
• 
Is associated with an overdose 
• 
Is a pregnancy or pregnancy outcome of spontaneous abortion, missed abortion, 
benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage, or stillbirth. 
 
Events not considered to be SAEs are hospitalizations for:  
• 
Admissions as per protocol for a planned medical/surgical procedure or to facilitate 
a procedure 
• 
Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy)  
• 
Medical/surgical admission for purpose other than remedying ill health state and 
was planned prior to entry into the study. Appropriate documentation is required in 
these cases.  
• 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, care-giver respite, family circumstances, administrative). 
• 
Admissions for monitoring of treatment-related infusion reactions that do not 
otherwise meet the criteria for a SAE. 
 
7.2 
Assessment of Causality 
 
The relationship of an AE to the administration of the study drug is to be assessed by the 
investigator according to the following definitions:  
 
• No (unrelated, not related, no relation):  The time course between the administration of 
study drug and the occurrence or worsening of the adverse event rules out a causal 
relationship and another cause (concomitant drugs, therapies, complications, etc.) is 
suspected.  
 
• Yes (related): The time course between the administration of study drug and the occurrence 
or worsening of the adverse event is consistent with a causal relationship and no other cause 
(concomitant drugs, therapies, complications, etc.) can be identified.  
 
The following factors should also be considered:  
• The temporal sequence from study drug administration - The event should occur after the 
study drug is given. The length of time from study drug exposure to event should be 
evaluated in the clinical context of the event.  


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• Underlying, concomitant, intercurrent diseases - Each report should be evaluated in the 
context of the natural history and course of the disease being treated and any other disease 
the subject may have.  
• Concomitant medication - The other medications the subject is taking or the treatment the 
subject receives should be examined to determine whether any of them might be recognized 
to cause the event in question.  
• Known response pattern for this class of study drug - Clinical and/or preclinical data may 
indicate whether a particular response is likely to be a class effect.  
• Exposure to physical and/or mental stresses - The exposure to stress might induce adverse 
changes in the recipient and provide a logical and better explanation for the event.  
• The pharmacology and pharmacokinetics of the study drug - The known pharmacologic 
properties (absorption, distribution, metabolism, and excretion) of the study drug should 
be considered.  
 
Assessment of Grade: 
 
The investigator will make an assessment of grade for each AE and SAE reported during the study, 
which will be recorded in the CRF. The assessment will be based on the National Cancer Institute’s 
CTCAE (Version 5.0) and graded as shown below: 
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living 
• 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• 
Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
 
Any AE that changes in grade during its course will be recorded in the CRF at the highest level 
experienced by the subject. 
 
7.3 
Expectedness 
 
Unexpected AE: An AE, which varies in nature, intensity or frequency from information on the 
investigational drug/agent provided in the product IB, package insert or safety reports. Any AE 
that is not included in the IB, package insert, safety reports or informed consent is considered 
“unexpected”. An expected AE with a fatal outcome should be considered unexpected unless the 
IB specifically states that the AE might be associated with a fatal outcome. 
 
Expected (known) AE: An AE, which has been reported in the IB, package insert or safety reports. 
An AE is considered “expected”, only if it is included in the IB document as a risk. 
 
7.4  
Handling of Expedited Safety Reports 
 
In accordance with local regulations, the IND Sponsor (or designee) and Incyte will notify 


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investigators of all SAEs that are unexpected (i.e., not previously described in the IB), and related 
to retifanlimab. An event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of a 
SUSAR Report that is to be e-mailed to the investigators and the study coordinators. Upon 
receiving such notices, the investigator must review and retain the notice with the IB and where 
required by local regulations, the investigator will submit the SUSAR to the appropriate IRB. The 
investigator and IRB will determine if the informed consent requires revision. The investigator 
should also comply with the IRB procedures for reporting any other safety information. 
 
7.5 
Reporting 
 
7.5.1  Adverse Events and Serious Adverse Events 
 
All AEs (both related and unrelated) will be captured on the appropriate study-specific 
CRFs. All AEs experienced by subjects will be collected and reported from the first dose 
of the investigational agent, throughout the study, and will be followed for 28 days after 
last dose of study drug unless related to the investigational agent.   
 
Subjects who experience a grade 2 or higher retifanlimab-related AE should be discussed 
with the IND Sponsor.  
 
Report AEs to the IND Sponsor within 24 hours once identified as an unacceptable 
toxicity (defined in Section 5.6).   
 
Nilofer Azad: 
 
All 
adverse 
event 
information 
is 
reported 
to 
Incyte 
on 
the 
Principal 
Investigator’s/Institution’s Adverse Event Report Form, or a CIOMS-I or MedWatch Form 
FDA 3500A, or on an Adverse Event Report Form which may be provided by Incyte upon 
request. The Principal Investigator does not provide medical records (e.g., discharge 
summary) to Incyte, unless specifically requested 
 
All SAEs (including deaths) occurring from the first dose of the study drug through 90 
days (+ 14 day reporting window) after the last dose of retifanlimab or within 7 days prior 
to initiation of a new antineoplastic treatment (whichever comes first) will be collected and 
reported. All SAEs (including deaths) that the investigator considers related to study drug 
occurring after the follow-up period must be reported. 
 
Subjects who have an ongoing AE/SAE related to the study procedures and/or 
medication(s) may continue to be periodically contacted by a member of the study staff 
until the event is resolved or determined to be irreversible by the investigator. 
 
All SAEs will be reported promptly to the IND Sponsor and Incyte within 24 hours 
of initial notification of the SAE using the form found in Appendix D. SAE reports 
should be for a single subject. SAE forms should be sent with a cover sheet and any 
additional attachments. Medical records (e.g., discharge summary) should not be provided 
to Incyte, unless specifically requested. If this falls on a weekend or holiday, an email 


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32
notification is acceptable but must be followed by an SAE reporting form on the next 
business day. 
 
SAE reports and any other relevant safety information are to be sent to:  
 
Nilofer Azad: 
Incyte:  
 
7.5.2 Follow-up of Adverse Events and Serious Adverse Events 
 
After the initial AE or SAE report, the investigator is required to proactively follow each 
subject and provide further information to the safety department in regards to the subject’s 
condition. 
 
All AE(s) and SAE(s) will be followed until: 
• 
Resolution 
• 
The condition stabilizes 
• 
The event is otherwise explained 
• 
The subject is lost to follow-up 
• 
Death 
 
As soon as relevant information is available, a follow-up SAE report will be submitted to 
the IND Sponsor and Incyte (per Section 7.5.9). 
 
7.5.3 Reconciliation of SAEs 
 
The IND Sponsor (or designee) will reconcile the clinical database SAE cases (case level 
only) transmitted to the IND Sponsor and Incyte. Frequency of reconciliation should be 
approximately every 3 months and prior to the database lock or final data summary. Incyte 
will email, upon request from the Investigator, the reconciliation report. Requests for 
reconciliation should be sent to 
. The data elements listed on 
the Incyte reconciliation report will be used for case identification purposes. If the Sponsor 
determines a case was not transmitted to the IND Sponsor and Incyte, the case should be 
sent immediately to the IND Sponsor and Incyte. 
 
