Conditions: Oral Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
Up to 31 subjects diagnosed with oral squamous cell carcinoma received one application of a permeation enhancer 3 treatment applications of a Cisplatin drug-loaded patch to the tumor site at each of the 4 treatment visits. These 4 treatment visits were scheduled to occur during the 3 weeks prior to the standard of care tumor resection.

Funding Source: FDA OOPD

Detailed description:
Up to 31 subjects diagnosed with oral squamous cell carcinoma received one application of a permeation enhancer and 3 treatment applications of a Cisplatin drug-loaded patch to the tumor site at each of 4 treatment visits. These 4 treatment visits were scheduled to occur during the 3 weeks prior to the standard of care tumor resection. After the surgery, subjects were followed for 6 months for disease recurrence.

Ten subjects were enrolled in the study. Up to 21 additional subjects could have been enrolled in Stage 2, if safety and efficacy endpoints were not met. The dose was not changed. All subjects were followed for 6 months post-surgery for disease recurrence.

During and at the conclusion of the treatment period, subjects were monitored for local and systemic safety, tumor response due to the treatment, and systemic drug exposure.

Arms:
arm 1: Subjects received 3 treatment applications of PRV111 (Cisplatin Transmucosal System) at each of the 4 planned visits within 3 weeks prior to their tumor surgery.

Interventions: intervention 1: PRV111 (Cisplatin Transmucosal System)
Intervention descriptions: intervention 1: Each treatment visit will include one application of a permeation enhancer and then 2, 3 or 5 PRV111 (Cisplatin Transmucosal System) applications depending on the Stage subject is enrolled in.

Protocol document:
ICF_002.pdf: 
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TITLE: 
Phase 1/2, Open-Label, Single-Arm, Safety and Efficacy Dose-
Finding, Systemic Exposure, and Device Technical Effects of 
PRV111 (Cisplatin Transmucosal System) in Subjects with Oral 
Squamous Cell Carcinoma 
 
 
 
 
NCT NUMBER:                   NCT03502148 
 
 
 
 
DATE:                                    28FEB2020 
 
 


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Consent to Participate in Human Research 
Informed Consent Form 
 
TITLE: 
Phase 1/2, Open-Label, Single-Arm, Safety and Efficacy Dose-
Finding, Systemic Exposure, and Device Technical Effects of 
PRV111 (Cisplatin Transmucosal System) in Subjects with Oral 
Squamous Cell Carcinoma 
 
PROTOCOL NO.: 
CLN-001 
 
 
 
 
 
SPONSOR: 
Privo Technologies, Inc. 
 
INVESTIGATOR: 
 
 
 
 
 
STUDY-RELATED 
PHONE NUMBER(S): 
 
 
 
 
 
 
SUBJECT NAME: __________________________ 
Date of Birth: ________________ 
 
Introduction 
You are being asked to take part in a clinical trial, a type of research study, of an investigational 
product (PRV111) because you have been diagnosed with oral cancer. Clinical trials include only 
people who choose to take part. Please take your time to understand the study, ask questions and 
then make your decision. You may discuss your decision with your family, friends and your 
health care provider. If you have any questions, you can ask your study doctor for more 
explanation. 
 
Before you learn about the study, it is important that you know the following: 
• 
Your participation is entirely voluntary. 
• 
You may decide not to participate or, if you do participate, you may withdraw from the 
study at any time. You may decide not to participate or to withdraw your consent without 
anyone objecting and without penalty or loss of any benefits that you are otherwise 
entitled. 
• 
There may be unforeseeable risks and side effects of PRV111 that are not yet known. If 
any new information is learned or the study is changed in a way that could affect your 


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willingness to participate, you will be told about the change(s). You may be asked to sign 
a revised informed consent form. 
• 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U. S. Law. This Web site will not include information that can identify you. 
At most, the Web site will include a summary of the results. You can search this Web site 
at any time. 
 
Once you understand the study and its possible risks and benefits, if you decide to participate, 
you will be asked to sign and date this informed consent form. You will receive a copy of the 
informed consent form. By signing it you are telling us that you: 
• Understand what you have read; 
• Consent to take part in the study; 
• Consent to the tests and treatments that are described; 
• Consent to the use of your personal and health information and biological samples, as 
described. 
 
Why is this study being done? 
The purpose of this study is to evaluate the safety, tolerability and anti-tumor effects of the 
PRV111 chemotherapy patch. The PRV111 patch includes a chemotherapy drug called cisplatin, 
which is a Food and Drug Administration (FDA) approved drug that is known to be effective for 
oral cancer. Cisplatin is usually injected into the bloodstream intravenously (an injection in to 
your vein) to treat oral cancer. PRV111 includes cisplatin within a patch applied in your mouth 
and is designed to keep the drug locally to the tumor tissue. 
 
Study Description 
You are being asked to be a part of this study because you have been diagnosed with oral cancer. 
 
Up to 31 subjects will be enrolled in the United States. All subjects will receive PRV111. 
 
Your participation in the study will be for approximately 9 months. This will consist of up to 
28 days to perform assessments to assess your eligibility called Screening. If you qualify and 
choose to be part of the study, you will receive the treatment 
 prior to your 
scheduled surgery. After the surgery, you will be asked to return at 1 month, 3 months and 6 
months for the study doctor to monitor your progress and check for any possible issues. (NOTE: 
There will be other standard consent forms for your surgery.) 
 
Prior to surgery, you will have 4 treatment visits and will receive either 3 or 5 treatment 
applications of the PRV111 patch. 
 
 
 
 These applications will take approximately 35 
minutes. The 4 treatment visits will be separated by 2 to 6 days (at least 48 hours between visits). 
 
What will happen if I take part in the study? 
After you sign this consent form, you will begin the first part of the study called Screening. You 
will have the following assessments: 


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• Answer questions about your medical history including past and present illnesses, drug 
and alcohol use, all prescribed medications, over-the-counter medications and 
supplements you have taken in the last 30 days 
• A physical examination that includes examination of your mouth and neck 
• Confirmation of cancer diagnosis as standard of care. 
• Checking for presence of human papillomavirus (viral infection passed from skin-to-skin 
contact) from tumor tissue collected as standard of care. 
• Vital signs (heart rate, blood pressure and oral temperature) and height and weight 
• A 12-lead electrocardiogram which is a test used to measure the electrical activity of the 
heart, after resting for at least 10 minutes 
• Computed tomography (CT) scan or magnetic resonance imaging (MRI) of your head 
and neck, and a CT scan of your chest 
• Provide blood and urine samples for routine safety labs 
• If you are a woman and able to get pregnant, you will provide a sample (blood) for a 
pregnancy test. The results of the pregnancy test must be negative in order for you to be 
in the study 
 
After all the study assessments are performed and if your study doctor considers this study 
suitable for you, you will be invited to return to the clinic on Treatment Visit 1. 
 
