Clinical trial NCT04231981
Conditions: Penile Cancer
Keywords: Penile Cancer Penile squamous cell carcinoma Locally advanced penile cancer Metastatic penile cancer Unresectable locally advanced penile cancer Unresectable penile cancer PSqCC PSCC Penile Cancer stage IV
Sponsor: MedSIR
Start date: 2020-04-28; Completion date: 2022-08-26
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of INCMGA00012 in Advanced Penile Squamous Cell Carcinoma

Detailed description:
Men age ≥ 18 years with locally advanced unresectable or metastatic PSqCC stage 4 (i.e. T4 or N3 or M1) that are presenting with radiologic progression of disease (PD) following or not standard treatment with chemotherapy.

After signing the ICF and confirmed eligibility, patients will receive INCMGA00012 500 mg by intravenous infusion on Day1 of each cycle, once every four weeks for up to 2 years.

Patients will receive treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason.

Patients discontinuing the study treatment period will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every 3 months (± 14 days) from the last dose of investigational product until the end of study (EoS).

Arms: arm 1: Patients will receive INCMGA00012 500 mg by intravenous infusion on Day1 of each cycle.
Interventions: intervention 1: Retifanlimab
Intervention descriptions: intervention 1: INCMGA00012 500 mg will be administered on Day1 of each cycle (once every four weeks), for up to 2 years.

Protocol documents:
ICF_002.pdf: 
 
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PATIENT INFORMATION SHEET 
 
Protocol Title: “A Multicenter, Open-Label, Single-Arm, Phase II Clinical Trial to Evaluate the 
Efficacy and Safety of INCMGA00012 in Advanced Penile Squamous Cell Carcinoma”. 
Phase II Study of the Efficacy of INCMGA00012 in Penile Squamous Cell Carcinoma 
(ORPHEUS)  
EudraCT#: 2019-001172-11 
Protocol Number#: MedOPP239 
Version: [Country/centre-specific version. To be specified in the document header too] 
Study Sponsor: Medica Scientia Innovation Research, SL (MedSIR) 
Investigator: [For site-specific ICF: Insert Investigator’s name and contact information (i.e. 
phone number and address if different from institution address below)]. 
Institution: [For site-specific ICF: Insert institution name and address]. 
 
Overview 
You are being asked to take part in a clinical research study of an investigational drug. Before 
you agree to take part in this research study it is important that you read and understand this 
document. 
This document describes the purpose, procedures, responsibilities and potential risks and benefits 
involved in taking part in this clinical trial. In this document you will also find the alternative 
procedures that are available to you and your right to withdraw from the study at any time without 
having to give any reasons and without this being detrimental to your health care. 
If this document uses any terms you do not understand, or you have any question, ask your doctor 
or a member of the staff involved in the clinical trial to explain it to you. If you decide to take part 
in this study, you will be asked to sign this consent form. A copy of this signed form will be given 
to you to keep. 
 
What is this purpose of this study?  
We invite you to participate in this research study because you have been diagnosed with a penile 
squamous cell carcinoma that cannot be treated with surgery with curative intent (called 


 
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"unresectable locally advanced or metastatic penile cancer"). You have received prior 
chemotherapy regimens or radiotherapy (or not) but you have just recently progressed. 
The main purpose of this study is to assess the efficacy of INCMGA00012 in patients who has 
unresectable locally advanced or metastatic PSqCC.  
You should know that there are other treatments for the type of penile cancer that you have. The 
study doctor will discuss with you about the possible advantages and disadvantages of being part 
of this study as well as other options treatments that you can choose. 
This study includes also additional scientific research to analyze your proteins and genes, which 
are stored in almost every cell in your body and provide the instructions to doing their jobs 
properly. The first goal of this research is to determine the status of different genes and/or proteins, 
that could be used as potential markers of tumor reproduction; and the second goal is to assess 
whether the status of these markers is related to treatment response. The analysis of human 
biological materials and data obtained or to be obtained from them has been recognized as an 
important instrument for current and future medical research. 
Blood and tissue samples collected in this study will be used to perform research studies related 
to the objective of the current research. 
Who is sponsoring and conducting this research?  
This research study is being sponsored globally by Medica Scientia Innovation Research, SL 
(MedSIR). 
 
Who has reviewed this research?  
This study has been approved by {Name of IRB/EC}, an organization that is responsible for 
protecting the rights and safety of patients who take part in research studies in your country. 
 
How many people will take part in the study? 
About 18 patients from different hospitals located in several countries in Europe are expected to 
take part in this clinical trial. 
 
What will happen if I take part in this research study?  
You are being asked to take part in this study because you have been diagnosed with Unresectable 
locally advanced or metastatic penile squamous cell carcinoma (PSqCC) and your doctor thinks 


 
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that you are a good candidate to receive INCMGA00012 treatment. Your study doctor will 
confirm to you whether you meet other clinical criteria necessary to take part in the study. 
Before you begin the study, you will need to undergo the following tests or procedures to find out 
if you can be included in the study. Some of them may be part of your regular medical care and 
may be done even if you do not take part in the study. If you have had some of them recently, 
they may not need to be repeated. 
• 
Discussion of this study and review and signing of this Informed Consent Form. 
• 
Recording of your demographic information, including your age. 
• 
Review of your medical history and any medications (including herbal or dietary 
supplements) that you are taking or have taken within the last 28 days. 
• 
Complete physical examination. 
• 
Measurement of your height and weight. 
• 
Measurement of your vital signs (respiratory rate, heart rate, blood pressure, and body 
temperature). 
• 
The extent of your disease to the thorax, abdomen, and pelvis will be also evaluated by the 
following medical imaging techniques, commonly used in radiology: computerized scan (CT) 
or magnetic resonance imaging (MRI) and bone scan.  
• 
Electrocardiogram (ECG). An ECG is a measurement of the electrical activity of your heart. 
• 
Collection of about 10 mL of blood for standard laboratory tests (including blood chemistry 
and blood cells count).  
• 
Viral serology and Mantoux tuberculin skin test (TST) to confirm eligibility. 
• 
Collection of urine to analyze pH, glucose, protein, ketones, and blood.  
• 
Assessment of any side effects associated with screening procedures. 
If you agree, and the study doctor determines that you are a suitable candidate to participate in 
the trial, you will be included in the study. 
If you decide to take part in this research, several samples of blood and tumor need to be collected 
for genetic research. Participation in this research will not result in any changes to the type of 
treatment you are receiving or will receive later. 
If you consent to participate in the study, blood samples (up to 20 mL of blood) will be collected 
for genetic analysis before first dose of study treatment, after 8 weeks from treatment initiation, 
and at the end of study (prior to start alternative anticancer therapy). A whole blood aliquot will 
be preserved to obtain DNA and compare genetic data from tumoral and normal tissue. These 
blood samples will be collected in addition to any blood samples that will be drawn for the purpose 
of your medical care. 


 
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By signing this document you also authorize the collection of tumor tissue from metastatic lesions, 
whenever possible. This biopsy might be part of the standard clinical care or could be done 
specifically for this research. In case the collection of the metastatic sample is not possible, the 
archival sample obtained during the initial diagnosis may be used for this research study. 
 
During study treatment  
If you are finally included in the study, you will receive INCMGA00012 500mg by intravenous 
infusion on Day 1 of each cycle, once every four weeks for up to 2 years.  
During the treatment period you will be asked to attend to the clinic at least once every 4 weeks 
where you will undergo the tests and procedures described below. All these procedures are part 
of the standard clinical care for your disease, unless it is indicated otherwise. 
During all the study visits, you will be asked about any changes in your health since the previous 
visit. The treatment side effects will be written down exactly as you tell your doctor. 
You will have a physical check-up including weight and vital signs within 72 hours prior to Day 
1 of each cycle (every 4 weeks), prior to the end of treatment visit and prior to the end of the 
study. 
A basic routine blood test (approximately 10 mL of blood) will be done by the study personnel to 
check the number of cells in your blood and how well your liver and kidneys are working.  Before 
study treatment administration, a urinalysis will be done (every 2 cycles). 
The extent of your disease will be also evaluated by thorax, abdomen, and pelvis CT scan or MRI 
every 8 weeks during the 6 initial months of treatment and every 12 weeks afterwards. If you have 
a known history of bone metastases or have new bone pain during screening, a bone scan should 
be obtained prior to study entry.  A bone scan at follow-up will be required only in case that you 
develop new or worsening symptoms 
ECGs should be performed before prior to study entry. Additional ECGs will be repeated as per 
your doctor decision. 
If you consent to participate in this study, you should use a barrier contraceptive method (e.g. 
condom with spermicidal foam) or maintain sexual abstinence.   
You should continue to use highly effective methods of contraception throughout the trial and up 
to 180 days following the end of the study treatment. 
 


 
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How long will I be in the study? 
You will continue to receive the study treatment until the confirmation of progressive disease, 
unless treatment has to be interrupted because your doctor considers it is harmful or have 
unacceptable side effects. 
If you have a serious side effect during the study, the study doctor will ask you to visit the clinic 
for follow-up examinations, even after you have completed your regular study visits. 
 
What are my responsibilities? 
As a participant in this trial, you have certain responsibilities that will help to ensure your safety 
is properly guaranteed during the study. These responsibilities are: 
• 
Keep your study appointments. If you cannot keep an appointment, contact your study doctor 
or study staff to reschedule as soon as you know that you will miss the appointment.  
• 
Tell your study doctor or study staff about any medications you are taking. 
• 
Inform your doctor or any study staff about any side effects, other doctor visits, or 
hospitalizations that you may have whether or not you think they are related to the study 
treatment. 
• 
Tell your study doctor if you have been in a research study in the last 28 days or are in another 
research study now. While participating in this research study, you cannot take part in any 
other research study. 
• 
Inform your doctor if you do not wish to continue receiving treatment as part of the clinical 
trial. In this case, you will be asked to attend a study final visit.  
• 
Inform your doctors that you are taking part in this study. 
• 
Carry with you at all times during the study a card that states that you are taking part in this 
study. 
 
Will I be told about new information? 
During the study, you will be told in a timely manner about new information or changes in the 
study that may affect your health or your willingness to continue in the study. If based on this 
potential new information, you agree to continue in the study, you will be asked to sign an updated 
Consent Form. 
 


 
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Are there benefits to taking part in the study? 
Taking part in this study may or may not involve any type of direct medical benefit to you. While 
doctors hope that treatment with INCMGA00012 could be beneficial against penile cancer, there 
is no proof of this yet. 
It is possible that your participation in this study could benefit future penile cancer patients thus 
contributing to the development of possible future treatments and can help doctors to learn more 
on this condition. 
 
What side effects or risks and discomforts can I expect from being in the study? 
Although medication is carefully studied before being administered to humans, adverse events 
may occur. 
Besides the side effects described below, there may be other side effects that are currently 
unknown. You or your legal representative will be properly informed if new information on the 
medication used in this study comes to light that may be relevant to you continuing to take part 
in the trial. If your doctor decides to stop the study treatment because of an adverse reaction you 
will be offered alternative treatment your doctor considers more appropriate in your case. 
 
Risk and side effects related to lNCMGA00012 
Adverse reactions for INCMGA00012 is mainly based on data collected in clinical trials. Risk 
and side effects are classified by frequency, with the most frequent shown at the beginning: 
• 
Very common (in ≥ 10%): Fatigue (tiredness or lack of energy), diarrhea, nausea, and fever 
• 
Common (< 10 % and ≥ 1%): ALT increased (high levels of an enzyme produced by the 
liver), colitis (inflammation of the large intestine), abnormal taste, hyperthyroidism 
(overactive thyroid gland), hypothyroidism (underactive thyroid gland), flu-like illness, 
infusion-related reaction, lipase increased (abnormal digestive blood test), muscle pain, 
itching, rash (includes different types of rash, such as itchy rash or rash all over the body or 
rash that looks like a flat, red area on the skin that is covered with small merging bumps) 
• 
Rare, but serious (< 1%): Pneumonitis (lung inflammation, possible difficulty breathing) 
 
 
 
 


 
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Possible risks and discomfort associated with drawing blood 
During this study, small amounts of blood will be drawn from a vein and used for tests that allow 
your study doctors to see how you are doing. Drawing blood may cause pain where the needle is 
inserted, and there is a small risk of bruising or infection at the place where the needle is inserted. 
Some people experience dizziness, upset stomach, or fainting when their blood is drawn. 
Precautions will be taken to avoid these side effects. Whenever possible, blood for the additional 
scientific research discussed above will be drawn at the same time as samples for other required 
laboratory tests. If not, an additional needle stick may be required. 
Risks associated with obtaining biopsies 
Tissue biopsies will be obtained during the study. The risks associated are pain, bruising, 
perforation, or penetration of the needle into the blood vessels which may produce bleeding, 
infection, color changes, and blood clots. All precautionary measures will be taken to ensure that 
the biopsy procedure will have the smallest chance of possible risks. 
Risks associated with unauthorized use of data in scientific research 
Strict privacy and confidentiality procedures for this research have been adopted (For major 
details, please see section “How will health information that identifies me be used and 
disclosed?”). However, there is still very small risks associated with a loss of privacy or 
confidentiality. For example, if your identity as a participant in scientific research or your 
identifiable genetic or health information were disclosed to unauthorized persons, there is the 
possible risk of discrimination by employers or insurance providers.  
Possible risks and discomfort associated with CT scans 
CT scans are special X-ray tests used to study the internal organs and bones of your body, and 
they are necessary for measuring your response to this treatment. You would likely undergo these 
scans even if you were not participating in this research study because your doctor would need to 
monitor your disease. 
You will be exposed to radiation from CT scans approximately every 8 weeks every 8 weeks 
during the 12 initial months of treatment and every 12 weeks afterwards. Scientists disagree on 
whether radiation doses at these low levels are harmful. A possible effect that could occur at doses 
associated with this study is a slight increase in the risk of developing cancer later in life. Since 
the effects of radiation can build up over time, it is important to know of your past radiation 
exposure. If you have been exposed to radiation through CT scans, X-rays, or other means in the 
past 12 months, please inform study personnel. If it is determined that your prior radiation 
exposure exceeds current guidelines, it is possible that you will not be allowed to participate in 
this study for safety reasons. 


 
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As part of the CT scan, a contrast agent may need to be taken by mouth and/or injected into your 
vein to make certain organs and disease sites visible on the scan. Oral contrast may cause side 
effects such as nausea, constipation, diarrhea, and abdominal bloating. Pain, bruising, redness, 
swelling, or infection may occur at the site where a needle is inserted to administer the contrast 
material into your vein. It is normal to experience a warm, flushing feeling when the injected 
contrast material is given. You may have an allergic reaction to the injected contrast material that 
may cause rash, hives, shortness of breath, wheezing, and itching, and rarely may cause your heart 
to stop beating ("cardiac arrest"). The use of contrast material during these tests would be a normal 
part of measuring your response to therapy, even if you were not participating in this research 
study. 
Possible risks and discomfort associated with MRI scans 
MRI scans are specialized imaging procedures that are necessary for measuring your response to 
this treatment. For most patients, the risks or side effects associated with undergoing MRI are 
minimal. An MRI scan does not involve ionizing radiation like conventional X-rays. Instead, 
images are generated using a magnetic field and radio signals. Because an MRI scanner uses 
strong magnets, you cannot have any metal implants in your body to have an MRI scan. People 
with an artificial heart valve, metal plate, pin, or other metallic objects in their body (including 
gun shot or shrapnel) are not eligible for MRI scans. Study personnel will ask you questions to 
make sure you can safely have an MRI scan. 
There may be some anxiety and claustrophobia (fear of being in small places) associated with the 
scanner. Staff at the imaging center use techniques to help reduce these feelings in patients. Your 
study doctor may also prescribe mild sedatives or anti-anxiety drugs to help manage your 
symptoms. As part of the standard MRI scan, a contrast agent containing gadolinium is injected 
into your vein to enhance visibility. The risks associated with the contrast agent include mild 
nausea, headache, hives, temporary low blood pressure, chest pain, back pain, fever, weakness, 
and seizures. There have been reports of a severe and potentially fatal condition known as 
nephrogenic systemic fibrosis (a scarring condition that can lead to kidney failure) that has 
occurred in some patients who received gadolinium-based contrast agents. This has not been seen 
in patients with normal working kidneys or mild problems in kidney function. Prior to study entry, 
your study doctor will run tests to determine if your kidneys are working properly to make sure 
that the contrast agent is safe for you. 
 
Will I be paid to participate in this study? 
There will be no charge to you for your participation in this study. The study medication 
(INCMGA00012), study-related procedures, and study visits will be provided at no charge to you. 


 
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Examinations, scans, laboratory tests, and other medical procedures and treatments that would 
routinely be needed to monitor and treat your illness are known as “standard of care”. Certain 
standard of care services and treatments will be performed as part of your participation in the 
study. If you have any questions about costs to you that may result from taking part in this research 
study, please speak with the study team. 
The costs for research-related services will be covered by the study sponsor. 
Information from this study may lead to discoveries and inventions or development of a 
commercial product. You and your family will not receive any financial benefits or compensation 
from or have rights in any developments, inventions, or other discoveries that might come from 
this information. 
 
What other options do I have besides participating in this study? 
If you do not want to be part of this study, your treatment as prescribed by your doctor will still 
continue and your healthcare will not be affected in any way. 
You should discuss treatment alternatives that may be right for you with your doctor. 
If you decide to take part in the trial but the treatment does not manage to control your disease 
your doctor will provide another treatment from among those currently available that, according 
to his/her criteria, is most appropriate for your case. 
 
Sample collection, storage, distribution, and destination 
Samples (blood and tumor tissue for scientific research) will be sent to a sample storage facility 
(IMIM, Instituto Hospital del Mar de Investigaciones Medicas) located in Barcelona, España. 
These samples will be used for the analysis planned in the current study.  
After trial period is finished, and there are remaining samples not used in the analysis planned in 
the present study, if you agree to do so, your samples will be maintained in a research line 
collection. In this case, your samples can be used for future research in penile cancer for analysis 
not strictly related to the objectives of the current research, and with previous approval from a 
Research Ethics Committee. In case you do not agree to the use of your remaining samples for 
future research studies in penile cancer not strictly related to the objectives of the current research, 
these samples will be returned to your destination center.  
Once the 15-year term of sample conservation mentioned above has expired and if you give your 
consent, the samples not used in the planned analysis of the study and/or in future research studies 
of penile cancer not strictly related to the objectives of this research, and prior authorization of a 


 
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Research Ethics Committee, will be transferred to a Biobank. Otherwise, if you don’t give your 
consent to do so, your samples will be destroyed. 
 
How will health information that identifies me be used and disclosed? 
The Study Sponsor undertakes to comply with Regulation (EU) 2016/679 of the European 
Parliament and of the Council, of 27 April 2016, on the protection of natural persons with regard 
to the processing of personal data and on the free movement of such data and repealing Directive 
95/46/EC (hereinafter, the “General Data Protection Regulation”). 
Both the Institution and the Study Sponsor are responsible for the processing of your data and 
undertake to comply with the data protection regulations in force. The data collected for the study 
will be identified by a code, so that no information that can identify you is included, and only 
your study doctor/collaborators will be able to relate this data to you and your medical history. 
Therefore, your identity will not be disclosed to anyone else except the health authorities, when 
required or in cases of medical emergency.  
The Research Ethics Committees, the representatives of the Health Authority in inspection 
matters (Spanish Agency for Medicines and Health Products, foreign health authorities), and the 
personnel authorized by the Study Sponsor (study monitors, auditors), may only have access to 
verify personal data, clinical trial procedures and compliance with good clinical practice 
standards, always maintaining the confidentiality of the information in accordance with current 
legislation. 
The data will be collected in an investigation file under the responsibility of the Institution 
and processed as part of its participation in this study. 
The Investigator and the Study Sponsor are required to retain the data collected for the study for 
at least twenty-five (25) years after its completion. Subsequently, your personal information will 
only be retained by the Institution for your health care and by the Study Sponsor for other 
scientific research purposes, if you have given your consent to do so, and if permitted by 
applicable law and ethical requirements. In the latter cases, the Study Sponsor will take 
appropriate measures to ensure the protection of your privacy and will not allow your data to be 
cross-checked with other databases that may allow to identify them. 
In accordance with data protection legislation, you may exercise your rights of access, 
rectification, erasure (“right to be forgotten”), restriction of the processing of data that is 
incorrect, request a copy of or transfer to a third party the data you have provided for the study 
(data portability), and the right to object and not be the subject of a decision based solely on 
automated processing, including profiling. To exercise your rights, please contact the principal 


 
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investigator of the study or the Data Protection Officer of the Institution at (*). We remind you 
that data cannot be deleted even if you stop participating in the trial, to ensure the validity of the 
investigation and to comply with legal duties and medication authorization requirements. You 
also have the right to contact the Spanish Data Protection Agency if you are not satisfied. 
If you decide to withdraw your consent to participate in this study, no new data will be added 
to the database, but those already collected will be used. 
If we transfer your encrypted data outside the European Union to entities in our group, to service 
providers or to research scientists working with us, your data will be protected by safeguards such 
as contracts or other mechanisms set up by the data protection authorities. If the participant wishes 
to know more about this, he can contact the Data Protection Officer of the Study Sponsor (*). 
As part of this research study, your study doctor, nurses, and other {Study Site} staff will collect 
and record medical and personal information about you, such as information about your general 
health, how you have responded to the study treatment, any side effects you may have 
experienced, and the results of any tests performed during the study. The information collected 
about you will be held by {Study Site} and MedSIR. This information will remain part of the 
study data collected in order to protect the integrity of the study. Your participation in this study 
should be specified in your medical records. 
To ensure that your personal information is kept confidential, your name, or any other information 
that allows your identification will not be entered on the forms/electronic systems or included in 
any records or samples the study doctor provides to MedSIR. Instead, you will only be identified 
by a code. 
Your samples collected for scientific research will be identified with the same code number that 
identifies your data in the clinical part of the study. 
Scientific research is not intended to provide you with clinical information. The data that is 
maintained in databases and created during scientific studies is for research purposes only. 
MedSIR will not initiate the return of any of the genetic information to you or your doctor. 
Information resulting from the research will not be entered into your medical records. 
MedSIR may work with other laboratories, investigators, commercial or academic third parties to 
perform part of the analysis planned in the scientific research. If these agents assist in the research, 
your sample and some of your health information will be shared with them. MedSIR will ensure 
that these agents protect your privacy. 
A clinical study report containing the results of this trial will be made available to anyone who 
requests a copy. Before this report is provided, additional steps will be taken to protect your 
information from being linked to you. If information from this study is published in a medical 


 
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journal or presented at scientific meetings, you will not be identified by name, picture, or any 
other personally identifying information. It is possible that this information is used and processed 
in scientific or medical research projects related to the drug used in this trial. You can request to 
be provided with general information about research studies where your data is used. 
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, the 
information will be also available in www.clinicaltrialsregister.eu [Additional web sites as per 
local regulations]. These web sites will not include information that can identify you. At most, 
the web site will include a summary of the results. You can search this web site at any time. 
By signing this form, you agree to participate in this trial and agree that your personal data are 
used in the described conditions. 
 
What happens if I change my mind? 
Your participation in this study is voluntary. You can choose not to take part in this study at the 
beginning or at any time during the study, without having to give any reasons. Your decision will 
not have a negative effect on your present or future health care. That is, you will not receive any 
penalty or loss of medical benefits that otherwise you would have been entitled to. 
If you wish to withdraw from the study, you should contact your study doctor. He/she will tell 
you the best way to withdraw from it. In this case you will be asked if your decision is related to 
any side effect. 
The study doctor may continue to use the information collected about you prior to your 
withdrawal from the study. The information already sent to the study sponsor cannot be 
withdrawn. 
At any time, the study doctor or the MedSIR group may discontinue your participation in this 
study without your consent. Some reasons for this to happen include you are not following the 
doctor´s instructions or if, in the opinion of the doctor, INCMGA00012 is not being effective 
drug, are harmful or has unacceptable side effects, or other reasons at the discretion of the doctor. 
If you withdraw from the study, or if it finishes, you will stop receiving study medication and to 
ensure your safety, you will be asked to take the required medical tests and follow-up, to assess 
your health and safety. 
MedSIR shall be entitled to retain and use any research results that were obtained prior to your 
withdrawal of consent. However, if you withdraw your consent and samples are not analyzed or 
are partially analyzed, the non-analyzed samples or the part of the samples that are not analyzed 


 
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will be destroyed, if you request to do so, but the results obtained from the part of the sample 
already analyzed before you withdraw consent will be retained. 
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, if you feel that you have been injured because of 
taking part in this study. You can tell the doctor in person or call him or her at the number shown 
below. 
MedSIR will pay for the reasonable costs of immediate care for any physical injury to you that 
specifically result from the study drug. 
MedSIR as sponsor of the clinical trial is liable for damage to your health resulting from injury 
caused by the study treatment and holds appropriate and adequate insurance to cover this study 
related damage. 
There is a policy of liability insurance that covers any damage you may suffer as a result of your 
participation in this trial, in accordance with the regulations currently in force [include reference 
to applicable local regulations], that covers the legal civil liability of the policy holder, as Sponsor 
of the trial, of the investigator and his staff, the hospital or the site where the study is conducted 
and their titular, and that will provide you with the compensation and indemnity in case of 
impairment of your health or injuries that might happen in relation to the participation in this trial. 
This insurance has been taken out with the company Chubb European Group.  
You understand, however, that you have not waived any of your legal rights by signing this 
consent form. 
 
Who to contact to ask questions or to report a possible injury or an adverse event 
related to this clinical research?  
If you have any questions regarding your participation in this study or if you consider that you 
have experienced an injury related with this clinical trial or an adverse event related to the study 
drugs you can contact to: 
 
Dr _______________________________________________________________ 
 
Contact phone ________________________ 


 
Protocol#: MedOPP239 
 
Master Patient Information Sheet and Informed Consent Form 
Master version: 2.0 dated on 4-FEB-2020 
 
 
14 of 16 
You will receive a card indicating that you are participating in this study. The card will include 
the name and phone number of the study doctor. Please have this card with you at all times, as 
long as you remain in the study. 
For questions about your rights while taking part in this study, or if you feel that you have not 
been informed enough about your privacy rights about your health information, or you feel that 
the privacy of your health information has not been protected, you can contact your doctor. 
 
 


 
Protocol#: MedOPP239 
 
Master Patient Information Sheet and Informed Consent Form 
Master version: 2.0 dated on 4-FEB-2020 
 
 
15 of 16 
INFORMED CONSENT FORM 
 
I was informed about the study and had my first discussions with the study doctor or research 
staff about that information. 
I have read and understand the information in this Patient Information Sheet/ Informed Consent 
document. 
I have had an opportunity to ask questions and all of my questions have been answered to my 
satisfaction. 
I voluntarily agree to take part in this study. I do not give up any of my legal rights by signing 
this consent document.  
I have been told that I will receive a signed and dated copy of this document.  
 
I also agree to: 
Blood samples not used on the analysis planned in the present study will be 
maintained in a research collection line for a maximum of 15 years. My 
samples can be used for future research in penile cancer for analysis not 
strictly related to the objectives of the current research, with prior approval 
of a Research Ethics Committee. 
Yes 
  No 
 
 
Tissue samples not used on the analysis planned in the present study will be 
maintained in a research collection line, for a maximum of 15 years. My 
samples can be used for future research in penile cancer for analysis not 
strictly related to the objectives of the current research, with prior approval 
of a Research Ethics Committee.  
Yes 
  No 
 
 
Samples not used beyond the storage period (up of 15 years) are transferred 
to a biobank (if box is unticked non-used samples will be destroyed). 
Yes 
  No 
 
 
 
__________________________________________________ 
Printed name of study participant 
 
 
_________________________________  
 
 
 
________________ 
Signature of study participant   
 
 
 
 
Date of signature1 
 


 
Protocol#: MedOPP239 
 
Master Patient Information Sheet and Informed Consent Form 
Master version: 2.0 dated on 4-FEB-2020 
 
 
16 of 16 
 
 
________________________________________________________  
 
 
Printed Name of the Person Conducting the Consent Discussion2  
 
 
__________________________________________________  
___________________ 
Signature of the Person Conducting the Consent Discussion 
 
Date of signature 
 
 
CONSENT FOR STUDY PARTICIPANT WHO CANNOT READ 
 
Complete this section only if the Signature of an impartial witness is required. (It is required if 
the subject or subject’s legally authorized representative cannot read.) 
 
The study participant has indicated that he is unable to read. An impartial witness should be 
present during the entire consent discussion. One or more members of the study team read the 
consent document to the study participant, discussed it with the study participant and gave the 
study participant an opportunity to ask questions. The witness signs and personally dates the 
consent form. By doing so the witness attests that the consent information was accurately 
explained and that the subject apparently understood and informed consent was given freely. 
 
 
_________________________________________ 
Printed name of impartial witness3 
 
 
___________________________________ 
 
 
_________________ 
Signature of impartial witness  
 
 
 
Date of signature1 
 
(1) Subject / impartial witness must personally date their signature.  
(2) The investigator, or a suitably qualified and trained person designated by the, must sign and date 
the consent document during the same interview when the subject signs the consent document. 
(3) Impartial Witness: A person, who is independent of the study, who cannot be unfairly influenced 
by people involved with the study, who attends the informed consent process if the subject cannot 
read, and who reads the informed consent and any other written information supplied to the 
subject. Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance. 

Prot_000.pdf: 
 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
1 
 
Clinical Study Protocol (CSP) 
 
A Multicenter, Open-Label, Single-ARm, PHase II Clinical Trial to Evaluate the Efficacy 
and Safety of INCMGA00012 (retifanlimab) in Advanced Penile SquamoUS Cell 
Carcinoma. ORPHEUS 
 
Phase II Study of the Efficacy of INCMGA00012 (retifanlimab) in Penile Squamous Cell 
Carcinoma 
(ORPHEUS) 
 
 
Study Drug(s):  
 
 
INCMGA00012 (retifanlimab) 
EudraCT#: 
 
 
 
2019-001172-11 
Clinical Trials.gov#: 
 
 
NCT04231981 
Study Code#:   
 
 
MedOPP239 
CSP Version and Date:  
 
2.0, 24-Feb-2021 
CSP Review History 
Initial Approved version: 
 
Spain 1.2; 17 Feb 2020 
 
 
 
 
 
Italy 1.3; 11 Jun 2020 
 
 
 
 
 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
2 
I. SPONSOR’S SIGNATURE PAGE 
 
CSP Title: “A Multicenter, Open-Label, Single-ARm, PHase II Clinical Trial to Evaluate the 
Efficacy and Safety of INCMGA00012 (retifanlimab) in Advanced Penile SquamoUS Cell 
Carcinoma. ORPHEUS”. 
 
CSP Short Title: “Phase II Study of the Efficacy of INCMGA00012 (retifanlimab) in Penile 
Squamous Cell Carcinoma (ORPHEUS)”. 
 