7.5.4 Overdose 
 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as SAEs. 
 
7.5.5 Potential Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of potential 
DILIs, meeting the defined criteria, must be reported as SAEs under the seriousness 
category checked as ‘other medically important event’. Potential drug induced liver injury 


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33
is defined as: 
 
1) ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
3) No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic 
or acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
7.5.6 Pregnancy Reporting 
 
Although pregnancy and lactation are not always serious by regulatory definition, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them) that occurs during the trial or within 6 months 
of completing the trial. This also includes the pregnancy of a male subject's female partner 
who has provided written consent to provide information regarding pregnancy, which 
occurs during the trial or within 6 months of completing the trial.   
 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to the 
IND Sponsor 
 and Incyte (
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” or equivalent must be completed 
and emailed to the IND Sponsor 
within 30 days after 
delivery, so that the IND Sponsor and Incyte are provided with information regarding the 
outcome of the pregnancy.  If the pregnancy results in any event(s) 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. 
 
7.5.7  Institutional Review Board (IRB)  
 
Serious adverse events will be reported to the IRB per institutional standards. Upon 
receipt, follow-up information will be given to the IRB (as soon as relevant information 
is available) per institutional standards. 
 
7.5.8  Food and Drug Administration (FDA) 
 
All reporting to the FDA will be completed by the IND Sponsor. 
 
7.5.8.1 Expedited IND Safety Reports 
 
7 Calendar-Day Telephone or Fax Report:   
The IND Sponsor is required to notify the FDA of any fatal or life-threatening 
adverse event that is unexpected and assessed by the investigator to be possibly 


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34
related to the investigational agent.  Such reports are to be emailed to the 
regulatory project manager and faxed (301-796-9845) to the FDA within 7 
calendar days of first learning of the event. Follow-up information will be 
submitted to the FDA as soon as relevant information is available.  
 
15 Calendar-Day Written Report:   
The IND Sponsor is required to notify the FDA of any SAE that is unexpected 
and related to the investigational agent in a written IND Safety Report.   
 
Written IND Safety Reports should include an Analysis of Similar Events in 
accordance with regulation 21 CFR § 312.32.  All safety reports previously filed 
with the IND concerning similar events should be analyzed.  The new report 
should contain comments on the significance of the new event in light of the 
previous, similar reports.   
 
Written IND safety reports with Analysis of Similar Events are to be submitted 
to the FDA within 15 calendar days of first learning of the event. Follow-up 
information will be submitted to the FDA as soon as relevant information is 
available. 
 
7.5.8.2 IND Annual Reports 
 
In accordance with the regulation 21 CFR § 312.33, the IND Sponsor shall within 
60 days of the anniversary date that the IND went into effect submit a brief report 
of the adverse events and progress of the investigation.  Please refer to Code of 
Federal Regulations, 21 CFR § 312.33 for a list of the elements required for the 
annual report.  All IND annual reports will be submitted to the FDA by the IND 
Sponsor. 
 
 


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8. PHARMACEUTICAL INFORMATION 
8.1.3 Description 


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36
 
8.1.10 Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Incyte or designee, the amount dispensed to, and returned by the subjects 
and the amount remaining at the conclusion of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
 
 


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9. CORRELATIVE/SPECIAL STUDIES 
 
We have incorporated numerous correlative studies that will allow us to better understand ASQ 
anti-PD-1 response and resistance mechanisms. We plan to test tissue pre and post treatment for 
markers of immunogenicity and susceptibility to immunotherapy. This will be accomplished 
through immunohistochemical and multiplex immunofluorescence staining studies of tumor cells 
and TME immune cells and next-generation sequencing of pre and post treatment samples. These 
results will be correlated with response or resistance to retifanlimab. 
 
We plan to explore: 
• Immunosuppressive molecules and immune checkpoint proteins (PD-L1, PD-1, LAG3, TIM3, 
VISTA and IDO).  
• Immune infiltrating pro and anti-inflammatory cells (T cell subsets via IHC for CD4+, CD8+, 
CD20, FOXP3, and CD68, myeloid-derived suppressor cells, dendritic cells etc.).  
• Gene signatures of tumor and immune cells including molecular mutational status and tumor 
mutation burden.  
• Further sequencing of T cell receptor (TCR) genes to evaluate infiltrating T cell repertoire. 
 
Several CLIA-certified laboratories now offer molecular profiling of cancer specimens in 
commercial and noncommercial settings and provide these results to patients and their physicians 
(e.g. Foundation Medicine, PGDx, Michigan Center for Translational Pathology, or JHU CLIA 
Laboratories). It is possible, therefore, that some of our research analyses will be conducted in 
these CLIA-certified environments.  If tissue or cells are evaluated with next generation 
sequencing strategies to provide a molecular profile of individual cancer specimens in a CLIA-
certified facility, these results will be made available to the patient and their physician.  Patient 
confidentiality will be maintained, and the patient’s identity will not be publicly linked to any 
study results.  Researchers may use the data set generated in the CLIA assay setting to study genetic 
alterations across a large number of genes important in cancer. Germline mutations are only 
identified in punitive cancer genes. Researchers will use the data set for exploratory research to 
study cancer cell heterogeneity. Some of the sequencing data obtained from the NGS strategies 
will be uploaded to government sponsored databases, such as GEO and dbGAP.  The results of the 
research studies may be published but subjects will not be identified in any publication. 
 
If a germline alteration of clinical importance (as judged by the Investigator) to the subject and his 
or her family members is identified by a CLIA-certified test in the course of this analysis, attempts 
will be made in writing to contact the subject and/or family members for genetic counseling 
referral. Results from the sequencing studies will not be released to the patients.  
 
For patients whose tumors have not been sent to CLIA-certified sequencing laboratories, 
sequencing on archival tissue or biopsy tissue collected for the studies are for research purposes 
only, and the sequencing studies are not using a clinically validated platform and will be performed 
as batched analysis for research rather than real time. Accordingly, they will not be released to the 
patients. 
 
 


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9.1 
Tumor Tissue Studies 
 
Tumor biopsies will be collected (if a subject’s tumor is thought to be reasonably safe and easy to 
biopsy) at baseline and at Cycle 3 (4-6 cores per time point). Fine needle aspiration will not be 
acceptable. Additional optional biopsies may be obtained later in the course of study treatment.  
 
Attempts will be made to obtain archived tissue samples from all subjects.  Archived FNA biopsy 
samples do not contain sufficient tissue and will not be collected.   
 
Detailed instructions for tissue collection, processing, storage, and shipment will be provided in 
the Laboratory Manual. 
 
9.2 
Peripheral Blood Mononuclear Cells (PBMCs) 
 
Whole blood for isolation of PBMCs will be collected prior to dosing on Day 1 of Cycles 1, 2, 3, 
and 5 as well at the time of progression or off-study. Pre- and post-treatment changes in PBMCs 
including effector, helper, and regulatory T cells, NK cells, and macrophages through cell 
phenotyping analysis and gene expression profiling will be measured. Detailed instructions for 
collection, processing, storage, and shipping are provided in the Laboratory Manual. 
9.3 
Serum and Plasma Marker and Liquid biopsy/ctDNA Studies 
 
Sera will be collected at the same time points as whole blood sampling, as described above. 
Potential therapeutic targets, biomarkers, and predictors of response and autoimmune toxicity will 
be evaluated. Detailed instructions for collection, processing, storage, and shipping are provided 
in the Laboratory Manual. 
 