Treatment Visits 1, 2, 3 and 4 
You will return to the clinic and the following assessments will be performed: 
 
Prior to receiving drug: 
• A physical exam that includes examination of your mouth and neck 
• Tumor measurement and photographs 
• Provide blood and urine samples for routine safety labs (Visits 1 and 3 only) 
• Provide a blood sample to find out what happens to the study drug in the body called 
pharmacokinetics 
• Urine pregnancy test for women (Visits 1 and 4) 
• The study doctor may numb your tongue prior to applying the study drug to prevent your 
tongue from removing the patches 
 
Once these assessments are performed, a clinic staff member will begin applying the PRV111 
patches in your mouth. 
 


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After receiving drug: 
• Ask you how you are feeling 
 
• Report any medication you have taken 
• Provide a blood sample at several time points to find out what happens to the study drug 
in the body called pharmacokinetics 
 
The sponsor may have a representative present at the first enrolled patient's first dose at each site.  
Please ask the study doctor if you have any questions. 
 
Treatment Visit 5 
You will return to the clinic prior to your surgery for the following assessments: 
• Computed tomography (CT) scan at a separate location: Norton Hospital Radiology 
• Ask you how you are feeling 
• Report any medication you have taken 
• A physical exam that includes examination of your mouth and neck 
• 12 lead ECG 
• Tumor measurement and photographs 
 
Safety Follow-up Visits at Months 1, 3 and 6 (Visits may also be scheduled to coincide with 
your standard of care visits) 
• Ask you how you are feeling 
• Report any medication you have taken 
• A physical exam that includes examination of your mouth and neck 
• Provide blood and urine samples for routine safety labs 
 
The total amount of blood taken from the time of Screening through the Month 6 Follow-up Visit 
will be less than 1 cup. Additional blood (approximately 1-2 teaspoons each) may be collected if 
you have any adverse events or abnormal laboratory results that require repeating the tests. 
 
What will happen when the study ends? 
A final report will be provided to the study doctor who may share study results with you, if 
requested. The disclosure of published results will be available to all participants. You will not 
be identified by name in any of these reports. 
 
What possible risks can I expect from taking part in this study? 
In people who have ever been infected with hepatitis B virus, there is a risk that the virus can 
flare up during treatment with drugs that affect your immune system (such as chemotherapy).  
This could lead to liver failure or even death.  This risk of hepatitis B virus flaring up may 
continue for several months after you stop taking these types of drugs. 
 
You are to confirm at the baseline visit if you have or have ever had Hepatitis B, C and/or HIV 
and you will be excluded from the study if you have active disease and/or history of disease at 
any time prior to the screening visit.  It is possible that you could be infected with hepatitis C, B 
and HIV with no symptoms.  Therefore, it is your responsibility to confirm you do not have and 
have never tested positive for Hepatitis B, C and HIV.   
 


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State/Provincial law requires positive test results for certain communicable diseases, including 
HIV, hepatitis, sexually transmitted infections, and tuberculosis, to be reported to a local health 
agency.  Some of the tests for this study must be reported when positive. The study doctor can 
discuss this with you. 
 
This is the first time the PRV111 patch has been tested in humans, so there may be side effects 
that are not known. It has been tested in laboratory animals that were watched closely for up to 
2 years. In animals that were treated with this patch, PRV111 did not show most of the bad and 
toxic side effects known to occur when the same chemotherapy (cisplatin) is administered 
intravenously (into the vein). 
 
The study doctor will go through the risks associated with study participation prior to signing 
this informed consent form. You will be closely monitored. You should also talk to your study 
doctor about any side effects that you have while taking part in this study. Tell the study doctor if 
you notice or feel anything different so they can see if you are having a side effect. The study 
doctor may be able to treat some side effects, or they may have to adjust the study treatment to 
try to reduce side effects. Some side effects caused by cisplatin may go away soon, some may 
last a long time, or some may never go away. Some side effects may be serious. If important new 
side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of PRV111 (Related to Cisplatin in Patch): 
• Metallic taste 
• Oral mucositis (inflammation of the lining cells in your mouth) 
• Nausea and vomiting 
 
Rare: 
• Decrease in blood counts that may cause infection, bleeding, and bruising 
• Loss of appetite 
• Hearing loss or ringing in the ears 
• Muscle cramps or spasms 
• Loss of coordination while moving 
• Involuntary movements or shaking 
• Rash 
• Vision problems 
• Hair loss 
• Low mineral levels in your blood 
• Decrease in liver function causing temporary elevation in blood tests 
• Loss of muscle or nerve function, which may cause weakness or numbness in your hands 
and feet 
• Decreasing ability of the kidneys to handle the body’s waste, which may be permanent 
• Allergic reactions, which can cause difficulty in breathing, fast heartbeat, and sweating 
• Acute myeloid leukemia 
 
 


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• 
 
 
Other Risks and Discomforts 
Risks from blood draws and electrocardiograms: 
Routine needle sticks for blood samples may cause pain, bruising, dizziness and rarely infection, 
at the site where blood is drawn. You may experience some minor irritation from the adhesive 
(sticky pads) used for the electrocardiograms. 
 
Risks from CT scans and MRI: 
CT scans send x-rays through the body at many different angles. You will be exposed to a small 
dose of radiation. All radiation adds up over a lifetime and may increase the risk of new cancer 
forming. Some people may feel “closed in” while lying in the scanner. However, the scanner is 
open at both ends, and an intercom allows you to talk with doctors and staff. If you feel ill or 
anxious during scanning, doctors and/or radiology technicians will give comfort, or the scanning 
will be stopped. You may drink liquid to help define various organs. This may cause nausea 
and/or vomiting. Solution may also be given by vein to make the x-ray pictures more accurate. 
This may cause flushing, nausea, and/or severe allergic reactions. It can damage your kidneys. 
The solution injection may also cause pain, bleeding, bruising, hives, and/or itching. 
 
During the MRI, you may feel mild vibrations throughout your body. The machine will produce 
a loud knocking noise. This is normal. You will be given earplugs to protect your ears. Some 
people, especially those who tend to feel uncomfortable in small or closed spaces, may feel 
“closed in” and become anxious while in the scanner. The scanner has an intercom, which will 
allow you to speak to the staff during the procedure. If you feel ill or anxious during scanning, 
tell the MRI staff and the scanning will be stopped if you wish. 
 
The magnetic field used in MRI scanning may harm you if you have certain types of metal in 
your body (as might be found in pacemakers, neurostimulators, or certain clips). It may cause 
problems with devices, such as pacemakers. If you have metal in your body or devices such as a 
pacemaker, you should discuss this with the study doctor. 
 