Study Code: MedOPP239 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
Marta Martínez de Falcón 
Sponsor 
 
 
Signature 
 
Signature date 
 (DD-Mmm-YYYY) 
 
Xavier Garcia del Muro, M.D. Ph.D. 
Principal Investigator 
 
 
Signature 
 
Signature date 
 (DD-Mmm-YYYY) 
 
David Páez, M.D. Ph.D. 
Sponsor’s Medical Monitor 
 
 
Signature 
 
Signature date 
 (DD-Mmm-YYYY) 
 
 
 
 
 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
3 
II. KEY CONTACTS 
 
Sponsor 
Name: 
 
Medica Scientia Innovation Research (MedSIR) 
Contact Name:  
Alicia García-Sanz, Ph.D. (Scientific Director) 
Address: 
 
Avinguda Diagonal, 211, 27th floor. 08018 – Barcelona (Spain) 
Phone / Fax:  
+34 932 214 135 / +34 932 992 382 
 
 
E-mail: 
 
alicia.garcia@medsir.org 
 
Name: 
 
Medica Scientia Innovation Research (MedSIR) 
Contact Name:  
Marta Martínez de Falcón (International Trial Lead) 
Address: 
 
Avinguda Diagonal, 211, 27th floor. 08018 – Barcelona (Spain) 
Phone / Fax:  
+34 932 214 135 / +34 932 992 382 
 
 
E-mail: 
 
marta.martinezdefalcon@medsir.org 
 
Principal Investigator 
Name: 
 
Xavier Garcia Del Muro, M.D. Ph.D. 
 
Position:  
 
Chief of Oncology Department, Genitourinary Cancer and Sarcoma Unit 
Institution: 
 
Catalan Institute of Oncology, Barcelona (Spain)  
Gran Via 199-203. 08908 – L´Hospitalet de Llobregat (Spain) 
Phone:  
 
+34 932 607 744 
E-mail: 
 
garciadelmuro@iconcologia.net 
 
Sponsor’s Medical Monitor 
Name: 
 
David Páez, M.D. Ph.D. 
Address: 
 
Hospital de la Santa Creu i Sant Pau, UAB – Barcelona (Spain) 
E-mail: 
 
david.paez@medsir.org  
 
Sponsor’s Safety Risk Management 
Name: 
 
Medica Scientia Innovation Research (MedSIR) 
Address: 
 
Avinguda Diagonal, 211, 27th floor. 08018 – Barcelona (Spain) 
Phone / Fax:  
+34 932 214 135 / +34 932 992 382 
E-mail: 
 
pharmacovigilance@medsir.org 
 
 
 
 
 
 
 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
4 
STEERING COMMITTEE 
Name 
Role 
Dr Xavier García del Muro 
Principal Investigator 
Dr David Páez 
Sponsor’s Medical Monitor 
Dr Isabel Tena 
Sponsor’s Medical Scientist 
Principal Investigators of the ORPHEUS Trial 
 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
5 
III. DECLARATION OF INVESTIGATORS 
 
CSP Title: “A Multicenter, Open-Label, Single-ARm, PHase II Clinical Trial to Evaluate the 
Efficacy and Safety of INCMGA00012 (retifanlimab) in Advanced Penile SquamoUS Cell 
Carcinoma. ORPHEUS”. 
CSP Short Title: “Phase II Study of the Efficacy of INCMGA00012 (retifanlimab) in Penile 
Squamous Cell Carcinoma (ORPHEUS)”. 
Study Code: MedOPP239 
 
I have received, reviewed and understood the following: 
a) Protocol version: 2.0, dated on 24-Feb-2021; 
b) Investigator’s Brochure (IB) for INCMGA00012 (retifanlimab), with details of clinical and 
nonclinical data relevant to the study of the products in human subjects. 
§ 
I have been adequately informed about the development of the investigational products to 
date. I will confirm the receipt of updated IBs. I have read this study protocol and agree that 
it contains all the information required to conduct the study. I agree to conduct the study as 
set out in this protocol. 
§ 
I fully understand that any changes instituted by the investigator(s) without previous 
agreement with the Sponsor would constitute a violation of the protocol, including any 
ancillary studies or procedures performed on study patients (other than those procedures 
necessary for the wellbeing of the patients). I am aware that I cannot deviate from or apply 
changes to the protocol without prior approval or the favorable opinion of the Institutional 
Review Board (IRB) or Ethics Committee (EC) and/or before Sponsor’s agreement to avoid 
immediate risk to the trial patients. If this occurs, I agree to inform the Sponsor as to the 
deviation or changes in writing and their reasons, as soon as possible. 
§ 
I will not enroll the first patient in the study until I have received approval from the appropriate 
IRB/EC and until all legal and regulatory requirements in my country have been fulfilled. 
§ 
The study will be conducted in accordance with the moral, ethical, and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and its amendments, the 
International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines 
(ICH E6[R2] GCP) and applicable regulations and laws. 
§ 
I agree to obtain, in the manner described in this protocol and in (ICH E6[R2] GCP), written 
informed consent form (ICF) by the patient or witnessed verbal ICF to participate for all 
patients whose participation in this study is proposed to and before any patient’s study 
specific procedure is done. 
§ 
I will ensure that the study drug(s) supplied by the Sponsor are being used only as described 
in this protocol. 


 
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CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
6 
§ 
I am aware of the requirements for the correct reporting of serious adverse events, and I 
commit to document and to report such events as required by the Sponsor and in accordance 
with Health Authority Regulatory requirements. 
§ 
I agree to supply – upon request – the Sponsor or Sponsor’s representative with evidence of 
current laboratory accreditation, the name and address of the laboratory, and a list of normal 
values and ranges. 
§ 
I agree with the use of results of the study for the purposes of national and international 
registration, publication, and information for medical and pharmaceutical professionals. 
§ 
I agree to keep all source documents and case report forms as specified in the relevant 
sections of this protocol. 
§ 
I will provide all required Regulatory Authority forms, up-to-date curriculum vitae of myself, 
sub-investigators and of any member of my study team (if requested) before the study starts, 
which may be submitted to regulatory authorities. 
§ 
I am aware of the possibility of being audited by the Sponsor or its delegate or inspected by 
regulatory authorities for the performance of this study. I will permit monitoring, auditing and 
inspection and provide direct access to source data/documents and reports for these 
purposes. 
§ 
Furthermore, I confirm herewith that the Sponsor is allowed to enter and utilize my 
professional contact details and function in an electronic database for internal purposes and 
for submission to Health Authorities worldwide. 
 
 
Name:  _____________________________________________________________________ 
 
 
 
Signature: _________________________ 
 
Date: __________________________ 
 
 
 
 
 
 
 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
7 
IV. CSP SYNOPSIS 
CSP Title: 
“A Multicenter, Open-Label, Single-ARm, PHase II Clinical Trial to 
Evaluate the Efficacy and Safety of INCMGA00012 (retifanlimab) in 
Advanced Penile SquamoUS Cell Carcinoma. ORPHEUS”. 
CSP Short Title 
“Phase II Study of the Efficacy of INCMGA00012 (retifanlimab) in 
Penile Squamous Cell Carcinoma (ORPHEUS)”. 
Study Code: 
MedOPP239 
EudraCT Number: 
2019-001172-11 
Investigational 
Medicine Product: 
INCMGA00012 (retifanlimab)  
Trial Design: 
This is a multicenter, open-label, single-arm, phase II clinical trial. 
Target Disease: 
Unresectable locally advanced or metastatic penile squamous cell 
carcinoma (PSqCC). 
Patients: 
Men age ≥ 18 years with locally advanced unresectable or metastatic 
PSqCC stage 4 (i.e., T4 or N3 or M1) that are presenting with 
radiologic progression of disease (PD) following or not standard 
treatment with chemotherapy. PD must be based on Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 criteria. 
Patients are not eligible if they are candidates for a local treatment 
with a curative intention. Patients must present Eastern Cooperative 
Oncology Group (ECOG) Performance Status (PS) 0-1 and with 
adequate organ function. 
Formalin-fixed paraffin-embedded (FFPE) tumor biopsy and blood 
samples are mandatory for performing exploratory analyses. 
Number of Patients: 
18 patients. 
Study Objectives 
Primary objective: 
• 
To assess the efficacy –as determined by the objective response 
rate (ORR)– of INCMGA00012 (retifanlimab) in patients with 
unresectable locally advanced or metastatic PSqCC. 
 
Secondary objectives: 
• 
To assess the efficacy –as determined by clinical benefit rate 
(CBR), the progression-free survival (PFS), the 6-month 
progression-free survival (PFS), duration of response (DoR), 
time to progression (TTP), overall survival (OS), and maximum 
tumor shrinkage– of INCMGA00012 (retifanlimab) in these 
patients. 
• 
To evaluate the safety and tolerability of INCMGA00012 
(retifanlimab) in these patients. 


 
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8 
 
Exploratory objectives: 
• 
To determine the efficacy –as determined by the ORR, CBR and 
6-month PFS based on immune-related RECIST (irRECIST). 
• 
To evaluate predictive or prognostic, tumor- and/or immune-
related biomarkers associated with disease activity status or 
response to treatment. 
• 
To identify possible mechanisms of resistance to study 
treatments through the comparative analysis of potential 
biomarkers from paired pre-treatment and post-progression 
tumor and/or blood samples. 
• 
To assess impact of INCMGA00012 (retifanlimab) on HIV control 
in participants who are known to be HIV-positive. 
Study Endpoints 
Primary endpoint: 
• 
ORR will be evaluated according to the investigator as per 
RECIST v.1.1. 
 
Secondary endpoints: 
• 
OS, and CBR, PFS, 6-month PFS, DoR, TTP, and maximum 
tumor shrinkage that will be evaluated as per RECIST v.1.1. 
• 
The safety and tolerability will be evaluated by incidence of 
adverse events (AEs), incidence of prespecified AEs, change 
from baseline in targeted vital signs, and change from baseline 
in targeted clinical laboratory test results. 
 
Exploratory endpoints: 
• 
ORR, CBR and 6-month PFS as per irRECIST. 
• 
Relationship 
between 
tumor- 
and/or 
immune-related 
biomarkers, and efficacy in tumor tissue and/or liquid biopsy. 
• 
Changes from baseline in the CD4-positive cell count and HIV 
viral load in participants who are known to be HIV-positive. 
Selection criteria: 
Inclusion criteria: 
Patients must meet ALL of the following inclusion criteria to be 
eligible for enrolment into the study: 
1. 
Patients have been informed about the nature of study, and 
have agreed to participate in the study, and signed the informed 
consent form (ICF) prior to participation in any study-related 
activities. 
2. 
Male patients ≥ 18 years of age at the time of signing ICF. 


 
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9 
3. 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status (PS) 0-1. 
4. 
Life expectancy ≥12 weeks. 
5. 
Histologically-proven PSqCC. 
6. 
Locally advanced unresectable or metastatic stage 4 PSqCC 
that is not amenable to resection with curative intent (T4 or N3 
or M1). 
7. 
Radiological evidence of locally advanced or metastatic 
disease. 
8. 
Patients must have measurable disease or evaluable disease 
according to Response Evaluation Criteria in Solid Tumors 
(RECIST) version (v.)1.1 criteria. 
9. 
Patients must agree to provide a tumor tissue sample from a 
metastatic site or the primary tumor at the time of study entry, 
with the exception of patients whom tumor biopsies cannot be 
obtained (e.g., inaccessible tumor or subject safety concern) 
that may submit an archived tumor specimen only upon 
agreement from the Sponsor. If feasible, patients will also be 
given the option of providing a tumor tissue sample at disease 
progression from metastasis or primary tumor (if tumor biopsies 
cannot be obtained for inaccessible lesion or subject safety 
concern). 
10. Willingness and ability to provide blood samples (liquid biopsy) 
at the time of inclusion, after 2 cycles of study treatment (C3D1), 
and upon PD or study termination.  
11. Adequate organ function: 
a. 
Hematological: White blood cell (WBC) count > 3.0 x 109/L, 
absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet 
count ≥ 75.0 x109/L, and hemoglobin > 9.0 g/dL. 
b. 
Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× 
ULN) (< 3 x ULN in the case of Gilbert’s disease); aspartate 
transaminase (AST), and alanine transaminase (ALT) ≤ 
2.5 times × ULN (in the case of liver metastases ≤ 5 × 
ULN); Albumin > 2.5 mg/mL. 
c. 
Renal: Serum creatinine ≤ 1.5 x ULN; alternately measured 
or calculated creatinine clearance ≥30 mL/min with 
creatinine levels >1.5 × institutional ULN (glomerular 
filtration rate [GFR] can also be used in place of creatinine 
or creatinine clearance).  
d. 
Coagulation: Activated Partial Thromboplastin Time 
(aPTT) ≤1.5 X ULN and International Normalized Ratio 
(INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject 
is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants. 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
10 
12. Patients who are willing and able to comply with scheduled 
visits, treatment plan, laboratory tests, and other study 
procedures. 
13. Subjects should agree to use an adequate method of 
contraception starting with the first dose of study therapy 
through 180 days after the last dose of study treatment. 
14. Patients that have received prior chemotherapy regimens or 
radiotherapy for locally recurrent and/or metastatic disease are 
not excluded but patients naïve of systemic treatment can also 
be included. 
15. For 
pretreated 
patients, 
last 
dose 
of 
chemotherapy 
administered ≥ 28 days from study entry. 
 
Exclusion criteria 
Patients will be excluded from the study if they meet ANY of the 
following criteria: 
1. Locally PSqCC candidate for curative treatment. 
2. Prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 
agent. 
3. Known 
hypersensitivity 
to 
any 
of 
the 
excipients 
of 
INCMGA00012 (retifanlimab). 
4. Receipt of anticancer therapy or participation in another 
interventional clinical study within 28 days before the first 
administration of study drug; 6 weeks for mitomycin C. 
5. Radiotherapy within 14 days of first dose of study treatment with 
the following caveat: 28 days for pelvic radiotherapy.  
6. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or 
baseline (with the exception of any grade of alopecia and 
anemia not requiring transfusion support). Endocrinopathy, if 
well-managed, is not exclusionary and should be discussed 
with Sponsor’s medical monitor. 
7. Major surgery (defined as requiring general anesthesia) or 
significant traumatic injury within 4 weeks of start of study drug, 
or patients who have not recovered from the side effects of any 
major surgery, or patients who may require major surgery 
during the study. 
8. Known active uncontrolled or symptomatic Central Nervous 
System (CNS) metastases, carcinomatous meningitis, or 
leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with a 
history of CNS metastases or cord compression are eligible if 
they have been definitively treated (e.g., radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants 
and steroids for at least 4 weeks before randomization. 
9. Cardiovascular: patients that have any of the following within 6 
months of randomization: severe/unstable angina, myocardial 
infarction, symptomatic pericarditis, symptomatic congestive 
heart 
failure 
(New 
York 
Heart 
Association 
functional 


 
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CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
11 
classification 
III-IV), 
cerebrovascular 
accident 
including 
transient ischemic attack, or symptomatic pulmonary embolism, 
coronary/peripheral artery bypass graft, ongoing cardiac 
dysrhythmias 
of 
National 
Cancer 
Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) v.5.0 
grade ≥2, including, ventricular arrhythmias ‒except for benign 
premature ventricular contractions‒, supraventricular and nodal 
arrhythmias requiring a pacemaker or not controlled with 
medication, any conduction abnormality requiring a pacemaker 
or any cardiac arrhythmia not controlled with medication. 
10. Metabolic: Uncontrolled hyper/hypothyroidism or diabetes 
mellitus type 1 (T1DM). Patients with hypothyroidism stable on 
hormone replacement will not be excluded from the trial. 
Patients with controlled T1DM on a stable insulin regimen may 
be eligible for this study. 
11. Diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or immunosuppressive therapy within seven days prior 
to study treatment initiation. 
12. Active autoimmune disease that has required systemic 
treatment in past 2 years (i.e., with use of disease modifying 
agents, corticosteroids, or immunosuppressive drugs). 
Note: Replacement therapy (e.g., thyroxine, insulin, or 
physiologic steroid replacement therapy (≤ 10 mg prednisone 
daily) for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
13. Prior allogenic stem cell or solid organ transplantation. 
14. Has received a live vaccine within 28 days of the planned start 
of study drug. 
Note: Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, chicken pox/zoster, 
yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, 
intranasal influenza vaccines (e.g., FluMist®) are live-
attenuated vaccines and are not allowed. 
15. Active/history of pneumonitis requiring treatment with steroids 
or active/history of interstitial lung disease. 
16. Active uncontrolled infection at the time of screening. 
17. Latent tuberculosis determined by a positive TST followed by 
confirmation by pulmonologists. 
18. Participants who are known to be human immunodeficiency 
virus (HIV)-positive, unless all of the following criteria are met: 
a. CD4-positive count ≥ 300/μL; 
b. Undetectable viral load; 
c. Receiving highly active antiretroviral therapy. 
19. Active hepatitis A virus (HAV) (positivity for HAV IgM antibody), 
hepatitis B virus (HBV) (patients with negative hepatitis B 
surface antigen [HBsAg] test and a positive antibody to HBsAg 
[anti–HBsAg] test at screening are eligible) or hepatitis C virus 
(HCV) (patients with a positive antibody to hepatitis C [anti–


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
12 
HCV] are eligible only if polymerase chain reaction [PCR] is 
negative for virus hepatitis C ribonucleic acid [RNA]). 
20. Known additional malignancy that is progressing or requires 
active treatment, or history of other malignancy within 3 years 
of study entry with the exception of cured basal cell or 
squamous cell carcinoma of the skin, superficial bladder 
cancer, prostate intraepithelial neoplasm, or other noninvasive 
or indolent malignancy, or cancers from which the participant 
has been disease-free for >1 year, after treatment with curative 
intent. 
21. Patients have any other concurrent severe and/or uncontrolled 
medical condition that would, in the Investigator’s judgment 
contraindicate patient participation in the clinical study. 
Treatment: 
After signing the ICF and confirmed eligibility, patients will receive 
INCMGA00012 (retifanlimab) 500 mg by intravenous infusion on 
Day1 of each cycle, once every four weeks for up to 2 years. 
Patients 
will 
receive 
treatment 
until 
disease 
progression, 
unacceptable toxicity, death, or discontinuation from the study 
treatment for any other reason.  
Patients discontinuing the study treatment period will enter a post-
treatment follow-up period during which survival and new anti–
cancer therapy information will be collected every 3 months (± 14 
days) from the last dose of investigational product until the end of 
study (EoS).  
Study 
Procedures, 
Efficacy and Safety 
Assessments: 
Patient visits: 
Visits are organized in programmed cycles of 28 days (if there are 
no delays in treatment owing to the occurrence of an AE). After 
baseline, all visits must occur within ± 3 working days from the 
scheduled date, unless otherwise noted in the schedule of 
assessments, and every 12 weeks after documented PD. 
Assessments scheduled for Day 1 of each cycle must be performed 
within 72 hours prior to study treatment administration, unless 
otherwise indicated in the schedule of assessments, in order to 
confirm to the patient if treatment can be followed up. 
 
Efficacy assessments: 
Tumor assessments will be performed until radiographically and/or 
clinically documented PD as per RECIST criteria v.1.1, study 
treatment discontinuation, initiation of new anticancer therapy, or 
discontinuation of patient from overall study participation (i.e., death, 
patient's request, lost to follow-up), whichever occurs first. 
 


 
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CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
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Clinical assessment. Examination of the penis and/or inguinal 
region: 
Radiographic assessment: [computerized tomography (CT) of the 
chest, abdomen, and pelvis or magnetic resonance imaging (MRI) of 
the abdomen and pelvis with a non-contrast CT scan of the chest in 
patients for whom CT scans with contrast are contraindicated] will be 
performed using RECIST v.1.1 every 8 weeks (± 7 days) from the 
first dose of study treatment up to 6 months (more frequently if 
clinically indicated). All subjects who remain on treatment for 6 
months will subsequently have imaging performed every 12 weeks 
(± 7 days). Imaging should continue to be performed until radiologic 
evidence of PD, treatment discontinuation, the start of new anti–
cancer treatment, withdrawal of consent, death, or the EoS, 
whichever occurs first. Bone scans will also be used to assess bone 
metastases. If a subject has a known history of bone metastases or 
has new bone pain during screening, a bone scan should be 
obtained prior to study entry. A bone scan at follow-up is required 
only if they develop new or worsening symptoms or if the site 
believes they have attained a complete response (CR). If a subject 
has no known metastatic disease in the bone or active symptoms, a 
bone scan at baseline is not needed.  
After PD by RECIST v.1.1, if the site Investigator determines the 
subject is clinically stable and will benefit from continued treatment, 
the subject will then be managed by irRECIST. 
Each assessment will be performed as scheduled according to the 
calendar regardless of any dosing delay to prevent the introduction 
of bias into the assessment of efficacy. Failure to perform any of the 
required disease assessments will result in the inability to determine 
disease status for that time point.  
Tumor samples for molecular analysis are required for patient 
participation and patients must agree to provide tissues from a 
metastatic site or the primary penile tumor at the time of study entry 
(that should be available for at least 60% of patients) and at the time 
of PD. Provision of previous archival tissue is acceptable for patients 
with non-measurable disease, or inaccessible lesions.  
Blood samples for molecular analysis will be collected at the time of 
baseline, after 2 cycles of study treatment (C3D1), and upon PD or 
EoS. 
 
Safety assessments:  
The occurrence and maximum grade of AEs observed throughout 
the study will be listed. Any AE that the Investigator reports as 
unrelated to the drug will also be reported. In this study, AEs will be 
assessed according to the NCI-CTCAE v.5.0. 
Statistics: 
The sample size calculation is based on an exact binomial test. The 
clinical trial is designed to demonstrate an ORR of at least 25% and 


 
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to exclude a rate of less than 5% (p0=0.05, p1=0.25, α =0.05, 
β=0.80, A’hern’s exact design). At least 3 responders (18.8%) 
among 16 evaluable patients will be adequate to justify the 
investigation of this strategy in further clinical trials. Considering a 
drop-out rate of 10%, a sample size of 18 patients will be needed to 
attain 80% power at nominal level of one-sided alpha of 0.05. 
The full analysis set will be considered the primary population for the 
analysis. 
Study Periods 
Recruitment period: 
Estimated at least 12 months in order to enroll 18 patients. 
End of study: 
EoS will occur 12 months after the last patient has been enrolled in 
the study (treatment start).  


 
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V. TABLE OF ABBREVIATIONS 
Definition 
Abbreviation 
AE 
Adverse event 
ALK 
Alkaline phosphatase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
BCG 
Bacillus Calmette–Guérin 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
CNS 
Central Nervous System 
CR 
Complete response 
CRF 
Case report form 
CRO 
Clinical Research Organization 
DEHP 
(2-ethylhexyl) phthalate 
DNA 
Deoxyribonucleic acid 
DoR 
Duration of response 
EC 
Ethics Committee 
ECI 
Event of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EoS 
End of study 
EoT 
End of treatment 
ESA 
Erythropoiesis-stimulating agents 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed and paraffin-embedded 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyl transferase 
HAV 
Hepatitis A virus 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HNSqCC 
Head and neck region 
HPV 
Human papillomavirus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICI 
Immune checkpoint inhibitor 
IFN 
Interferon 
IMP 
Investigational medicinal product 
INR 
International Normalized Ratio 
irAE 
Immune-related adverse event 
IRB 
Institutional Review Board 
irRECIST 
Immune-related RECIST 
ITT 
Intention-to-treat 
mAb 
Monoclonal antibody 


 
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Definition 
Abbreviation 
MMR 
Mismatch repair 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for 
Adverse Events 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PCR 
Polymerase chain reaction 
PD 
Progressive disease 
PD-1 
Programmed cell death protein 1 
PD-L1 
Programmed Death-ligand 1 
PES 
Polypropylene and polyethersulfone 
PFS 
Progression-free survival 
PP 
Per protocol 
PR 
Partial response 
PS 
Performance Status 
PSqCC 
Penile squamous cell carcinoma 
PT 
Prothrombin Time 
PVC 
Polyvinylchloride 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SCAC 
Squamous Carcinoma of the Anal Canal 
SD 
Stable disease 
SqCC 
Squamous cell carcinoma 
T1DM 
Diabetes mellitus type 1 
TEAE 
Treatment Emergent Adverse Event 
TMB 
Tumor mutational burden 
TRAE 
Treatment-related AE 
TSH 
Thyroid-stimulating hormone 
TST 
Mantoux tuberculin skin test 
TTP 
Time to progression 
ULN 
Upper limit of normal 
UPN 
Unique Patient Number 
WBC 
White blood cell 
 
 


 
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VI. TABLE OF CONTENTS 
 
I. SPONSOR’S SIGNATURE PAGE ........................................................................................................... 2 
II. KEY CONTACTS ................................................................................................................................. 3 
III. DECLARATION OF INVESTIGATORS .................................................................................................. 5 
IV. CSP SYNOPSIS ................................................................................................................................. 7 
V. TABLE OF ABBREVIATIONS ............................................................................................................. 15 
VI. TABLE OF CONTENTS .................................................................................................................... 17 
VII. LIST OF TABLES ............................................................................................................................ 19 
VIII. LIST OF FIGURES ......................................................................................................................... 19 
1 
STUDY BACKGROUND AND RATIONALE .................................................................................... 20 
1.1 
INTRODUCTION ............................................................................................................................ 20 
1.2 
PD-1 CHECKPOINT INHIBITION AND CANCER TREATMENT .................................................................... 21 
1.3 
PRECLINICAL STUDIES WITH PD-1 ICIS ............................................................................................. 21 
1.4 
ROLE OF IMMUNOTHERAPY IN UROTHELIAL CANCERS AND SQUAMOUS NON-SMALL CELL LUNG CANCER ..... 22 
1.5 
THE ROLE OF IMMUNOTHERAPY IN HPV-RELATED CANCER .................................................................. 23 
1.6 
INCMGA00012 (RETIFANLIMAB) .................................................................................................. 24 
1.6.1 
Preclinical Efficacy .............................................................................................................. 24 
1.6.2 
Clinical Efficacy ................................................................................................................... 25 
1.6.3 
Clinical Safety ..................................................................................................................... 27 
1.6.3.1 
General Information ................................................................................................................ 31 
1.6.3.2 
Dermatologic Toxicity .............................................................................................................. 31 
1.6.3.3 
Diarrhea ................................................................................................................................... 31 
1.6.3.4 
Hepatotoxicity ......................................................................................................................... 31 
1.6.3.5 
Endocrinopathies ..................................................................................................................... 32 
1.6.3.6 
Less Common irAEs .................................................................................................................. 32 
1.7 
RATIONALE FOR DOSE SELECTION OF INCMGA00012 (RETIFANLIMAB) ................................................ 32 
1.8 
STUDY RATIONALE ....................................................................................................................... 33 
2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 34 
2.1 
PRIMARY OBJECTIVE ..................................................................................................................... 34 
2.1.1 
Primary Endpoint ................................................................................................................ 34 
2.2 
SECONDARY OBJECTIVES ............................................................................................................... 34 
2.2.1 
Secondary Endpoints .......................................................................................................... 34 
2.3 
EXPLORATORY OBJECTIVES ............................................................................................................. 34 
2.3.1 
Exploratory Endpoints ........................................................................................................ 35 
3 
STUDY DESIGN .......................................................................................................................... 35 
3.1 
DESCRIPTION OF STUDY DESIGN ...................................................................................................... 35 
3.2 
STUDY SCHEDULE SUMMARY .......................................................................................................... 36 
3.2.1 
Screening Phase ................................................................................................................. 36 
3.2.2 
Treatment Phase ................................................................................................................ 36 
3.2.3 
End of Treatment Visit ........................................................................................................ 36 
3.2.4 
Follow-up after treatment discontinuation ........................................................................ 36 
4 
PATIENT SELECTION .................................................................................................................. 37 
4.1 
STUDY POPULATION ..................................................................................................................... 37 
4.2 
INCLUSION CRITERIA ..................................................................................................................... 37 
4.3 
EXCLUSION CRITERIA ..................................................................................................................... 39 
5 
TREATMENT .............................................................................................................................. 41 


 
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5.1 
FORMULATION, PACKAGING, AND HANDLING .................................................................................... 41 
5.2 
DOSAGE AND ADMINISTRATION ...................................................................................................... 41 
5.3 
TREATMENT MODIFICATION ........................................................................................................... 42 
5.4 
MODIFICATION OF THE AMOUNT OF STUDY DRUG ADMINISTERED DUE TO CHANGES IN PATIENT’S WEIGHT . 42 
5.4.1 
Drug Extravasation ............................................................................................................. 47 
5.5 
GENERAL CONCOMITANT MEDICATION AND ADDITIONAL ASSISTANCE GUIDELINES ................................... 47 
5.6 
PROHIBITED CONCOMITANT MEDICATIONS ....................................................................................... 48 
5.7 
MEDICATION ERRORS AND OVERDOSE ............................................................................................. 49 
5.8 
TREATMENT COMPLIANCE ............................................................................................................. 50 
6 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................. 50 
6.1 
INFORMED CONSENT FORM ........................................................................................................... 50 
6.2 
VISIT SCHEDULE ........................................................................................................................... 51 
6.3 
DEMOGRAPHIC DATA AND MEDICAL HISTORY ................................................................................... 51 
6.4 
EFFICACY ASSESSMENTS ................................................................................................................ 52 
6.4.1 
Tumor and Response Evaluations ...................................................................................... 52 
6.4.2 
Response Assessment ......................................................................................................... 52 
6.4.3 
OS and PFS Definitions ....................................................................................................... 53 
6.4.4 
irRECIST .............................................................................................................................. 54 
6.5 
SAFETY AND TOLERABILITY ASSESSMENTS ......................................................................................... 55 
6.5.1 
Laboratory Assessments ..................................................................................................... 55 
6.5.1.1 
HIV Management Control ........................................................................................................ 56 
6.5.2 
Pregnancy and Assessment of Fertility ............................................................................... 56 
6.5.3 
Physical Examination .......................................................................................................... 56 
6.5.4 
Vital Signs ........................................................................................................................... 56 
6.5.5 
ECOG PS .............................................................................................................................. 57 
6.6 
TRANSLATIONAL RESEARCH ............................................................................................................ 57 
6.6.1 
Tumor Samples ................................................................................................................... 58 
6.6.2 
Blood Samples .................................................................................................................... 58 
6.7 
DISCONTINUATION OF PATIENT, STUDY, OR SITE PARTICIPATION ........................................................... 58 
6.7.1 
Patient Discontinuation ...................................................................................................... 58 
6.7.2 
Study and Site Discontinuation ........................................................................................... 59 
7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ............................................................ 59 
7.1 
AES DEFINITIONS ......................................................................................................................... 60 
7.1.1 
Infusion-related reactions .................................................................................................. 61 
7.1.2 
Expected Treatment Emergent Immune-Related Adverse Events (irAEs) ........................... 62 
7.2 
SAES ......................................................................................................................................... 63 
7.3 
EVENTS OF CLINICAL INTEREST (ECI) FOR INCMGA00012 (RETIFANLIMAB) ........................................... 65 
7.4 
AES REPORTING AND OTHER SAFETY RELATED ISSUES REPORTING ......................................................... 66 
7.5 
SAE REPORTING AND TIMEFRAME .................................................................................................. 67 
7.6 
EXPEDITED REPORTING TO HAS, INVESTIGATORS, IRBS, AND ECS .......................................................... 67 
7.7 
OTHER SAFETY-RELATED REPORTS .................................................................................................. 68 
7.8 
PREGNANCY REPORTING ............................................................................................................... 69 
8 
STASTICAL CONSIDERATIONS AND ANALYSIS PLAN ................................................................... 69 
8.1 
SAMPLE SIZE ............................................................................................................................... 69 
8.2 
JUSTIFICATION OF SAMPLE SIZE ....................................................................................................... 69 
8.3 
ANALYSIS SETS ............................................................................................................................ 70 
8.4 
STATISTICAL PLAN ........................................................................................................................ 71 
8.4.1 
Primary Efficacy Endpoint .................................................................................................. 71 
8.4.2 
Secondary Efficacy Endpoints ............................................................................................. 71 
8.4.3 
Exploratory Endpoints ........................................................................................................ 71 
8.4.4 
Analysis of Baseline and Demographic Variables ............................................................... 71 
8.4.5 
Decision Rules and Adjustment of Alpha in The Study ....................................................... 71 