9.4 
Diagnostic Tissue Samples 
 
Tissue, fluid, or blood may be collected from standard of care procedures used to treat or diagnose 
immune-related toxicities. 


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10. STUDY CALENDAR 
 
Study Procedures 
Screen17 
Cycle (28 days)18 
EOT20 
Safety 
FU21 
Clinical 
FU22 
Survival 
FU23 
Day 1 
Day 15 
Visit Windows (days)1 
-21 to D1 
- 
+3 
±7 
+14 
±14 
±14 
Retifanlimab 
 
X 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical, Cancer, & Con Med History2 
X 
 
 
 
 
 
 
Con Meds, Adverse Events3 
 
X 
X19 
X 
X 
 
 
Physical Exam, ECOG  PS3 
X 
X 
 
X 
 
 
 
Vitals, Weight, Pulse Ox, & Height4 
X 
X 
 
X 
 
 
 
Hematology, Chemistry5, 11 
X 
X 
X 
X 
 
 
 
Endocrine6, 11 
 
X 
 
X 
 
 
 
Urinalysis7 
X 
 
 
 
 
 
 
Virology8 
X 
 
 
 
 
 
 
Coagulation panel9 
X 
 
 
 
 
 
 
Pregnancy Test10, 11 
X 
X 
 
 
 
 
 
CA19-911 
X 
X 
 
X 
 
 
 
ECG12 
X 
 
 
 
 
 
 
CT/MRI, RECIST/iRECIST13 
X 
X 
 
X 
 
X 
 
Whole blood for PBMC14 
 
X 
 
 
 
 
 
Whole blood for plasma14 
 
X 
 
 
 
 
 
Whole blood for Serum14 
 
X 
 
 
 
 
 
Archival Tissue15 
X 
Tumor Biopsies16 
X 
 
 
X 
 
 
 
Survival Follow-up 
 
 
 
 
 
 
X 
 
In order to minimize the need for research-only in-person visits, telemedicine visits may be substituted for in-
person clinical trial visits or portions of clinical trial visits where determined to be appropriate and where 
determined by the investigator not to increase the participants risks. Prior to initiating telemedicine for study visits 
the study team will explain to the participant, what a telemedicine visit entails and confirm that the study 
participant is in agreement and able to proceed with this method. Telemedicine acknowledgement will be obtained 
in accordance with the Guidance for Use of Telemedicine in Research. In the event telemedicine is not deemed 
feasible, the study visit will proceed as an in-person visit. Telemedicine visits will be conducted using HIPAA 
compliant method approved by the Health System and within licensing restrictions. 


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1:   If necessary, a scheduled cycle may be delayed for up to 1 week. Longer delays to be approved by the 
IND Sponsor. 
2: Cancer history includes: primary site of cancer, gross location of primary tumor, secondary sites of 
cancer, histology, histologic grade, date of initial diagnosis, date of metastatic diagnosis, prior cancer 
therapy regimens, MSI testing, and tumor mutation testing. 
3: Complete physical examination and assessment of ECOG PS will be completed at baseline; focused 
physical examinations and assessment of ECOG PS will be conducted thereafter.  Day 1 Physical 
examination and ECOG status may be done up to 1 day prior to dosing. 
4:   Blood pressure, pulse, and temperature are required as indicated. Weight and pulse oximetry will be 
obtained at baseline and prior to each cycle.  Height will be taken at or prior to screening only. 
Retifanlimab vitals will be collected prior to and at the end of the infusion (-5/+ 15 minutes).  
5:  Clinical hematology: CBC with differential ANC, ALC, AEC, and platelet count; Serum chemistry: 
sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, 
total bilirubin, direct bilirubin, lipase, total protein, albumin, calcium, magnesium, and phosphate. LDH 
at baseline only. Any unexpected Grade 3 or greater laboratory abnormalities should be repeated within 
24-72 hours. Grade 3 or greater creatinine, AST, ALT, and bilirubin should be repeated within 24-72 
hours as well. 
6:   TSH (Total T3 and free T4 if TSH abnormal and clinically indicated). 
7:   Bilirubin, blood, glucose, ketones, leukocytes, nitrite, pH, color, protein, RBC and WBC count, and 
specific gravity. 
8:  Virology screen: HIV antibody, hepatitis B surface antigen and hepatitis C antibody; additional virology 
may also be evaluated. Subjects who are hepatitis C antibody positive and confirmed negative viral 
load at screening will be allowed to enroll. Window for viral screen is -60 days to D1. 
9:  Coagulation panel: international normalized ratio of prothrombin time, APTT 
10: Pregnancy tests will be administered to WOCBP: serum pregnancy test is required at screening; urine 
pregnancy tests are required before each dose of retifanlimab.  
11: Labs may be collected within a window of up to 3 days prior to dosing. 
12: ECG should be performed at baseline.  
13: Spiral CT of thorax, abdomen and pelvis (and other imaging studies as clinically indicated to evaluate 
suspected sites of metastatic disease). If a subject cannot have a CT scan (e.g., allergy to contrast dye), 
an MRI should be performed. 3-D CT scans and RECIST reads will not be used to determine eligibility 
at baseline. On study radiologic evaluations and tumor measurements (RECIST and iRECIST per 
Appendix B and Appendix C) will be performed every 8 weeks (± 1 week; starting from the date of 
first treatment) including the EOT evaluation (± 4 weeks). If the EOT visit occurs early, scans do not 
need to be repeated if one has been done within the past 6 weeks. Weeks are in reference to calendar 
week and should not be adjusted due to dosing delays. 
14: Up to 120 mL of whole blood for PBMC isolation will be drawn cycle 1, 2, 3, and 5 and must be 
processed by sponsor-qualified operators within 6 hours of collection and stored in liquid nitrogen. 
Approximately 20 mL of whole blood for plasma collection and another approximately 5 mL of blood 
for serum for immune monitoring. Detailed instructions for tissue collection, processing and shipment 
are provided in the Laboratory Manual. Patients who discontinue retifanlimab with SD or better and 
later restart after off-treatment progression will have additional research bloods collected (same volume 
and type as above) at similar intervals as at the start of study:  i.e. prior to the 1st, 2nd, 3rd, and 5th cycles 
of retreatment (though the actual cycle numbers will continue where subject was discontinued). 