Reproductive risks: 
The effects of the study drug on an unborn baby are not known. If you are a woman, you should 
not become pregnant or breastfeed a baby while taking part in the study. You will be required to 
have a negative pregnancy test prior to the start of the study. If you are a man, you should not 
father a baby while taking part in the study. 
Surface Prep Tool: 
This will be used at the investigator’s discretion prior to patch application and you may have 
bleeding, pain and/or infection from use of this surface prep tool.   
 
It is important that you and your partner understand that you need to use birth control while in 
this study. If you are a female participant and become pregnant or the female partner of a male 
participant and become pregnant, you must tell the study doctor right away. The study doctor 
will notify the sponsor to discuss any follow-up with you. 
 


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Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better. Toxicities related to pre-
operative therapy could lead to delay in definitive potentially curative therapy (e.g., salvage 
surgery). The study will also provide knowledge toward more effective treatments for oral cancer 
patients. The information from this study will help researchers learn more about the effects of 
PRV111 as a treatment for oral cancer.  
 
What are my other choices if I do not take part in this study? 
If you decide not to take part in this study, you have other choices. For example: 
• You may choose to have radiotherapy alone, surgery with or without additional 
radiotherapy and/or chemotherapy, as this is the standard treatment; 
• You may choose to take part in a different study, if one is available; 
• Or you may choose not to be treated for cancer but you may want to receive comfort care 
to relieve symptoms.  Comfort care includes pain medication and other support.  It aims 
to maintain your comfort and dignity rather than cure disease.  Usually this care can be 
provided at home. 
 
Can I stop being in the study? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can complete follow-up tests for safety. This 
study visit will protect you from any unexpected side effects and will document your condition 
upon leaving the study. 
 
Your participation may be discontinued without your consent by the study doctor, the sponsor or 
a regulatory agency for the following reasons: 
• If your health changes and the study is no longer in your best interest 
• If new information becomes available 
• If you do not follow directions for taking part in the study 
• If the study is cancelled 
 
If you withdraw your consent during the study, personal information already collected will be 
retained to ensure the results of the study are measured properly. You should be aware that data 
collected by the sponsor up to the time you withdraw will form part of the study results. 
 
What are the costs of taking part in this study? 
The costs for the PRV111 patches will be supplied at no charge while you take part in this study. 
You or your insurance company/third party payer will be billed for all routine procedures and the 
cost of treating injuries resulting from routine procedures. Routine procedures and drugs are 
those that you would likely receive whether or not you are in this study. You will be responsible 
for any deductibles or co-payments that are associated with your insurance coverage. 
 
Will I receive compensation for my participation? 
All Subjects: 


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To compensate you for time and expenses for participating in this study, you may receive a $50 
stipend at the end of each of the following study visits: Screening, Visit 1, Visit 2, Visit 3 and 
Visit 4 to cover parking and travel costs. The total amount you can receive is $250. 
 
Non-Local Subjects: 
If you travel to a visit, the study sponsor may reimburse you for study-related travel costs 
and/or expenses. Study staff will review the reimbursement plan with you at the beginning of 
the study to see if you qualify. 
 
1. Mileage at the standard rate of ($0.59/mile) plus any tolls incurred. 
2. Reimbursement for a reasonable public transportation method (including bus, train, 
Uber, Lyft, or taxi) up to $100.00/day. 
3. Meals may also be reimbursed (up to $50.00/day) and lodging (not to exceed 
$150.00/night). 
 
Payments will be made to you on a prepaid debit card. Payments will be loaded onto your card 
within one day of your visit. 
 
If you receive compensation for being a part of this research study, you may be asked to 
complete a W-9 tax form to report the compensation to the Internal Revenue Service. The 
amount you receive will count as income and may affect your income taxes. Your social security 
number will be required to complete the W-9 tax form. 
 
What if I am injured from participating in the study? 
If you think that you have been hurt by taking part in this research, 
 
(24 hours), as soon as possible.  If needed, emergency medical care will be 
provided. If the injury is a direct result of a study-related procedure or because you are taking 
PRV111 patch, the cost of the emergency medical care will be paid by the sponsor. The Sponsor 
has no plans to pay for medical care for any other injury whether or not it might be related to 
taking part in this research. 
 
You voluntarily consent to take part in this study. If you feel that you have been injured as a 
result of being in this study, you should immediately contact the study doctor.  The study doctor 
will treat you or will refer you for treatment. 
 
If the study doctor and sponsor determine that the injury is a direct result of receiving the study 
drug or the properly conducted study procedures due to your participation in the study, and you 
have followed the study doctor’s instructions, the sponsor will reimburse you for any reasonable 
cost of emergency and/or acute medical care you received for treatment. Injury that is the direct 
result of effects of receiving the study drug or the properly conducted study procedures due to 
your participation in the study does not include any underlying pre-existing medical condition. 
Other compensation, such as for lost wages, disability or discomfort, is not available. 
 
Be aware that your health care payer/insurer might not cover the costs of study-related injuries or 
illnesses. 
 


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If you are injured as a result of this study, you do not give up your right to pursue a claim 
through the legal system. 
 
Confidentiality: 
Your privacy is very important and the study staff will make every effort to protect it. Your 
identity and records throughout the study will be kept as confidential as possible in accordance 
with applicable law. All of your test results and medical reports will be identified by a unique 
code and the list that links the code to your name will be kept separate from your tests and 
medical reports. The list will not be sent to the sponsor, Privo Technologies. 
 
Medical information collected during this study and the results of any test or procedure that may 
affect your medical care may be included in your medical record. The information included in 
your medical record will be available to health care providers and authorized persons including 
your insurance company. 
 
Other groups may need to look at your medical records and study forms to make sure that the 
information is correct and to evaluate the conduct of this research study. These include the 
following: 
• The sponsor of this study, Privo Technologies 
• Western IRB, a group of people who review the research with the goal of protecting the 
people who take part in the study. 
• Regulatory agencies in the United States, such as the Food and Drug Administration 
(FDA), Department of Health and Human Services and the Office for Human Research 
Protections 
• The University of Cincinnati 
 
A federal regulation known as the Privacy Rule gives you certain rights concerning the privacy 
of your health information.  Researchers covered by this regulation are required to get your 
authorization (permission) to use and disclose (share with others) any health information that 
could identify you. You should have received a Notice of Privacy Practices when you received 
health care services here.  If not, let us know and a copy will be given to you. 
 
If you sign this informed consent form, you are giving permission for the use and disclosure of 
your health information for purposes of this research study.  You do not have to give this 
permission.  Your health care outside of the study, payment for your health care, and your health 
care benefits will not be affected if you choose not to sign this form.  However, if you do not 
sign this form, you will not be able to participate in the study. 
 
Who Will Use and Disclose My Health Information? The study doctor and research staff (the 
study team) may use your health information to conduct, review, and determine the results of the 
study.  The study team may also use your information to prepare reports or publications about 
the study.  However, your name will not appear in any report or publication without your 
permission. 
 