 
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8.4.6 
Primary Efficacy Analysis .................................................................................................... 72 
8.4.7 
Secondary Efficacy Outcomes ............................................................................................ 72 
8.4.8 
Subgroup Efficacy Analysis ................................................................................................. 72 
8.4.9 
Exploratory Analysis ........................................................................................................... 73 
8.5 
SAFETY OUTCOMES ...................................................................................................................... 73 
8.6 
MISSING DATA MANAGEMENT ....................................................................................................... 74 
8.7 
STEERING COMMITTEE REVIEW ...................................................................................................... 74 
9 
ETHICAL CONSIDERATIONS ....................................................................................................... 74 
9.1 
REGULATORY AND ETHICS COMPLIANCE ........................................................................................... 74 
9.2 
IRBS/IECS ................................................................................................................................. 75 
9.3 
INFORMED CONSENT .................................................................................................................... 75 
9.4 
DATA PROTECTION ....................................................................................................................... 76 
10 
SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE ......................... 76 
10.1 
SOURCE DATA DOCUMENTATION .................................................................................................... 76 
10.2 
STUDY MONITORING AND SOURCE DATA VERIFICATION ...................................................................... 77 
10.3 
RETENTION OF RECORDS ............................................................................................................... 78 
10.4 
DATA QUALITY ASSURANCE ........................................................................................................... 78 
11 
DATA MANAGEMENT ............................................................................................................... 79 
11.1 
DATA ENTRY AND MANAGEMENT ................................................................................................... 79 
11.2 
DATA CLARIFICATION .................................................................................................................... 79 
11.3 
DATA CODING PROCEDURES .......................................................................................................... 79 
12 
STUDY MANAGEMENT .............................................................................................................. 80 
12.1 
DISCONTINUATION OF THE STUDY ................................................................................................... 80 
12.2 
CHANGES TO THE PROTOCOL .......................................................................................................... 80 
12.3 
PUBLICATION POLICY PROTECTION OF TRADE SECRETS ........................................................................ 80 
13 
REFERENCES ............................................................................................................................. 81 
 
 
VII. LIST OF TABLES 
TABLE 1. TOXICITY MANAGEMENT GUIDELINES FOR IMMUNE-RELATED AES ASSOCIATED WITH 
INCMGA00012 (RETIFANLIMAB). .......................................................................................... 44 
TABLE 2. GUIDELINES FOR MANAGEMENT OF SUSPECTED INFUSION REACTIONS. ............................. 46 
TABLE 3. ECOG PS SCALE. .......................................................................................................... 57 
TABLE 4. TREATMENT EMERGENT IRAES ........................................................................................ 63 
TABLE 5. SAES ............................................................................................................................. 65 
 
 
VIII. LIST OF FIGURES 
FIGURE 1. INCMGA00012 (RETIFANLIMAB)-MEDIATED INHIBITION OF SOLUBLE PD-L1 OR PD-L2 
BINDING TO A PD-1 EXPRESSING CELL LINE (NS0/PDCD1). .................................................. 25 
FIGURE 2. INCMGA00012 (RETIFANLIMAB)-MEDIATED REVERSAL OF PD-1/PD-L1 INHIBITORY 
SIGNALING AS MEASURED BY LUCIFERASE GENE EXPRESSION IN A CO-CULTURE REPORTER 
ASSAY SYSTEM. ................................................................................................................... 25 
 
 
 


 
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1 
STUDY BACKGROUND AND RATIONALE 
1.1 
Introduction 
Squamous cell carcinoma (SqCC) is the most common primary neoplasm of the penis (95% 
of penile tumors), but only 0.4% to 0.6% of all malignant neoplasms among men in the United 
States and Europe. The incidence of penile SCC (PSqCC) is higher (up to 10%) among men in 
the developing countries of Asia, Africa, and South America (1). High risk human papillomavirus 
(HPV) is responsible for 30-80% of PSqCC tumors. HPV deoxyribonucleic acid (DNA) can be 
identified in around 30-80% of invasive penile cancer cases (2–5). Patients with stage IV PSqCC 
–defined by deep inguinal or pelvic lymph node involvement (stage N3) or distant metastases 
(M1)– have a 5-year overall survival (OS) rate <50% (6). 
Patients with PSqCC present typically in their late 50s or 60s and the vast majority does with 
clinically localized disease, for which organ-preserving surgical excision and/or radiation are 
usually sufficient for primary treatment (7). The mainstay of treatment for advanced disease has 
been palliative cisplatin-based chemotherapy, with only marginal survival benefit in term of overall 
response rate (ORR) and transient responses (8,9). Best supportive care remains an option for 
advanced cases. For these cases or cases refractory to systemic therapy or radiation therapy 
(RT), the National Comprehensive Cancer Network (NCCN) panel strongly recommends 
consideration of clinical trial participation as data are limited in the second-line setting. 
Although new therapies are being evaluated in PSqCC, very little information is available 
regarding due to limited knowledge of molecular alterations. Among them, Epidermal Growth 
Factor Receptor (EGFR) inhibitors, such as cetuximab have demonstrated a modest benefit in a 
retrospective study (10). Advances on progressive PSqCC present, thus, a therapeutic challenge 
and new approaches to increase efficacy in the field of PSqCC are urgently required. However, 
the rarity of this disease makes it difficult to perform prospective, randomized trials. 
Recent published data have demonstrated that high levels of programmed cell death protein 
1 (PD-1) and its ligand –Programmed Death-ligand 1 (PD-L1)– are found in the majority of primary 
and metastatic PSqCC patients (11–14) in line with other various SCC, suggesting that targeting 
immune checkpoint pathways may be beneficial in these patients. PSqCC, SCC of the head and 
neck region (HNSqCC) and cervical SCC have reasonably high tumor mutational burden (TMB), 
being ranked just behind melanoma, lung, bladder and esophageal and colorectal cancer (15,16). 
The use of immune checkpoint inhibitors (ICIs) such as nivolumab or pembrolizumab –two 
humanized antibodies against PD-1‒ has been a successful strategy in patients with many of 
these tumors gaining the approval by the U.S. Food and Drug Administration (FDA) for several 
indications. 
In addition, a single institution study very recently demonstrated that PSqCC is genomically 
similar to other more common HPV-related tumors, with a TMB value as high as lung SqCC and 
HNSqCC but with no significant correlation with HPV infection (15). 


 
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For HPV-related cancers, immune responses appear to be driven by a combination of both 
viral and non-viral antigens (17) and the role of HPV in PD-1 pathway and the efficacy of ICIs is 
still controversial. These data provide a rational basis for further investigation of anti–PD-1 and 
anti–PD-L1 immunotherapeutic in patients with advanced PSqCC. Of the patients who do 
respond, many can have long-term survival and therefore there is much interest in identifying 
these patients using prognostic and predictive biomarkers (18). 
 
1.2 
PD-1 Checkpoint Inhibition and Cancer Treatment 
The basis of immunotherapy is to boost the host immune response against the tumor. PD-1 
cells to suppress T cell activation and therefore promote immune evasion. The importance of 
intact immune surveillance in controlling outgrowth of neoplastic transformation has been known 
for decades. Extensive evidence has demonstrated a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and prognosis in several tumor types (19–25). 
The PD-1 receptor-ligand interaction is critical to suppress immune control. The normal 
function of PD-1, expressed on the cell surface of activated T cells under healthy conditions, is to 
down-modulate excessive immune responses. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T lymphocyte–associated 
antigen 4 (CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2). Binding of PD-L1 to PD-1 inhibits T cell 
activation triggered through the T cell receptor in peripheral tissues, whereas PD-L2 is thought to 
control immune T cell activation in lymphoid organs (26).  
PD-L1 and PD-L2 are constitutively expressed or can be induced in a variety of cell types. 
Their interaction with the PD-1 receptor on tumor-specific T cells plays a decisive role in immune 
evasion by tumors. As a consequence, the PD-1/PD-L1 pathway is an attractive target for 
therapeutic intervention in cancer. 
The first immune checkpoint inhibitor to be approved for clinical use was the anti–CTLA4 
antibody ipilimumab. Since then, anti–PD-1 (nivolumab and pembrolizumab) and anti–PD-L1 
(atezolizumab) agents have been approved for various types of cancers. 
 
1.3 
Preclinical Studies with PD-1 ICIs 
Preclinical data from mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction increases infiltration of tumor-specific CD8-positive T cells and finally 
guides to tumor rejection, either as a monotherapy or in combination with other treatment 
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Anti–mouse PD-1 or PD-L1 antibodies have demonstrated antitumor responses in models of 
SqCC, pancreatic carcinoma, melanoma, breast carcinoma, acute myeloid leukemia, and 
colorectal carcinoma, among others. In these studies, tumor infiltration by CD8-positive T cells 
and increased interferon (IFN)-γ, granzyme B, and perforin expression were observed, reflecting 
that the principal mechanism that probably justify the antitumor activity of PD-1 checkpoint 
inhibition involved local infiltration and activation of effector T cell function in vivo. 
 
1.4 
Role of Immunotherapy in Urothelial Cancers and Squamous Non-Small Cell Lung 
Cancer  
Nivolumab and pembrolizumab –two humanized IgG4 (S228P) monoclonal antibody that 
targets PD-1– received FDA accelerated approval for the treatment of urothelial carcinoma after 
unsuccessful front- and second-line chemotherapy (29–31). Both agents have been 
demonstrated to be superior in terms of efficacy and safety to other second-line approved agents 
(paclitaxel, docetaxel, or vinflunine). Nivolumab provided meaningful ORR and pembrolizumab 
was able to prolong OS in almost 3 months irrespective of PD-L1 expression. Atezolizumab also 
has demonstrated to be effective and safe as first-line agent for the treatment of patients with 
locally advanced and unresectable or metastatic urothelial cancer and comorbidities (32) and 
was approved as fist-line agent in ‘unfit’ patients. Currently, pembrolizumab in the first-line setting 
is being further assessed in the Phase III KEYNOTE-361 trial (NCT02335424).  
Regarding squamous non-small cell lung cancer (NSCLC), nivolumab was able to almost 
double 1-year OS compared to standard chemotherapy (docetaxel) in patients with metastatic 
squamous NSCLC who had experienced progressive disease (PD) during or after one prior 
platinum-based chemotherapy (9.2 months, 95% confidence interval [CI] 7.3–13.3 vs. 6 months, 
95% CI 5.1–7.3) (33) and is recommended by the FDA for patients with NSCLC in this setting, 
particularly in those with squamous histology. In these studies, PD-L1 expression ‒in line with 
other ICIs studies‒ was neither prognostic nor predictive biomarker of benefit, because some 
patients with negative PD-L1 status showed a response to PD-1 blockade.  
Regarding PSqCC, recent observations address that the use of ICIs such as pembrolizumab 
is effective in PSqCC that present with DNA mismatch repair (MMR)-deficiency (34). These 
represent a very low proportion of patients, however.  
Currently, several ongoing clinical trials are evaluating the role of the anti–PD-L1 in PSqCC 
patients. Whereas it is truth that for fit patients, another clinical trial (NCT04224740) –not still 
recruiting–, will be evaluating the role of the anti–PD-L1 pembrolizumab in combination with 
cisplatin-based chemotherapy as first-line (HERCULES), the majority of clinical trials are using 
immunotherapy as a single modality of treatment in both chemo-naive or pretreated with cisplatin-
based chemotherapt patients. The NCT03686332 trial evaluating the role of atezolizumab to 
control locoregional lymph node disease is directed to chemo-naïve patients, whereas the 


 
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NCT03391479 trial is evaluating the role of avelumab in patients with advanced disease who are 
unfit for or have progressed after platinum-based chemotherapy. In the NCT02721732 study 
pembrolizumab is administered in patients –pretreated or not–, with tumors that cannot be 
removed by surgery or are metastatic, and the combination of nivolumab with ipilimumab in 
another study also includes chemo-naive PSqCC patients (NCT03333616 and NCT02834013). 
Regarding second-line, another study (NCT02837042) evaluating pembrolizumab following prior 
chemotherapy or advanced PSqCC has just been terminated. Regarding maintenance therapy, 
the PULSE study (NCT03774901) is evaluating the role of avelumab in patients who are in 
response or with stable disease after first line platinum-containing chemotherapy. 
 
1.5 
The Role of Immunotherapy in HPV-Related Cancer  
HPV is implicated in a significant proportion of oropharyngeal cancers as well as most cervical, 
penile and anal cancers. Although the presence of TILs and PD-L1 expression is less common in 
the HPV-related throat/cervical tumors, patients with HPV-related tumors represent a 
considerable proportion of PD-L1-positive tumors given their high prevalence. Studies 
demonstrating the efficacy of immunotherapy in squamous HPV-related throat carcinoma are 
based on vaccines such as MEDI0457 (35) and AXAL (36) in monotherapy or in AXAL in 
combination for advanced HPV-related throat and cervical carcinoma. 
However, for HPV-related cancers, immune responses is also driven by non-viral antigens 
(17) and all patients will eventually fail to the above mentioned therapies.  
PD-1/PD-L1 are highly expressed among up to 70% HPV-related HNSqCC (37). 
Pembrolizumab is significantly more effective in term of ORR in relapsed/refractory patients with 
HNSqCC HPV-positive compared with HPV-negative (25%, 95% CI 7–52 vs. 14%, 95% CI 4-32) 
(38). 
Nivolumab demonstrated a significant improvement in OS in platinum-resistant HNSqCC 
compared with standard chemotherapy (1-year OS 36% vs. 16.6%) and showed preliminary 
evidence that patients with PD-L1 expression 1% or p16INK4a positive tumors (indicating HPV 
positivity) may derive greater benefit from nivolumab (39). Despite these results, the role of HPV 
in PD-1 pathway is still controversial. 
Regarding other HPV-related tumors, nivolumab and pembrolizumab have also demonstrated 
excellent activity in cervical cancer (18,40,41) and in patients with metastatic SqCC of the anal 
canal (42,43). Regarding cervical cancer, ORR induced by nivolumab was reported as high as 
30% (phase I/II) (18,40). In the partial responders, the median duration of response was 5.4 
months, irrespective of PD-L1 or HPV status (40). For pembrolizumab, the KEYNOTE 158 trial 
has demonstrated ORR of 14.1% (18). Interestingly, 91% of patients had response duration of 
greater than or equal to 6 months. No responses were observed in patients whose tumors had a 


 
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PD-L1 combined positive score (CPS) < 1 (defined as the total number of PD-L1-positive cells 
[tumor, lymphocytes, and macrophages] divided by the total number of tumor cells) (41). 
Following the results of the KEYNOTE 158 trial (18), pembrolizumab was recently approved for 
patients with recurrent or metastatic cervical cancer that progressed on or after chemotherapy 
whose tumors express PD-L1 (CPS ≥1). A higher benefit in HPV-positive patients was not 
confirmed. 
Finally, two studies trying to stratify PD-L1 positivity for HPV status in PSqCC failed to show 
any correlation. Moreover, PD-L1 was expressed mainly in HPV-negative tumors (11,12). 
However, few patients were analyzed, and these results should be interpreted with caution. 
Ongoing trials continue to investigate the role of ICIs in these HPV-related tumors 
(NCT02635360, NCT03073525, NCT03614949, NCT03738228, and NCT03811015). Design of 
future clinical trials should include stratification based on HPV status. 
 
1.6 
INCMGA00012 (retifanlimab) 
1.6.1 
Preclinical Efficacy 
INCMGA00012 –also known as MGA012 or retifanlimab– is a highly selective, hinge-stabilized 
humanized IgG4κ isotype monoclonal antibody (mAb) against PD-1 that is currently under 
development as a therapeutic candidate for the treatment of multiple solid tumors, both as a 
monotherapy and in combination with other potentially immunoactive agents. Upon binding PD-
1, INCMGA00012 (retifanlimab) inhibits the interaction of PD-1 with PD-L1/PD-L2 and disrupts 
the negative signaling axis to restore T-cell function. Consistent with its intended mechanism of 
action and functional properties, INCMGA00012 (retifanlimab) has been shown to inhibit the 
binding of PD-L1 and PD-L2 to PD-1, to disrupt the PD-1/PD-L1 inhibitory axis, and to enhance 
IFN-γ secretion in staphylococcus enterotoxin B-stimulated human peripheral blood mononuclear 
cells with activity comparable to pembrolizumab and nivolumab replicas (generated by 
MacroGenics, Inc. and based on the published sequences of these antibodies) ( 
 
 
 
Figure 1 and Figure 2). INCMGA00012 (retifanlimab) does not induce antibody-dependent 
cellular cytotoxicity or complement dependent cytotoxicity, mitogenic activity, hemolysis, or 
cytokine release. The clinical translational results demonstrate that retifanlimab is biologically 
active at all evaluated dose regimens and activity is as anticipated for a PD-L1 inhibitor. 
 
 
 
 


 
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Figure 1. INCMGA00012 (retifanlimab)-Mediated Inhibition of Soluble PD-L1 or PD-L2 
Binding to a PD-1 Expressing Cell Line (NS0/PDCD1). 
 
 
Figure 2. INCMGA00012 (retifanlimab)-Mediated Reversal of PD-1/PD-L1 Inhibitory 
Signaling as Measured by Luciferase Gene Expression in a Co-Culture Reporter Assay 
System. 
 
 
1.6.2 
Clinical Efficacy 
As of 23 September 2020, 289 participants have received INCMGA00012 (retifanlimab) 
monotherapy in Study INCMGA 0012-101. Preliminary activity in terms of durable RECIST v1.1 
response has also been seen in multiple other tumor types. Based on the available data, the 
efficacy profile of INCMGA00012 (retifanlimab) is expected to be consistent with that of other PD-
(L)1 inhibitors. 
INCMGA00012 (retifanlimab) has shown meaningful clinically activity in platinum-refractory 
Squamous Carcinoma of the Anal Canal (SCAC). Preliminary activity in terms of durable RECIST 
v1.1 responses has also been seen in multiple other tumor types (NSCLC (44), cervical cancer 


 
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(45), biomarker-unselected endometrial cancer (45), sarcoma (45), Merkel cell carcinoma (46), 
and endometrial carcinoma with high levels of MicroSatellite Instability (MSI-H) or deficient 
MisMatch Repair (dMMR) (47). 
 
Efficacy in SCAC (Study INCMGA 0012-202) 
As of 08 June 2020, 94 participants with locally advanced or metastatic SCAC whose cancer 
had progressed on or who were intolerant of platinum-based therapy had received retifanlimab 
500 mg every 4 weeks (Q4W). The study excluded participants with autoimmune disease that 
required systemic immunosuppression and those with an ECOG performance score ≥ 2. 
Participants with well-controlled HIV infection (CD4+ count ≥ 300/μL and undetectable viral load) 
and receiving antiretroviral therapy were included. Prior PD-L1 therapy was not allowed. 
Participants received retifanlimab 500 mg as an intravenous (IV) infusion Q4W for up to 2 years. 
Treatment continued until progression of disease, unacceptable toxicity, or completion of planned 
treatment. Participants with initial radiographic disease progression could receive additional 
doses of treatment in the absence of clinical deterioration until radiographic confirmation of 
progression. Assessment of tumor status was performed every 8 weeks throughout the treatment 
period. 
As of 08 June 2020, the median duration of treatment was 85 days (range: 1 day to 19.4 months 
[592 days]). Eighteen participants (19.1%) were continuing to receive retifanlimab, and 54 
participants (57.4%) remained in the study, either continuing to receive retifanlimab or being 
followed for survival and/or safety. 
Median age was 64 years (range: 37 to 94 years), 64.9% of participants were female, 76.6% were 
Caucasian, and the ECOG performance score was 0 (41.5%) or 1 (58.5%). Most participants 
(80.9%) had distant metastases at baseline and the most common sites of disease were the 
lymph nodes (64.9%) and liver (41.5%). Nine participants (9.6%) were HIV-positive. All but 3 
participants (97.0%) had received prior platinum-based chemotherapy. The majority of 
participants (87.2%) had also received prior radiotherapy, either as chemoradiotherapy (73.4%) 
or radiotherapy alone (17.0%). 
The expansion study (Study INCMGA 0012-101, POD1UM-101, NCT03059823) contained 4 
tumor-specific cohorts (endometrial, cervical, soft tissue sarcoma, and NSCLC) and 2 tumor-
agnostic flat dose cohorts (500 and 750 mg once Q4W). All patients were ≥18 years old and had 
PD during or following 1–5 prior treatments, measurable disease per RECIST v1.1, and no prior 
immune checkpoint inhibitors. The primary endpoint was safety. Adverse events (AEs) were 
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(NCI-CTCAE) v.4.03. Response was evaluated by RECIST v1.1 with treatment past progression 
allowed at the discretion of the investigator. 
Results as of July 10, 2018, a total of 157 patients had been treated with INCMGA00012 
(retifanlimab), of whom 127 patients in the tumor-specific cohorts (29 endometrial, 33 
cervical, 32 sarcoma, and 33 NSCLC), and 15 each in the two tumor-agnostic flat-dose 
cohorts. Median (range) age was 59 (18–86) years. The majority of patients were female 
(66.9%), white (85.4%), and had present Eastern Cooperative Oncology Group (ECOG) 
Performance Status (PS) of 1 (67.5%). RECIST responses (confirmed and unconfirmed) 
were observed in all 4 tumor types (6/25 evaluable patients with cervical cancer, 6/26 with 
NSCLC, 3/29 with endometrial cancer, and 1/22 with sarcoma). 
INCMGA00012 (retifanlimab) in monotherapy as a first-line of treatment is being currently 
investigated in several phase 2 trials for other specific tumors: treatment-naïve NSCLC with 
EGFR-negative, 
alkaline 
phosphatase 
(ALK)- 
or 
ROS-negative 
(POD1UM-203; 
NCT03679767); urothelial carcinoma in non-eligible patients for cisplatin therapy (POD1UM-
203; NCT03679767); unresectable or metastatic melanoma (POD1UM-203; NCT03679767); 
naïve metastatic merkel cell carcinoma (POD1UM-201; NCT03599713), naïve locally 
advanced or metastatic renal cell carcinoma with clear cell component (with or without 
sarcomatoid features) (POD1UM-203; NCT03679767), metastatic Merkel cell carcinoma 
(POD1UM201; NCT03599713), metastatic solid tumors stage IIIB not amenable to curative 
therapy to stage IV Non-small cell lung cancer advanced/metastatic unresectable malignant 
pleural mesothelioma (POD1UM-105; NCT03920839). Also, is being studied in combination 
in naive non-small cell lung cancer and squamous head and neck tumors. Regarding patients 
with stage III non-small cell lung cancer is being evaluated in combination with platinum-based 
chemotherapy INCMGA00012 (POD1UM-304; NCT04205812) or chemoradiation (POD1UM-
301; NCT04203511). Regarding Squamous Cell Carcinoma of the Head & Neck is being 
evaluated in combination with Enoblituzumab (NCT04129320). 
 
1.6.3 
Clinical Safety 
As of the data cutoff date (23 SEP 2020), 578 unique participants have been exposed to 
INCMGA00012 (retifanlimab) as monotherapy. An additional 96 participants have been exposed 
to INCMGA00012 (retifanlimab) in combination with other anticancer agents, in combination with 
epacadostat INCB024360 (53 participants), in combination with parsaclisib (22 participants), or 
in combination with pemigatinib INCB054828 (15 participants) and 6 participants in combination 
with INCB001158. 
The safety data presented in the IB v.7.0 demonstrate that the safety profile of INCMGA00012 
(retifanlimab) is acceptable and consistent with the profile described for the PD-(L)1 inhibitor 


 
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class. Adverse drug reactions in participants treated with INCMGA00012 (retifanlimab) 
monotherapy include the following: 
• 
Very common: fatigue, asthenia, diarrhea, nausea, pruritus, and pyrexia. 
• 
Common: hypothyroidism, rash, hyperthyroidism, alanine aminotransferase increased, 
myalgia, lipase increased,, influenza-like illness, infusion-related reaction, rash maculo-
papular, dysgeusia, pneumonitis, and rash erythematous. 
• 
Uncommon: colitis, nephritis, blood thyroid stimulating hormone decreased, pruritus 
generalized, rash macular, rash pruritic, adrenal insufficiency, blood thyroid stimulating 
hormone increased, dermatitis, interstitial lung disease, myositis, rash papular, 
autoimmune hepatitis, autoimmune thyroiditis, dermatitis acneiform, pancreatitis, rash 
pustular, thyroid disorder, diabetic ketoacidosis, hypophysitis, hypopituitarism, immune-
mediated enterocolitis, iritis, myocarditis, palmar-plantar erythrodysesthesia syndrome, 
radiculopathy, thyroiditis, tri-iodothyronine decreased, tri-iodothyronine increased, type 1 
diabetes mellitus, and uveitis. 
Study INCMGA 0012-101 is an ongoing, open-label, dose-escalation and cohort expansion 
study in participants with relapsed/refractory, unresectable, locally advanced or metastatic solid 
tumors. As of 23 September 2020, 289 participants have been exposed to INCMGA00012 
(retifanlimab) monotherapy. Treatment-emergent AEs (TEAEs) were reported in 272 participants 
(94.1%). TEAEs reported for ≥ 10% of participants included fatigue, anemia, diarrhea, nausea, 
asthenia, and vomiting. Grade 3 or higher TEAEs occurring in > 5 participants were anemia 
(6.6%), pulmonary embolism (2.8%), blood alkaline phosphatase increased and lipase increased 
(2.4%), and hyponatremia (2.1%). Fatal TEAEs occurred in 5 participants (0.3%; hemiparesis, 
nephritis, cardiovascular insufficiency, pulmonary embolism, and renal failure). All fatal TEAEs 
were considered not related to INCMGA00012 (retifanlimab) by the investigator. Serious TEAEs 
occurred in 85 participants (29.4%). Serious TEAEs that occurred for > 2 participants included 
urinary tract infection (1.4%), pleural effusion (1.4%), pulmonary embolism (1.4%), pneumonia 
(1.0%), and dyspnea (1.0%). TEAEs that led to discontinuation of INCMGA00012 (retifanlimab) 
occurred in 26 participants (9.0%): colitis 4 participants, 1.4%), pulmonary embolism (2 
participants, 0.7% each), and autoimmune hepatitis, brain edema, cardiovascular insufficiency, 
diarrhea, dry mouth, failure to thrive, female genital tract fistula, general physical health 
deterioration, iritis, myocardial infarction, myocarditis, nephritis, edema peripheral, pneumonitis, 
pneumothorax, polymyalgia rheumatica, transaminases increased (tumor pain, and type 1 
diabetes mellitus (1 participant, 0.3% each). No dose-limiting toxicities (DLTs) occurred, and the 
maximum tolerated dose (MTD) was not reached. 
Study INCMGA 0012-104 is an ongoing, open-label, multicenter study of INCMGA00012 
(retifanlimab) monotherapy, INCB001158 (arginase inhibitor) monotherapy, and INCMGA00012 
(retifanlimab) + INCB001158 combination therapy in Japanese participants with advanced solid 


 
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tumors. As of 23 September 2020, 6 participants have been exposed to INCMGA00012 
(retifanlimab) 500mg Q4W monotherapy in the study. TEAEs occurred in all 6 participants 
(100%). TEAEs reported for > 1 participant included rash (3 participants, 50.0%), constipation (2 
participants 33.3%), amylase increased (2 participants [33.3%]), and pruritus (2 participants 
[33.3%]). Grade 3 or higher TEAEs occurred in 2 participants (33.3%) and included femoral neck 
fracture, ileus, lymphocyte count decreased, and pyelonephritis (1 participant [16.7%] each). No 
fatal TEAEs occurred in participants receiving retifanlimab monotherapy. Serious TEAEs 
occurred in 2 participants (33.3%) and included ileus, pyelonephritis, and femoral neck fracture 
(1 participant [16.7%] each). No serious TEAEs were considered related to INCMGA00012 
(retifanlimab). There were no TEAEs that led to discontinuation of INCMGA00012 (retifanlimab). 
There have been no DLTs reported in participants receiving INCMGA00012 (retifanlimab) 
monotherapy in this study. 
Study INCMGA 0012-201 is an ongoing open-label, single-arm, multicenter study in 
participants with advanced/metastatic Merkel cell carcinoma. As of 23 September 2020, 68 
participants have been exposed to INCMGA00012 (retifanlimab) monotherapy. As of the data 
cutoff date, 4 participants (5.9%) have received ≥ 1 year of continuous treatment with 
INCMGA00012 (retifanlimab) monotherapy. In participants receiving retifanlimab monotherapy, 
TEAEs occurred in 50 participants (73.5%). TEAEs reported in ≥ 10% of participants included 
asthenia (14 participants [20.6%]), pruritus (13 participants [19.1%]), diarrhea (9 participants 
[13.2%]), nausea (9 participants [13.2%]), and pyrexia (8 participants [11.8%]). Grade 3 or higher 
TEAEs occurring in > 1 participant (2.9%) were anemia, asthenia, neutropenia, and pneumonia 
(2 participants [2.9%] each). Fatal TEAEs occurred in 3 participants (4.4%; acute respiratory 
failure, asthenia, and Chronic lymphocytic leukemia (CLL) [reported term: progression of CLL]). 
Only the event of CLL was considered related to retifanlimab. The event occurred in a 70-year-
old participant with a 4-year ongoing medical history of CLL, for which the participant never 
received therapy. After 3 cycles of retifanlimab, the participant was hospitalized with Grade 3 
anemia, Grade 2 thrombocytopenia, and Grade 1 neutropenia. Retifanlimab was then 
discontinued due to progression of CLL and Merkel cell carcinoma, and treatment for CLL was 
started with chlorambucil and obinutuzumab. The event was complicated by pleuropneumopathy 
that was resistant to antibiotics. The investigator indicated that the relationship to retifanlimab 
cannot be excluded due to rapid worsening of the hematologic disease. Serious TEAEs occurred 
in 13 participants (19.1%). The only serious TEAE to occur in >1 participant was asthenia (2 
participants [2.9%]). TEAEs that led to discontinuation of retifanlimab occurred in 7 participants 
(10.3%): asthenia (with a fatal outcome), atrial fibrillation, CLL (with a fatal outcome 
[aforementioned progression of CLL]), infusion-related reaction, pancreatitis, polyarthritis, and 
radiculopathy (1 participant [1.5%] each). 
 