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15: Attempts to obtain surgical or biopsy archival tumor samples will be made for every subject until the 
sample is obtained or documentation that the sample cannot be obtained. Detailed instructions for tissue 
collection, processing and shipment are provided in the Laboratory Manual.  
16: Tumor biopsies to be taken (if a subject’s tumor is thought to be reasonably safe and easy to biopsy) at 
baseline and at Cycle 3 (4-6 cores per timepoint). The Cycle 3 biopsy has a ± 1 week window. 
Additional optional biopsies may be obtained later in the course of study treatment or at progression. 
Fine needle aspiration will not be acceptable. Detailed instructions for tissue collection, processing and 
shipment are provided in the Laboratory Manual. Patients who discontinue retifanlimab with SD or 
better and later restart after off-treatment progression may have an additional biopsy collected prior to 
resuming study treatment. 
17: Patients who stop retifanlimab with SD or better may be eligible for additional retifanlimab therapy if 
they progress after stopping study drug, they meet the criteria listed in Section 5.9.2, and undergo the 
following evaluations: interval medical and cancer history, physical exam, vitals, weight, PS, 
hematology and chemistry profile, endocrine panel, urinalysis, serum or urine pregnancy test, CA19-9, 
radiographic evaluations, and tumor measurements. Subjects who restart treatment after relapse should 
resume at the next cycle which they would have received prior to discontinuation. Additional research 
samples will also be collected prior to restarting treatment and while on study (see footnotes 14 and 16 
for details). 
18: Cycle 1 Day 1 evaluations do not need to be repeated if they were conducted within 3 days of the 
screening evaluations. 
19: Day 15 (± 1 day) adverse event assessments may be conducted by telephone or email after cycle 2 day 
1. 
20: Subjects will return to the study site for an EOT evaluation. EOT follow-up will occur 28 (±7) days 
after the last dose of study drug. NOTE: CT scan assessment at EOT will occur 28 days (± 4 weeks) 
after the final dose. If the EOT visit occurs early (or if the patient cannot return due to disease 
progression), an assessment for AEs should be made by telephone or email on day 28 (±1) after last 
study dose. Subjects who restart study drug after off-treatment progression should have a second EOT 
visit performed when they stop study drug a second time. 
21: Subjects who discontinue treatment should be contacted by telephone or email at 90 days (+ 14 day 
reporting window) from their last dose of study drug or within 7 days before initiation of a new 
antineoplastic treatment (whichever comes first) to assess for treatment related toxicities. In addition, 
all SAEs occurring during this time should be reported as well. 
22: Subjects who discontinue treatment without disease progression should continue to be monitored for 
disease status by radiologic imaging (Section 5.12.2). Disease monitoring should continue to be 
assessed every two months (± 2 weeks) for the first 2 years and then every 3 months (± 4 weeks) until: 
1) start of a new antineoplastic therapy (information of the new cancer therapy will be collected), 2) 
disease progression, 3) death, 4) withdrawal of consent, or 5) study closure, whichever occurs first. 
23: Subjects who discontinue treatment will enter the survival follow-up portion of the trial (Section 
5.12.3). Subjects should be contacted every 12 weeks (± 2 weeks) to monitor overall survival. 
Information of other cancer therapies after discontinuation from the study treatment will be collected 
as well. 


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11.  
STUDY ENDPOINTS 
 
11.1 
Primary Endpoint 
 
The primary endpoint is DCR at 4 months following the start of treatment with retifanlimab, which 
is defined as the proportion of subjects with PR or CR or stable disease according to RECIST 1.1 
following 4 months from the start of therapy. Subjects who discontinue due to toxicity prior to 
post-baseline tumor assessments will be evaluable and considered treatment failures.  Otherwise, 
subjects who discontinue or do not have any post-baseline scans for other reasons including 
withdrawal of consent or being lost to follow-up prior to C2D1 will be replaced and not included 
in the primary efficacy analysis. 
 
11.2 
Secondary Endpoints 
 
The secondary endpoints are as follows: 
 
• ORR is defined as the proportion of subjects with PR or CR according to RECIST 
1.1. Subjects who discontinue due to toxicity or clinical progression prior to post-
baseline tumor assessments will be considered as non-responders.  Otherwise, 
subjects who discontinue or do not have any post-baseline scans for other reasons 
including withdrawal of consent or being lost to follow-up prior to C2D1 will be 
replaced and not included in the primary efficacy analysis. 
• Progression-free survival (PFS) is defined as the number of months from the first 
dose of retifanlimab to radiographic disease progression (PD or relapse from CR 
as assessed using RECIST 1.1 criteria), documented clinical progression as 
assessed by the treating provider, or death due to any cause. PFS will be censored 
at the date of the last scan for subjects without documentation of disease 
progression at the time of analysis. 
• Safety assessed by the following measures: 
– Number of patients who have grade 3 or above drug-related toxicities 
– Frequency of drug-related toxicity by grade 
– Retifanlimab-related infusion reactions 
– Immune-related AEs 
– Unacceptable toxicities 
– Vital signs: BP, pulse, temperature 
– Physical examination 
– Changes in ECG readings  
– Clinical hematology: complete blood count (CBC) with differential ANC, 
ALC, AEC, and platelet count 
– Clinical serum chemistry: sodium, potassium, chloride, bicarbonate, glucose, 
blood urea nitrogen (BUN), creatinine, lactate dehydrogenase (LDH), ALT, 
AST, alkaline phosphatase, lipase, bilirubin (total), total protein, albumin, 
calcium, magnesium and phosphate 
 
 


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11.3 
Exploratory Endpoints 
 
• OS, DOR, TTP. 
− 
Overall survival (OS) is defined as the number of months from the first dose of 
retifanlimab until death or end of follow-up (OS will be censored on the date 
the subject was last known to be alive for subjects without documentation of 
death at the time of analysis). 
− 
Duration of Response (DOR) is defined as the number of months from the first 
documentation of a response to date of disease progression.  
− 
Time to-progression (TTP) is defined as the number of months from the first 
dose of retifanlimab to the date of documented disease progression (PD or 
relapse from CR as assessed using RECIST 1.1 criteria). It differs from PFS in 
that it does not include death in the definition of an event.  TTP will be censored 
at the date of the last scan for subjects without documentation of disease 
progression at the time of analysis. 
− 
Disease control rate (DCR) is defined as the proportion of subjects with 
complete response, partial response and stable disease 
• Disease control rate, objective response rate, progression-free survival, and 
duration of response measured by iRECIST  
• Immune subset analyses by IHC, next generation sequencing and gene expression 
profiling of tumor tissue  
• Immune subset analyses in PBMCs including effector, helper, and regulatory T 
cells, NK cells, and macrophages  
• Circulating cytokine analysis in patient sera 
• Immune checkpoint analysis by IHC and gene expression profiling 
• Tumor marker kinetics measured by change in serum CA19-9 concentrations from 
baseline  
 
 
12.  
DATA REPORTING / REGULATORY REQUIREMENTS 
 
AE guidelines and instructions for AE reporting can be found in Section 7.0 (Adverse Events: 
List and Reporting Requirements). 
 
Dr. Nilofer Azad will be holding the IND for this study.  She will comply with all regulated 
reporting requirements to the FDA, local regulations, including ICH E6 guidelines for Good 
Clinical Practices. 
 
12.1 
Data Collection and Processing 
 
All information will be collected on study-specific CRFs by study staff. These data will be 
reviewed for completeness and accuracy by the Principal Investigator at each site.  
 
CRFs will be used to capture study results and data. The study coordinator or other authorized 


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study personnel will transcribe data from source documents onto eCRFs. Before or between visits, 
the IND Sponsor, or designee may request copies of the CRFs for preliminary medical review. 
Once the CRFs are complete and source-verified, the investigator must sign and date all required 
pages, verifying the accuracy of all data contained within the CRF.  
 