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What Health Information will be Used and Disclosed?  The study team will record your 
medical history, the treatment you receive, and the results of examinations and tests done during 
the study on study forms.  The study team will send the completed study forms to the study 
sponsor.  Representatives from the groups identified below may need to look at your medical 
records to make sure that the information on the study forms is correct or that the study was 
conducted properly. Your medical records may include other health information about you and 
may include documents that directly identify you.  Reviews like that will take place at the study 
center or where the medical records are stored and can take place after the study is over. 
 
Who Will Receive My Health Information? Your study information or medical records (as 
described above) or both may be shared with the following people or groups: 
 
• The study sponsor or its representatives, including companies it hires to provide study-related 
services 
• Researchers who are conducting this study at other study centers 
• Institutional Review Board and any other committees responsible for overseeing the research 
• Staff of 
 
• 
employees providing service or care to you 
• Federal and State agencies, such as the U.S. Food and Drug Administration (FDA), 
Department of Health and Human Services (DHHS), the National Institutes of Health (NIH), 
and other US and non-US government bodies that oversee or review research 
 
Will My Information be Protected by the Privacy Rule After it is Disclosed to Others? 
 required by the Privacy Rule to protect your health information.  
After your information is shared with others, such as the study sponsor, it may no longer be 
protected by the Privacy Rule.  The people who receive this information could use it in ways not 
discussed in this form and could disclose it to others.  The sponsor will use and disclose your 
information only for research or regulatory purposes or to prepare research publications.  In 
addition to using it for this study, the sponsor may reanalyze the study data at a later date or 
combine your information with information from other studies for research purposes not directly 
related to this study.  The goal of any such research would be to learn more about drugs or 
diseases or to help design better studies in the future.  When using your information in these 
ways, the sponsor may share it with regulatory authorities, other researchers, its business 
partners, or companies it hires to provide research-related services. 
 
What Happens if I Leave the Study Early?  If you stop participating in the study early for any 
reason, the study team will tell the sponsor why.  If the study team asks you to come to any more 
study visits and you agree, the study team will send the sponsor information from those visits as 
well.  All information collected about you may continue to be used and disclosed. 
 
Will My Authorization Ever Expire?  This Authorization does not have an expiration date.  
The study team may need to correct or provide missing information about you even after your 
study participation is over and a review of your medical records may also take place after the 
study is over. 
 


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May I Take Back My Authorization? You have the right to take back (revoke) your 
Authorization at any time by writing to the person in charge of this research study whose 
information is listed on the front of this form.  If you revoke your Authorization, the study team 
will not collect any new health information about you.  However, they can continue to use and 
disclose any already-collected information if that is necessary for the reliability of the study.  The 
sponsor can also still keep and use any information that it has already received.  If you revoke 
your Authorization, you can no longer continue to participate in the study. 
 
May I Look At My Study Information? You have a right to see and make copies of your 
medical records.  However, to ensure the reliability of the study, you will need to wait to see 
your study records until the study is completed. 
 
Who can answer my questions about the study? 
You can talk to the study doctor about any questions, complaints, or concerns on this study or to 
report side effects or injuries. 
 
Contact the study doctor 
(24 hours). 
Please call if you: 
 
• Think the research has hurt you. 
• Have general questions about giving consent or your rights as a research participant 
in this research study. 
• Have questions, concerns, suggestions and/or complaints about the research. 
 
This research is being overseen by an Institutional Review Board (“IRB”). An IRB is a group of 
people who perform independent review of research studies. You may talk to them at (800) 562-
4789, help@wirb.com if: 
o You have questions, concerns, or complaints that are not being answered by the research 
team. 
o You are not getting answers from the research team. 
o You cannot reach the research team. 
o You want to talk to someone else about the research. 
o You have questions about your rights as a research subject. 
 
To report complaints or concerns to an independent agency in an anonymous and confidential 
manner, please call the Research Compliance Hotline at 1-800-889-1547. 
 
Use of Tissue and Blood for Research: Consent Form 
 
About Using Tissue and Blood for Research: 
After you complete study treatment, you will have surgery as part of your oral cancer treatment. 
Your doctor will remove the cancer tissue. The tissue removed during the surgery will be 
microscopically examined by a pathologist. The pathologist will check the tissue specimen and 
tell the status of your cancer, the number of viable tumor cells in the specimen and other 
parameters of the cancer and the margins. Your surgical specimen will also be tested for the level 


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of some cancer marker levels. The results of these tests will be given to you by your doctor and 
will be used to plan your care. 
 
You will sign a separate consent form before the surgery. This will be a standard surgical 
consent form from the institution where the surgery and pathological sample will take 
place. 
 
We would like to keep some of the tissue that is left over for future research. The samples will be 
labeled with a code number. To ensure your privacy, your name and information will not appear 
on these samples. If you agree, this tissue will be kept and may be used in research between us 
and our research collaborators to learn more about cancer and other diseases. Please read the 
information sheet called "Providing Your Tissue for Research: What You Need to Know" to 
learn more about tissue research. This information sheet is available to all at the following web 
site: https://www.cancer.gov/publications/patient-education/providing-tissue.pdf. 
 
As a result of your participation in the trial, you also will have blood tests performed before you 
start treatment, during and at completion of your treatment. We would like to keep for future 
research about 3 tablespoons of the blood taken at that time. If you agree, this blood will be kept 
and may be used in research to learn more about cancer and other diseases. 
 
The research that may be done with your tissue and blood is not designed specifically just to help 
you. It might help people who have cancer and other diseases in the future. Reports about future 
research done with your tissue and blood will not be given to you or your doctor. These reports 
will not be put in your health record. The research will not have an effect on your care. 
 
Old tissue Samples: 
A biopsy (pathology samples) or tissue block from your oral cancer has been taken, at the time 
you were diagnosed with oral cancer. It’s important for the researchers to evaluate and compare 
your initial biopsy (that was obtained before the study treatment) with the cancer tissue obtained 
during your surgery. We seek permission to look at older biopsy samples and tissue blocks. 
 
Things to Think About: 
We appreciate the use of tissue and blood for cancer research but the choice is yours to allow us 
to keep them for future research. No matter what you decide to do, it will not affect your care or 
your participation in the main part of the study. If you decide now that your tissue and blood can 
be kept for research, you can change your mind at any time and let us know of your decision by 
contacting us. As the result, any tissue and blood that remain will no longer be used for research. 
In the future, people who do research may need to know more about your health. While the 
Doctor/institution may give them reports about your health, he/she will not provide your name, 
address, phone number, or any other information that can identify you. 
 
Benefits: 
The benefits of researchers using tissue and blood include learning more about causes of 
different cancers and developing ways to prevent or treat them. 
 