Study INCMGA 0012-202 is an ongoing open-label, single-arm, multicenter study in 
participants with locally advanced or metastatic squamous carcinoma of the anal canal who have 


 
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progressed on or after a standard-of-care platinum-based chemotherapy regimen. As of 23 
September 2020, 94 participants have been exposed to INCMGA00012 (retifanlimab) 
monotherapy. As of the data cutoff date, 3 participants (3.2%) have received ≥ 1 year of 
continuous treatment with INCMGA00012 (retifanlimab) monotherapy. TEAEs occurred in 90 
participants (95.7%). TEAEs reported for ≥ 15.0% of participants were asthenia (22 participants 
[23.4%]), diarrhea (19 participants [20.2%]), anemia (18 participants [19.1%]), fatigue (17 
participants [18.1%]), nausea (15 participants [16.0%]), and vomiting (15 participants [16.0%]). 
Grade 3 or higher TEAEs occurring in > 2 participants were anemia (6 participants [6.4%]), 
general physical health deterioration (4 participants [4.3%]), pelvic pain (4 participants [4.3%]), 
abdominal pain, asthenia, dyspnea, fatigue, hyponatremia, intestinal obstruction, proctalgia, and 
urinary tract infection (3 participants [3.2%]). Fatal TEAEs occurred in 10 participants (10.6%). 
Only 1 fatal event (lymphangiosis carcinomatosa) was considered by the investigator to be related 
to retifanlimab. Serious TEAEs occurred in 50 participants (53.2%). Serious TEAEs reported most 
frequently were abdominal pain, anemia, and urinary tract infection (all 4 participants [4.3%]). 
TEAEs that led to discontinuation of retifanlimab occurred in 7 participants (7.4%): coma hepatic, 
diffuse 
large 
B-cell 
lymphoma, 
immune-mediated 
enterocolitis, 
palmar-plantar 
erythrodysaesthesia syndrome, pleural effusion, pneumonitis, and pseudomonas infection (1 
participant [1.1%] each).  
 
Study INCMGA 0012-203 is an ongoing open-label, multicenter study in participants with 
advanced solid tumors. As of 23 September 2020, enrolment has been completed with 121 
participants having received INCMGA00012 (retifanlimab) monotherapy. As of the data cutoff 
date, 6 participants (5.0%) have received ≥ 1 year of continuous treatment with retifanlimab 
monotherapy. In participants receiving retifanlimab monotherapy, TEAEs occurred in 106 
participants (87.6%). TEAEs reported for ≥ 10% of participants included asthenia (21 participants 
[17.4%]), arthralgia (18 participants [14.9%]), decreased appetite (17 participants [14.0%]), 
pruritus (15 participants [12.4%]), rash (13 participants [10.7%]), and urinary tract infection (13 
participants [10.7%]). Grade 3 or higher TEAEs occurring in > 2 participants were anemia (5 
participants [4.1%]), pneumonia (5 participants [4.1%]), sepsis (4 participants [3.3%]), ALT 
increased (3 participants [2.5%]), and chronic obstructive pulmonary disease (3 participants 
[2.5%]). Fatal TEAEs occurred in 6 participants (5.0%), none of which were considered by the 
investigator to be related to retifanlimab. Serious TEAEs occurred in 31 participants (25.6%). 
Serious TEAEs that occurred in ≥ 2 participants were pneumonia (5 participants [4.1%]), chronic 
obstructive pulmonary disease (4 participants [3.3%]), sepsis (3 participants [2.5%]), 
hepatocellular injury, and pulmonary embolism (2 participants [1.7] each). TEAEs that led to 
discontinuation of retifanlimab occurred in 13 participants (10.7%): sepsis (2 participants [1.7%]), 
and alanine aminotransferase increased, azotemia, blood creatinine increased, cerebrovascular 
accident, chronic obstructive pulmonary disease, general physical health deterioration, 


 
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hemorrhage, hepatic failure, hepatocellular injury, myelodysplastic syndrome, and right 
ventricular failure (1 participant [0.8%] each). 
 
1.6.3.1 
General Information 
Fatigue is the most common side effect observed with immune checkpoint inhibitors, with an 
estimated overall frequency around 20% percent for the anti–PD-1 and anti–PD-L1 agents. 
However, the most relevant toxicities in clinical practice associated with these agents are 
immune-related adverse events (irAE). 
 
1.6.3.2 
Dermatologic Toxicity 
Skin toxicity is the most common irAE related to immune checkpoint inhibitors, and 
approximately 30-40% of patients treated with anti–PD-1 and anti–PD-L1 agents will develop 
dermatologic complications. This toxicity usually is the earliest irAE, with a median time to onset 
of 3.6 weeks after treatment initiation. Typical physical examination findings consist of a reticular 
and maculopapular erythematous rash on the trunk or extremities. Severe rashes such as 
Stevens-Johnson syndrome/toxic epidermal necrolysis have been also reported in rare cases. 
 
1.6.3.3 
Diarrhea 
Diarrhea is a very common clinical AE in patients undergoing treatment with immune 
checkpoint inhibitors. The onset of this toxicity occurs later than dermatologic toxicity, 
approximately six weeks after treatment initiation. Diarrhea of any grade has been reported in 
approximately 14,4% of patients treated with these agents, although grade 3 and 4 immune-
mediated colitis has been seen in only 1-2% of cases. Potential risk of gastrointestinal perforation 
should be taken into consideration on patients with immune-related colitis. 
 
1.6.3.4 
Hepatotoxicity 
Elevations in serum levels of the hepatic enzymes, aspartate aminotransferase (AST) and 
alanine aminotransferase (ALT), have been observed with anti–PD-1 and anti–PD-L1 agents in 
less than 5% of patients with grade 3 and 4 events being extremely rare. Most episodes are 
asymptomatic laboratory abnormalities, but occasionally patients have an associated fever. 
Increases in total and direct bilirubin are exceptional, and usually occur in association with a 
prolonged period of AST and ALT elevations. The most frequent time of onset is around two or 
three months after initiation of treatment, although early or delayed events may also be seen. 


 
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1.6.3.5 
Endocrinopathies 
Inflammation of the pituitary, thyroid, or adrenal glands as a result of checkpoint blockade 
often presents with imprecise symptoms such as nausea, headache, fatigue, and vision changes. 
Although it has been difficult to establish the exact incidence of endocrinopathies associated with 
these compounds, clinically significant events are thought to occur in less than 5-10% of patients 
treated with anti–PD-1 and anti–PD-L1 agents. The most common endocrinopathies are 
hypophysitis and autoimmune thyroid disease, principally primary hypothyroidism secondary to a 
destructive thyroiditis. Hyperthyroidism associated with Graves disease and adrenal insufficiency 
has also been reported with these compounds. 
 
1.6.3.6 
Less Common irAEs 
Other less common irAEs have been attributed to anti–PD-1 and anti–PD-L1 agents, including: 
• 
Nephritis (renal insufficiency, granulomatous interstitial nephritis, and lupus membranous 
nephropathy). 
• 
Respiratory complications (sarcoidosis, pneumonitis, and organizing inflammatory 
pneumonia). 
• 
Eye disorders (episcleritis, conjunctivitis, uveitis, or ophthalmopathy associated with Graves’ 
disease). 
• 
Pancreatic alterations [asymptomatic elevated levels of serum amylase and lipase and type 
1 diabetes mellitus (T1DM)]. 
• 
Neurologic syndromes (myasthenia gravis, Guillain-Barre syndrome, posterior reversible 
encephalopathy syndrome, aseptic meningitis, enteric neuropathy, and transverse myelitis). 
• 
Hematologic disorders (red cell aplasia, neutropenia, and thrombocytopenia). 
 
1.7 
Rationale for Dose Selection of INCMGA00012 (retifanlimab) 
INCMGA00012 (retifanlimab) will be administered at 500 mg Q4W. The selection of this dose was 
based on modeling of clinical PK data from the first-in-human monotherapy study, INCMGA 0012-
101 (NCT03059823), in which 37 participants from dose escalation phase were treated at doses 
of 1 mg/kg every 2 weeks (Q2W), 3 mg/kg Q2W, 3 mg/kg Q4W, 10 mg/kg Q2W, and 10 mg/kg 
Q4W and clinical experience with flat dosing in the expansion cohorts of the same study. 
Simulations demonstrated that the median steady-state trough concentration of retifanlimab 500 


 
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mg Q4W and 375 mg Q3W was approximately 21.1 μg/mL, which is the median trough 
concentration for pembrolizumab 2 mg/kg Q3W (48). 
These dose regimens were further supported by the linear PK of retifanlimab and the final 
population PK analysis from 506 participants in 5 studies where body weight was identified as a 
statistically significant covariate for Vc but not for CL. Lack of correlation between CL and body 
weight minimizes an advantage of weight-based dosing over flat dosing on PK variability, 
especially for total exposure, as body size was believed to be a major contributor to inter-individual 
PK variability for mAb therapies  
Based on these observations, 500 mg Q4W was chosen as the dose regimen. Preliminary 
efficacy data demonstrate clinical activity of INCMGA00012 (retifanlimab) based on durable 
RECIST responses in multiple tumor types (45). 
 
1.8 
 Study Rationale 
Currently, patients with patients with PSqCCs presenting with advanced disease continue to 
present poor prognosis and OS of <1 year. Best supportive care remains an option for advanced 
in this setting and consideration of clinical trial is strongly recommended by the NCCN panel of 
experts. 
The majority of primary PSqCC tumors express PD-L1. On the other hand, in a recent study 
it has been showed that PSqCC presents an identical genotype compared to other HPV-related 
SqCC tumors and very similar to squamous NSCLC. These data provide a rational basis for 
further investigation of anti–PD-1 and anti–PD-L1 immunotherapeutic in patients with advanced 
PSqCC. Of the patients who do respond, many can have long-term survival and therefore there 
is much interest in identifying these patients using prognostic and predictive biomarkers. 
For HPV-related cancers, the role of HPV as molecular marker ICIs-based therapy is quite 
scarce and not conclusive and future clinical trials should include the HPV status in the evaluation 
of prognostic/predictive biomarkers. 
Preliminary data with INCMGA00012 (retifanlimab) in ~200 patients have shown promising 
antitumor activity, resulting in response rates similar to those observed with other ICIs. However, 
no data are available so far with anti–PD-1 and anti–PD-L1 agents used in this tumor subtype. In 
order to determine if immunotherapy could benefit this population, this multicenter, open-label, 
phase II clinical trial will evaluate the efficacy and safety of the of anti–PD1 INCMGA00012 
(retifanlimab) in patients with advanced PSqCC previously treated or not with chemotherapy. 
Unlike other currently ongoing studies, this trial will evaluate the activity of immunotherapy in a 
series of patients with advanced PSqCC regardless of their prior treatment and extension of the 
disease. 


 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective 
• 
To assess the efficacy –as determined by the objective response rate (ORR)– of 
INCMGA00012 (retifanlimab) in patients with unresectable locally advanced or metastatic 
PSqCC. 
 
2.1.1 
Primary Endpoint  
• 
ORR will be evaluated according to the investigator as per RECIST v.1.1. 
 
2.2 
Secondary Objectives  
• 
To assess the efficacy –as determined by the clinical benefit rate (CBR), PFS, 6-month PFS, 
duration of response (DoR), time to progression (TTP), OS, and maximum tumor shrinkage– 
of INCMGA00012 (retifanlimab) in these patients. 
• 
To evaluate the safety and tolerability of INCMGA00012 (retifanlimab) in these patients. 
 
2.2.1 
Secondary Endpoints  
• 
OS, and clinical benefit rate (CBR), PFS, 6-month PFS, DoR, TTP, and maximum tumor 
shrinkage that will be evaluated as per RECIST v.1.1. 
• 
The safety and tolerability will be evaluated by incidence of AEs, incidence of prespecified 
AEs, change from baseline in targeted vital signs, and change from baseline in targeted 
clinical laboratory test results. 
 
2.3 
Exploratory Objectives  
• 
To determine the efficacy –as determined by the ORR, CBR, and 6-month PFS based on 
immune-related RECIST (irRECIST). 
• 
To evaluate predictive or prognostic, tumor- and/or immune-related biomarkers associated 
with disease activity status or response to treatment. 
• 
To identify possible mechanisms of resistance to study treatments through the comparative 
analysis of potential biomarkers from paired pre-treatment and post-progression tumor and/or 
blood samples. 


 
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• 
To assess impact of INCMGA00012 (retifanlimab) on HIV control in participants who are 
known to be HIV-positive. 
 
2.3.1 
Exploratory Endpoints  
• 
ORR, CBR, and 6-month PFS as per irRECIST. 
• 
Relationship between tumor- and/or immune-related biomarkers, and efficacy in tumor tissue 
and/or liquid biopsy. 
• 
Changes from baseline in the CD4-positive cell count and HIV viral load in participants who 
are known to be HIV-positive. 
 
3 
STUDY DESIGN 
3.1 
Description of Study Design 
This is a multicenter, open-label, single-arm, phase II clinical trial to evaluate the efficacy and 
safety of the INCMGA00012 (retifanlimab) in progressive advanced PSqCC patients, previously 
treated or not with chemotherapy. 
The study population consists of male patients age ≥ 18 years with advanced PSqCC that are 
presenting with progressive disease. Patients that have received prior treatment of locally 
recurrent and/or metastatic disease with platinum-based chemotherapy regimens are not 
excluded. 
In the absence of progression of disease or unacceptable toxicity, treatment with 
INCMGA00012 (retifanlimab) will continue based on physician’s criteria for up to 2 years. 
Tumor assessments per RECIST v.1.1 and irRECIST will be performed approximately every 
eight weeks (± 7 days) for the first 6 months and every 12 weeks (± 7 days) thereafter until PD, 
treatment discontinuation, the start of new anti–cancer treatment, withdrawal of consent, death, 
or the end of study (EoS), whichever occurs first. Tumor assessments will be performed on the 
specified schedule regardless of treatment delays. 
For estimation of ORR, CBR, DoR, and PFS tumor response will be based on RECIST v.1.1. 
In patients who continue treatment beyond radiographic PD per RECIST v.1.1, tumor response 
(ORR, CBR, and PFS) may continue to be assessed using irRECIST criteria until study treatment 
discontinuation. 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory 
abnormalities graded per the NCI-CTCAE v.5.0. Laboratory safety assessments will include the 
regular monitoring of hematology, blood chemistry, coagulation, and thyroid function testing. A 
schedule of assessments is provided in Appendix 1. 


 
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3.2 
Study Schedule Summary 
The study will consist of a 28-day screening phase, a treatment phase, and a post-treatment 
phase (end of treatment [EoT] visit and EoS) that includes safety, efficacy, and survival follow-
up. 
 
3.2.1 
Screening Phase 
During this phase, subject eligibility is determined, including the documentation of baseline 
characteristics. This phase of the study will begin once the informed consent from (ICF) is signed 
by the patient and the procedures to be performed are described in Section 6 of the protocol. 
One re-screening is allowed in patients that are screening failure in this study. Patient has to 
re-consent the ICF before any study procedure is done. 
 
3.2.2 
Treatment Phase 
Patients will receive study treatment according to the protocol and will be discontinued if one 
of the following situations arises: 
• 
AEs which, according to the protocol or in the opinion of the Investigator, can cause serious 
or permanent damage or which rule out further treatment with the study drug. 
• 
Progression of disease is confirmed radiologically and unequivocally assessed according to 
the RECIST criteria version 1.1 and/or irRECIST. 
• 
Major study protocol non-compliance. 
• 
Patient’s withdrawal from the study. 
• 
Death. 
• 
Study is cancelled by the Sponsor. 
 
3.2.3 
End of Treatment Visit 
EoT visit will be 28 days (± 7 days) after the last dose of study treatment.  
 
3.2.4 
Follow-up after treatment discontinuation 
EoS will occur 12 months after the last patient has been enrolled in the study (treatment start).  


 
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Patients discontinuing the study treatment period will enter a post-treatment follow-up period 
during which survival and new anti–cancer therapy information will be collected every 3 months 
(± 14 days) from the last dose of investigational product until the end of study (EoS). 
During this visit, status survival and post study anti–cancer therapy evaluation will be collected 
(telephone contact is acceptable).  
LPLV: 12 months after first study dose of the last patient or progressive disease experienced 
in all patients or when the trial is terminated by the Sponsor, whichever is earlier. 
 
4 
PATIENT SELECTION 
The following eligibility criteria can be used in the screening of patients for whom the protocol 
treatment is deemed suitable. In order to determine whether this protocol is suitable for a given 
patient, all medical and non-medical criteria should be taken into consideration. 
Patient eligibility will be reviewed and documented by a suitable member of the Investigator’s 
study team before the patients are enrolled in the study. 
 
4.1 
Study Population 
Male patients age ≥ 18 years with progressive locally advanced ‒not amenable to curative 
treatment‒ or metastatic PSqqCC (i.e., T4 or N3 or M1) previously treated with chemotherapy 
regimens or patients naïve of systemic treatment. 
The patient’s signed ICF should be obtained before any trial related activities and according 
to local guidelines. 
 
4.2 
Inclusion Criteria 
Patients must meet ALL the following inclusion criteria to be enrolled in the study: 
1. Patients have been informed about the nature of study, and have agreed to participate in the 
study, and signed the informed consent form (ICF) prior to participation in any study-related 
activities. 
2. Male patients ≥ 18 years of age at the time of signing ICF. 
3. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1. 
4. Life expectancy ≥12 weeks. 
5. Histologically-proven PSqCC. 


 
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6. Locally advanced unresectable or metastatic stage 4 PSqCC that is not amenable to 
resection with curative intent (T4 or N3 or M1). 
7. Radiological evidence of locally advanced or metastatic disease. 
8. Patients must have measurable disease or evaluable disease according to Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 criteria. 
9. Patients must agree to provide a tumor tissue sample from a metastatic site or the primary 
tumor at the time of study entry, with the exception of patients for whom tumor biopsies cannot 
be obtained (e.g., inaccessible tumor or subject safety concern) that may submit an archived 
tumor specimen only upon agreement from the Sponsor. If feasible, patients will also be given 
the option of providing a tumor tissue sample at disease progression from metastasis or 
primary tumor (if tumor biopsies cannot be obtained for inaccessible lesion or subject safety 
concern). 
10. Willingness and ability to provide blood samples (liquid biopsy) at the time of inclusion, after 
2 cycles of study treatment (C3D1), and upon PD or study termination.  
11. Adequate organ function: 
• Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count 
(ANC) ≥ 1.5 x 109/L, platelet count ≥ 75.0 x109/L, and hemoglobin > 9.0 g/dL. 
• Hepatic: Bilirubin ≤ 1.5 times the upper limit of normal (× ULN) (< 3 x ULN in the case of 
Gilbert’s disease); aspartate transaminase (AST), and alanine transaminase (ALT) ≤ 
2.5 times × ULN (in the case of liver metastases ≤ 5 × ULN); Albumin > 2.5 mg/mL. 
• Renal: Serum creatinine ≤ 1.5 x ULN; alternately measured or calculated creatinine 
clearance ≥30 mL/min with creatinine levels >1.5 × institutional ULN (glomerular 
filtration rate [GFR] can also be used in place of creatinine or creatinine clearance). 
CLcr (mL/min) =(*Cockcroft-Gault equation: ([{140 – age in years} × {ACTUAL WEIGHT in 
kg}] divided by [{72 × serum creatinine in mg/dL} multiplied by 0.85 if female])). 
eGFR =175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x1.212 [if Black]. From MDRD (49) 
 
• Coagulation: Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN and 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless 
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants. 
12. Patients who are willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures. 
13. Subjects should agree to use an adequate method of contraception starting with the first dose 
of study therapy through 180 days after the last dose of study treatment. 


 
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14. Patients that have received prior chemotherapy regimens or radiotherapy for locally recurrent 
and/or metastatic disease are not excluded but patients naïve of systemic treatment can also 
be included. 
15. For pretreated patients, last dose of chemotherapy administered ≥ 28 days from study entry. 
 
4.3 
Exclusion criteria 
Any patient meeting ANY of the following criteria will be excluded from the study: 
1. Locally PSqCC candidate for curative treatment. 
2. Prior therapy with an anti–PD-1, anti–PD-L1, or anti–PD-L2 agent. 
3. Known hypersensitivity to any of the excipients of INCMGA00012 (retifanlimab). 
4. Receipt of anticancer therapy or participation in another interventional clinical study within 28 
days before the first administration of study drug; 6 weeks for mitomycin C. 
5. Radiotherapy within 14 days of first dose of study treatment with the following caveat: 
a. 28 days for pelvic radiotherapy. 
6. Toxicity of prior therapy that has not recovered to ≤ Grade 1 or baseline (with the exception 
of any grade of alopecia and anemia not requiring transfusion support). Endocrinopathy, if 
well-managed, is not exclusionary and should be discussed with Sponsor’s medical monitor. 
7. Major surgery (defined as requiring general anesthesia) or significant traumatic injury within 
4 weeks of start of study drug, or patients who have not recovered from the side effects of 
any major surgery, or patients who may require major surgery during the study. 
8. Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases, 
carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, 
cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or 
cord compression are eligible if they have been definitively treated (e.g., radiotherapy, 
stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 
weeks before randomization. 
9. Cardiovascular: patients that have any of the following within 6 months of randomization: 
severe/unstable angina, myocardial infarction, symptomatic pericarditis, symptomatic 
congestive heart failure (New York Heart Association functional classification III-IV), 
cerebrovascular accident including transient ischemic attack, or symptomatic pulmonary 
embolism, coronary/peripheral artery bypass graft, ongoing cardiac dysrhythmias of 
NCI-CTCAE v.5.0 grade ≥2, including, ventricular arrhythmias ‒except for benign premature 
ventricular contractions‒, supraventricular and nodal arrhythmias requiring a pacemaker or 
not controlled with medication, any conduction abnormality requiring a pacemaker or any 
cardiac arrhythmia not controlled with medication. 
10. Metabolic: Uncontrolled hyper/hypothyroidism or diabetes mellitus type 1 (T1DM). Patients 
with hypothyroidism stable on hormone replacement will not be excluded from the trial. 
Patients with controlled T1DM on a stable insulin regimen may be eligible for this study. 


 
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11. Diagnosis 
of 
immunodeficiency 
or 
is 
receiving 
systemic 
steroid 
therapy 
or 
immunosuppressive therapy within seven days prior to study treatment initiation. 
12. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with 
use of disease modifying agents, corticosteroids, or immunosuppressive drugs). 
Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic steroid replacement 
therapy (≤ 10 mg prednisone daily) for adrenal or pituitary insufficiency, etc.) is not considered 
a form of systemic treatment. 
13. Prior allogenic stem cell or solid organ transplantation. 
14. Has received a live vaccine within 28 days of the planned start of study drug. 
Note: Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live-
attenuated vaccines and are not allowed. 
15. Active/history of pneumonitis requiring treatment with steroids or active/history of interstitial 
lung disease. 
16. Active uncontrolled infection at the time of screening. 
17. Latent tuberculosis determined by a positive TST followed by confirmation by pulmonologists. 
18. Participants who are known to be human immunodeficiency virus (HIV)-positive, unless all of 
the following criteria are met: 
a. CD4-positive count ≥ 300/μL; 
b. Undetectable viral load; 
c. Receiving highly active antiretroviral therapy. 
19. Active hepatitis A virus (HAV) (positivity for HAV IgM antibody), hepatitis B virus (HBV) 
(patients with negative hepatitis B surface antigen [HBsAg] test and a positive antibody to 
HBsAg [anti–HBsAg] test at screening are eligible) or hepatitis C virus (HCV) (patients with a 
positive antibody to hepatitis C [anti–HCV] are eligible only if polymerase chain reaction [PCR] 
is negative for virus hepatitis C ribonucleic acid [RNA]). 
20. Known additional malignancy that is progressing or requires active treatment, or history of 
other malignancy within 3 years of study entry with the exception of cured basal cell or 
squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial 
neoplasm, or other noninvasive or indolent malignancy, or cancers from which the participant 
has been disease-free for >1 year, after treatment with curative intent. 
21. Patients have any other concurrent severe and/or uncontrolled medical condition that would, 
in the Investigator’s judgment contraindicate patient participation in the clinical study. 
 


 
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5 
TREATMENT 
5.1 
Formulation, Packaging, and Handling 
Study drug packaging will be overseen by the Sponsor’s Clinical Trial Supplies department 
and bear a label with the identification required by local law, the protocol number, drug 
identification, and dosage. The packaging and labeling of the study drug will be in accordance 
with Sponsor standards and local regulations. Local packaging in some countries may be 
different. 
The study drug must be stored according to the details on the Product Information. The drug 
label indicates the storage temperature. Upon arrival of investigational products at the site, site 
personnel should check them for damage, verify proper identity, quantity, integrity of seals, and 
temperature conditions, and report any deviations or product complaints upon discovery.  
INCMGA00012 (retifanlimab) drug product for IV administration will be supplied in a glass vial 
for single use. Each vial contains INCMGA00012 (retifanlimab) at a concentration of 25 mg/mL. 
Upon receipt, INCMGA00012 (retifanlimab) vials are to be refrigerated at 2-8 ºC (36-46 ºF) in a 
locked storage area protected from light with limited access. Do not freeze. INCMGA00012 
(retifanlimab) vials should not be used beyond the expiration date provided by the manufacturer. 
 
5.2 
Dosage and Administration 
INCMGA00012 (retifanlimab) should be administered intravenously, at flat dose of 500 mg 
over one hour (± 15 minutes) or 30 minutes ( ± 15 min) using a filter on day 1 of each 28-day 
cycle (every 4 weeks). Infusion rate may be reduced if an infusion reaction occurs. 
INCMGA00012 (retifanlimab) was observed to be compatible with the following materials: 
polyvinylchloride (PVC) with (2-ethylhexyl) phthalate (DEHP), PVC (without DEHP), polyolefin, 
polyethylene, polypropylene and polyethersulfone (PES). Study drug administration supplies (i.e., 
IV bags and tubing) should be made only of these materials. 
INCMGA00012 (retifanlimab) will be prepared by adding the drug product directly to a bag 
containing 0.9% sodium chloride (normal saline) injection United States Pharmacopeia (or local 
equivalent) and delivered through an IV administration set including a 0.2 micron low protein 
binding preferably in-line filter made of PES. The final concentration range for INCMGA00012 
(retifanlimab) must be within 0.3mg/mL to 12mg/mL in the normal saline IV bag. It is 
recommended to use 100 mL normal saline IV bags for infusion preparation, however, in case of 
supply constraints, 250 mL normal saline IV bags may be used if needed. 
The total time at room temperature for prepared infusion solution should not exceed 6 hours 
inclusive of infusion time. 
 


 
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5.3 
Treatment Modification 
Safety and tolerability of all patients will be closely monitored throughout study treatment and 
the follow-up period using the NCI-CTCAE v.5.0. Patients will be assessed in order to detect any 
AEs before administering new study treatment during each treatment visit. Treatment will only be 
administered if clinical evaluation and local laboratory test results are acceptable. 
Patients who have treatments withheld for more than 12 weeks must discontinue study 
treatment and are considered off study. Patients whose treatment is interrupted or permanently 
discontinued due to an AE, including abnormal laboratory value, must be followed until resolution 
or stabilization of the event, whichever comes first, which includes all study assessments 
appropriate to monitor the event. 
Intrapatient dose reductions are not permitted for INCMGA00012 (retifanlimab). If a dose 
interruption is necessary for management of treatment-related TEAEs, INCMGA00012 
(retifanlimab) will be reinitiated at the dose at which it was interrupted. 
Patients should meet the following re-treatment criteria before proceeding with subsequent 
cycles:  
• 
Hemoglobin ≥ 8 g/dL. 
• 
ANC ≥ 1.0 × 109/L. 
• 
Platelet count ≥ 75 × 109/L. 
• 
ALT/AST/bilirubin level < Grade 2. 
• 
Resolution of all immune-related TEAEs to ≤ Grade 1 (with the exception of hyperglycemia 
[allowed to Grade 2] and endocrinopathy that is controlled on hormonal replacement). 
• 
Resolution of all non–immune-related TEAEs to ≤ Grade 1 or baseline (with the exception of 
Grade 2 alopecia and fatigue). Transient asymptomatic laboratory elevations ≤ Grade 3 do 
not require dose interruption if the participant is asymptomatic and if the elevation is clinically 
insignificant and has been discussed with the medical monitor. 
If retreatment criteria are not met, then re-treatment should be delayed, and the participant 
should be re-evaluated weekly or more frequently as clinically indicated. INCMGA00012 
(retifanlimab) may be interrupted for a maximum of 12 weeks due to toxicity. 
 
5.4 
Modification of the Amount of Study Drug Administered Due to Changes in Patient’s 
Weight 
INCMGA00012 (retifanlimab) is administered as a fixed dose irrespective of the patient´s body 
weight. AEs (both non-serious and serious) associated with INCMGA00012 (retifanlimab) 


 
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exposure may represent an immunologic etiology. These AEs may occur shortly after study 
treatment initiation or several months after the last dose of treatment. INCMGA00012 
(retifanlimab) must be withheld for certain drug-related toxicities and severe or life-threatening 
AEs as per Table 1 below. Dose reduction of INCMGA00012 (retifanlimab) is not permitted. 
INCMGA00012 (retifanlimab) should be permanently discontinued: 
• 
For grade 4 toxicity except for endocrinopathies that are controlled with replacement 
hormones. 
• 
If steroid dosing cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 
weeks. 
• 
If a treatment-related toxicity does not resolve to grade 0-1 within 12 weeks after last dose of 
INCMGA00012 (retifanlimab). 
• 
If any event occurs a second time at grade ≥ 3 severity (also for recurrent grade 2 
pneumonitis). 


 
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Table 1. Toxicity Management Guidelines for Immune-related AEs Associated with INCMGA00012 (retifanlimab). 
Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With 
INCMGA00012 (retifanlimab) 
AE Management With Corticosteroid and/or 
 Other Supportive Care Therapies 
Pneumonitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
• 
Administer systemic corticosteroids per local practice 
followed by taper. 
• 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid treatment. 
• 
Add prophylactic antibiotics for opportunistic infections. 
Grades 3 or 4, or recurrent 
Grade 2 
Permanently discontinue. 
Diarrhea/colitis 
Grade 1 
No action. 
None. 
Grades 2 or 3 
Withhold until ≤ Grade 1. 
• 
Consider prompt initiation of standard anti-diarrheal 
agents. 
• 
Administer systemic corticosteroids per local practice 
followed by taper. 
• 
Consider prophylactic antibiotics per local practice. 
• 
Consider gastrointestinal consultation and performing 
endoscopy to rule out colitis. 
Grade 4 or recurrent 
Grade 3 
Permanently discontinue. 
AST/ALT elevation 
and/or increased 
bilirubin/Hepatitis 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
• 
Administer systemic corticosteroids per local practice 
followed by taper. 
• 
Consider monitoring liver enzymes weekly (or more 
frequently) until liver enzyme value returns to baseline or 
is stable. 
Grade 3 or 4,  
or in participants with liver 
metastasis with baseline 
Grade 2 elevation of AST 
or 
ALT, hepatitis with AST or 
ALT increases ≥ 50% and 
lasts ≥ 1 week 
Permanently discontinue. 
Endocrinopathies 
Type 1 diabetes 
mellitus 
Grades 1 and 2 
No action. 
None. 
Grades 3 and 4 
hyperthyroidism 
No action. 
For hypothyroidism, initiate thyroid replacement hormones (eg, 
levothyroxine or liothyronine) per standard of care. 