Protocol Chair 
The Protocol Chair and/or designee is responsible for performing the following tasks: 
• Coordinating, developing, submitting, and obtaining approval for the protocol as well as 
its subsequent amendments. 
• Assuring that all participating institutions are using the correct version of the protocol. 
• Taking responsibility for the overall conduct of the study at all participating institutions 
and for monitoring the progress of the study. 
• Reviewing and ensuring reporting of SAE 
• Reviewing data from all sites. 
 
Coordinating Center (Johns Hopkins University) 
The Coordinating Center (or its representative) is responsible for performing the following tasks: 
• Ensuring that IRB approval has been obtained at each participating site prior to the first 
subject registration at that site, and maintaining copies of IRB approvals from each site. 
• Monitoring subject registration. 
• Collecting and compiling data from each site. 
• Establishing procedures for documentation, reporting, and submitting of AE’s and SAE’s 
to the Protocol Chair, and all applicable parties. 
• Facilitating audits by securing selected source documents and research records from 
participating sites for audit, or by auditing at participating sites. 
 
Participating Sites 
Participating sites are responsible for performing the following tasks: 
• Following the protocol as written, and the guidelines of Good Clinical Practice (GCP). 
• Submitting data to the Coordinating Center. 
• Consent subjects promptly. 
• Providing sufficient experienced clinical and administrative staff and adequate facilities 
and equipment to conduct a collaborative trial according to the protocol. 
• Maintaining regulatory binders on site and providing copies of all required documents to 
the Coordinating Center. 
Collecting and submitting data according to the schedule specified by the protocol. 
 
12.2 
Safety Meetings 
 
Scheduled meetings will take place weekly (or as needed based on enrollment) and will include 
the protocol principal investigator, study coordinator(s), research nurse(s), sub-investigators (as 
appropriate), collaborators (as appropriate), and biostatisticians (as appropriate) involved with the 
conduct of the protocol. During these meetings, matters related to the following will be discussed: 
safety of protocol participants, validity and integrity of the data, enrollment rate relative to 
expectation, characteristics of participants, retention of participants, adherence to protocol 
(potential or real protocol violations), data completeness, and progress of data for objectives. 


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Monthly teleconferences will be scheduled (or as needed based on enrollment) to include the 
Coordinating Center and the clinical trial site(s). During these meetings, the Coordinating Center 
and clinical trial sites shall discuss the following: study protocol updates, safety data, enrollment 
status, and progress of data for objectives.  
 
12.3 
Monitoring 
 
This is a medium risk study under the Johns Hopkins Sidney Kimmel Comprehensive Cancer 
Center (SKCCC) Data Safety Monitoring Plan (DSMP, 2/21/2019). Data monitoring of this 
protocol will occur on a regular basis with the frequency dependent on the rate of subject accrual 
and the progress of the study. Eligibility for all sites will be monitored by the Protocol Chair. The 
IND Sponsor and PI at each site shall internally monitor the progress of the trial, including review 
and confirmation of all safety/treatment-related outcomes, response assessments, safety reports 
and/or any related source documentation. Additional data and safety monitoring oversight will also 
be performed by the SKCCC Safety Monitoring Committee (SMC - as defined in the DSMP). 
External monitoring will occur according to the following guidelines: 
 
Johns Hopkins SKCCC: The protocol will be monitored externally by the SKCCC CRO in 
accordance with SKCCC guidelines. Trial monitoring and reporting will be done through the 
Safety Monitoring Committee (SMC) at SKCCC.  
 
Participating site(s): The protocol will be monitored by authorized representatives of the 
coordinating center. A report of the reviews will be submitted to the IND Sponsor and the SKCCC 
CRO. 
 
Authorized representatives of the Coordinating Center may visit the satellite site(s) to perform 
audits or inspections, including source data verification. The purpose of these audits or inspections 
is to systematically and independently examine all trial-related activities and documents to 
determine whether these activities were conducted and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), and any applicable 
regulatory requirements. 
 
12.4 
Study Documentation 
 
12.4.1 Informed Consent and Authorization for use and Disclosure of Protected 
Health Information 
 
Written informed consent and authorization of use and disclosure of protected health 
information (PHI) must be obtained from each subject (or the subject’s legally authorized 
representative) before performing any study-specific screening/baseline period 
evaluations. The ICF and authorization for use and disclosure of PHI, which is prepared by 
the investigator or the site, must be reviewed and approved by the IND Sponsor, the study 
monitor (if applicable), and the site’s IRB before the initiation of the study.  
 
 
 


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12.4.2 Investigator Study Files 
 
The IND Sponsor or designee will be responsible for maintaining original and backup of 
all CRF data. Investigator will maintain backup of all electronic data systems used for 
primary documentation or source documentation. Backup of electronic data will be 
performed periodically. Backup records will be stored at a secure location on site and 
backup and recovery logs will be maintained to facilitate data recovery. 
 
Changes to any electronic records require an audit trail, in accordance with 21 CFR 
11.10(e), and should include who made the changes and when and why the changes were 
made. An audit trail is defined as a secure, computer-generated, time-stamped electronic 
record that will allow reconstruction of the course of events relating to the creation, 
modification and deletion of an electronic record. Audit trails must be created 
incrementally, in chronological order and in a manner that does not allow new audit trail 
information to overwrite existing data. Audit trails should be in a readable format and 
readily available at the study site and any other location where electronic study records are 
maintained. 
 
Audit trails are generated automatically for eCRFs. The investigator is responsible for 
maintaining audit trails of all electronic data systems used for primary documentation or 
source documentation. 
 
12.4.3 Case Report Forms and Source Documentation 
 
The investigator must make study data accessible to the site monitor, to other authorized 
representatives of the IND Sponsor (or designee) and to the appropriate regulatory 
authority inspectors. 
 
12.4.4 Retention of Study Documents 
 
According to ICH E6, Section 4.9, all CRFs, as well as supporting paper and electronic 
documentation and administrative records, must be retained for at least 2 years after the 
last approval of a marketing application and until there are no pending or contemplated 
marketing applications, or at least 2 years have elapsed since the formal discontinuation of 
clinical development of an individual product. Longer retention periods may apply.  
 
Audit trails for electronic documents will be retained for a period at least as long as that 
required for the subject electronic records to which they pertain. The investigator will retain 
either the original or a certified copy of audit trails. 
 
12.4.5 Data Confidentiality and Subject Anonymity 
 
All information about the nature of the proposed investigation provided by the IND 
Sponsor or their representative to the investigator (with the exception of information 
required by law or regulations to be disclosed to the IRB, the subject or the appropriate 
regulatory authority) must be kept in confidence by the investigator. 
 