Risks: 


Privo Technologies, Inc. 
PRV111 
Version 6.0 – 28 February 2020 
Feb 28, 2020 
 
Page 14 of 15 
The greatest risk to you is the release of information from your health records. We will do our 
best to make sure that your personal information will be kept private. The chance that this 
information will be given to someone else very unlikely. 
 
Making Your Choice: 
Please read each sentence below and think about your choice. After reading each sentence, check 
"Yes" or "No". If you have any questions, please talk to your clinician or nurse. 
 
No matter what you decide to do, it will not affect your care. 
 
1. My specimens may be kept for use in research to learn about, prevent, or treat cancer, as 
follows: 
• Tissue 
Yes 
No 
• Blood 
Yes 
No 
 
2. Someone may contact me in the future to ask me to take part in more research. 
 
Yes 
No 
 
3. I agree that data (Samples/reports) regarding my old pathology tissue samples will be used for 
research aims. 
 
Yes 
No 
 
You will get a copy of this form. If you want more information about this study, ask your 
study doctor. 
 


Privo Technologies, Inc. 
PRV111 
Version 6.0 – 28 February 2020 
Feb 28, 2020 
 
Page 15 of 15 
Consent and Signature 
 
I have read or someone has read to me, this Informed Consent Document which describes the 
purpose and nature of this research. I have had time to review this information and have been 
encouraged to ask questions. If I do not participate or if I discontinue my participation, I will not 
lose any benefits or any legal rights. My participation in this research is completely voluntary. I 
have received (or will receive) a copy of this signed and dated form for my records and future 
reference. I have been given the information about the use and disclosure of my health 
information for this research study. I give my consent to participate. 
 
 
 
 
Subject Name (printed) 
 
 
 
 
 
 
 
 
Signature of Subject 
Date 
Time 
 
 
 
 
Name of Person Obtaining Informed Consent 
 
 
 
 
 
 
Signature of Person Obtaining Informed Consent 
Date 

Prot_000.pdf: 
 
 
 
Confidential Property of Privo Technologies, Inc. 
Page 1 of 59 
 
CLINICAL STUDY PROTOCOL 
TITLE PAGE 
 
Title: 
Phase 1/2, Open-Label, Single-Arm Safety, Tolerability, 
Anti-Tumor Effects, Systemic Exposure, and Device 
Technical Effects of PRV111 (Cisplatin Transmucosal 
System) in Subjects with Oral Squamous Cell Carcinoma 
Test Product: 
PRV111 (Cisplatin Transmucosal System) Drug Product 
Protocol Identification: 
CLN-001 
Sponsor Name, Address, and 
Telephone Number: 
Privo Technologies 
200 Corporate Place, Suite 6B, Peabody, MA 01960 
Phone : 978-587-2322 
Fax : 978-278-5114 
Compliance Statement: 
The trial will be conducted in accordance with standards of 
Good Clinical Practice, as defined by the International 
Council for Harmonization and all applicable national and 
local regulations. 
Date of Original Protocol: 
3 August 2017 
Date of Amendment 1: 
Date of Amendment 2: 
Date of Amendment 3: 
Date of Amendment 4: 
Date of Amendment 5: 
17 October 2017 
11 May 2018 
26 March 2019 
24 May 2019 
23 March 2020 
 
 
 
        Date: March 23, 2020 
                        
 
 
                                               
Signature                                    Date : March 23, 2020 
Confidential Information 


 
 
 
Confidential Property of Privo Technologies, Inc. 
Page 2 of 59 
 
The information contained herein is confidential and may not be used, divulged, published, or otherwise disclosed 
without the prior written consent of Privo Technologies, Inc.  


Privo Technologies, Inc. 
Protocol CLN-001 Amendment 5  
 
Confidential Property of Privo Technologies, Inc. 
Page 3 of 59 
 
PROTOCOL SIGNATURE PAGE 
Protocol : CLN-001 
Title:  Phase 1/2, Open-Label, Single-Arm Safety and Efficacy Dose-Finding, Systemic 
Exposure, and Device Technical Effects of PRV111 (Cisplatin Transmucosal System) in 
Subjects with Oral Squamous Cell Carcinoma 
Amendment 5: 23 March 2020 
Investigator Statement:  I have received and completely reviewed the above-named protocol, 
including all appendices and amendments. As Investigator, I agree to conduct the trial in 
accordance with all stipulations of the protocol and in accordance with 21 Code of Federal 
Regulations (CFR) Part 50, International Council for Harmonization (ICH) Guidelines for Good 
Clinical Practices (GCP), and the Declaration of Helsinki. 
INVESTIGATOR SIGNATURE AND CONTACT INFORMATION 
Investigator (signature) 
 
Investigator (please print) 
 
Date of Signature 
 
Investigator’s Address 
 
City, State, Country, Zip Code 
 
Telephone No. 
 
Fax No. 
 
Email 
 
 
Signature on this page assures Privo Technologies that, to the best of the Investigator’s knowledge, the affiliated 
Institutional Review Board operates in accordance with applicable local and national regulations, and that the 
Investigator understands and agrees to abide by all regulatory obligations and ICH GCP Guidelines while 
conducting this clinical trial. 
 
Once signed, the original of this form should be detached from the protocol and returned to the Sponsor. 
(Please retain a copy for your files) 
 
 


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Confidential Property of Privo Technologies, Inc. 
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STUDY CONTACT INFORMATION 
Unless otherwise instructed, Serious Adverse Event and Serious and Unexpected Suspected 
Adverse Reaction reports are to be submitted to:  
 
 
 
Who will forward a copy to: 
Medical Monitor: 
 
 
 


Privo Technologies, Inc. 
Protocol CLN-001 Amendment 5  
 
Confidential Property of Privo Technologies, Inc. 
Page 5 of 59 
 
1 
SYNOPSIS 
Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
Title of Study: Phase 1/2, Open-Label, Single-Arm, Safety and Efficacy Dose-Finding, Systemic Exposure, and 
Device Technical Effects of PRV111 (Cisplatin Transmucosal System) in Subjects with Oral Squamous Cell 
Carcinoma 
Phase of Development: Phase 1/2 
Objectives:  
Primary Objectives 
• 
Determine a safe and efficacious dose of PRV111 (Cisplatin Transmucosal System) (cisplatin drug-loaded 
patch + permeation enhancer [PE]) under the conditions of the trial. 
Secondary Objectives 
• 
Evaluate tumor response  
• 
Assess the safety and tolerability of the treatment 
• 
Evaluate systemic, tumor and lymph node (if available) platinum levels following administration 
• 
Evaluate device technical success including the residual cisplatin level in the patch after the application 
period 
Methodology: This is a Phase 1/2, open-label, prospective, single-arm study of the safety and efficacy dose-
finding, systemic exposure, and device technical success of PRV111 (Cisplatin Transmucosal System) (cisplatin 
drug-loaded patch+PE) in subjects with oral squamous cell carcinoma (SCC) amenable to surgery.  
 