 
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Immune-Related 
Adverse Event 
Toxicity Grade or 
Conditions (CTCAE v5.0) 
Action Taken With 
INCMGA00012 (retifanlimab) 
AE Management With Corticosteroid and/or 
 Other Supportive Care Therapies 
Hyperglycemia 
Hyperthyroidism 
Hypothyroidism 
Hypophysitis 
Adrenal insufficiency 
 
Grades 3 or 4 
Withhold until ≤ Grade 1. 
May restart INCMGA00012 
(retifanlimab) if endocrinopathy has 
improved to ≤ Grade 2 and is 
controlled with hormone 
replacement, if indicated, and 
steroid taper is complete. 
• 
For Type 1 diabetes mellitus, initiate insulin replacement 
therapy. 
• 
For hyperglycemia, administer antihyperglycemic. 
• 
For hyperthyroidism, treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as appropriate. 
• 
For hypophysitis or adrenal insufficiency, administer 
corticosteroids and initiate hormonal replacements as 
clinically indicated. 
Nephritis and renal 
dysfunction 
Grade 1 
No action. 
None. 
Grade 2 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 3 or 4  
Permanently discontinue. 
Rash 
Grade 1 
No action. 
None. 
Grade 2 
No action. 
Manage with topical steroids with or without drug interruption. 
Grade 3i) or persistent 
Grade 2 (≥ 2 weeks) or 
suspected Stevens-
Johnson syndrome or toxic 
epidermal necrolysis 
Withhold until ≤ Grade 1. 
Administer corticosteroids per local practice followed by taper. 
Grade 4 or confirmed 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Permanently discontinue. 
Myocarditis 
Grade 2 
Withhold until ≤ Grade 1. 
• 
Treatment with systemic corticosteroids should be initiated 
(initial dose of 1-2 mg/kg per day of prednisone or 
equivalent). Taper as appropriate. 
• 
Management of cardiac symptoms according to standard 
of care and with guidance from cardiology. Consider 
cardiac MRI and myocardial biopsy for diagnosis. 
Grades 3 or 4 
Permanently discontinue. 
All other irAEs 
Grade 3 or intolerable/ 
persistent Grade 2 
Withhold until ≤ Grade 1. 
Based on severity of AE, administer corticosteroids. 
Recurrent Grade 3 
Consider discontinuation. 
Grade 4 
Permanently discontinue. 


 
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Table 2. Guidelines for Management of Suspected Infusion Reactions. 
Grade 
Descriptioni) 
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, non-
steroidal anti-inflammatory drugs 
[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 
orally) and acetaminophen/ 
paracetamol (500-1000 mg orally). 
• 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. 
i) 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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5.4.1 
Drug Extravasation 
As a general recommendation, in the event of extravasation, the following advice should be 
considered: 
• 
Stop the infusion immediately. 
• 
Do not remove the needle or cannula. 
• 
Aspirate with the same needle as much infiltrated drug as possible from the subcutaneous 
site. 
• 
Apply ice to area for 15 to 20 minutes every four to six hours for the first 72 hours. 
• 
Paint the skin over the extravasated site with 100% dimethyl sulfoxide (or hyaluronidase) four 
times daily for two weeks. 
Watch the area closely during the following days in order to determine whether a surgical 
excision and skin graft is necessary. 
 
5.5 
General Concomitant Medication and Additional Assistance Guidelines 
Concomitant treatment and prior medication are defined as non-investigational medicinal 
product (IMP). Concomitant treatment includes any prescribed medication or phytotherapy 
between the 28 days prior to the administration of the first treatment dose and the last safety visit 
during treatment period. All concomitant treatments will be recorded. After this time, information 
will only be collected on any anti–cancer drugs taken by the patient until EoS. 
Information on concomitant medication will include start date, end date, brand or generic 
name, route of administration, dose, and treatment indication. The following concomitant 
treatments are permitted during the study: 
• 
Erythropoiesis-stimulating agents (such as Procrit®, Aranesp®, Epogen®) for the supportive 
treatment of anemia. Blood transfusions are permitted during the study. 
• 
The prophylactic use of granulocyte-Colony Stimulating Factor is not allowed during the first 
treatment cycle but can be used for cases of neutropenia arising during treatment, in 
accordance with the NCCN guidelines.  
• 
Bisphosphonates and denosumab for the prevention of skeletal events.  
• 
Prophylactic or therapeutic anticoagulation therapy such as low-molecular weight heparin or 
warfarin at a stable dose level. 
• 
Mineralcorticoids (e.g., fludrocortisone). 
• 
Medications for the treatment of diarrhea, nausea, anorexia, or vomiting. 
• 
Any medications deemed necessary to ensure patient safety and well-being may be 
administered at the discretion of the Investigator. 


 
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5.6 
Prohibited Concomitant Medications 
INCMGA00012 (retifanlimab) belongs to the class of IgG antibodies that are administered 
parenterally and cleared by protein catabolism, extrinsic factors such as food and drug-drug 
interactions are not anticipated to affect its exposure. Specifically, drugs that affect cytochrome 
P450 and other metabolizing enzymes are not expected to interfere with the catabolism of 
INCMGA00012 (retifanlimab) (50). It is unlikely that INCMGA00012 (retifanlimab) would be a 
victim or a perpetrator of PK drug-drug interactions (51,52). Dedicated drug-drug interaction 
studies of retifanlimab have not been performed. 
INCMGA00012 (retifanlimab) is known to increase some proinflammatory cytokine levels. This 
is a known class effect of checkpoint inhibitory monoclonal antibodies (mAbs) (53)(54) but is 
unlikely to modulate CYP enzymes or drug transporters, based on clinical evidence with other 
agents of this class (50). It is unlikely that retifanlimab would be a perpetrator of drug-drug 
interactions, and the potential for clinically significant drug-drug interaction is low. 
HIV antiretroviral medications, used according to protocols as appropriate by HIV-positive 
participants in retifanlimab studies, may be substrates, inhibitors, or inducers of the P-glycoprotein 
and multidrug-resistant protein transporters and the cytochrome P450 enzyme system. None of 
the highly active antiretroviral therapies are immunosuppressors (55). Since retifanlimab is not 
expected to be a victim or perpetrator of drug transporters or cytochrome P450 enzymes, the 
potential of drug-drug interaction between antiretroviral drugs and retifanlimab is low (51). No 
clinically important differences in the CL of retifanlimab were found in HIV-positive participants 
taking antiretroviral medications compared to participants who were not HIV-positive. 
Glucocorticoid co-administration was explored as a time series covariate in the population 
pharmacokinetics model. Results show that glucocorticoid co-administration is not a predictor for 
retifanlimab clearance in the model. 
Hormonal contraceptives are metabolized by the cytochrome P450 enzyme system, and 
retifanlimab is not expected to be a victim or perpetrator of cytochrome P450 enzymes. Therefore, 
the potential for pharmacokinetic drug interactions between hormonal contraceptives and 
retifanlimab is low (56). 
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial: 
• 
Immunotherapy not specified in the protocol. 
• 
Chemotherapy not specified in the protocol. 


 
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• 
Targeted therapy 
• 
RT. 
Note: RT is allowed during screening, as long as it is completed at least two weeks prior to 
first dose of study treatment and may be allowed to treat a symptomatic bone lesion or the 
brain after consultation with Sponsor. 
• 
Herbal supplements. 
• 
Probiotics. 
• 
Live vaccines within 30 days prior to first dose of study treatment and while participating in 
the trial. Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella, herpes zoster, yellow fever, rabies, BCG, and typhoid (oral) 
vaccines. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed. However, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines, and are not allowed. 
• 
Immunosuppressive agents within seven days prior to first dose of study treatment. 
• 
Steroids for any purpose other than to modulate symptoms from an event of clinical interest 
of suspected immunologic etiology.  
Note: The use of physiologic doses of steroids (≤ 10 mg prednisone daily) is allowed and 
does not require Sponsor consultation. 
Note: The use of systemic steroids to premedicate patients for whom computerized 
tomography (CT) scans with contrast are contraindicated is allowed. Magnetic resonance 
imaging (MRI) of abdomen and pelvis with a non-contrast CT scan of the chest may also be 
performed in these patients. 
Note: Local applications and inhaled steroids for management of asthma are allowed.  
Subjects who, per Investigator’s assessment, require any of the aforementioned medications for 
clinical management should be discontinued from study treatment. There are no prohibited 
therapies during the post-treatment follow-up phase. 
 
5.7 
Medication Errors and Overdose 
Medication errors in this study may arise when the drug is administered at the wrong time or 
when the wrong dose strength is taken. Patient medication errors should be recorded on the 
relevant section in the case report form (CRF). In the event of an error in the administration of the 
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Medication errors must be reported irrespective of the presence of an associated AE/SAE, 
including: 
• 
Medication errors involving patient exposure to the IMP. 
• 
Any possible medication errors or use of the medication not defined in the protocol which 
implicates the participating patient or not. 
Regardless of whether the medication error is accompanied by an AE or not, in the judgment 
of the Investigator, the medication error should be properly documented and recorded. 
 
5.8 
Treatment Compliance 
Patients will receive treatment under physician supervision. Personnel will check the 
administration volume and total administered dose. The administered dose of each treatment will 
be recorded in the source data and the appropriate CRF. 
 
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Informed Consent Form 
Written ICF from the patient must be signed before performing any study procedure. However, 
tumor assessments available and performed as part of clinical practice prior to obtaining ICF and 
within 28 days prior to treatment start may be used; such evaluations do not need to be repeated 
for screening. Bone scans performed within 60 days prior to treatment start are acceptable. 
By giving their consent, patients will be informed as to the nature of the study drug and will 
receive pertinent information regarding the study objectives, possible benefits, and potential AEs. 
They will also receive information on the follow-up procedures and possible risks they will be 
exposed to. This document also informs patients about how biological samples will be obtained 
and collected and its legal implications. After receiving the document, the patient will read it (or 
receive information verbally before witnesses) and will sign the previously approved ICF. The 
patient will receive a signed copy of the ICF. The patient can withdraw his consent and discontinue 
the study; this will not affect any future medical treatment. One re-screening is allowed in patients 
that are screening failure in this study. Patient has to re-consent ICF before any study procedure 
is done. 
At inclusion: 
• 
The Sponsor will request the patient’s demographic and clinical data related to screening 
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• 
Each patient will be given a Unique Patient Number (UPN) for this study, provided by the 
Sponsor. All data will be recorded in the appropriate CRF using this identification number. 
This number will be provided to the central laboratory to ensure traceability of study samples. 
Confirmation of patient’s eligibility for study participation will be recorded on the CRF.  
 
6.2 
Visit Schedule  
All screening tests and evaluations must be completed and reviewed to confirm that patients 
meet all eligibility criteria within 28 days prior to the first administration of study medication 
(dosing).  
The Investigator will maintain a screening log to record details of all patients screened and to 
confirm eligibility or record reasons for screening failure, as applicable. 
Visits are organized in programmed cycles of 28 days (if there are no delays in treatment 
owing to the occurrence of an AE). All visits must occur within ± 3 working days from the 
scheduled date, unless otherwise noted in the schedule of assessments. 
Assessments scheduled for day 1 (before treatment) of all cycles must be performed within 
72 hours prior to study treatment administration, unless otherwise indicated in the schedule of 
assessments, to confirm to the patient if treatment can be followed up. If a mandatory procedure 
described in the protocol falls on a bank holiday and/or weekend, this procedure should be 
performed on the day before or after the holiday (i.e. within a period of ± 3 working days). The 
summary of all study assessments is included in Appendix 1. 
EoT visit will be performed within 28 days after last study treatment dose. Patients will be 
followed up for survival and post-study anticancer therapy evaluation every 3 months until the 
EoS. Telephone contact is acceptable. 
 
6.3 
Demographic Data and Medical History 
Demographic data include age, and self-reported race/ethnicity. Medical history comprises 
clinically significant diseases, surgical interventions, history of cancer (including prior 
antineoplastic treatments and procedures), history of smoking, alcoholism, drug addiction, as well 
as any medications (e.g., prescribed drugs, over-the-counter drugs, medicinal plants, 
homeopathic remedies, or food supplements) used by the patient in the 28 days prior to screening 
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6.4 
Efficacy Assessments 
6.4.1 
Tumor and Response Evaluations 
All measurable and evaluable lesions should be assessed and documented at the screening 
visit and re-assessed at each subsequent tumor evaluation. Tumor assessments will be 
performed at screening, every 8 weeks (± 7 days) for the first 6 months following first dose of 
study treatment, and every 12 weeks (± 7 days) thereafter until PD, treatment discontinuation, 
withdrawal of consent, the start of new anticancer treatment, death, or study termination by the 
Sponsor, whichever occurs first. The same radiographic procedures and technique must be used 
throughout the study for each patient. 
Tumor assessment during the screening period should consist of clinical exam ‒with 
examination of the penis and/or inguinal region‒ and of anatomical imaging consisting of 1) CT 
scan of the chest, abdomen, and pelvis (MRI of the abdomen and pelvis with a non-contrast CT 
scan of the chest in patients for whom CT scans with contrast are contraindicated), 2) bone scan 
if a subject has a known history of bone metastases or has new bone pain during screening, and 
3) any other imaging studies as clinically indicated by the treating physician [brain imaging during 
the trial should be performed in subjects with known brain metastases (every nine weeks for first 
year, then every 12 weeks) and those with worsening and/or new neurological symptoms]. 
Tumor assessment after the screening period should consist of clinical exam ‒with examination 
of the penis and/or inguinal region‒ and of anatomical imaging consisting of 1) CT scan of the 
chest, abdomen, and pelvis (MRI of the abdomen and pelvis with a non-contrast CT scan of the 
chest in patients for whom CT scans with contrast are contraindicated). In the event a positron 
emission tomography (PET)/CT scan is used for tumor assessments, CT portion of PET/CT is 
usually of lower quality, and should not be used instead of dedicated diagnostic CT. If the CT 
scan is of high quality, with oral and IV contrast, may be used with caution. Additional information 
from PET may bias CT assessment. 2) bone scan if a subject develops new or worsening 
symptoms or if the site believes they have attained a complete response (CR), and 3) any other 
imaging studies felt to be clinically indicated by the treating physician. All known sites of disease 
documented at screening should be re-assessed at each subsequent tumor evaluation. 
After progression of disease by RECIST v.1.1, if the site Investigator determines the subject 
is clinically stable and will benefit from continued treatment, the subject will then be managed by 
irRECIST as described in Section 6.4.4 of the protocol. 
 
6.4.2 
Response Assessment 
CBR is defined as the number of patients with CR, partial response (PR) or stable disease 
(SD) (for at least 12 weeks) divided by the number of patients in the analysis set. Tumor response 


 
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will be defined as best response, based on local investigator’s assessment according to RECIST 
criteria guidelines (version 1.1).  
ORR is defined as the proportion of the subjects in the analysis set who have a CR or PR 
based on RECIST v.1.1: 
• 
CR: Complete disappearance of all target lesions. Any pathological lymph nodes (target 
or non-target) must have reduction in short axis to < 10 mm. 
• 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference 
the baseline sum diameters.  
• 
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. 
• 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference 
the smallest sum diameters while on study. The development of new, previously 
undetected lesions is also considered progression. 
DoR is defined as the time from first documented CR or PR until disease progression or death 
from any cause, based on local investigator’s assessment according to RECIST criteria v.1.1. In 
case of the patient first reaching PR and later CR, the duration of CR will be measured and 
reported separately, starting from the date when first documented, and ending when a 
progressive disease is diagnosed, or the patient dies. 
Maximum tumor shrinkage is defined as the percentage of tumor shrinkage from baseline 
(obtained from the sum of the largest diameters of the target lesions), based on local investigator’s 
assessment according to RECIST criteria v.1.1. 
  
6.4.3 
OS and PFS Definitions 
OS is defined as the time from the date of first dose of study treatment until death by any 
cause or the last date the patient was known to be alive. Patients who are lost to follow-up and 
the patients who are alive at the date of data cut-off will be censored at the date the patient was 
last known alive. 
PFS is defined as the time from the date of first dose of study treatment until the first 
documented PD based on RECIST v.1.1 or death due to any cause, whichever occurs first based 
on local investigator’s assessment according to RECIST criteria v.1.1. Patients with no 
progression or death will be assessed until patient discontinues study treatment, so they will be 
censored at the date of their last evaluable imaging. 
Finally, 6-months PFS rate is defined as the proportion of patients who are alive and 
progression-free at 6 months from the date of first dose of study treatment based on irRECIST 
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6.4.4 
irRECIST 
Immunotherapeutic agents such as INCMGA00012 (retifanlimab) may induce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response patterns 
observed with these compounds may be different to the typical time course of responses seen 
with classical cytotoxic agents and can manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Standard RECIST v.1.1 may, therefore, 
not provide a precise response assessment of immunotherapeutic agents such as INCMGA00012 
(retifanlimab). 
irRECIST is RECIST v.1.1 adapted to account for the unique tumor response seen with 
immunotherapeutic agents. In this way, in subjects who have initial evidence of radiological PD 
by RECIST v.1.1, it is at the discretion of the Investigator whether to continue a subject on study 
treatment until repeat imaging is obtained. Subjects may receive study treatment and tumor 
assessment should be repeated at least four weeks later in order to confirm PD by irRECIST. Any 
subject deemed clinically unstable should be discontinued from trial treatment at first radiologic 
evidence of PD and is not required to have repeat imaging for PD confirmation. Clinical stability 
is defined as the following: 
• 
Absence of symptoms and signs indicating clinically significant PD, including worsening of 
laboratory values. 
• 
No decline in ECOG performance status. 
• 
Absence of rapid PD. 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention. 
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site Investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s). Scenarios where PD is confirmed at repeat imaging if any of the 
following occur by irRECIST: 
• 
Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir. 
• 
Non-target disease resulting in initial PD is worse (qualitative assessment). 
• 
New lesion resulting in initial PD is worse (qualitative assessment). 
• 
Additional new lesion(s) since last evaluation. 
• 
Additional new non-target progression since last evaluation. 
 
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
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subject continues to be clinically stable, treatment may continue and follow the regular imaging 
schedule. 
Note: If a subject with confirmed radiographic PD per irRECIST, but the subject is achieving a 
clinically meaningful benefit, and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered following 
consultation with the Sponsor. In this case, if treatment is continued, tumor imaging should 
continue to be performed following the intervals as outlined in Appendix 1. 
Note: In subjects who discontinue study treatment without documented PD, every effort should 
be made to continue monitoring their disease status by tumor imaging following the intervals as 
outlined in Appendix 1 until the start of new anti–cancer treatment, PD, death, or the EoS, 
whichever occurs first. 
 
6.5 
Safety and Tolerability Assessments  
6.5.1 
Laboratory Assessments 
Laboratory tests will be performed in accordance to local standard treatment and clinical 
indications. These values will include:  
• 
Hematological test [hemoglobin, hematocrit, red blood cell count, platelet count, WBC with 
differential count (ANC, lymphocytes, monocytes, eosinophils and basophiles)], coagulation, 
chemistry with renal function analysis (serum creatinine or measured/calculated creatinine 
clearance or GFR), liver function [AST, ALT, alkaline phosphatase (ALP), gamma-glutamyl 
transferase (GGT), total and direct bilirubin], glucose, sodium, potassium, calcium, chloride, 
magnesium, uric acid, total protein, albumin, and lactate dehydrogenase. 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood). 
• 
Thyroid function testing [thyroid-stimulating hormone (TSH), free T3, and free T4]. 
• 
HAV serology (positivity for HAV IgM antibody). 
• 
HIV serology. 
• 
HBV serology [HBsAg, anti–HBsAg]. 
• 
HCV serology (anti–HCV). In patients with a positive anti–HCV, HCV RNA detection and 
quantification by PCR will be additionally performed. 
• 
Mantoux or Quantiferon tuberculin skin test (TST)  
 


 
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6.5.1.1 
HIV Management Control 
In participants who are known to be HIV-positive, additional HIV tests will be required every 8 
weeks during 1st year of study treatment, every 3 months during the 2nd year and every 6 months 
during the follow-up period in order to monitor the following laboratory criteria: 
a) CD4-positive count ≥ 300/μL; 
b) Undetectable viral load. 
Moreover, a final sample will be collected at the EoT visit or, if no separate EoT visit is performed, 
at the 28-day follow-up visit. 
 
6.5.2 
Pregnancy and Assessment of Fertility 
Carcinogenicity studies have not been conducted and male participants should use barrier 
contraception (i.e., condom) or maintain sexual abstinence while receiving INCMGA00012 
(retifanlimab) and up to 180 days following the end of the study treatment. Accidental exposure 
of pregnant partners through the insemination route is unlikely to result in fetal exposures of 
concern given the low Cmax in semen that has been described with other IgG antibodies and the 
limited vaginal absorption that is likely to occur. 
 
6.5.3 
Physical Examination 
A complete physical examination will include an examination of head, eyes, ears, nose, and 
throat, examination of the penis and/or inguinal region, as well as cardiovascular, dermatological, 
musculoskeletal, respiratory, digestive, genitourinary, and neurological systems. A limited 
physical exam will consist of a symptom-directed physical examination. 
Changes to abnormalities identified during the baseline period should be recorded at all 
subsequent physical examinations. New or worsening abnormalities should be recorded as AEs, 
if applicable. 
 
6.5.4 
Vital Signs 
These will include the measurement of height (only during screening), weight, respiratory rate, 
heart rate, blood pressure, and body temperature. Abnormal or significant changes in vital signs 
from baseline should be recorded as AEs, if appropriate. 
 


 
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6.5.5 
ECOG PS 
PS will be determined using the ECOG performance status scale (see Table 3). Wherever 
possible, the patient’s performance status should always be assessed by the same personnel 
throughout the study. 
 
Table 3. ECOG PS Scale. 
Grade 
Scale 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead. 
(http://www.ecog.org/general/perf_stat.html) 
 
6.6 
Translational Research 
The molecular study involves the collection, processing, temporary storage, and shipment of 
samples from consenting patients enrolled in centers selected for participation in the study. The 
study plan includes collection and initial processing of tumor tissues and blood samples to a 
central laboratory that will be used to identify dynamic biomarkers that may be of prognostic value 
or predictive of response/resistance to INCMGA00012 (retifanlimab) treatment. 
The exploratory analysis will be performed only if an adequate number of samples is available 
at the EoS. Since the identification of new markers that correlate with disease activity and the 
efficacy or safety of treatment is rapidly developing, the definitive list of analyses remains to be 
determined, but may include determination of markers such as but not limited to PD1, PD-L1, 
HIV, and HPV status. 
Tumor-based biomarkers may include description of immune cells, gene expression profiling 
including tumor mutation burden, and/or measurement of protein levels for immune-related and 
tumor-related proteins. 
 
Blood-based biomarkers may include serum cytokines, circulating immune cells, and 
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6.6.1 
Tumor Samples 
Patients must agree to provide a tumor tissue sample from a metastatic site or primary tumor 
at the time of study entry, within 28 days prior to the first administration of study medication, with 
the exception of patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor 
or subject safety concern) that may submit an archived primary/metastatic tumor specimen only 
upon agreement from the Sponsor. 
If feasible, patients will also be given the option of providing a tumor tissue sample 
from metastasis or primary tumor obtained at disease progression. 
Exploratory studies will be performed on tumor biopsies, or formalin-fixed and paraffin-embedded 
(FFPE) or frozen tumor samples (blocks), or unstained glass slides. 
Details on tumor tissue samples preparation, processing, storage, and shipment will be 
provided in a separate study manual. 
 
6.6.2 
Blood Samples 
Blood samples are required for all patients during the screening period, within 28 days prior to 
the first administration of study medication, after two cycles of study treatment, and upon 
progression or study termination. 
Additional tests will be required for all participants who are known to be HIV-positive in order 
to confirm CD4-positive count and the undetectable viral load following timepoints shown in 
Section 6.5.1.1. 
 
6.7 
Discontinuation of Patient, Study, or Site Participation 
6.7.1 
Patient Discontinuation 
Patients have the right to withdraw from the study at any time for any reason. The Investigator 
also has the right to withdraw patients from the study in the event of intercurrent illness, AEs, and 
treatment failure after a prescribed procedure, protocol violation, administrative reasons, or for 
other reasons. An excessive rate of withdrawals can render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Should a patient decide to withdraw, all efforts should be made to complete and report the 
observations as thoroughly as possible. The Investigator should contact the patient or a 
responsible relative by telephone or through a personal visit to establish as completely as possible 
the reason for the withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
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for removal of a patient from the study is an AE, the principal specific event will be recorded on 
the CRF. 
In the case that the patient decides to prematurely discontinue study treatment, he should be 
asked if he can still be contacted for further information. The outcome of that discussion should 
be documented in both the medical records and in the CRF. 
 
6.7.2 
Study and Site Discontinuation 
The Sponsor reserves the right to terminate this study at any time. Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or seriousness of AEs in this or other studies indicates a potential health risk 
to patients. 
• 
Patient enrollment is unsatisfactory. 
• 
Data recording is inaccurate or incomplete. 
• 
Excessively slow recruitment. 
• 
Poor protocol adherence. 
• 
Non-compliance with the International Conference on Harmonization (ICH) guideline for 
Good Clinical Practice (GCP). 
 
7 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
Safety assessments will consist of monitoring and recording protocol-defined AEs, events of 
clinical interest (ECI), and SAEs; measurement of protocol-specified hematology, clinical 
chemistry, measurement of protocol-specified vital signs; and other protocol-specified tests that 
are deemed critical to the safety evaluation of the study drug(s). 
The Sponsor or its designee is responsible for reporting relevant SAEs to competent 
authorities, other applicable regulatory authorities, and participating investigators, in accordance 
with ICH guidelines, and/or local regulatory requirements. 
The Sponsor or its designee is responsible for reporting unexpected fatal or life-threatening 
events associated with the use of the study drug(s) to the regulatory agencies and competent 
authorities within seven calendar days after being notified of the event. The Sponsor or its 
designee will report other relevant SAEs associated with the use of the study medication to the 
appropriate competent authorities (according to local guidelines), investigators, by a written safety 
report within 15 calendar days of notification. 
 


 
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7.1 
AEs Definitions 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, regardless of whether it is considered related to the IMP or not. 
An abnormal test finding should only be reported as an AE if meets any of the following criteria: 
• 
Is associated with accompanying symptoms and a general diagnostic term, including the 
symptoms and the abnormal test finding, cannot be defined. 
• 
Requires additional diagnostic testing or medical/surgical intervention, leads to a change in 
study drug(s) dosing or discontinuation from the study. 
• 
Needs additional concomitant drug treatment. 
• 
Is considered to be an AE by the investigator or by the Sponsor. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs. However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE. For example, an acute appendicitis that 
begins during the AE reporting period should be reported as the AE and the resulting 
appendectomy should be recorded as treatment of the AE. 
The causal relationship between an AE and the IMP will be defined as follows: 
Unrelated: The temporal association between the AE and the administration of the IMP makes a 
causal relationship unlikely, or the subject/patient’s clinical state or the study procedure/conditions 
provide a sufficient explanation for the AE. 
Related: The temporal association between the AE and the administration of the IMP makes a 
causal relationship possible, and the subject/patient’s clinical state or the study 
procedure/conditions do not provide a sufficient explanation for the AE. 
Each AE must be assessed by the Investigator as to whether or not there is a reasonable 
possibility of causal relationship to the IMP. 
The descriptions and grading scales found in the revised NCI-CTCAE v.5.0 criteria will be utilized 
for all toxicity reporting. A copy of the NCI-CTCAE v.5.0 criteria can be downloaded from the 
CTEP website: 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_
Reference_8.5x11.pdf). 
Grade refers to the intensity (severity) of the AE. The CTCAE displays grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline: 


 
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o 
CTCAE grade 1 Mild: Asymptomatic or mild symptoms. It does not interfere with normal daily 
activities. Clinical or diagnostic observations only; intervention not indicated. 
o 
CTCAE grade 2 Moderate: It causes some interference with daily activities; minimal, local 
or noninvasive intervention or treatment indicated. 
o 
CTCAE grade 3 Severe: Medically significant but not immediately life-threatening. Normal 
daily activities are substantially impaired; hospitalization or prolongation of hospitalization 
indicated and/or intervention or treatment is required. 
o 
CTCAE grade 4 Life-threatening consequences: Normal daily activities are substantially 
impaired; hospitalization and/or urgent intervention or treatment is indicated. 
o 
CTCAE grade 5 Fatal-death: Death related to AE. 
o 
Not applicable: Clinically significant and asymptomatic laboratory test abnormalities or 
abnormal assessments, for which no CTCAE grading guidance is applicable but which are 
considered as AEs. 
A mild, moderate, or severe AE may or may not be serious (see definition below). These 
terms are used to describe the intensity of a specific AE. However, a severe AE (such as 
severe headache) may be of relatively minor medical significance and is not necessarily 
serious. For example, nausea lasting several hours may be rated as severe, but may not be 
clinically serious. Fever of 39°C that is not considered severe may become serious if it 
prolongs hospital discharge by a day. Seriousness rather than severity serves as a guide for 
defining regulatory reporting obligations. 
 
7.1.1 
Infusion-related reactions 
Infusion-related reactions may be associated with the administration of therapeutic antibodies 
and are known to occur with the PD-1 inhibitor class. As of the data cutoff date, infusion-related 
reactions occurred in 38 (6.6%) of the participants receiving retifanlimab monotherapy. The 
incidences of infusion-related reactions in participants receiving retifanlimab in Study INCMGA 
0012-203 (30-minute infusions) and Studies INCMGA 0012-101, INCMGA 0012-104, INCMGA 
0012-201, and INCMGA 0012-202 (60-minute infusions) were generally similar. 
All infusion-related reactions were Grade 1 or 2 in severity with the exception of 2 Grade 3 
infusion-related reactions Infusion-related reactions were observed in Study INCMGA 0012-101 
regardless of whether prophylaxis was administered; therefore, routine prophylaxis is not 
recommended. Primary prophylaxis with antipyretics and histamine blockers should be strongly 
considered for participants who have had previous systemic reactions to protein product infusions 
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for participants who have experienced infusion-related reactions to retifanlimab. Routine 
prophylaxis is not required. Monitor participants for signs and symptoms of infusion-related 
reactions. Interrupt or slow the rate of infusion or permanently discontinue retifanlimab based on 
severity of reaction. Participants who experience life-threatening infusion-related reactions should 
not be retreated with retifanlimab. Guidance for prophylaxis and management of infusion-related 
reactions is provided in all study protocols. 
 
7.1.2 
Expected Treatment Emergent Immune-Related Adverse Events (irAEs) 
Immune-related adverse reactions, including severe cases, have occurred in participants 
receiving INCMGA00012 (retifanlimab). With the exception of endocrinopathies, the majority of 
immune-related adverse reactions occurring during treatment with retifanlimab were managed 
with interruptions of retifanlimab, administration of corticosteroids and/or supportive care. 
Immune-related adverse reactions may occur after the last dose of retifanlimab. Immune-related 
adverse reactions affecting more than one body system can occur simultaneously. irAEs in 
participants exposed to INCMGA00012 (retifanlimab) were generally consistent with approved 
PD-1 inhibitors in frequency and severity. Guidance for assessment, management, and reporting 
of these immune-related toxicities is provided in the study protocol. 
 