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The anonymity of participating subjects must be maintained. Subjects will be identified by 
their initials and an assigned subject number on CRFs and other documents retrieved from 
the site or sent to the IND Sponsor, study monitor, Incyte, regulatory agencies, or central 
laboratories/reviewers. Documents that identify the subject (e.g., the signed ICF) will be 
maintained in strict confidence by the investigator, except to the extent necessary to allow 
auditing by the appropriate regulatory authority, IND Sponsor or their representative. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Sample Size calculation and justification 
 
Simon's two-stage optimal design will be used 18. The null hypothesis that the true disease control 
rate at 4 months is 5% will be tested against a one-sided alternative of 30% disease control rate at 
4 months. In the first stage, 7 patients will be accrued. If there are zero patients with disease control 
by 4 months, the study will be stopped. Otherwise, 14 additional patients will be accrued for a total 
of 21 patients. The null hypothesis (disease control rate of 5%) will be rejected if 3 or more patients 
with disease control at 4 months are observed in stage 1 and 2 combined. This design yields a type 
I error rate of 0.064 (target type I error 0.1) and power of 90% when the true disease control rate 
is 30%. The probability of stopping the trial early for futility is 70% if the true DCR is 5%.  
 
We plan to enroll 25 subjects to ensure 21 would be evaluable for DCR. As this is a rare tumor 
subtype patients will be recruited at several sites including Johns Hopkins Hospital, Memorial 
Sloan Kettering Cancer Center and the Mayo Clinic. We do not anticipate any difficulties in trial 
enrollment. We expect an accrual rate of at least 2 patients per month across the sites, completing 
trial enrollment in 12 months. 
 
Patients are evaluable for DCR if they receive at least one dose of retifanlimab, and have at least 
one post-baseline tumor assessments or discontinue due to toxicity or clinical progression prior to 
post-baseline tumor assessments. The study plans to enroll 25 subjects to ensure 21 would be 
evaluable for the primary efficacy endpoint. 
 
There is no reliable historical control data documenting response rates and disease control rates 
with chemotherapy or any other agent in ASQ. Previous clinical trials of single agent checkpoint 
inhibitors in pancreatic cancer have reported 0% ORR (anti-PD1, PDL1, CTLA4)2–6. A recent trial 
investigating anti-PDL1 combined with anti-CTLA4 therapy or anti-PD-L1 alone in metastatic 
PDAC reported ORR of 3.1% and 0% with the combination and single agent, respectively. This 
trial also reported a median PFS of 1.5 months in both cohorts, DCR at 3 months of 9.4% and 6.1% 
and PFS rate at 6 months of 9.4% and 3.6% in the combination and single agent cohorts, 
respectively5. Given the results of these trials, the phenomenon that immunotherapy often has a 
delayed effect compared to chemotherapy and ASQ being an aggressive disease with limited 
treatment options the primary endpoint of this study will be a 30% DCR at four months. 
 
 


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13.2 
Data and Analysis Plan  
 
Analysis of Primary Endpoint 
 
The primary endpoint of the study will be disease control (DC) at four months using RECIST 1.1. 
DC is defined as complete response, partial response and stable disease at 4 months, per RECIST 
1.1. Disease control rate (DCR) will be estimated as the proportion of patients who achieve DC at 
4 months, along with 95% confidence interval 
 
 
Analysis of Secondary Clinical Endpoint 
 
The objective response rate defined as the proportion of response evaluable subjects who have a 
complete response (CR) or partial response (PR) using RECIST 1.1 criteria at any time during the 
study. The evaluable population includes all subjects who have completed at least one dose of 
retifanlimab and have received at least one follow-up scan or discontinue due to toxicity or clinical 
progression prior to post-baseline tumor assessments. Response rate will be reported with exact 
95% confidence interval.  
 
Progression-free Survival (PFS) is defined as the time from cycle 1, day 1 of retifanlimab until 
first documented local progression or death due to any cause. Disease progression will be assessed 
using RECIST (version 1.1) and/or documented clinical progression as assessed by the treating 
provider. Due to the expectation that some patients may experience delayed clinical responses to 
therapy, patients with disease progression by radiographic imaging or laboratory parameters 
during a 12-week evaluation period but without rapid clinical deterioration or significant change 
in performance status that requires additional immediate therapy may continue to receive treatment 
on study. Subjects that meet the above criteria and continue on study therapy must discontinue 
treatment upon documentation of disease progression on the second scan. The date of progression 
will be backdated to the time of first RECIST criteria progression. Tumor assessments will be 
made using RECIST 1.1 and immune RECIST (iRECIST). Individuals will be censored at the date 
of the last scan prior to initiation of an alternative therapy for PFS if no event occurs before the 
start of the alternative therapy.  
 
PFS will be summarized descriptively using the Kaplan-Meier method. Analysis of PFS will be 
restricted to evaluable individuals who complete at least one dose of retifanlimab.  
 
Analysis of Safety Endpoints 
 
The safety analysis will be performed in all subjects who receive at least one dose of study drug. 
A baseline measurement and at least 1 laboratory or other safety-related measurement obtained 
after at least 1 dose of study treatment may be required for inclusion in the analysis of a specific 
safety parameter (e.g., lab shifts from baseline). A complete list of all AE data will be provided 
along with an assessment of NCI CTCAE grade and relationship to study drug. The incidence of 
AEs will be tabulated by subgroups of interest (e.g. grade 3 or higher, organ class, relationship to 
study drug). For analyses at the individual level, the highest grade and relationship to study drug 
will be assumed if multiple events have occurred. Toxicity will be tabulated by type and grade and 
will be summarized with descriptive statistics. Other safety data will be assessed in terms of 


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49
physical examination, clinical chemistry, hematology, vital signs, and ECGs. Negative binomial 
regression and Cox proportional hazards models will be used to assess the rate of AE and time to 
first toxicity, respectively. 
 
Exploratory Clinical Analysis 
 
Overall survival is defined as the duration of time from start of study treatment to time of death. 
For subjects lost to follow-up or whose vital status is unknown, every effort will be made to 
determine the date such subjects were last known to be alive. Such efforts may include phone calls, 
certified mail, and the checking of public records. Subjects who are alive or lost to follow-up as of 
the data analysis cutoff date will be right-censored. The censoring date will be determined from 
the date the subject was last known to be alive.  
 
OS will be summarized descriptively using the Kaplan-Meier method. Analysis of OS will be 
restricted to evaluable individuals who complete at least one dose of retifanlimab. Median event-
free survival will be reported and the associated 95% confidence interval will be estimated. 
 
DOR and TTP were defined in second 11.3.  
 
Exploratory Biomarker Analysis 
 
To specifically evaluate the impact of therapy on the tumor microenvironment, we will compare 
biopsies obtained at baseline vs. after two cycles of retifanlimab (refer to section on Trial Design).  
In addition, immune effector cell phenotype circulating in peripheral blood will be assessed. 
Exploratory data analyses will include plots and summary statistics of these immunologic 
correlative markers at baseline as well as at the various time points. Patterns of change in the 
longitudinal data on these markers will be evaluated in this manner for each of the correlative 
outcomes of interest. Exploratory analyses can also be conducted to examine potential differences 
in various immune biomarkers between patients who have disease control (prolonged SD or any 
response vs. those with progressive disease). Linear mixed models can also be used to explore 
differences in these markers between the two outcome groups along with graphical analyses that 
plot marker values across time for the two groups to assess potentially different patterns of change 
between these groups. Appropriate transformations of the various correlative markers will be used 
in the presence of skewed data distributions.  
 