Study Design: This is a 2-stage adaptive study. For Stage 1, up to 10 subjects will be enrolled for the purpose of 
5 evaluable subjects for the 1st stage of the study to determine a safe and efficacious dose. For Stage 2, the target 
goal is 11 evaluable subjects for the efficacy analysis of the final dose. If the dose remains the same as Stage 1, 
Stage 2 will target 6 additional evaluable subjects but up to 21 subjects will be recruited if the dose is changed 
between Stage 1 and 2.  
For the purpose of dose selection, tolerable dose is defined as a dose where fewer than 33% of subjects being 
evaluated within the safety population present with dose-limiting toxicities (DLTs). Effective dose is determined 
based on the evaluable population as described in the Statistical Methods section.  
The 2 stages of the study are described below:   
 
Stage 1: Up to 10 subjects will be enrolled for the purpose of 5 evaluable subjects and undergo 3 treatment 
applications at each of the 4 planned treatment visits. Each treatment visit will include 1 ml of the PE which 
will be applied pre and post patch application (see Pharmacy Manual for details). Starting approximately 5 
minutes after application of the PE, 1 or 2 patches (depending on tumor size) will be applied. A total of 3 
treatment applications of patches will occur. These successive applications will span approximately 35 
minutes. The 3 applications provide a total of 6 mg of cisplatin per visit (12 mg if 2 patches are applied at the 
same time). The 4 treatment visits will be separated by 2 to 6 days (at least 48 hours apart).  
The following decisions will be made based on safety and efficacy of the dose: 
Dosing Rules for Stage 1: 
1) If fewer than 2 subjects experience DLTs, then the following scheme will be considered for stage 2 
dosing: 
a. If fewer than or equal to 2 of the evaluable subjects have a response (Tumor volume change from 
baseline (CFB) expressed as percent change from baseline (PCFB) complete response [CR], strong 
response [SR] or partial response [PR]) the dose will be escalated from 3 to 5 treatment applications 
per treatment visit for Stage 2. 


Privo Technologies, Inc. 
Protocol CLN-001 Amendment 5  
 
Confidential Property of Privo Technologies, Inc. 
Page 6 of 59 
 
Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
b. If 3 or more evaluable subjects have a response (as tumor volume PCFB complete response [CR], 
strong response [SR] or partial response [PR]), the dose will remain the same for Stage 2 (3 
applications per treatment visit). 
2) If 2 or more subjects experience DLTs at any time during Stage 1, the following scheme will be 
considered for dose de-escalation in Stage 2: 
a. If there are 5 evaluable subjects in Stage 1: 
- If out of 5 evaluable subjects, 2 or more subjects have a response (as tumor volume PCFB complete 
response [CR], strong response [SR] or partial response [PR]), the dose will be de-escalated to 2 
applications per treatment visit. 
- If out of 5 evaluable subjects, fewer than 2 have a response (as tumor volume PCFB complete 
response [CR], strong response [SR] or partial response [PR]), the dose will be considered 
ineffective and the study will be stopped. 
b. If Stage 1 dosing was stopped prior to having 5 evaluable subjects, the dose will be de-escalated from 3 
applications to 2 applications per treatment visit. 
Stage 1 Dose Determination Scheme: 
 
 
Stage 2: In case of dose escalation or de-escalation, Stage 2 will be conducted in 2 parts: Stage 2a and Stage 
2b. 
Subjects will receive 2, 3, or 5 treatment applications at each of the 4 planned treatment visits, depending on 
the results of Stage 1. 
 
  
 
Stage 2a: This stage will include 5 subjects (Stage 2a flowcharts). In this stage, only safety outcomes will be 
considered for determining the dosing regimen for the set of subjects to be enrolled in Stage 2b. All subjects 
enrolled in this stage will be monitored for possible DLTs.    


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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
1) If fewer than 2 subjects with DLTs in Stage 2a, enrollment will continue for the remaining number of 
subjects required in Stage 2b at the same dose. 
2) If 2 subjects experience DLTs in Stage 2a, dosing will be re-considered. It may be stopped or, when 
possible, decreased for the remaining subjects enrolled in Stage 2b: 
a. 
If “Stage 2a - Escalated Dose”, the original dose will be used for up to 10 additional evaluable 
subjects enrolled for Stage 2b.  
b. If “Stage 2a - De-escalated Dose”, the study will stop, as no safe dose could be determined. 
 
 
 
Stage 2a Safety Scheme in Case of Escalated Dose Decision: 
 
 


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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
Stage 2a Safety Scheme in Case of De-escalated Dose Decision: 
 
 
 
Stage 2b: In this stage both safety and efficacy will be evaluated.  All subjects will be monitored for possible 
DLTs (Stage 2b – All Doses flowchart).  
Stopping Rules at Stage 2b:   
If 3 subjects with DLTs, no additional subjects will be dosed.  
Efficacy Rules at Stage 2b: 
Efficacy rules are described in the statistical plans for this stage since it is end of the study. 


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Confidential Property of Privo Technologies, Inc. 
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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
Stage 2b Safety and Efficacy Scheme: 
 
Note: The PRV111 treatment should not cause a delay to the scheduled surgery. Visit 1 can be performed within 
42 days prior to the scheduled surgery. 
All subjects will subsequently undergo standard of care, surgical ablation of the tumor and satellite nodes, and 
possibly additional radiotherapy and chemotherapy. All subjects will be followed for up to 6 months post-surgery 
at 3 visits: 1 month, 3 months, and 6 months or standard of care (discretion of the investigator) post-surgery for 
loco-regional response and safety.  
 
 
Diagnosis and Main Criteria for Inclusion:  
In order to be eligible to participate in the study, an individual must meet all of the following criteria: 
1. Adult subjects, men and women, defined by age ≥18 years at the time of screening. 