 
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Table 4. Treatment Emergent irAEs 
 
 
 
7.2 
SAEs 
Per definition, a SAE is defined as any AE that either: 
• 
Results in death (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening (i.e., the AE, in the view of the investigator, places the subject/patient at 
immediate risk of death when it occurs). 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability/incapacity (disability is defined as a substantial 
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• 
Constitutes a congenital anomaly/birth defect (in a neonate/infant born to a mother exposed 
to the investigational product(s). 
Definition of life-threatening: An AE is life-threatening if the subject/patient was at immediate risk 
of death from the event as it occurred, i.e., does not include an event that might have caused 
death if it had occurred in a more serious form. For instance, drug induced hepatitis that resolved 
without evidence of hepatic failure would not be considered life-threatening even though drug 
induced hepatitis can be fatal. 
Definition of hospitalization: AEs requiring hospitalization should be considered serious. In 
general, hospitalization means that the subject/patient has been detained (usually involving an 
overnight stay) at the hospital or emergency ward for observation and/or treatment which would 
not have been appropriate at the study site. When in doubt as to whether hospitalization occurred 
or was necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of an 
AE, do not need to be notified according to immediate reporting criteria. If anything untoward is 
reported during any procedure, this must be reported as an AE and either ‘serious’ or ‘non-serious’ 
attributed according to the usual criteria. 
According to immediate reporting criteria, a hospitalization or prolongation of hospitalization in 
the absence of a precipitating clinical AE, do not need to be notified. Some examples include: 
• 
Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (i.e., for work-up of persistent 
pretreatment lab abnormality). 
• 
Social admission (i.e., subject/patient has no place to sleep). 
• 
Administrative admission (i.e., for yearly physical examination). 
• 
Protocol-specified admission during a study (i.e., for a procedure required by the study 
protocol). 
• 
Optional admission not associated with a precipitating clinical AE (i.e., for elective cosmetic 
surgery). 
• 
Hospitalization for observation without a medical AE. 
• 
Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation and/or for the individual subject/patient. 
• 
Admission exclusively for the administration of blood products. 
Definition of clinically/medically significant event: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a SAE when, based upon 
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or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. Clinically/medically significant events 
MUST be reported as SAEs. 
In this clinical trial and as defined in this protocol, SAEs and hospitalizations unequivocally and 
solely related to established tumor progression of disease will NOT be treated as SAEs for 
reporting obligations. 
Selected non-serious and serious AEs are also known as ECI and must be reported within 24 
hours to the Sponsor. 
For the time period beginning when the consent form is signed until treatment allocation first dose 
of study treatment, any ECI, or follow up to an ECI, that occurs to any subject must be reported 
within 24 hours to the Sponsor if it causes the subject to be excluded from the trial or is the result 
of a protocol-specified intervention. 
For the time period beginning at treatment allocation first dose of study treatment through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Incyte, must be reported within 24 hours to the Sponsor. 
 
7.3 
Events of clinical interest (ECI) for INCMGA00012 (retifanlimab) 
The table 5 shows the expected SAE. 
 
Table 5. SAEs 
 
 
Please refer to the most updated INCMGA00012 (retifanlimab) IB for further detailed 
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Overdose of INCMGA00012 (retifanlimab) product. There are no human or animal data 
regarding overdose of INCMGA00012 (retifanlimab). Treatment of overdose should consist of 
general supportive measures”. 
All SAEs/ECIs that have not resolved by the EoS, or that have not resolved upon 
discontinuation of the subject/patient's participation in the study, must be followed until any of the 
following occurs: 
• 
The event resolves. 
• 
The event stabilizes. 
• 
The event returns to baseline, if a baseline value/status is available. 
• 
The event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct. 
• 
It becomes unlikely that any additional information can be obtained (subject/patient or health 
care practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
 
7.4 
AEs Reporting and Other Safety Related Issues Reporting 
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides ICF. 
Reporting period for SAEs/ECIs that are NOT related with the study IMP INCMGA00012 
(retifanlimab) and also all non-serious AEs is as follows: 
• 
If patient discontinues treatment during the study, until 90 calendar days after the last 
administration of any of the study IMP. 
All study patients will be carefully monitored for the occurrence of AEs (including SAEs and 
ECIs) during the above specified AE reporting period. 
If the investigator becomes aware of a SAE/ECI at any time after the end of administration of 
study treatment and believes that it is POSSIBLY RELATED to INCMGA00012 (retifanlimab), the 
investigator should notify the serious adverse reaction to the Sponsor immediately irrespective 
of the time elapsed since last administration of the study IMP. 
For all ≥ grade 3 AEs with causal relationship to the investigational product, a follow-up by 
the Investigator may be required until the event or its sequelae resolve or stabilize at the 
acceptable level to the Investigator, and the Sponsor concurs with that assessment. 


 
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Clearly related signs, symptoms, and abnormal diagnostic procedure results should be 
grouped together and reported as a single diagnosis or syndrome whenever possible. Any 
additional events that fall outside this definition should also be reported separately. 
All AEs must be recorded in the CRF. 
 
7.5 
SAE Reporting and Timeframe 
Reporting requirements will comply with all EU safety reporting requirements as detailed in 
current legislation and all applicable local regulations for safety reporting. 
The investigator or investigator’s team will report all protocol defined SAEs and ECIs to the 
Sponsor (MedSIR) no later than 24 hours of any site study team staff becoming aware of the 
event as follows: 
• 
The full details of the SAE and/or ECI should be collected and fully documented using the 
SAE form and sent to the Sponsor (MedSIR). 
• 
Follow-up information, copies of any relevant test results, event outcome and the opinion of 
the investigator as to the relationship between the IMP and the SAE and ECI, accompanied 
by other applicable documentation when it is requested, will be sent along with the SAE form, 
if available on the day the event is reported or as soon as possible if it is not. 
• 
The original SAE reporting form and the confirmation from the Sponsor must be kept with the 
CRF documentation at the study site(s). 
All SAE forms will be sent by the investigator or investigator’s team to the Sponsor (MedSIR) 
according to the reporting instructions provided by MedSIR at the site initiation visit and filed in 
the Investigator’s File. 
SAEs and ECIs will be followed until resolved, a stable outcome is reached, subject/patient 
is lost to follow-up, or dies. 
As sponsor, MedSIR will be responsible for ensuring that events are reported within the 
mandated timeframe to the European Medicines Agency (EMA), other competent authorities, 
Institutional Review Boards (IRBs)/ECs, and investigator(s), as necessary and in accordance with 
all applicable guidelines, approved directives and regulations. All safety reporting local regulatory 
requirements will be followed. 
 
7.6 
Expedited reporting to HAs, investigators, IRBs, and ECs 
To determine reporting requirements for single SAE cases, MedSIR (as Sponsor) or its 
designee will assess the expectedness of these events using the following reference documents: 


 
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- 
INCMGA00012 (retifanlimab) IB. 
MedSIR (as Sponsor) or its designee will compare the severity of each event and the 
cumulative event frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality and 
seriousness, with allowance for upgrading by the Sponsor as needed. 
Within seven calendar days after being notified of the event, MedSIR (as Sponsor) or its 
designee will report unexpected fatal or life-threatening events associated with the use of the 
study drug to the regulatory agencies and competent authorities, to the investigators and Ethics 
Committees (ECs). MedSIR (as Sponsor) or its designee will report other unexpected SAEs 
associated with the use of the study medication to the appropriate competent authorities 
(according to local guidelines), investigators, and ECs by a written safety report within 15 calendar 
days of notification. All safety expedited reports will be reported in accordance with all regulatory 
reporting obligations (including timelines) and local regulatory requirements. 
 
7.7 
Other Safety-Related Reports 
As Sponsor, MedSIR will assess constantly the benefit/risk rate of the trial that means a 
continuous evaluation of the safety profile of the drugs under investigation will be done using all 
available information. MedSIR will provide the regulatory agencies and competent authorities and 
the investigators with any relevant information that may affect the benefit/risk rate of the trial. An 
annual DSUR safety report for study INCMGA00012 (retifanlimab) will be prepared and 
distributed by MedSIR or its designee in accordance with all regulatory reporting obligations and 
local regulatory requirements. 
In order to ensure the correct and necessary exchange of safety related information between 
MedSIR (as Sponsor) and Incyte a contract will be established and signed between MedSIR and 
these companies. 
MedSIR or its designee will report any finding of noncompliance (as failure to follow any 
applicable regulation or institutional policies that govern human subjects’ research) and/or serious 
noncompliance (as noncompliance that materially increases risks that result in substantial harm 
to subjects or others, or that materially compromises the rights or welfare of participants) 
according to any reporting obligation and local regulatory requirements. 
 


 
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7.8 
Pregnancy Reporting  
Irrespective of the treatment received by the subject/patient, any patient’s partner pregnancy 
occurring during study treatment or during the 7 months following study drug discontinuation must 
be reported within 24 hours of investigator’s knowledge of the event. 
Pregnancies will be treated as SAEs and the investigator will complete a pregnancy form, and 
forward it to the sponsor according to the reporting instructions provided by MedSIR at the site 
initiation visit and filed in the Investigator’s File. 
The subject/patient will be asked to provide follow-up information on the outcome of the 
pregnancy, including premature termination should the case arise. Spontaneous miscarriage and 
congenital abnormalities will also be reported as SAEs. 
The follow-up period will be deemed to have ended when the health status of the child has 
been determined at 12 months of the infant’s life. 
Additional follow up information on any INCMGA00012 (retifanlimab) exposed pregnancy and 
infant will be requested at specific time points (i.e., after having received the initial report, at the 
end of the second trimester, 2 weeks after the expected date of delivery, and at 3, 6, and 12 
months of the infant’s life). 
Follow-up queries may be sent, asking for further information, if required for a comprehensive 
assessment of the case. 
 
8 
STASTICAL CONSIDERATIONS AND ANALYSIS PLAN 
8.1 
Sample Size 
A total of 18 patients with unresectable locally advanced or metastatic PsqCC will be enrolled 
into this trial. 
 
8.2 
Justification of Sample Size 
This is a multicenter, open-label, single arm, phase II trial evaluating the efficacy and safety 
of INCMGA00012 (retifanlimab) in unresectable locally advanced or metastatic PSqCC. The 
defined primary endpoint is ORR.  
In the single arm phase II trial VinCap (57) patients with locally advanced PSqCC were treated 
with vinflunine. The trial evaluated CBR and ORR after 4 cycles. The 45.5% and 27.3% of patients 
achieved clinical benefit and objective response, respectively. These data suggest that excluding 
an ORR ≤5% while targeting the improvement of the ORR to ≥25% would be an adequate 
approach to assess a new antineoplastic strategy in this patient population. 


 
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The sample size calculation is based on an exact binomial test. The clinical trial is designed 
to demonstrate an ORR of at least 25% and to exclude a rate of less than 5% (p0=0.05, p1=0.25, 
α =0.05, β=0.80, A’hern’s exact design). At least 3 responders (18.8%) among 16 evaluable 
patients will be adequate to justify the investigation of this strategy in further clinical trials. 
Considering a drop-out rate of 10%, a sample size of 18 patients will be needed to attain 80% 
power at nominal level of one-sided alpha of 0.05. 
 
8.3 
Analysis Sets 
Full analysis and safety set. 
The full analysis and safety set includes patients who receive at least one dose of study 
medication. 
 
Per-protocol set 
All patients that accomplish selection criteria, receive at least one drug exposure, and receive 
the protocol required study drug exposure and processing. Criteria for determining the “per 
protocol” (PP) group assignment would be established by the Steering Committee before the 
statistical analysis begins. This analysis will only occur if this set differs by ≥ 10% from the full 
analysis set. 
 
Exploratory analysis set 
All patients with biomarker evaluable samples with the assay and alternative platforms that 
accomplish selection criteria and receive at least one drug exposure. 
 
Analysis set schedule 
Primary, secondary and irRECIST endpoints will be analyzed on the full analysis set, and per-
protocol populations. Full analysis set will be considered the primary population for the analysis. 
Biomarker and correlation between biomarkers and clinical outcomes will be analyzed on 
exploratory analysis set. Safety analysis will be performed on the safety set. 
The estimands for the study based on ICH E9 (R1) addendum will be fully described in the 
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8.4 
Statistical Plan 
8.4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint for the present study is the ORR. The ORR is defined as the 
number of patients with CR and PR divided by the number of patients in the analysis set. Tumor 
response will be defined as best response based on local investigator’s assessment according to 
RECIST criteria v.1.1. 
 
8.4.2 
Secondary Efficacy Endpoints 
The secondary efficacy variables are CBR, DoR, PFS, OS, and maximum tumor shrinkage. 
For an exhaustive definition of efficacy endpoints, please refer to the Section 6.4.2. 
 
8.4.3 
Exploratory Endpoints 
The exploratory endpoints are PFS, CBR, and ORR based on irRECIST (see Section 2.3.1) 
and predictive biomarkers (such as but not limited to PD-1, PD-L1, HIV status). 
The objective of the exploratory analyses of irRECIST is the characterization of 
INCMGA00012 (retifanlimab) clinical activity. We will also compare RECIST and irRECIST criteria 
for evaluation of the clinical response. 
The objective of the statistical analyses of biomarkers is the identification of those markers or 
combinations of markers which show best association with positive clinical outcome of the study 
treatment. We will measure the clinical efficacy of that analysis in terms of ORR, CBR, PFS and 
irPFS. 
 
8.4.4 
Analysis of Baseline and Demographic Variables 
The demographics and baseline characteristics including disease history and prior therapy are 
summarized using descriptive statistics. 
 
8.4.5 
Decision Rules and Adjustment of Alpha in The Study 
The study would be defined as positive at final analysis, if the ORR in the INCMGA00012 
(retifanlimab) arm is statistically significantly better (p<0.05) than expected under the null 
hypothesis (H0: ORR≤5%). Decisions will be based on exact binomial test. 


 
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For all secondary and exploratory tests, we will use two-sided p-values with alpha ≤ 0.05 level 
of significance. The p-values emerging from these analyses will not be interpreted in a 
confirmative sense; they will be considered of descriptive nature only. 
 
8.4.6 
Primary Efficacy Analysis 
We will describe number and proportion of responders. We will estimate the ORR with the 
95% Clopper-Pearson confidence intervals and the p-value with exact binomial test. Analysis will 
be performed on the full analysis and PP sets. ITT will be considered the primary set for the 
analysis. 
 
8.4.7 
Secondary Efficacy Outcomes 
We will describe number and proportion of patients with clinical benefit and 6-month PFS. We 
will estimate the proportion with the 95% Pearson-Clopper confidence intervals. For time to event 
endpoints (PFS, OS, irPFS and DOR), we will use the Kaplan-Meier method. Number and 
proportion of events, median survival time and survival rates, with corresponding 95%Cl, will be 
calculated in both arms. For continuous outcome (maximum tumor shrinkage) we will use 
statistics of central tendency (median with 95%CI) and dispersion [range and interquartile range]. 
We provide waterfall plots of maximum tumor shrinkage from baseline. The duration of response 
has also plotted with bar plots. 
Analysis will be performed on the ITT, and PP sets. ITT will be considered the primary 
population for the analysis. For all tests, we will use two-sided p-values with alpha ≤ 0.05 level of 
significance. 
 
8.4.8 
Subgroup Efficacy Analysis 
CBR, 6-month PFS, DoR, TTP, ORR, and OS according to RECIST v.1.1 together with ORR, 
CBR, and 6-month PFS according to irRECIST will be analyzed in patients’ subgroups 
categorized based on baseline factors of potential prognostic value. The baseline factors will 
include but not limited to the following: (1) Prior treatments; (2) Number of previous regimens; (3) 
Type of previous regimens (e.g., platinum agents, radiotherapy); (4) Age; (5) Sites of metastases; 
(6) Race and geographic location (if applicable). We will utilize the Kaplan-Meier method and 
LogRank test. Multivariable Cox proportional hazards model for adjusting for multiple prognostic 
factors will be used to test the association between prognostic factors and the outcomes if sample 
size is adequate. Covariate estimates, hr and corresponding 95% Cis, applicable test statistics, 
and P-values will be presented. We will use the Breslow method for tie handling in survival 


 
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analysis. P-values and 95% CIs for hr will be based on Wald test. The assumption of proportional 
hazards will be assessed by plotting the hazards over time. 
For binary outcomes we will use chi-squared test for binary outcomes followed by multivariate 
logistic regression for adjusting for multiple prognostic factors. We will examine the residuals to 
assess model assumptions. 
For all tests, we will use two-sided P-values with alpha ≤ 0.05 level of significance and P-
values ≤ 0.05 will indicate statistical significance. The P-values emerging from these analyses will 
not be interpreted in a confirmative sense but will be considered of descriptive nature only. 
Analysis will be performed on the ITT and PP sets. ITT will be considered the primary population 
for the analysis. 
 
8.4.9 
Exploratory Analysis 
The exploratory analysis will be performed only if an adequate number of samples is available 
at the EoS. Markers (such as but not limited to PD1, PD-L1, HIV, and HPV status) will be 
evaluated on a univariate level regarding their potential for prediction of the clinical endpoints 
(ORR, CBR, PFS and irPFS). 
Biomarker and response correlations with clinical covariates will be investigated. It will be 
checked whether covariates can improve the prediction and whether there is an interaction with 
the biomarkers. Further multivariate techniques (e.g. Multiple Logistic Regression, Cox 
regression and penalized regressions models) will be deliberated in order to study combinations 
of markers. Techniques to control false discovery rate and overfitting (cross-validation) may be 
considered. Analysis will he performed on exploratory analysis set. 
 
8.5 
Safety Outcomes 
Patient safety and AEs will be assessed using the NCI-CTCAE v.5.0. Analysis of safety-related 
data will be considered at three levels: 
• 
First, the extent of exposure (dose, duration, number of patients) will be examined to 
determine the degree to which safety can be assessed from the study. 
• 
Second, we will describe and compare clinically relevant test, concomitant medications, and 
AEs reported in every study group. For AEs, we will report intensity, expectability, casualty, 
relation, body system, action taken, and outcome. 
• 
Finally, SAEs, deaths, and study discontinuations will be described and examined. 
 


 
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8.6 
Missing Data Management 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. 
We will report reasons for withdrawal. Patient with missing in response outcomes (ORR and CBR) 
will considered as no responders. Other outcomes will be managed with simple imputations 
methods. The effect that any missing data might have on results will be assessed via sensitivity 
analysis of study sets. 
For PFS and DoR, patients without a date of disease progression or death will be analyzed as 
censored observations on the date of last tumor assessment. If no post-baseline tumor 
assessment is available, patients will be censored at the date of randomization + 1 day. Data for 
patients with an event who missed two or more scheduled assessments immediately prior to the 
event will be censored at the last tumor assessment prior to the missed visits. 
For OS, patients who are not reported as having died will be analyzed as censored 
observations on the date they were last known to be alive. If no post-baseline data are available, 
OS will be censored at the date of randomization + 1 day. 
 
8.7 
Steering Committee Review 
A Steering Committee will be established for this study. It will be composed of the 
investigators, the sponsor’s medical scientist and the scientific global coordinator. Further details 
on the steering committee and its responsibilities will be provided in a separate document. 
The Steering Committee will meet on demand to review, discuss, and evaluate all of the 
gathered efficacy and safety data. In case of any arising safety concern, these meetings can also 
be called at any time at request of a participating investigator. At these meetings, the Sponsor 
and the participating investigators must reach a consensus on study data. The Sponsor will 
prepare minutes from these meetings and circulate them to each investigator for comment prior 
to finalization. 
Study site investigators and the Sponsor will review patient data at least every six months. 
Each study site investigator will monitor patient’s data for serious toxicities on an ongoing basis. 
 
9 
ETHICAL CONSIDERATIONS 
9.1 
Regulatory and Ethics Compliance 
The study will be performed and reported in accordance with the guidelines of the ICH, and 
the ethical principles laid down in the Declaration of Helsinki. The study will be also compliance 
with European Directive 2001/20/EC and any applicable local regulations. 
 


 
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9.2 
IRBs/IECs 
Conduct of the study must be approved by an appropriately constituted IRB/IEC. Approval is 
required for the study protocol, protocol amendments, ICFs, study subject information sheets, 
and advertising materials. The IRB/IEC must also be contacted in the event of any major protocol 
violation or any SAE. 
It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate 
and timely information is provided at all phases during the study. 
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/EC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC. Investigators are also responsible for promptly 
informing the IRB/EC/CA of any protocol amendments (approval is required before 
implementation of substantial amendments). 
In addition to the requirements to report protocol-defined AEs to the Sponsor, investigators 
are required to promptly report to their respective IRB/EC/CA all unanticipated problems involving 
risk to human patients. Some IRBs/ECs/CA may want prompt notification of all SAEs, whereas 
others require notification only about events that are serious, assessed to be related to study 
treatment, and are unexpected. Investigators may receive written safety reports or other safety 
related communications from the Sponsor. Investigators are responsible for ensuring that such 
reports are reviewed and processed in accordance with regulatory requirements and with the 
policies and procedures established by their IRB/EC/CA and archived in the site’s study file. 
 
9.3 
Informed Consent 
For each study subject, written ICF will be obtained prior to any protocol related activities. As 
part of this procedure, the study site Investigator or designee must explain orally and in writing 
the nature, duration, and purpose of the study, and the action of the drug in such a manner that 
the study subject is aware of the potential risks, inconveniences, or adverse effects that may 
occur. The study subject should be informed that he is free to withdraw from the study at any 
time. The subject will receive all information that is required by local regulations and ICH 
guidelines. 
The Consent Form must be signed and dated by the patient before his participation in the 
study. The case history or clinical records for each patient shall document the informed consent 
process and that written ICF was obtained prior to participation in the study. 
A copy of each signed Consent Form must be provided to the patient. 
All signed and dated Consent Forms must remain in each patient’s study file and must be 
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The ICF should be revised whenever there are changes to procedures outlined in the ICF or 
when new information becomes available that may affect the willingness of the patient to 
participate. 
For any updated or revised Consent Forms, the case history for each patient shall document 
the informed consent process and that written ICF was obtained for the updated/revised Consent 
Form for continued participation in the study. The final revised IRB/EC-approved ICF must be 
provided to the Sponsor for regulatory purposes. 
 
9.4 
Data Protection 
The Sponsor will ensure the confidentiality of patient’s medical information in accordance with 
all applicable laws and regulations. 
The Sponsor as Data Controller according to the EU Data Protection Directive (95/46/EC) and 
the General Data Protection Regulation (2016/679) (GDPR) on the protection of individuals with 
regard to the processing of personal data and on the free movement of such data confirms 
herewith compliance to Directive 95/46/EC and GDPR in all stages of Data Management. 
Data generated by this study must be available for inspection upon request by representatives 
of national and local health authorities, the Sponsor monitors, representatives, and collaborators, 
and the IRB/EC for each study site, as appropriate. 
 
 
10 SOURCE DOCUMENTATION, STUDY MONITORING, AND QUALITY ASSURANCE 
10.1 Source Data Documentation 
Source data refers to all information in original records and certified copies of original records 
of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). 
Source documents are original documents, data, and records (i.e., hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects' diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
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Sponsor’s Quality Assurance group may assist in assessing whether electronic records 
generated from computerized medical record systems used at investigational sites can serve as 
source documents for the purposes of this protocol. 
If a site’s computerized medical record system is not adequately validated for the purposes of 
clinical research (as opposed to general clinical practice), applicable hardcopy source documents 
must be maintained to ensure that critical protocol data entered into the eCRFs can be verified. 
At a minimum, source documentation must be available to substantiate subject identification, 
eligibility, and participation; proper informed consent procedures; dates of visits; adherence to 
protocol procedures; adequate reporting and follow-up of AEs; administration of concomitant 
medication; study receipt/dispensing/return records; study administration information; and date of 
completion and reason. 
Data recorded on the CRF will be verified by checking the CRF entries against source 
documents (i.e., all original records, laboratory reports, medical records) in order to ensure data 
completeness and accuracy as required by study protocol. The Investigator and/or site staff must 
make CRFs and source documents of subjects enrolled in this study available for inspection by 
MedSIR or its representative at the time of each monitoring visit. 
The source documents must also be available for inspection, verification, and copying, as 
required by regulations, officials of the regulatory health authorities (i.e., FDA, EMEA, and others), 
and/or ECs/IRBs. The Investigator and study site staff must comply with applicable privacy, data 
protection, and medical confidentiality laws for use and disclosure of information related to the 
study and enrolled subjects. 
The patient must also allow access to the patients’ medical records. Each patient should be 
informed of this prior to the start of the study. 
 
10.2 Study Monitoring and Source Data Verification 
Study progress will be monitored by MedSIR or its representative (i.e., a Clinical Research 
Organization [CRO]) as frequently as necessary to ensure: 
• 
That the rights and well-being of human subjects are protected; 
• 
The reported trial data are accurate, complete, and verifiable from the source documents; 
and 
• 
The conduct of the trial is in compliance with the current approved protocol/amendment(s), 
GCP, and applicable regulatory requirements. 
Contact details for the team involved in study monitoring will be identified in a handout located 
in the Investigator Site File. 
Data recorded on the CRF will be verified by checking the CRF entries against source 
documents (i.e., all original records, laboratory reports, medical records, subject diaries) in order 


 
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to ensure data completeness and accuracy as required by study protocol. The Investigator and/or 
site staff must make CRFs and source documents of subjects enrolled in this study available for 
inspection by the Sponsor or its representative at the time of each monitoring visit. 
 
10.3 Retention of Records 
Investigators must retain all study records required by the applicable regulations in a secure 
and safe facility. The Investigator must consult a Sponsor representative before disposal of any 
study records and must notify the Sponsor of any change in the location, disposition, or custody 
of the study files. 
Essential documents must be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product. “Essential documents” are defined as 
documents that individually and collectively permit evaluation of the conduct of a trial and the 
quality of the data produced. These documents should be retained for a longer period, however, 
if required by the applicable e regulatory requirements or by an agreement with the Sponsor. The 
CHMP requires retention for the maximum period of time permitted by the institution, but not less 
than 15 years (ICH E6[R2], 4.9.5). It is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained (ICH E6[R2], 
5.5.12). 
The study site Investigator must not dispose of any records relevant to this study without either 
(1) written permission from the Sponsor or (2) providing an opportunity for the Sponsor to collect 
such records. The study site Investigator shall take responsibility for maintaining adequate and 
accurate electronic or hard copy source documents of all observations and data generated during 
this study. Such documentation is subject to inspection by the Sponsor and the FDA and/or EMA 
(or respective individual EU country regulatory authorities). 
These principles of record retention will also be applied to the storage of laboratory samples, 
provided that the integrity of the stored sample permits testing. 
 
10.4 Data Quality Assurance 
During and/or after completion of the study, quality assurance auditor (s) named by the 
MedSIR or the regulatory authorities may wish to perform on-site audits. The Investigators will be 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator 
for the purpose of inspecting the facilities and, upon request, inspecting the various records of 


 
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the clinical study (i.e., CRFs and other pertinent data) provided that patient confidentiality is 
respected. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
in the course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH E6[R2] GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from the Sponsor’s (or designee’s) Quality Assurance Department. 
Inspection of site facilities (i.e., pharmacy, drug storage areas, laboratories) and review of study-
related records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP (ICH E6 [R2]), and applicable country regulatory requirements. 
 
11 DATA MANAGEMENT 
11.1 Data Entry and Management 
In this study, all data will be entered onto CRFs in a timely fashion by the Investigator and/or 
the Investigator’s dedicated site staff. 
The Investigator must review data recorded in the CRF to verify their accuracy. 
Reconciliation of the data will be performed by the designated CRO. At the conclusion of the 
study, the occurrence of any protocol violations will be identified and recorded as part of the 
clinical database. After these actions have been completed and the database has been declared 
to be complete and accurate, it will be locked and will become available for statistical data 
analysis. 
 
11.2 Data Clarification 
As part of the conduct of the trial, MedSIR may have questions about the data entered by the 
site, referred to as queries. The monitors and the Sponsor or designees are the only parties that 
can generate a query. 
 
11.3 Data Coding Procedures 
Coding of AEs, medical history, and prior and concomitant medications will be performed using 
standard dictionaries as described in the Data Management Plan. 
 


 
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12 STUDY MANAGEMENT 
12.1 Discontinuation of the Study 
MedSIR reserves the right to discontinue the study for safety or administrative reasons at any 
time. Should the study be terminated and/or the site closed for whatever reason, all investigational 
drugs pertaining to the study must be returned to MedSIR. Any actions required to assess or 
maintain study subject safety will continue as required, in spite of termination of the study. 
 
12.2 Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment or administrative 
letter that must be approved by MedSIR, the Scientific Global Coordinator, the study site 
Investigator, and the IRB/IE/CA before implementation. This requirement for approval should in 
no way prevent any immediate action from being taken by the study site Investigator or MedSIR 
in the interests of preserving the safety of all subjects included in the trial. If an immediate change 
to the protocol is felt to be necessary by the study site Investigator and is implemented for safety 
reasons, MedSIR should be notified as soon as possible (within 24 hours if possible) and the 
IRB/IEC/CA should be informed as necessary. 
 
12.3 Publication Policy Protection of Trade Secrets 
All information generated in this study must be considered highly confidential and must not be 
disclosed to any persons not directly concerned with the study without prior written permission 
from the Scientific Global Coordinator and MedSIR. However, authorized regulatory officials, the 
Scientific Global Coordinator or the study site Investigator, and MedSIR personnel (or their 
representatives) will be allowed full access to inspect and copy the records. All clinical 
investigational drug, patient bodily fluids, and/or other materials collected shall be used solely in 
accordance with this protocol, unless otherwise agreed to in writing by Scientific Global 
Coordinator or the study site Investigator and MedSIR. 
The Sponsor will ensure that as far as possible results of this study will be published as 
scientific/clinical papers in high-quality peer-reviewed journals. Preparation of such manuscripts 
will be made with full collaboration of principal Investigators and in accordance with the current 
guidelines of Good Publication Practice. 
The Sponsor must be notified of any intent to publish data collected from the study and prior 
approval from Sponsor must be obtained prior to publication. 
 


 
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Appendix 1. Schedule of Study Assessments and Procedures. 
Assessment Window (Days) 
Screening 
All cycles 
End of Treatment visit 
Progression of 
disease 
End of Study 
(12 months after the first 
study dose of the last 
patient included) 
D –28 to –1 
1(± 3 days) 
28 days (± 3 days) after 
last dose 
 Informed consent form1 
X 
 
 
 
 
 Review of eligibility criteria 
X 
 
 
 
 
 Demographic data and medical history2 
X 
 
 
 
 
 Physical examination  
X 
X 
X 
 
X 
 ECOG performance status 
X 
X 
X 
 
X 
 Weight, Height, and Vital signs3 
X 
X 
X 
 
X 
 Concomitant medications reporting4 
X 
X 
X 
 
 
 AE reporting5 
X 
X 
X 
 
 
 12-lead electrocardiogram 
X 
Performed as clinically indicated 
 
 Assessment of symptoms 
X 
X 
X 
 
X 
 Tumor assessment6 
X 
See footnote (7) 
X 
 Hematology/Chemistry8 
X 
X (9) 
X 
 
X 
 TSH, free T3, free T4 
X 
X (9) 
 
 
 
 Coagulation panel (aPTT, INR or PTT) 
X 
 
 
 
 
Viral serology10 and Mantoux or Quantiferon 
tuberculin skin test (TST) 11 
X 
 
 
 
 
 Urinalysis12 
X 
Every 2 cycles12 
 
 
 
 Tumor samples for exploratory research13 
X 
 
 
X 
 
 Blood samples for exploratory research14 
X 
At C3D1 
X 
 
 
 INCMGA00012 (retifanlimab) infusion  
 
X 
 
 
 
 Survival and anti–cancer therapy follow-up  
 
 
 
X 
X 
Abbreviations: AE: Adverse event; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ANC: Absolute neutrophil count; aPTT: activated partial 
thromboplastin time; AST: Aspartate aminotransferase; CT: Computed tomography; DNA: Deoxyribonucleic acid; ECOG PS: Eastern Cooperative Oncology 
Group Performance Status; EoT: End of Treatment; GGT: Gamma-glutamyl transferase; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HBcAb: Hepatitis B 
core antibody; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; INR: International normalized ratio; MRI: 
Magnetic Resonance Imaging; NCI–CTCAE: National Cancer Institute–Common Terminology Criteria for Adverse Events; PTT: Partial thromboplastin time; 
RNA: Ribonucleic acid; TSH: Thyroid-stimulating hormone; WBC: White blood cells. 