13.3 
Safety Analysis 
 
The safety analysis will be performed in all treated subjects. AE data will be listed individually 
and incidence of AEs summarized by system organ class and preferred terms within a system organ 
class for each treatment group.  When calculating the incidence of AEs, each AE (based on 
preferred terminology defined by CTCAE version 5.0) will be counted only once for a given 
subject.  In analyses of grade and causality, if the same AE occurs on multiple occasions, the 
highest grade and strongest relationship to study drug will be assumed.  If 2 or more AEs are 
reported as a unit, the individual terms will be reported as separate experiences. 
 
Changes in vital signs, hematology and clinical chemistry parameters from baseline to the end of 
the study will be examined.  Toxicity will be tabulated by type and grade. Toxicities will be 


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50
characterized according to the CTCAE version 5.0.  Treatment-emergent changes from normal to 
abnormal values in key laboratory parameters will be identified. 
 
13.4 
Safety monitoring and stopping guidelines 
 
Adverse events will be monitored during the trial. The occurrence of unacceptable AEs, as defined 
in Section 5.6, at any time during the treatment will be the endpoint for safety monitoring.  If the 
events of unacceptable AEs appear to be higher than 33%, we will temporarily halt the study 
pending safety evaluation. A Beta (1.5, 5.5) prior, representing a toxicity rate of 21%, a slightly 
conservative estimate, was used in the development of the stopping guidelines.  The therapy will 
be re-evaluated if the posterior probability that the toxicity rate exceeds the 33% boundary is 
greater than 60%.  Table 5 summarizes the stopping boundaries for unacceptable toxicities. 
 
Table 5.  The number of unacceptable toxicities needed to trigger stopping guidelines throughout 
the course of the study.   
 
Number of Subjects 
Number of unacceptable toxicities 
needed to trigger re-evaluation 
2 
2 
3-5 
3 
6-7 
4 
5-10 
5 
11-13 
6 
14-16 
7 
17-19 
8 
20-22 
9 
23-25 
10 
 
Operating characteristics of the stopping rule based on 10000 simulations are shown below. 
 
 
 
  
 
 
True probability of 
unacceptable toxicity 
Probability of triggering 
stopping guidelines 
5% 
0.4% 
10% 
1.8% 
15% 
6% 
20% 
14% 
25% 
27.5% 
30% 
44.9% 
35% 
62.3% 
40% 
78% 
45% 
89.2% 


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51
REFERENCES 
 
1. Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of 
thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014). 
2. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2016. CA Cancer J Clin 66, 7–30 
(2016). 
3. Burris, H. A. et al. Improvements in survival and clinical benefit with gemcitabine as first-
line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 
15, 2403–2413 (1997). 
4. Conroy, T. et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. New 
England Journal of Medicine 364, 1817–1825 (2011). 
5. Von Hoff, D. D. et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus 
Gemcitabine. New England Journal of Medicine 369, 1691–1703 (2013). 
6. Borazanci, E. et al. Adenosquamous carcinoma of the pancreas: Molecular characterization 
of 23 patients along with a literature review. World J Gastrointest Oncol 7, 132–140 (2015). 
7. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced 
cancer. N. Engl. J. Med. 366, 2455–2465 (2012). 
8. Patnaik, A. et al. Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal 
Antibody) in Patients with Advanced Solid Tumors. Clin. Cancer Res. 21, 4286–4293 
(2015). 
9. Royal, R. E. et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally 
advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 33, 828–833 (2010). 
10. Okudaira, K. et al. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse 
pancreatic cancer model. Int. J. Oncol. 35, 741–749 (2009). 
11. Lutz, E. R. et al. Immunotherapy converts nonimmunogenic pancreatic tumors into 
immunogenic foci of immune regulation. Cancer Immunol Res 2, 616–631 (2014). 
12. Soares, K. C. et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector 
T-cell infiltration into pancreatic tumors. J. Immunother. 38, 1–11 (2015). 
13. Nomi, T. et al. Clinical significance and therapeutic potential of the programmed death-1 
ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 
2151–2157 (2007). 
14. Gao, H.-L. et al. The clinicopathological and prognostic significance of PD-L1 expression in 
pancreatic cancer: A meta-analysis. HBPD INT 17, 95–100 (2018). 
15. Zhuan-Sun, Y. et al. Prognostic value of PD-L1 overexpression for pancreatic cancer: 
evidence from a meta-analysis. Onco Targets Ther 10, 5005–5012 (2017). 
16. Tanigawa, M. et al. PD-L1 expression in pancreatic adenosquamous carcinoma: PD-L1 
expression is limited to the squamous component. Pathol. Res. Pract. 214, 2069–2074 
(2018). 
17. Mehnert, J. M. et al. First-in-Human Phase 1 Study of INCMGA00012 in Patients With 
Advanced Solid Tumors: Interim Results of the Cohort Expansion Phase. 1 
18. Simon, R. Optimal two-stage designs for phase II clinical trials. Controlled Clinical Trials 
10, 1–10 (1989). 
19. Wang-Gillam, A. et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in 
metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a 
global, randomised, open-label, phase 3 trial. Lancet 387, 545–557 (2016). 
20. Seymour, L. et al. iRECIST: guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol. 18, e143–e152 (2017). 


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


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APPENDIX B: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
 
RECIST version 1.1 will be used in this study for assessment of tumor response.  While either CT 
or MRI may be used utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.   
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable unless there is evidence of progression in the irradiated site. Malignant 
lymph nodes.  To be considered pathologically enlarged and measurable, a lymph node must 
be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm).  At baseline and in follow-up, only the short axis will be measured 
and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not 
followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions 
are present in the same subject, these are preferred for selection as target lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded and 
measured at baseline.  Target lesions should be selected on the basis of their size (lesions with the 
longest diameter), be representative of all involved organs, but in addition should be those that 
lend themselves to reproducible repeated measurements.  It may be the case that, on occasion, the 
largest lesion does not lend itself to reproducible measurement in which circumstance the next 
largest lesion which can be measured reproducibly should be selected.  A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated 
and reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, then 
only the short axis is added into the sum.  The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the disease. 
 


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Non-target lesions:  All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline.  Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest 
on study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a subject 
to be considered in complete clinical response. 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression 
of existing non-target lesions.  Unequivocal progression should not normally trump target lesion 
status.  It must be representative of overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the treating 
physician should prevail in such circumstances, and the progression status should be confirmed at 
a later time by the review panel (or Principal Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started).  The subject's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 


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For Subjects with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall 
Response when 
Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. 
Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. 
Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least 
once >4 wks. from 
baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of 
a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
 
Note: Subjects with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease 
progression at that time should be reported as “symptomatic 
deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
Reference 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1).  Eur J Cancer. 2009 Jan;45(2):228-47. 
 
 
 


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APPENDIX C: Description of the iRECIST Process for Assessment of Disease Progression  
 
Assessment at Screening and Prior to RECIST 1.1 Progression 
 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
 
Assessment and Decision at RECIST 1.1 Progression 
 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide 
whether to continue a participant on study treatment until repeat imaging is obtained using the 
criteria outlined in Section 5.9.1. 
 