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Protocol CLN-001 Amendment 5  
 
Confidential Property of Privo Technologies, Inc. 
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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
2. Pathologically proven and clinically confirmed T1 (<2 cm) or T2 (>2 cm but ≤4 cm) SCC of the lip or oral 
cavity (anterior 2/3 of the tongue, floor of mouth, lower and upper gingiva, salivary gland, hard palate, and 
buccal mucosa). 
3. Tumor must be easily accessible, with no evidence of infection or active bleeding, encroaching major 
vessels or clinical evidence of neural invasion. Tumors should not have been previously irradiated. 
4. Tumor must be amenable to surgical resection no later than 42 days post Visit 1. 
5. Clinically and/or radiologically measurable tumor. 
6. Eastern Collaborative Oncology Group Performance Status of ≤2. 
7. Adequate renal function as demonstrated by renal creatinine clearance ≥50 mL/min (calculated using the 
Cockcroft-Gault formula). 
8. Adequate organ function defined as: ANC ≥1000/µL, platelet ≥100,000/µL; hemoglobin ≥9.0 g/dL; AST 
and ALT ≤2.5 times the upper limit of normal (ULN), serum bilirubin ≤1.5 times the ULN or direct 
bilirubin ≤ULN for subjects with total bilirubin >1.5 times the ULN. 
9. Candidates for standard of care treatment consisting of surgery. 
10. Male and female subjects of childbearing potential must agree to use 2 methods of effective contraception 
from screening and for at least 30 days after the final dose of investigational product. Appropriate birth 
control is defined as barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine 
devices, or naturally or surgically sterile (with documentation in the subject's medical records). 
Postmenopausal women are defined as presenting at least 12 months’ natural spontaneous amenorrhea, or at 
least 6 weeks following surgical menopause (bilateral oophorectomy). Females of childbearing potential 
must be non-lactating and have a negative serum hCG within 14 days of treatment initiation. 
11. Absence of any serious underlying medical conditions which could impair the ability of the subject to 
participate in the study. 
12. Have a life expectancy of ≥3 months. 
13. Willing and able to provide written informed consent. 
14. Able to return to study site for treatment and follow-up visits as defined in the Protocol. 
 
Criteria for Exclusion:  
An individual who meets any of the following criteria will be excluded from participation in the study: 
1. Known distant metastasis of the SCC of the oral cavity 
2. Systemic chemotherapy for the treatment of SCC of the head and neck less than 2 years prior to Screening 
3. Concurrent documented malignancy, with the exception of localized SCCs of the skin 
4. Exposure to any investigational agent within 3 months prior to Screening 
5. Known allergy or hypersensitivity to platinum-containing agents, or known intolerance to a prior platinum-
containing agent, or to any of the excipients, which, in the judgement of the physician will preclude re-
exposure to platinum-containing agent 
6. Active, uncontrolled infection requiring systemic therapy, such as but not limited to HIV, Hepatitis B or C 
7. Uncontrolled intercurrent illness that would risk subject safety, interfere with the objectives of the Protocol, 
or limit subject compliance with study requirements, as determined by the Investigator 
8. Known or suspected pregnancy, planned pregnancy, or lactation 
9. Any medical or psychiatric condition that may compromise the ability to give written informed consent 
Test Product, Dose and Mode of Administration: PRV111 (Cisplatin Transmucosal System) consists of: 
• PE solution 
 
 to be applied superficially to the malignant tumor to 
improve the drug permeation into the tumor (1 mL at each treatment visit) (Refer to the Pharmacy 
Manual). 


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Confidential Property of Privo Technologies, Inc. 
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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
• Patch with 
 polymeric matrix, embedded cisplatin-loaded 
 particles (CLPs), and a 
non-permeable backing. Each 2 cm x 2 cm PRV111 topical patch covers a tumor region of 4 cm2 and 
contains 0.5 mg/cm2 (total 2 mg) of cisplatin. 
patch(es). The number of patches used for each subject should remain consistent throughout treatment. Refer to 
the Pharmacy Manual for detailed instructions for use. 
Duration of Treatment: Up to 6 weeks of treatment prior to the scheduled resection of the tumor and 6 months 
post-surgical follow-up. Note: The PRV111 treatment should not cause a delay to the scheduled surgery. Visit 1 
can be performed within 42 days prior to the scheduled surgery. 
 
Criteria for Evaluation:  
Safety/Tolerability evaluation based on:  
• Adverse events   
• Physical examination, vital signs, and weight 
• Blood and urinary tests: complete blood count, chemistry panel, and urinalysis 
• Electrocardiogram 
• Oral examination: including observation for mucositis and other signs of local reaction to the test article  
• Neck lymph nodes examination 
 
Efficacy, based on:  
• Tumor volume change from baseline clinical assessment (CR, PR, SR, SD, or PD). Response defined as 
CR, SR, or PR; non-response defined as SD or PD. 
• Ruler or caliper measurements of tumor volume  
• 
 
 
 
• Tumor photography and measurements 
• Loco-regional control: subjects will be followed-up for disease recurrence and safety following surgery  
 
Pharmacokinetics: 
• Whole blood samples will be assessed for total platinum content 
 
Technical Success will be defined as: 
• Taste of the PE solution 
• Taste of the PRV111 patch 
• Adhesion, including the time of adhesion of PRV111 patch 
• PRV111 patch peel-off 
• Residual cisplatin level in the patch after the application period. All PRV111 patches will be assessed for 
the amount of residual cisplatin in each patch after each application period. If the product detaches 
prematurely, the residual cisplatin will be assessed and the time of detachment will be noted. 
Statistical Methods:  
Safety outcomes resulting in a DLT will be used during the conduct of this study to select doses being tested 
according to pre-defined thresholds of toxicity. 
• Local and systemic safety and tolerability will be summarized using descriptive statistics.   
The number of subjects with DLTs will be capped to be fewer than 2 subjects with DLTs out of 5 new 
subjects enrolled.  
The treatment regimen will be deemed tolerable if fewer than a third of the subjects exposed to it present 
DLTs. 


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Confidential Property of Privo Technologies, Inc. 
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Name of Sponsor/Company: Privo Technologies 
Name of Finished Product: PRV111 (Cisplatin Transmucosal System)  
Name of Active Ingredient: Cisplatin 
• Efficacy based on tumor volume CFB criteria will be summarized, and the null hypothesis that the 
probability of response is at most 30%, where a response is the occurrence of CR, SR or PR will be tested 
using a 1-sided test exact binomial test at level 0.018. 
• 
 
 
• Systemic and tumor and lymph nodes (if available) platinum levels will be summarized using descriptive 
statistics.  
• Variables measuring technical success (including residual cisplatin level in the patch) will be summarized 
using descriptive statistics. 
All summaries will be presented by dose, as appropriate. Incidence of pre-surgery AEs will be summarized using 
number and percent for each System Organ Class and Preferred Term (MedDRA), including Investigator 
assessment of relatedness and severity grade.  
All assessments will be listed and summarized using mean, standard deviation, median, minimum, and maximum 
for continuous variables and using number and percent for categorical assessments.  
Data from this study will be summarized at 2 timepoints: 
• 
Final report at End of Stage 2: after all subjects complete PRV111treatment, efficacy, pharmacokinetics, and 
technical data will be analyzed, including all available safety data from the long-term follow-up. 
• 
Long term safety report: after all subjects complete all observations.  
 