 
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1. Informed Consent Form: Signed written Informed Consent Form obtained prior to any trial-specific procedure. 
2. Demographic data and medical history: Demographic data include age and self-reported race/ethnicity. Medical history comprises clinically significant 
diseases, surgical interventions, history of cancer (including prior antineoplastic treatments and procedures), history of smoking, alcoholism, drug addiction, 
as well as any medications (e.g., prescribed drugs, over-the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the 
patient in the 28 days prior to screening visit. 
3. Weight, Height, and Vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse rate, and 
body temperature (oral, axillary, or tympanic temperature). 
4. Concomitant medication reporting: Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
5. AE reporting: All AEs occurring during the trial and until 90 days after treatment discontinuation visit (EoT visit) have to be recorded with grading according 
to the NCI–CTCAE v.5.0 criteria. 
6. Tumor assessment: All measurable and evaluable lesions should be assessed and documented at the screening visit. Evaluation consists of clinical exam 
with evaluation of the penis and/or inguinal region and anatomical imaging performed during the screening period should consist of: 
a) CT of the chest, abdomen, and pelvis or MRI of the abdomen and pelvis with a non-contrast CT scan of the chest in patients for whom CT scans with 
contrast are contraindicated; In the event a positron emission tomography (PET)/CT scan is used for tumor assessments, CT portion of PET/CT is 
usually of lower quality, and should not be used instead of dedicated diagnostic CT. If the CT scan is of high quality, with oral and IV contrast, may be 
used with caution. Additional information from PET may bias CT assessment. 
b) Bone scan if a subject has a known history of bone metastases or has new bone pain during screening; 
c) Any other imaging studies as clinically indicated by the treating physician. 
Tumor assessments will be performed at baseline, every 8 weeks (± 7 days) for the first 6 months following first dose of study treatment, and every 12 
weeks (± 7 days) thereafter, with additional scans as clinically indicated. All known sites of disease documented at screening should be re-assessed at each 
subsequent tumor evaluation. The same radiographic procedures and technique must be used throughout the study for each patient (bone scan will be 
performed only if a subject develops new or worsening symptoms or if the site believes they have attained a complete response). 
7. In subjects who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease 
status by tumor imaging following the intervals as outlined in footnote 3 until the start of new anti–cancer treatment, disease progression, death, or the end 
of the study, whichever occurs first. 


 
EudraCT#: 2019-001172-11 
 
Study Code: MedOPP239 
 
 
CSP Version and Date: 2.0, 24-Feb-2021 
 
 
 
 
 
 
 
 
87 
8. Hematology/Chemistry: Blood test will be performed as per local standard of care and clinical indication before treatment administration. These values 
should be included: hemoglobin, hematocrit, red blood cell count, platelet count, and WBC count with differential count (ANC, lymphocytes, monocytes, 
eosinophils, and basophiles), coagulation, chemistry with renal function analysis (serum creatinine or measured/calculated creatinine clearance or GFR), 
liver function (AST, ALT, ALP, GGT, total and direct bilirubin), glucose, sodium, potassium, calcium, chloride, magnesium, uric acid, total protein, albumin, 
and lactate dehydrogenase. 
9. Cycle 1 Day 1 panel assessments are not required if the panel was performed at screening within 72 hours prior to start of study treatment. 
10. Viral serology: HAV (IgM antibody), HBsAg, total HBcAb, HCV antibody; additional tests for HBV DNA or HCV RNA will be required to confirm eligibility; 
HIV. 
11. Mantoux or Quantiferon tuberculin skin test (TST): in case of positivity of the test results, the pulmonologists must rule out the presence of latent TBC. 
All patients with latent TBC will be excluded from the study. 
12. Urinalysis: Urinalysis include specific gravity, pH, glucose, protein, ketones, and blood. Every 2 cycles: Cycle 1 day 1, Cycle 3 day 1, cycle 5 day 1, cycle 
7 day 1, etc., before study treatment administration. 
13. Tumor samples for exploratory research: A tumor tissue sample from a metastatic site or the primary tumor must be collected at the time of study entry, 
with the exception of patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety concern) that may submit an archived 
primary or metastatic tumor specimen only upon agreement from the Sponsor. If feasible, patients will also be given the option of providing a tumor tissue 
sample from metastasis or primary tumor obtained at disease progression or study termination. 
14. Blood samples for exploratory research: Blood samples are required for all patients at the time of inclusion, after two cycles of study treatment, and upon 
progression or study termination. 
Note: Additional tests will be required for all participants who are known to be HIV-positive in order to confirm CD4-positive count and the undetectable viral 
load, every 8 weeks during 1st year of study treatment, every 3 months during the 2nd year and every 6 months during the follow-up period. A final sample 
will be collected at the EoT visit or, if no separate EoT visit is performed, at the 28-day follow-up visit. 

SAP_001.pdf: 
CONFIDENTIAL INFORMATION 
 
Statistical Analysis Plan (SAP) 
 
Final Version 1.0 
21st May 2021 
 
EudraCT Number 
2019-001172-11 
Protocol Number 
MedOPP239 
Protocol Version Date 
Version 1.1, 08-Nov-2019  
Version 1.2 Spain, 17-Feb-2020 
Version 1.3 Italy, 11-Jun-2020 
Title 
A Multicenter, Open-Label, Single-ARm, PHase II 
Clinical Trial to Evaluate the Efficacy and Safety of 
INCMGA00012 in Advanced Penile SquamoUS Cell 
Carcinoma. - ORPHEUS - 
Phase II Study of the Efficacy of INCMGA00012 
in Penile Squamous Cell Carcinoma 
Sponsor 
 
MEDSIR 
Torre Glòries. Av. Diagonal, 211 
Planta 27. 08018 Barcelona 
 
 
 
 
 
 
 
Performed by: 
 
Avenida Meridiana 350, 9 D 
08027 Barcelona (Spain) 
www.sail-biometria.com 
STATISTICAL ANALYSIS PLAN (SAP) 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      2                                                                   Final 
 
Signature Page 
 
 
EudraCT Number: 
2019-001172-11 
Protocol Number: 
MedOPP239 
 
 
Written by:  
Signature:  
                            ___________________________ 
Date:  
                            ___________________________ 
Xavier Masramon 
Biostatistician  
SAIL S.L. 
Barcelona, Spain 
 
 
Sponsor Signature: 
The undersigned hereby declare that they have examined the Statistical Analysis Plan document 
and agree to its form and content.  
Represented by: 
 
Signature: 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
__________________________ 
Signature: 
__________________________ 
Date: 
__________________________ 
Name: 
__________________________ 
Title: 
 
__________________________ 
 
 
 
25/05/2021
31/05/2021
Miguel Sampayo Cordero
MSc
Data Science Manager
Leonardo Mina
31/05/2021
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      3                                                                   Final 
 
SAP Revision History: 
 
Version 
Number 
Date 
Changes 
1.0 
May 21, 2021 
New 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      4                                                                   Final 
LIST OF ABBREVIATIONS 
Abbreviation Definition 
AE ADVERSE EVENT 
ALK ALKALINE PHOSPHATASE 
ALP ALKALINE PHOSPHATASE 
ALT ALANINE AMINOTRANSFERASE 
ANC ABSOLUTE NEUTROPHIL COUNT 
APTT ACTIVATED PARTIAL THROMBOPLASTIN TIME 
AST ASPARTATE AMINOTRANSFERASE 
BCG BACILLUS CALMETTE–GUÉRIN 
BOR BEST OVERALL RESPONSE 
CBR CLINICAL BENEFIT RATE 
CI CONFIDENCE INTERVAL 
CNS CENTRAL NERVOUS SYSTEM 
CR COMPLETE RESPONSE 
CRF CASE REPORT FORM 
CRO CLINICAL RESEARCH ORGANIZATION 
DEHP (2-ETHYLHEXYL) PHTHALATE 
DNA DEOXYRIBONUCLEIC ACID 
DOR DURATION OF RESPONSE 
EC ETHICS COMMITTEE 
ECI EVENT OF CLINICAL INTEREST 
ECOG EASTERN COOPERATIVE ONCOLOGY GROUP 
EGFR EPIDERMAL GROWTH FACTOR RECEPTOR 
EMA EUROPEAN MEDICINES AGENCY
EOS END OF STUDY 
EOT END OF TREATMENT 
ESA ERYTHROPOIESIS-STIMULATING AGENTS 
FAS FULL ANALYSIS SET 
FDA FOOD AND DRUG ADMINISTRATION 
FFPE FORMALIN-FIXED AND PARAFFIN-EMBEDDED 
GCP GOOD CLINICAL PRACTICE 
GDPR GENERAL DATA PROTECTION REGULATION 
GFR GLOMERULAR FILTRATION RATE 
GGT GAMMA-GLUTAMYL TRANSFERASE 
HAV HEPATITIS A VIRUS 
HBSAG HEPATITIS B SURFACE ANTIGEN 
HBV HEPATITIS B VIRUS 
HCV HEPATITIS C VIRUS 
HIV HUMAN IMMUNODEFICIENCY VIRUS 
HNSQCC HEAD AND NECK REGION 
HPV HUMAN PAPILLOMAVIRUS 
IB INVESTIGATOR’S BROCHURE 
ICF INFORMED CONSENT FORM 
ICH INTERNATIONAL CONFERENCE ON HARMONIZATION 
ICI IMMUNE CHECKPOINT INHIBITOR 
IFN INTERFERON 
IMP INVESTIGATIONAL MEDICINAL PRODUCT 
INR INTERNATIONAL NORMALIZED RATIO 
IRAE IMMUNE-RELATED ADVERSE EVENT 
IRB INSTITUTIONAL REVIEW BOARD 
IRRECIST IMMUNE-RELATED RECIST 
ITT INTENTION-TO-TREAT 
MAB MONOCLONAL ANTIBODY 
MMR MISMATCH REPAIR 
MTD MAXIMUM TOLERATED DOSE 
NCCN NATIONAL COMPREHENSIVE CANCER NETWORK 
NCI-CTCAE NATIONAL CANCER INSTITUTE-COMMON TERMINOLOGY CRITERIA FOR 
ADVERSE EVENTS 
NSCLC NON-SMALL CELL LUNG CANCER 
ORR OVERALL RESPONSE RATE 
OS OVERALL SURVIVAL 
PCR POLYMERASE CHAIN REACTION 
PD PROGRESSIVE DISEASE 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      5                                                                   Final 
Abbreviation Definition 
PD-1 PROGRAMMED CELL DEATH PROTEIN 1 
PD-L1 PROGRAMMED DEATH-LIGAND 1 
PES POLYPROPYLENE AND POLYETHERSULFONE 
PFS PROGRESSION-FREE SURVIVAL 
PP PER PROTOCOL 
PR PARTIAL RESPONSE 
PS PERFORMANCE STATUS 
PSQCC PENILE SQUAMOUS CELL CARCINOMA 
PT PROTHROMBIN TIME 
PVC POLYVINYLCHLORIDE 
RECIST RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
RNA RIBONUCLEIC ACID 
RT RADIATION THERAPY 
SAE SERIOUS ADVERSE EVENT 
SD STABLE DISEASE 
SQCC SQUAMOUS CELL CARCINOMA 
T1DM DIABETES MELLITUS TYPE 1 
TEAE TREATMENT EMERGENT ADVERSE EVENT 
TMB TUMOR MUTATIONAL BURDEN 
TRAE TREATMENT-RELATED AE 
TSH THYROID-STIMULATING HORMONE 
TST MANTOUX TUBERCULIN SKIN TEST 
TTR TIME TO RESPONSE 
TTP TIME TO PROGRESSION 
ULN UPPER LIMIT OF NORMAL 
UPN UNIQUE PATIENT NUMBER 
WBC WHITE BLOOD CELL 
 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      6                                                                   Final 
TABLE OF CONTENTS 
1 
INTRODUCTION ____________________________________________________ 8 
1.1 
General _________________________________________________________________________ 8 
1.2 
Type of Study ____________________________________________________________________ 8 
1.3 
Study Population _________________________________________________________________ 8 
1.4 
Study Design ____________________________________________________________________ 8 
1.5 
Study Schedule ___________________________________________________________________ 9 
1.6 
Sample Size ____________________________________________________________________ 10 
2 
STUDY OBJECTIVES ________________________________________________ 10 
2.1 
Primary objective ________________________________________________________________ 10 
2.2 
Secondary Objectives _____________________________________________________________ 10 
2.3 
Exploratory Objectives ____________________________________________________________ 10 
3 
DEFINITION OF ENDPOINTS _________________________________________ 10 
3.1 
Primary Endpoint ________________________________________________________________ 10 
3.2 
Secondary Endpoints _____________________________________________________________ 10 
3.3 
Safety Endpoints ________________________________________________________________ 10 
3.4 
Exploratory Endpoints ____________________________________________________________ 10 
4 
ANALYSIS SETS ___________________________________________________ 11 
5 
STATISTICAL METHODS _____________________________________________ 11 
5.1 
General Methodology _____________________________________________________________ 11 
5.2 
Subject Disposition _______________________________________________________________ 12 
5.3 
Baseline Characteristics ___________________________________________________________ 13 
5.4 
Efficacy Analysis _________________________________________________________________ 13 
5.4.1 
Response Efficacy Definitions ____________________________________________________ 13 
5.4.1.1 
RECIST V.1.1 _______________________________________________________________ 13 
5.4.1.2 
irRECIST __________________________________________________________________ 15 
5.4.2 
Primary Efficacy Analysis ________________________________________________________ 16 
5.4.3 
Decision Rules and Adjustment of Alpha for Primary Endpoint __________________________ 16 
5.4.4 
Secondary Efficacy Analysis ______________________________________________________ 16 
5.4.5 
Handling of Missing Data ________________________________________________________ 19 
5.4.6 
Subgroup Analysis _____________________________________________________________ 19 
5.4.7 
Exploratory Analysis ____________________________________________________________ 21 
5.5 
Safety _________________________________________________________________________ 21 
5.5.1 
Duration and Extent of Exposure of Study Treatment _________________________________ 21 
5.5.2 
Dose Delays, Reductions and Discontinuations ______________________________________ 22 
5.5.3 
Concomitant Medications ________________________________________________________ 22 
5.5.4 
Adverse Events _______________________________________________________________ 22 
5.5.5 
Clinical Laboratory Parameters ___________________________________________________ 24 
5.5.6 
Vital Signs ___________________________________________________________________ 24 
5.5.7 
Physical Examination ___________________________________________________________ 24 
5.6 
Interim Analysis of Safety _________________________________________________________ 25 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      7                                                                   Final 
5.7 
Changes of Analysis from Protocol __________________________________________________ 25 
5.8 
Deviations from SAP ______________________________________________________________ 25 
6 
APPENDICES _____________________________________________________ 26 
6.1 
Appendix 1 - SAS Codes ___________________________________________________________ 26 
6.2 
List of Tables, Listings, Figures _____________________________________________________ 26 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      8                                                                   Final 
1 
INTRODUCTION 
1.1 General 
The purpose of this statistical analysis plan (SAP) is to provide a protocol specific description of the statistical analysis 
that will be performed to produce an integrated clinical/statistical report. 
This SAP is based upon the following study documents: 
- 
Protocol version: 
Version 1.1, 08-Nov-2019. 
- 
eCRF last release version updated: 09-Feb-2021. 
1.2 Type of Study 
This is a multicenter, open-label, single-arm, phase II clinical trial to evaluate the efficacy and safety of the 
INCMGA00012 in progressive advanced PSqCC patients, previously treated or not with chemotherapy. 
1.3 Study Population 
Male patients age ≥ 18 years with progressive locally advanced ‒not amenable to curative treatment‒ or metastatic 
PSqCC (i.e., T4 or N3 or M1) previously treated with chemotherapy regimens or patients naïve of systemic treatment. 
1.4 Study Design 
A total of 18 patients with unresectable locally advanced or metastatic PSqCC will be enrolled into this trial. 
INCMGA00012 should be administered intravenously, at flat dose of 500 mg over one hour (± 15 minutes) or 30 
minutes (-5/+ 15 min) using a filter on day 1 of each 28-day cycle (every 4 weeks). Infusion rate may be reduced if 
an infusion reaction occurs. 
In the absence of progression of disease or unacceptable toxicity, treatment with INCMGA00012 will continue based 
on physician criteria for up to 2 years. 
Tumor assessments per RECIST v.1.1 and irRECIST will be performed approximately every 8 weeks (± 7 days) for the 
first 6 months and every 12 weeks (± 7 days) thereafter until PD, treatment discontinuation, the start of new anti–
cancer treatment, withdrawal of consent, death, or the end of study (EoS), whichever occurs first. Tumor assessments 
will be performed on the specified schedule regardless of treatment delays. 
The primary endpoint is ORR. 
For estimation of ORR, CBR, DoR, PFS, and OS, tumor response will be based on RECIST v.1.1. In patients who 
continue treatment beyond radiographic PD per RECIST v.1.1, tumor response (ORR, CBR, and PFS) may continue to 
be assessed using irRECIST criteria until study treatment discontinuation. 
Safety assessments will include the incidence, nature, and severity of AEs and laboratory abnormalities graded per the 
NCI-CTCAE v.5.0. Laboratory safety assessments will include the regular monitoring of hematology, blood chemistry, 
coagulation, and thyroid function testing. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      9                                                                   Final 
1.5 Study Schedule 
 
Abbreviations: AE: Adverse event; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ANC: Absolute neutrophil count; aPTT: activated partial thromboplastin time; AST: 
Aspartate aminotransferase; CT: Computed tomography; DNA: Deoxyribonucleic acid; ECOG PS: Eastern Cooperative Oncology Group Performance Status; EoT: End of Treatment; 
GGT: Gamma-glutamyl transferase; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HBcAb: Hepatitis B core antibody; HBsAg: Hepatitis B surface antigen; HCV: Hepatitis C virus; HIV: 
Human immunodeficiency virus; INR: International normalized ratio; MRI: Magnetic Resonance Imaging; NCI–CTCAE: National Cancer Institute–Common Terminology Criteria for 
Adverse Events; PTT: Partial thromboplastin time; RNA: Ribonucleic acid; TSH: Thyroid-stimulating hormone; WBC: White blood cells. 
1. Informed Consent Form: Signed written Informed Consent Form obtained prior to any trial-specific procedure. 
2. Demographic data and medical history: Demographic data include age and self-reported race/ethnicity. Medical history comprises clinically significant diseases, surgical interventions, 
history of cancer (including prior antineoplastic treatments and procedures), history of smoking, alcoholism, drug addiction, as well as any medications (e.g., prescribed drugs, over-
the-counter drugs, medicinal plants, homeopathic remedies, or food supplements) used by the patient in the 28 days prior to screening visit. 
3. Concomitant medication reporting: Relevant concomitant medication will be recorded at screening and on an ongoing basis. 
4. AE reporting: All AEs occurring during the trial and until 90 days after treatment discontinuation visit (EoT visit) have to be recorded with grading according to the NCI–CTCAE v.5.0 
criteria. 
5. Weight, Height, and Vital signs: Weight, height (only at screening), respiratory rate, blood pressure measurements (systolic and diastolic), pulse rate, and body temperature (oral, 
axillary, or tympanic temperature). 
6. Tumor assessment: All measurable and evaluable lesions should be assessed and documented at the screening visit. Evaluation consists of clinical exam with evaluation of the 
penis and/or inguinal region and anatomical imaging performed during the screening period should consist of: a) CT of the chest, abdomen, and pelvis or MRI of the abdomen and 
pelvis with a non-contrast CT scan of the chest in patients for whom CT scans with contrast are contraindicated; b) Bone scan if a subject has a known history of bone metastases or 
has new bone pain during screening; c) Any other imaging studies as clinically indicated by the treating physician. Tumor assessments will be performed at baseline, every 8 weeks 
(± 7 days) for the first 6 months following first dose of study treatment, and every 12 weeks (± 7 days) thereafter, with additional scans as clinically indicated. All known sites of 
disease documented at screening should be re-assessed at each subsequent tumor evaluation. The same radiographic procedures and technique must be used throughout the study 
for each patient (bone scan will be performed only if a subject develops new or worsening symptoms or if the site believes they have attained a complete response). 
7. In subjects who discontinue study treatment without documented disease progression, every effort should be made to continue monitoring their disease status by tumor imaging 
following the intervals as outlined in footnote 3 until the start of new anti–cancer treatment, disease progression, death, or the end of the study, whichever occurs first. 
8. Hematology/Chemistry: Blood test will be performed as per local standard of care and clinical indication before treatment administration. These values should be included: 
hemoglobin, hematocrit, red blood cell count, platelet count, and WBC count with differential count (ANC, lymphocytes, monocytes, eosinophils, and basophiles), coagulation, chemistry 
with renal function analysis (serum creatinine or measured/calculated creatinine clearance or GFR), liver function (AST, ALT, ALP, GGT, total and direct bilirubin), glucose, sodium, 
potassium, calcium, chloride, magnesium, uric acid, total protein, albumin, and lactate dehydrogenase. 
9. Cycle 1 Day 1 panel assessments are not required if the panel was performed at screening within 72 hours prior to start of study treatment. 
10. Viral serology: HAV (IgM antibody), HBsAg, total HBcAb, HCV antibody; additional tests for HBV DNA or HCV RNA will be required to confirm eligibility; HIV. 
11. Mantoux tuberculin skin test (TST): in case of positivity of the test results, the pulmonologists must rule out the presence of latent TBC. All patients with latent TBC will be excluded 
from the study. 
12. Urinalysis: Urinalysis include specific gravity, pH, glucose, protein, ketones, and blood. Every 2 cycles: Cycle 1 day 1, Cycle 3 day 1, cycle 5 day 1, cycle 7 day 1, etc., before study 
treatment administration. 
13. Tumor samples for exploratory research: A tumor tissue sample from a metastatic site or the primary tumor must be collected at the time of study entry, with the exception of 
patients for whom tumor biopsies cannot be obtained (e.g., inaccessible tumor or subject safety concern) that may submit an archived primary or metastatic tumor specimen only 
upon agreement from the Sponsor. If feasible, patients will also be given the option of providing a tumor tissue sample from metastasis or primary tumor obtained at disease 
progression or study termination. 
14. Blood samples for exploratory research: Blood samples are required for all patients at the time of inclusion, after two cycles of study treatment, and upon progression or study 
termination. 
Note: Additional tests will be required for all participants who are known to be HIV-positive in order to confirm CD4-positive count and the undetectable viral 
load, every 8 weeks during 1st year of study treatment, every 3 months during the 2nd year and every 6 months during the follow-up period. A final sample 
will be collected at the EoT visit or, if no separate EoT visit is performed, at the 28-day follow-up visit. 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      10                                                                   Final 
1.6 Sample Size 
A total of 18 patients will be enrolled and the defined primary endpoint is ORR. 
Justification of Sample Size: 
The sample size calculation is based on an exact binomial test. The clinical trial is designed to demonstrate an ORR of 
at least 25% and to exclude a rate of less than 5% (p0=0.05, p1=0.25, α =0.05, β=0.80, A’hern’s exact design). At 
least 3 responders (18.8%) among 16 evaluable patients will be adequate to justify the investigation of this strategy 
in further clinical trials. Considering a drop-out rate of 10%, a sample size of 18 patients will be needed to attain 80% 
power at nominal level of one-sided alpha of 0.05. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
To assess the efficacy, as determined by the objective response rate (ORR), of INCMGA00012 in patients with 
unresectable locally advanced or metastatic PSqCC. 
2.2 Secondary Objectives 
 
To assess the efficacy, as determined by the clinical benefit rate (CBR), PFS, 6-month PFS, duration of response 
(DoR), time to response (TTR), OS, and maximum tumor shrinkage, of INCMGA00012 in these patients. 
 
To evaluate the safety and tolerability of INCMGA00012 in these patients. 
2.3 Exploratory Objectives 
 
To determine the efficacy –as determined by the ORR, CBR, and 6-month PFS based on immune-related RECIST 
(irRECIST). 
 
To evaluate predictive or prognostic, tumor- and/or immune-related biomarkers associated with disease activity 
status or response to treatment. 
 
To identify possible mechanisms of resistance to study treatments through the comparative analysis of potential 
biomarkers from paired pre-treatment and post-progression tumor and/or blood samples. 
 
To assess impact of INCMGA00012 on HIV control in participants who are known to be HIV-positive. 
3 
DEFINITION OF ENDPOINTS 
3.1
Primary Endpoint
 
The primary efficacy endpoint for the present study is the ORR. 
3.2 Secondary Endpoints  
 
The secondary efficacy variables are CBR, DoR, TTR, PFS, OS and maximum tumor shrinkage by investigator 
RECIST response. 
3.3 Safety Endpoints  
 
The safety and tolerability will be evaluated by incidence of AEs, incidence of prespecified AEs, change from 
baseline in targeted vital signs, and change from baseline in targeted clinical laboratory test results. 
3.4 Exploratory Endpoints 
 
ORR, CBR, and 6-month PFS as per irRECIST. 
 
Relationship between tumor- and/or immune-related biomarkers, and efficacy in tumor tissue and/or liquid biopsy. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      11                                                                   Final 
 
Changes from baseline in the CD4-positive cell count and HIV viral load in participants who are known to be HIV-
positive. 
4 
ANALYSIS SETS 
The following sets will be analyzed: 
 
Screening: Patients who were present at the screening visit. 
 
Safety and FAS (Full Analysis Set) Set: patients who receive at least one dose of study medication. 
Efficacy and Safety endpoints will be analyzed on the Safety/FAS set. 
FAS set will be considered the primary population for the analysis. 
 
Per-protocol (PP) set: All patients that accomplish selection criteria, receive at least one drug exposure, and 
receive the protocol required study drug exposure and processing. Criteria for determining the “per protocol” (PP) 
group assignment would be established by the Steering Committee before the statistical analysis begins. This 
analysis will only occur if this set differs by ≥10% from the FAS set. 
The primary and secondary efficacy analyses will be performed on the FAS and PP sets.  
 
Exploratory Set: All patients with biomarker evaluable samples with the assay and alternative platforms that 
accomplish selection criteria and receive at least one drug exposure. 
Exploratory analysis will be performed on exploratory set. A separate analysis report for such assessments will be 
written. 
5 
STATISTICAL METHODS 
5.1 General Methodology 
The statistical analysis will be conducted following the principles as specified in International Conference on 
Harmonization (ICH) Topic E9 (CPMP/ICH/363/96). The significance level will be α=0.05 for all tests. As an exploratory 
study, multiple testing without adjustment of the significance level is considered acceptable. 
Definition of baseline: For each safety or efficacy parameter, the last valid assessment made before first study drug 
administration will be used as the baseline for all analyses of that safety or efficacy parameter unless otherwise 
specified. 
Continuous data will be summarized in terms of the number of observations, mean, standard deviation (SD), median, 
minimum, maximum, and first and third quartiles, unless otherwise stated. Where data are collected over time, both 
the observed data and change from baseline will be summarized at each time point. 
The minimum and maximum will be reported to the same number of decimal places as the raw data recorded in the 
database. The mean, median, and first and third quartiles will be reported to one more decimal place than the raw 
data recorded in the database. The SD will be reported to two more decimal places than the raw data recorded in the 
database. In general, the maximum number of decimal places reported shall be four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the relevant time point (n), 
frequency counts and percentages. Changes from baseline in categorical data will be summarized using shift tables 
where appropriate. 
Percentages will be presented to one decimal place. A percentage of 100% will be reported as 100%. Percentages will 
not be presented for zero counts. Unless otherwise stated, percentages will be calculated using n as the denominator, 
for frequency tables not assessed by time point the set will be used as denominator. If sample sizes are small, the 
data displays will show the percentages, but any textual report (e.g., clinical study report) will describe frequencies 
only. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places. However, if a P-value is 
only presented to four decimal places (by SAS) it will not be rounded again but will be presented to four decimal places. 
P-values less than 0.0001 will be presented as “<0.0001”. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      12                                                                   Final 
Confidence intervals will be presented to one more decimal place than the raw data. A two-sided significance level of 
5% will be used for confidence intervals. 
For binary endpoints, the 95% confidence intervals (CIs) will be constructed based on an exact binary distribution. 
The Kaplan-Meier method will be used to estimate the time to event function, the median of time to event and the 
95% confidence interval of the same will be calculated. These confidence intervals will be calculated based on the 
Greenwood method. Number and proportion of events, median survival time and survival rates, with corresponding 
95%Cl will be calculated.  
All scores and change from baseline will be summarized in terms of the number of observations, mean, standard 
deviation, 95%CI of mean, median, range and interquartile range. We will examine the residuals to assess model 
assumptions. 
All report outputs will be produced using SAS® version 9.4 version in a secure and validated environment. All report 
outputs will be provided to the Sponsor in a single Microsoft Word document. 
5.2 Subject Disposition 
Descriptive statistics will be provided for the following: 
- 
Overall number of subjects in the screening set, the number of patients eligible to participate in the study, and 
number of screen failures. 
- 
Number and percent of subjects in each of the analysis sets. 
- 
Number and percent of subjects excluded from each of the analysis sets along with reason for exclusion. 
- 
Listing of subjects excluded from each of the analysis sets along with reason for exclusion. 
- 
Listing of protocol deviations. 
- 
Study termination: 
 
Number and percent of subjects who completed the study. 
 
Frequency of premature termination reasons. 
 
Listing of all dropouts along with reason for termination, treatment group and time of termination. 
- 
Follow-up time (months), defined as the time from start dose until the last available follow-up date. 
- 
Follow-up Dates: 
 
Database cut-off date. 
 
Start date of treatment dose of the first patient. 
 
Start date of treatment dose of the last patient. 
 
End date of treatment dose of the last patient. 
 