If the Investigator decides to continue treatment, the participant may continue to receive study 
treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by 
iRECIST, per Investigator assessment. 
 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and 
≥ 5 mm from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and 
iCPD (confirmed progressive disease).  For purposes of iRECIST assessment, the first visit 
showing progression according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, 
regardless of which factors caused the progression. 
At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as 
usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds 
and rules as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 
lesions total (up to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters 
of these lesions will be calculated, and kept distinct from the sum of diameters for target lesions at 
baseline.  All other new lesions will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR). 


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Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, 
compared to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared 
to a prior iUPD time point; this does not have to meet the “unequivocal” standard of 
RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time 
point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which 
iUPD is seen.  This may correspond to the next visit in the original visit schedule.  The assessment 
of the subsequent confirmation scan proceeds in an identical manner, with possible outcomes of 
iCPD, iUPD, and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), 
or iCR if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, 


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whenever it occurs, is again classified as iUPD by iRECIST, and the confirmation process is 
repeated before a response of iCPD can be assigned.  
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (i.e., achievement of iSD/iPR/iCR), iUPD is indicated by 
any of the following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression.  The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD. 
o If non-target lesions had shown previous unequivocal progression, and this progression 
has not resolved, iUPD results from any significant further growth of non-target 
lesions, taken as a whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion 
sum of diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression 
must be confirmed before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one 
respect. If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the 
burden of new lesions has increased from its smallest value (for new target lesions, their sum of 
diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve to iSD or iPR. It will 
remain iUPD until either a decrease in the new lesion burden allows resolution to iSD or iPR, or 
until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication20. 
 
 
 
 
 


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Table 6: Comparison between RECIST 1.1 and iRECIST 
 
 
RECIST 1.1 
iRECIST 
Definitions of disease: 
numbers, sites and 
target or non 
Measurable are diameters greater 
than 10 mm (15 for nodes 
maximum of 5 (2 per organ) 
No change from RECIST 1.1 
CR, PR or SD 
Cannot have met criteria for 
progression 
Can have had iUPD (more than 
once) but not iCPD before iCR, 
iPR or iSD 
Confirmation of CR or 
PR 
Only in non-randomized studies 
As per RECIST 1.1 
Confirmation of SD 
Not required 
As per RECIST 1.1 
New lesions 
Progression: recorded but not 
measured 
iUPD but only becomes iCPD if 
on the next scan there are new 
lesions or the size increases by 
greater than 5 mm 
Confirmation of 
progression 
Not required 
Required 
Consideration of 
clinical status 
Not required 
Clinical stability considered at 
iUPD to decide treatment 
continuation 
 
 
 


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Table 7:    Trajectory of progression in iRECIST 
 
Target Lesions: iCR, Non-
target: iCR, no new lesions 
iCR 
iCR 
Target lesions: iCR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target Lesions: iPR, Non-
target: non iCR/non iUPD, no 
new lesions 
iPR 
iPR 
Target lesions: iSD, Non-
target: non iCR/non iUPD, no 
new lesions 
iSD 
iSD 
Target lesions: iUPD with no 
change or with a decrease 
from the last time point, Non-
target: iUPD with no change 
or decrease from last time 
point, new lesions 
NA 
 
 
New lesions confirm iCPD if new 
lesions previously identified and 
increased in size (≥ 5 mm in sum of 
measures for new lesions or any 
increase for new lesion non-target) or 
increase in number. If no change is 
seen in new lesions assignment remains 
iUPD 
Target lesions: iSD, iPR, 
iCR, non-target: iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD is 
confirmed by increase in the size of 
non-targets (does not need to meet 
RECIST 1.1 criteria) 
Target lesions: iUPD, non-
target: non iCR/non iUPD, no 
new lesions 
iUPD 
Remains iUPD unless iCPD confirmed 
on the basis of further increase ≥ 5 mm; 
otherwise stays as iUPD 
Target lesions: iUPD, non-
target: iUPD, no new lesions 
iUPD 
Remains iUPD unless iCPD confirmed 
on previously identified targets iUPD ≥ 
5 mm or non-target iUPD 
Target lesions: iUPD, non-
targets: iUPD, new lesions 
iUPD 
Remains iUPD unless iCPD confirmed 
by increase of ≥ 5 mm previously 
identified target, or non-target or an 
increase in size or number of new 
lesions 
Target lesions non iUPD or 
progression, non-targets: non 
iUPD or progression, new 
lesions 
iUPD 
Remains iUPD unless iCPD confirmed 
by increase in size or number of new 
lesions previously identified. 
Target lesions, non-target lesions and new lesions are defined according to RECIST 1.1 criteria: if 
no pseudoprogression occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD are the 
same. * Previously identified in the assessment prior to this time point. ‘I’ indicates immune 
responses assigned using iRECIST 
 
 


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APPENDIX D: SAE Reporting Form 


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Serious Adverse Event Reporting Form 
 
Please notify: Dr. Azad within 24 hours 
Incyte within 24 hours (email: 
 
Protocol Title: 
 
 
A Phase II trial of retifanlimab (INCMGA00012) in patients with previously 
treated unresectable or metastatic adenosquamous pancreatic or ampullary 
cancer 
Protocol #: 
I-0012-19-07 
J19106 
Principal Investigator: 
 
 
Signature of PI: 
 
 
Date: 
 
 
Report Type: 
Initial    
Follow-up 
Final Follow-up 
Death 
Addendum to: 
 
Serious Criteria (check all that apply): 
Death    
Life-threatening 
 Hospitalization or Elongation of Hospitalization 
 Other Important Medical Event 
 Cancer 
 Overdose 
 Other:________________ 
 
Hospital 
Admission Date: 
 
Date Event 
Discovered: 
 
Hospital 
Discharge Date:   
 
SAE ID: 
 
Section A: Subject Information 
Subject ID: 
 
Subject Gender: 
Male 
Female 
 
Subject Age: 
 
Section B: Event Information 
Event diagnosis or 
symptoms: 
 
Event Grade: 
 
Cause of death  
(if applicable): 
 
Event Outcome: 
 Not Recovered 
 Recovering 
 Recovered 
 Recovered with sequelae 
 Death 
 Unknown 
Event Onset Date (or Date of Death): 
 
Event End Date: 
Section C: Study Drug Information 
 
Investigational Product: Retifanlimab (500mg, IV, Q28 days)  
Indication: Previously treated unresectable or metastatic adenosquamous pancreatic or ampullary 
cancer 


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Number of Total Doses Given: 
 
Action taken with the study drug: 
 
None 
 Interrupted 
 Delayed  
 Discontinued  
Date of First Dose: 
 
Date of Last Dose prior to Event: 
 
Relationship to: 
Retifanlimab 
Underlying Disease 
Unrelated 
 
 
Related 
 
 
Section D: Brief Description of the Event: 
 
Section E: Relevant Tests/Laboratory Data 
 
Section F: Relevant Medical History 
 
Section G: Concomitant Drug (Not related to SAE) 
Name of the Drug 
Start Date 
Stop Date 
Route 
Dose 
Frequency 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section H: Comments 
Additional Documents: 
 Please specify