End date of follow-up of the last patient. 
No statistical tests are planned for these data. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      13                                                                   Final 
5.3 Baseline Characteristics 
Baseline characteristics will be provided for the FAS and PP set. 
Descriptive statistics, including number of subjects, mean, standard deviation (SD), median and range for continuous 
variables and frequency and percent for categorical variables will be provided. 
Baseline Characteristics: 
 
Demographics 
 
Vital Signs 
 
Toxic background 
 
Oncological history 
 
General Medical History 
 
Prior concomitant medication 
 
History of Penile Cancer 
 
Previous surgeries for penile cancer 
 
Previous early/advanced disease treatment for penile cancer 
 
HR status 
 
Penile cancer stage 
 
Viral Serology and TST 
 
Urinalysis 
 
Physical examination 
 
ECOG 
 
12-Lead ECG 
No statistical tests are planned for these data. 
A by-subject listing of all demographic and other baseline characteristics will be provided. 
5.4 Efficacy Analysis 
Efficacy results will be reported for the FAS and PP set. 
All efficacy analysis will be exploratory. 
5.4.1 Response Efficacy Definitions 
5.4.1.1 
RECIST V.1.1 
Overall response according RECIST v1.1 will be obtained from target lesion response, non-target lesion response and 
new lesions, as follows: 
Target Lesions 
Non-target Lesions 
New Lesions Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-CR/Non-PD or not all evaluated 
No 
PR 
SD 
Non-CR/Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      14                                                                   Final 
The following results will be reported in all patients and in patients with measurable disease. 
- 
The unconfirmed Best Overall Response, defined as the best overall response recorded from the start of the study 
treatment until 35 days after last dose administration date and confirmation of response is not required. 
 
When CR or PR is the best response across all time points, then best overall response will be CR or PR 
respectively.  
 
When SD is the best response for ≥ 12 weeks the best overall response will be SD ≥ 12 w.  
 
When SD is the best response for < 12 weeks the best overall response will be SD < 12 w. 
 
When non-target disease only and Non-CR/Non-PD is the best response for ≥ 12 weeks the best overall 
response will be SD ≥ 12 w.  
 
When non-target disease only and Non-CR/Non-PD is the best response for < 12 weeks the best overall 
response will be SD < 12 w.  
 
When PD is the best response across all time points, best overall response will be PD. 
 
When there is no evaluable tumor assessments best overall response will be NE. 
- 
The confirmed Best Overall Response, defined as the best overall response recorded from the start of the study 
treatment until 35 days after last dose administration date and confirmation of response is required. 
 
When CR or PR is the best response for ≥ 4 weeks then best overall response will be CR or PR respectively.  
 
When SD is the best response for ≥ 12 weeks the best overall response will be SD ≥ 12 w.  
 
When SD is the best response for < 12 weeks the best overall response will be SD < 12 w. 
 
When non-target disease only and Non-CR/Non-PD is the best response for ≥ 12 weeks the best overall 
response will be SD ≥ 12 w.  
 
When non-target disease only and Non-CR/Non-PD is the best response for < 12 weeks the best overall 
response will be SD < 12 w.  
 
When PD is the best response across all time points, best overall response will be PD. 
 
When there is no evaluable tumor assessments best overall response will be NE. 
- 
Unconfirmed Objective Response Rate (ORR) is defined as the proportion of patients with best overall response of 
unconfirmed CR or unconfirmed PR. 
- 
Unconfirmed Clinical Benefit Rate (CBR) is defined as the proportion of patients with best overall response of 
unconfirmed CR or unconfirmed PR or SD ≥ 12 w. 
- 
Confirmed Objective Response Rate (ORR) is defined as the proportion of patients with best overall response of 
confirmed CR or confirmed PR. 
- 
Confirmed Clinical Benefit Rate (CBR) is defined as the proportion of patients with best overall response of 
confirmed CR or confirmed PR or SD ≥ 12 w. 
- 
PFS is defined as the time from start dose until death by any cause or objective tumor progression according to 
RECIST v.1.1 or clinical disease progression. Patients with no progression or death will be censored at the date of 
their last evaluable imaging previous 35 days after last dose administration date. Censoring rules are specified 
below: 
Situation 
Date of progression or censoring 
Outcome 
Progression documented 
between scheduled visits  
Earliest of: 
• Date of assessment by investigator (if progression is 
based on clinical criteria); 
or 
• Date of assessment showing new lesion (if progression 
is based on new lesion); 
Progressed  
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      15                                                                   Final 
Situation 
Date of progression or censoring 
Outcome 
or 
• Date of last radiological assessment of 
measured lesions (if progression is based on 
increase in sum of measured lesions). 
Death before first progression 
disease (PD) assessment 
Date of death. 
Progressed  
Death between adequate 
assessment visits  
Date of death. 
Progressed  
No progression 
Date of last radiological assessment of measured lesions. Censored 
Treatment discontinuation for 
undocumented progression  
Date of last radiological assessment of measured lesions. Censored 
Treatment discontinuation for 
toxicity or other reason 
Date of last radiological assessment of measured lesions. Censored 
 
- 
6-months PFS rate is defined as the proportion of patients who are alive and progression-free at 6 months from 
the date of first dose of study treatment based on RECIST criteria. 
- 
The Overall Survival (OS) is defined as the time from start dose until death from any cause. Patients with no death 
will be censored on the last available follow-up date. 
- 
The duration of response (DoR) is defined as the time from start dose of first tumor response (either CR or PR) to 
disease progression or death due to any cause. The DoR will be calculated for the patients with unconfirmed CR 
or PR. 
- 
The Time to Progression (TTP) is defined as the time from start dose to objective tumor progression or clinical 
disease progression (TTP does not include deaths). Patients with no progression will be censored at the date of 
their last evaluable imaging previous 35 days after last dose administration date. 
- 
The Time to Response (TTR) is defined as the time from start dose to unconfirmed ORR date. Patients without 
ORR will be censored at the date of their last evaluable imaging previous 35 days after last dose administration 
date. 
- 
Maximum Tumor Shrinkage (best percentage of change from baseline in the size of target tumor lesions) is defined 
as the biggest percentage of tumor shrinkage from baseline (obtained from the sum of the largest diameters of 
the target lesions). 
5.4.1.2 
irRECIST 
The following results will be reported in all patients and in patients with measurable disease: 
- 
The response assessment of the tumor is defined as best response according to: 
 
irCR: complete disappearance of all measurable and non-measurable lesions. Lymph nodes must decrease 
to < 10 mm in short axis. Confirmation of response is not mandatory. 
 
irPR: decrease of ≥ 30% in Total Measured Tumor Burden (TMTB) relative to baseline, non-target lesions 
are irNN, and no unequivocal progression of new non-measurable lesions. 
 
irSD: failure to meet criteria for irCR or irPR in the absence of irPD. 
 
irNN: no target disease was identified at baseline and at follow-up the patient fails to meet criteria for irCR 
or irPD. 
 
irPD: minimum 20% increase and minimum 5 mm absolute increase in TMTB compared to nadir, or irPD 
for non-target or new non-measurable lesions. Confirmation of progression is recommended minimum 4 
weeks after the first irPD assessment. 
 
irNE, used in exceptional cases where insufficient data exists. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      16                                                                   Final 
- 
irORR is defined as the proportion of participants with irCR or irPR. Participants who do not have on-study 
radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to 
reaching an irCR or irPR, or who died, progressed, or dropped out for any reason prior to reaching an irCR or irPR 
will be counted as non-responders in the assessment of irORR.  
- 
irCBR is defined as the proportion of participants with irCR or irPR or irSD. Participants who do not have on-study 
radiographic tumor re-evaluation, who received anti-tumor treatment other than the study medication prior to 
reaching an irCR or irPR or irSD, or who died, progressed, or dropped out for any reason prior to reaching an irCR 
or irPR or irSD will be counted as non-responders in the assessment of irCBR.  
- 
irPFS: is defined as the period from the date of treatment initiation to the date of the first documentation of 
objective progression of disease (irPD) or death due to any cause in absence of documented irPD. Confirmation of 
progression is recommended minimum 4 weeks after the first irPD assessment. Participants lacking an evaluation 
of tumor response after treatment initiation will have their PFS time censored on the date of treatment initiation 
with the duration of a day. Participants with documentation of irPD or death after a long interval (2 or more 
incomplete or non-evaluable assessments) since the last tumor assessment will be censored at the time of last 
objective assessment that did not show PD. The length of irPFS will be calculated as irPFS time (months) = 
[(progression, death date or censor date) – treatment initiation date +1]/30.4. 
- 
6-months PFS rate is defined as the proportion of patients who are alive and progression-free at 6 months from 
the date of first dose of study treatment based on irRECIST criteria. 
5.4.2 Primary Efficacy Analysis 
ORR will be estimated with the 95% Clopper-Pearson confidence intervals and the P-value with exact binomial test.  
Primary efficacy results will be reported for the FAS and PP set. Full analysis set will be considered the primary set for 
the analysis. 
Table 1. Primary Efficacy Estimands 
Estimand 
Population 
Variable
Intercurrent event strategy 
Summary measure 
Primary 
FAS set 
Unconfirmed 
ORR 
- Patient with missing Unconfirmed 
ORR outcome will considered as 
no responders. 
- Patients without any post-
baseline assessment will be 
considered as non-responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper 
CI will be calculated. 
Sensitivity 1 to 
Primary 
PP set 
Unconfirmed 
ORR 
Same as above 
Same as above 
 
5.4.3 Decision Rules and Adjustment of Alpha for Primary Endpoint 
The study would be defined as positive at final analysis, if the ORR in the INCMGA00012 arm is statistically significantly 
better (p<0.05) than expected under the null hypothesis (H0: ORR≤5%). Decisions will be based on exact binomial 
test. 
For all secondary and exploratory tests, we will use two-sided P-values with alpha=0.05 level of significance. The P-
values emerging from these analyses will not be interpreted in a confirmative sense; they will be considered of 
descriptive nature only. 
5.4.4 Secondary Efficacy Analysis 
Secondary efficacy results will be reported for the FAS and PP set. 
For binary endpoints, the number and proportion of patients with response with the 95% Pearson-Clopper CI will be 
calculated.  
The time to event endpoints will be performed with maximum likelihood method (MLM) for exponential distribution 
test, at nominal level of 0.05. Number and percentage of events will be described. The median, 6-month, 1 and 2-year 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      17                                                                   Final 
survival rates and 95% confidence intervals will be provided based on exponential MLM and Kaplan-Meier method. 
Swimmer plots for time-to-event endpoints will be provided.  
For continuous outcome (maximum tumor shrinkage) we will use statistics of central tendency (median with 95%CI) 
and dispersion (range and interquartile range). We will provide waterfall plots of maximum tumor shrinkage from 
baseline. The duration of response has also plotted with bar plots. 
For all tests, we will use two-sided P-values with alpha=0.05 level of significance. P-values emerging from these 
analyses will not be interpreted in a confirmative sense; they will be considered of descriptive nature only. 
 
Table 2. Secondary Efficacy Estimands 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Secondary 1 
FAS set 
PFS 
- Patients with no progression or death 
will be censored at the date of their last 
evaluable imaging previous 35 days after 
last dose administration date. 
- If no post-baseline tumor assessment is 
available, patients will be censored at the 
date of treatment initiation + 1 day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last tumor 
assessment prior to the missed visits. 
Kaplan-Meier plot, 
number and proportion 
of events, median 
survival time, 6 months, 
1- and 2-year survival 
rates with corresponding 
95% Cl. 
 
Swimmer plot will be 
provided. 
Sensitivity 1 to 
Secondary 1 
PP set 
PFS 
Same as above 
Same as above 
Secondary 2 
FAS set 
 
BOR 
 
- When CR or PR is the best response 
across all time points, then best overall 
response will be unconfirmed CR or 
unconfirmed PR respectively.  
- When CR or PR is the best response for 
≥ 4 weeks then best overall response will 
be confirmed CR or confirmed PR 
respectively.  
- When SD is the best response for ≥ 24 
weeks the best overall response will be 
SD ≥ 24 w.  
- When SD is the best response for < 24 
weeks the best overall response will be 
SD < 24 w. 
- When non-target disease only and Non-
CR/Non-PD is the best response for ≥ 24 
weeks the best overall response will be 
SD ≥ 24 w.  
- When non-target disease only and Non-
CR/Non-PD is the best response for < 24 
weeks the best overall response will be 
SD < 24 w.  
- When PD is the best response across all 
time points, best overall response will be 
PD. 
- When there is no evaluable tumor 
assessments best overall response will be 
NE. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated.  
Sensitivity to 
secondary 2 
PP set 
 
BOR 
 
Same as above 
Same as above 
Secondary 3 
FAS set 
Confirmed 
ORR 
- Patient with missing confirmed ORR 
outcomes will considered as no 
responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      18                                                                   Final 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Sensitivity to 
secondary 3 
PP set 
Confirmed 
ORR 
Same as above 
Same as above 
Secondary 4 
FAS set 
Unconfirm
ed CBR 
- Patient with missing Unconfirmed ORR 
outcome will considered as no 
responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated. 
Sensitivity to 
secondary 4 
PP set 
Unconfirm
ed CBR 
Same as above 
Same as above 
Secondary 5 
FAS set 
Confirmed 
CBR 
- Patient with missing confirmed ORR 
outcomes will considered as no 
responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated. 
Sensitivity to 
secondary 5 
PP set 
Confirmed 
CBR 
Same as above 
Same as above 
Secondary 7 
FAS set 
OS 
- Patients who are not reported as having 
died will be analyzed as censored 
observations on the date they were last 
known to be alive. 
- If no post-baseline tumor assessment is 
available, patients will be censored at the 
date of treatment initiation + 1 day. 
Kaplan-Meier plot, 
number and proportion 
of events, median 
survival time, 1- and 2-
year survival rates with 
corresponding 95% Cl. 
Sensitivity to 
secondary 7 
PP set 
OS 
Same as above 
Same as above 
Secondary 8 
FAS set 
TTR 
- Patients with no response will be 
censored at the date of their last 
evaluable imaging previous 35 days after 
last dose administration date. 
Kaplan-Meier plot, 
number and proportion 
of events, median 
survival time, 1- and 2-
year survival rates with 
corresponding 95% Cl. 
Sensitivity to 
secondary 8 
PP set 
TTR 
Same as above 
Same as above 
Secondary 9 
FAS patients 
with overall 
response 
DoR 
- Patients with no progression or death 
will be censored at the date of their last 
evaluable imaging previous 35 days after 
last dose administration date. 
- If no post-response tumor assessment is 
available, patients will be censored at the 
date of treatment response + 1 day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last tumor 
assessment prior to the missed visits. 
Kaplan-Meier plot, 
number and proportion 
of events, median 
survival time, 1- and 2-
year survival rates with 
corresponding 95% Cl. 
Sensitivity to 
secondary 9 
PP patients 
with overall 
response 
DoR 
Same as above 
Same as above 
Secondary 11 
FAS set 
Maximum 
Tumor 
Shrinkage 
Only observed cases will be used 
Median, range, mean, 
standard deviation, and 
interquartile range. 
Waterfall plots 
describing the 
percentage of change in 
target tumor lesions 
Sensitivity to 
secondary 11 
PP set 
Maximum 
Tumor 
Shrinkage 
Same as above 
Same as above 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      19                                                                   Final 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
Secondary 12 
FAS set 
irPFS 
- Confirmation of progression is 
recommended minimum 4 weeks after the 
first irPD assessment 
- If no post-baseline tumor assessment is 
available, patients will be censored at the 
date of treatment initiation + 1 day. 
- Data for patients with an event who 
missed two or more scheduled 
assessments immediately prior to the 
event will be censored at the last tumor 
assessment prior to the missed visits. 
Kaplan-Meier plot, 
number and proportion 
of events, median 
survival time, 6-month, 
1- and 2-year survival 
rates with corresponding 
95% Cl. 
Sensitivity to 
secondary 12 
PP set 
irPFS 
Same as above 
Same as above 
Secondary 13 
FAS set 
irORR 
- Patient with missing confirmed ORR 
outcomes will considered as no 
responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated. 
Sensitivity to 
secondary 13 
PP set 
irORR 
Same as above 
Same as above 
Secondary 13 
FAS set 
irCBR 
- Patient with missing confirmed ORR 
outcomes will considered as no 
responders. 
- Patients without any post-baseline 
assessment will be considered as non-
responders. 
The number and 
proportion of patients 
with response with the 
95% Pearson-Clopper CI 
will be calculated. 
Sensitivity to 
secondary 13 
PP set 
irCBR 
Same as above 
Same as above 
 
 
5.4.5 Handling of Missing Data 
Study variables could be missing for patients who withdrawn from the trial or for specific visits. We will report reasons
for withdrawal.  
Patient with missing in response outcomes will considered as no responders. Patients without any post-baseline 
assessment will be considered as non-responders or without clinical benefit.  
The analysis of timed endpoints is based on a Kaplan-Meier method, therefore, not affected by patient withdrawals (as 
they are censored) provided that dropping out is unrelated to prognosis.  
For the analysis of maximum tumor shrinkage only observed cases will be used. 
The other variables will be managed with simple imputations methods (last observation carried forward). The effect 
that any missing data might have on results will be assessed via sensitivity analysis. 
5.4.6 Subgroup Analysis 
CBR, 6-month PFS, DoR, TTR, ORR, and OS according to RECIST v.1.1 together with ORR, CBR, and 6-month PFS 
according to irRECIST will be analyzed in patients’ subgroups categorized based on baseline factors of potential 
prognostic value. The baseline factors will include but not limited to the following: (1) Prior treatments; (2) Number of 
previous regimens; (3) Type of previous regimens (e.g., platinum agents, radiotherapy); (4) Age; (5) Sites of 
metastases; (6) Race and geographic location (if applicable). We will utilize the Kaplan-Meier method and LogRank 
test. Multivariable Cox proportional hazards model for adjusting for multiple prognostic factors will be used to test the 
association between prognostic factors and the outcomes if sample size is adequate. Covariate estimates, HR and 
corresponding 95% CIs, applicable test statistics, and P-values will be presented. We will use the Breslow method for 
tie handling in survival analysis. P-values and 95% CIs for hr will be based on Wald test. The assumption of proportional 
hazards will be assessed by plotting the hazards over time.  
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      20                                                                   Final 
For binary outcomes we will use chi-squared test for binary outcomes followed by multivariate logistic regression for 
adjusting for multiple prognostic factors. We will examine the residuals to assess model assumptions. 
For all tests, we will use two-sided P-values with alpha=0.05 level of significance and P-values ≤ 0.05 will indicate 
statistical significance. The P-values emerging from these analyses will not be interpreted in a confirmative sense but 
will be considered of descriptive nature only. Analysis will be performed on the ITT and PP sets. ITT will be considered 
the primary population for the analysis. 
Forest plots will be presented to describe all these analyses. 
 
Table 3. Time-to-Event Estimands 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
PFS subgroup 
analysis 
FAS set 
PFS 
Multivariate Cox proportional 
hazards model adjusted for 
baseline prognostic factors. 
Breslow method for tie handling in 
survival analysis will be used. 
P-values and the 95% confidence 
intervals for hazard ratio will be 
based on Wald test. 
Forest plot will report for 
each baseline prognostic 
subgroup: 
- number and % of patients 
- adjusted HR (95%CI) 
- interaction p-value 
- median survival time  
- 6-month survival rate 
(95%Cl) 
irPFS subgroups 
analysis 
FAS set 
irPFS 
Same as above 
Same as above 
TTR subgroups 
analysis
FAS set 
TTR 
Same as above 
Same as above 
DoR subgroups 
analysis 
FAS set 
DoR 
Same as above 
Same as above 
OS subgroups 
analysis 
FAS set 
OS 
Same as above 
Same as above 
 
Table 4. Binary Outcomes Estimands 
Estimand 
Population 
Variable 
Intercurrent event strategy 
Summary measure 
ORR subgroup 
analysis 
FAS set 
ORR 
Multivariate logistic regression 
model adjusted for baseline 
prognostic factors. 
P-values and the 95% confidence 
intervals for odds ratio will be 
based on Wald test. 
Forest plot will report for 
each baseline prognostic 
subgroup: 
- % patients (95%IC) 
- adjusted OR (95%CI) 
- interaction p-value 
- proportion difference 
(95%CI) 
CBR subgroup 
analysis 
FAS set 
CBR 
Same as above 
Same as above 
irORR subgroup 
analysis 
FAS set 
irORR 
Same as above 
Same as above 
irCBR subgroup 
analysis 
FAS set 
irCBR 
Same as above 
Same as above 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      21                                                                   Final 
5.4.7 Exploratory Analysis 
These statistical analyses will be exploratory. Exploratory analyses will be performed on the exploratory analysis set. 
A separate analysis report for such assessments will be written. 
We will compare RECIST and irRECIST criteria for evaluation of the clinical response. 
The objective of the statistical analyses of biomarkers is the identification of those markers or combinations of markers 
which show best association with positive clinical outcome of the study treatment. We will measure the clinical efficacy 
of that analysis in terms of ORR, CBR, PFS and irPFS. 
The exploratory endpoints are PFS, CBR, and ORR based on irRECIST and predictive biomarkers (such as but not 
limited to PD-1, PD-L1, HIV status).  The objective of the exploratory analyses of irRECIST is the characterization of 
INCMGA00012 clinical activity. The exploratory analysis will be performed only if an adequate number of samples is 
available at the EoS. Markers (such as but not limited to PD1, PD-L1, HIV, and HPV status) will be evaluated on a 
univariate level regarding their potential for prediction of the clinical endpoints (ORR, CBR, PFS and irPFS). 
Biomarker and response correlations with clinical covariates will be investigated. It will be checked whether covariates 
can improve the prediction and whether there is an interaction with the biomarkers. Further multivariate techniques 
(e.g., Multiple Logistic Regression, Cox regression and penalized regressions models) will be deliberated to study 
combinations of markers. Techniques to control false discovery rate and overfitting (cross-validation) may be 
considered. Analysis will he performed on exploratory analysis set. 
5.5 Safety 
All safety tables will list or summarize subjects on the safety set. 
These safety assessments will be subjected to clinical review and summarized by appropriate descriptive statistics. 
These data will include report of AEs, laboratory analysis, vital signs, ECOG PS, changes in ECG, time of trial dosing, 
and proportion of interruptions. Terms and severity of AE will be obtained and reported according to the NCI-CTCAE 
v.5. Statistical summaries of characteristics, frequency, grading, duration, and relationship with treatment will be 
presented. 
5.5.1 Duration and Extent of Exposure of Study Treatment 
The study treatment period is defined as the time between the study entry and the last dose of study therapy 
(INCMGA00012). 
Duration and extent of exposure will be based on the safety set. 
The following parameters will be calculated: 
 
b: “Actual Cycle Duration” is the difference between start and stop date dose.  
 
c: “Actual Cycle Dose Days” is the number of days with dose administration in the cycle, considering the 
interruptions. 
 
d: “Actual Total Dose” is the total dose a patient took in a cycle, considering interruptions and reductions. 
 
e: “Intended Daily Dose per Cycle”. 
 
f: “Intended Cycle Duration”. 
 
g: “Intended Cycle Dose Days”. 
 
A: “Total number of cycles” = 1 
 
B: “Treatment Duration” = Sum over all cycles of (b). 
 
C: “Days on drug” = Sum over all cycles of (c). 
 
D: “Total Actual Total Dose” = Sum over all cycles of (d). 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      22                                                                   Final 
 
E: “Mean Intended Daily Dose” = Mean over all cycles of (e). 
 
F: “Total Intended Duration” = Sum over all cycles of (f). 
 
G: “Total Intended Dose Days” = Sum over all cycles of (g). 
 
H: “Intended Total Dose” = G*E  
 
I: “Actual Average Daily Dose on Dose Days” = D/C 
 
J: “Ratio for Dose Interruption” = C/G 
 
K: “Ratio for Cycle Duration” = F/B 
 
L: “Actual Average Daily Dose Intensity” = I*J*K 
 
M: “Relative Dose Intensity (RDI)” = L/E*100 
The treatment duration (months), number of cycles, days on Drug and Treatment compliance (%) will be summarized 
in terms of the number of observations, mean, standard deviation (STD), median, minimum and maximum. 
Extent of exposure measured as RDI (dose level) will be described with median, interquartile range (IQR) and range. 
The RDI will be dichotomized in different cutoffs (≥50%, ≥70%, ≥80%, ≥90%, ≥100%) and described with 
frequencies and percentages. 
5.5.2 Dose Delays, Reductions and Discontinuations 
The following summaries will be provided: 
 
Subjects with at least one dose delay. 
 
Subjects with at least one dose delay due to adverse event. 
 
Subjects with at least one dose reduction. 
 
Subjects with at least one dose reduction due to adverse event. 
 
Subjects with permanently dose discontinuation. 
 
Subjects with permanently dose discontinuation due to adverse event. 
5.5.3 Concomitant Medications 
The number and percent of unique patients taking concomitant medications will be summarized by therapeutic 
classification, coded term, and dose level. Elective surgeries/procedures performed during the study will be presented 
in a listing. 
The following are conventions that will be used to classify individual medications as prior and/or concomitant: 
- 
Medications with stop dates prior to screening visit date will be considered prior. 
- 
Medications with missing stop dates or stop dates the day of or after screening visit date will be considered 
concomitant, regardless of start date.  Additionally, if the start date is prior to screening visit date or missing, the 
medication will also be considered prior. 
Frequencies and by-subject listing of all prior and concomitant medications will be provided, containing variables listed 
on Prior/Concomitant Assessment eCRF, their corresponding categories (Prior or Concomitant), and WHO Anatomical 
Therapeutic Chemical (ATC) level 2 and ATC Name. 
5.5.4 Adverse Events 
All AEs will be recorded on the eCRF “Adverse Events” page and will be coded using the current version of MedDRA® 
to give a system organ class (SOC) and preferred term (PT) for each event. All adverse event safety data will be 
updated to the version of MedDRA that is current at the time of the database lock and statistical analyses. Adverse 
events will be coded with grades defined according to CTCAE V5.0 criteria. 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      23                                                                   Final 
Treatment-emergent AEs (i.e., those events occur after the first study medication administration and were not present 
at baseline or worsened in severity following the start of treatment) will be tabulated. The TEAE will be tabulated 
according to intensity and causality. If intensity of an AE or causality of an AE to the study medication is missing, a 
worst-case scenario will prevail (severe in intensity or probably related will be assumed). In the summary tables the 
number of subjects with events and the number of events will be presented. 
The onset date of an AE will be compared to the date of first dose of study drug to determine whether the AE is 
treatment emergent. Adverse events with an onset date on or after the date of first dose of study drug will be classified 
as treatment emergent. 
All deaths and SAEs, regardless of cause, from treatment start until 28 days after final dose of treatment.  Non-fatal 
AEs occurring after treatment start regardless of cause, up until 28 days after final dose of treatment or until start of 
new anti-cancer treatment, whichever is first.  Disease progression is not considered a treatment emergent adverse 
event unless the patient dies of disease prior to 28 days after discontinuation of treatment. Events that are 
continuations of baseline abnormalities are considered treatment emergent adverse events only if there is an increase 
in grade over baseline, or if there is an increase following a decrease during the study. 
Treatment emergent adverse events with cause possibly, probably or definitely related to treatment as judged by the 
investigator.  Events that are continuation of baseline abnormalities are not considered treatment related unless there 
is an increase in grade, or if there is an increase following a decrease, and the increase is judged by the investigator 
to be due to treatment. 
Descriptive statistics will be used to characterize the profiles of treatment-related AEs, treatment-related deaths, SAEs, 
treatment-related delays, dose reductions, and/or treatment discontinuations. All AEs will be graded according to the 
current version of the NCI-CTCAE v.5 and the Medical Dictionary for Regulatory Activities (MedDRA). 
The following summaries will be provided: 
- 
Summary of Adverse Events 
 
Subjects with at least one Adverse Event (AE) 
 
Subjects with at least one Treatment Emergent AE (TEAE) 
 
Subjects with at least one related study drug TEAE 
 
Subjects with at least one grade 3 or 4 or 5 TEAE 
 
Subjects with at least one related grade 3 or 4 or 5 TEAE 
 
Subjects with at least one serious TEAE 
 
Subjects with at least one related serious TEAE 
 
Subjects with at least one non-serious TEAE 
 
Subjects with at least one Adverse Event of Special Interest (AESI) 
 
Deaths due to TEAE 
 
Subjects with TEAE leading to Discontinuation of Study Treatment 
 
Subjects dropped out due to AE. 
- 
Summary by SOC and PT of the number and percentage of subjects reporting each: 
 
Treatment Emergent Adverse Events 
 
Treatment Emergent Adverse Events by Treatment and Hematologic 
 
Treatment Emergent Adverse Event Related to Study Drug 
 
Related Treatment Emergent Adverse Event by Treatment and Hematologic 
 
AESI Treatment Emergent Adverse Events 
 
Treatment Emergent Adverse Events with Grade 3 or 4 or 5 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      24                                                                   Final 
 
Related Treatment-Emergent Adverse Event with Grade 3 or 4 or 5 
 
Serious Treatment Emergent Adverse Event 
 
Serious and Related Treatment Emergent Adverse Event 
 
Treatment Emergent Adverse Event by Maximum Severity 
 
Treatment Emergent Adverse Event Leading to Discontinuation of Study Drug 
5.5.5 Clinical Laboratory Parameters 
The following summaries will be produced for all hematology and biochemistry laboratory parameters: 
- 
Shift tables of low, normal, high distribution (n; %) with respect normal ranges of center, at each post-baseline 
cycle by baseline (cycle 1 day 1) distribution. 
- 
Shift tables of low, normal, high distribution (n; %) of clinically significant at each post-baseline cycle comparing 
with baseline (cycle 1 day 1) distribution. 
- 
The value distribution will be displayed using a serial box plot at each cycle. 
5.5.6 Vital Signs 
The following summaries will be produced for all vital sign’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 day 1) 
distribution. 
5.5.7 Physical Examination 
The following summaries will be produced for all physical examination’s parameters: 
- 
Shift tables of low, normal, high distribution (n; %) at each post-baseline cycle by baseline (cycle 1 day 1) 
distribution. 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      25                                                                   Final 
5.6 Interim Analysis of Safety 
No interim analysis is planned. 
 
5.7 Changes of Analysis from Protocol 
- 
The level of significance ⍺ has been changed from ≤ to = in some paragraphs. 
- 
We have included the time to response as secondary endpoint. We have dropped the time to progression. 
 
 
5.8 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final clinical study report. 
 
 
 
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Study Code: 2019-001172-11 (ORPHEUS)                                                                  Statistical Analysis Plan 
 
   May 21, 2021                                                      26                                                                   Final 
6 
APPENDICES 
6.1 Appendix 1 - SAS Codes
All report outputs will be produced using SAS® version 9.4 (TS1M5) version in a secure and validated environment. 
ORR will be estimated with the 95% Clopper-Pearson confidence intervals and the P-value with exact binomial test.  
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6.2 List of Tables, Listings, Figures 
A complete list of tables, listings and figures (TLFs) will be given in a separate document which can be updated without 
updating the SAP. The list will serve as a reference for both the Sponsor, the trial statistician and the statistical 
programmer and includes the totality of statistical output to be produced. 
All output will be headed with an appropriate heading specifying the study ID and abbreviated study title. 
All output will be dated and have page numbers in the form 'Page [x / y]' where x denotes the current page within an 
output and y the total number of pages of that output. 
All statistical output will identify the underlying analysis sets and indicate the number of patients/events in this set (N) 
and the number of patient/events actuals contributing to the output (n). All statistical output will be presented per 
treatment (if applicable). 
All patient listings will contain additionally to the patient identification the analysis set and the treatment.  
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