Power and Sample Size 
  
  
In the first stage, 5 evaluable subjects will be accrued. If there are 2 or fewer responses in these 5 subjects, the 
dose will be escalated. Otherwise, the dose will remain the same or de-escalated based on safety data. Additional 
subjects will be accrued for a total of 11 evaluable subjects at the final dose. 
If the dose is not increased after Stage 1, the test will be performed using all evaluable subjects from Stage 1 and 
2. If the dose is adjusted after Stage 1, the test will be performed using all evaluable subjects from Stage 2. 
Based on Simon's 2-stage procedure, the null hypothesis that the true response rate is 0.30 will be tested against a 
one-sided alternative. The null hypothesis will be rejected if 7 or more responses are observed at the final dose. 
This design yields a type I error rate of 0.018 and power of 96.44% when the true response rate is 0.85. 
Null response rate: P0 
Alt. response rate: P1 
Alpha one-tailed 
Power 
n1 
r1 
N 
R 
 0.30 
0.85 
0.018 
96.44% 
5 
2 
11 
6 
N is the total number of evaluable subjects at the final dose 
n1 is the number of evaluable subjects accrued during Stage 1 
r1, if r1 or fewer responses are observed during stage 1, escalate the dose if safety requirements are met  
R, if R or fewer responses are observed by the end of Stage 2 in N subjects, then an effective dose is not found 
 
 
 
 
 


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Table 1. Schedule of Events 
 
Screening 
Within 
28 
Days Prior to 
Visit 1 
Days 
Surgery 
Months Post Surgery 
Treatment Visits 
Post Treatment 
Pre-Op 
Standard of Care (SOC) 
Follow-up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7, 8, 9 
0 
1 
≥48 and ≤ 144 hours, post 
previous visit 
≥72 hours post 
last treatment 
≤42 
days 
post Visit 1 
1, 3, & 6 months (all can 
be +/-3 weeks) SOC visits 
Confirmed SCC 
X 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
Schedule study visits 
X 
X 
X 
X 
X 
X 
 
 
Demographic, 
medical/history 
X 
 
 
 
 
 
 
 
Physical examination,b,s 
 
 VSc 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
Anti-emetics 
 
Xa 
Xa 
Xa 
Xa 
 
 
 
  
X 
 
 
 
 
 
 
 
Oral cavity examinationd 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
Neck lymph nodes exam 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
ECG s 
X 
 
 
 
 
X 
 
 
,  
X 
 
 
 
 
X 
 
 
Clinical labsf 
X 
Xa 
 
Xa 
 
X 
Xo 
 
HPV s 
Xg 
 
 
 
 
 
 
 
Pregnancy test 
Xh 
Xa 
 
 
X 
 
 
 
PK sampling 
 
Xi 
Xj 
Xj 
Xi 
 
 
 
Tumor resection 
 
 
 
 
 
 
Xk 
 
PRV111 patch treatment 
 
Xp 
Xp 
Xp 
Xp 
 
 
 
Tumor measurementsq 
 
Xa 
Xa 
Xa 
Xa 
X 
 
 


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Screening 
Within 
28 
Days Prior to 
Visit 1 
Days 
Surgery 
Months Post Surgery 
Treatment Visits 
Post Treatment 
Pre-Op 
Standard of Care (SOC) 
Follow-up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7, 8, 9 
0 
1 
≥48 and ≤ 144 hours, post 
previous visit 
≥72 hours post 
last treatment 
≤42 
days 
post Visit 1 
1, 3, & 6 months (all can 
be +/-3 weeks) SOC visits 
Tumor Volume change from 
baseline (CFB) criteria 
 
 
Xa 
Xa 
Xa 
X 
 
 
Tumor photographs 
 
Xl 
Xl 
Xl 
Xl 
X 
 
 
Loco-regional recurrence 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Technical successn 
 
X 
X 
X 
X 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
 
X 
AE assessment 
X 
X 
X 
X 
X 
Xr 
 
 
Abbreviations: AE=adverse event; 
; ECG=electrocardiogram; HPV=human papilloma virus; 
; PE=permeation 
enhancer; PK=pharmacokinetics; SCC=squamous cell carcinoma; VS=vital signs.  
 
a Performed prior to dosing. 
b  If a physical exam was performed within 14 days prior to the screening visit, it does not need to be repeated at the screening. 
c VS: seated blood pressure and pulse will be measured after the subject has been sitting for at least 3 minutes, respiration, temperature, height and weight will be recorded 
at every visit. VS will be obtained pre-dose at all visits and subject will also be monitored at 30+5 minutes, 60+5 minutes and 120+5 minutes following application of the last 
patch applied at Visits 1 and 4 and at 30+5 minutes post last patch application at Visits 2 and 3. 
d  Take photos of the tumor region for further assessment of tumor shrinkage. 
. 
f     CBC and chemistry panel (creatinine to determine the creatinine clearance, BUN, LFT, electrolytes (potassium, magnesium, calcium, and sodium), urinalysis. 
g  Tissue will be collected at Screening but the HPV status will be ascertained at any time during the study using immunohistochemistry for p16 according to institutional 
clinical protocols. 
h  Serum pregnancy test to establish eligibility for female subjects of childbearing potential. A negative urine pregnancy test must be documented within 7 days prior to the 
first treatment visit, and at Visit 5. 
i  Visit 1 & 4: PK blood samples for total platinum collected pre- treatment (time -15 to 0 minutes), and 30±5 minutes, 60±5 minutes and 120±5 minutes post removal of last 
patch. 
j     Visit 2 & 3: PK blood samples for total platinum collected pre- treatment (time -15 to 0 minutes), and 30±5 minutes, post removal of last patch and PE application. 
k    Sampling for tumor and lymph nodes (if available) platinum levels. 
l      Photos need to be taken prior to patch application. 
      m   Confirmation of tumor histology by a clinical pathologist is required prior to enrollment. 
 
 
n Taste of the PE solution and patch, adhesion, peel-off, residual cisplatin level in the patch.  
o  Performed after surgery if possible  


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p PE should be applied to the tumor area prior to first patch and allow to stay for 5 minutes. 
 Note that the mouth should 
be kept open for the saliva not wash off the PE.  
q Use “0.05” cm for the “Height” of a flat tumor. If a concave tumor, the “Height” can be shown as a negative number. If a non-measurable dent, use “-0.05” cm. 
 
r Only SAEs within 30 days post visit 5 need to be recorded.  
s. May use historical SOC information prior to consent if collected within 28 days prior to first treatment. 


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2 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................. 1 
PROTOCOL SIGNATURE PAGE ................................................................................................ 3 
STUDY CONTACT INFORMATION .......................................................................................... 4 
1 
SYNOPSIS ..................................................................................................................... 5 
2 
TABLE OF CONTENTS ............................................................................................. 16 
2.1 
List of Tables................................................................................................................ 19 
2.2 
List of Figures .............................................................................................................. 20 
3 
LIST OF ABBREVIATIONS AND TERMS .............................................................. 21 
4 
INTRODUCTION ....................................................................................................... 23 
4.1 
Background of Disease ................................................................................................ 23 
4.2 
Privo’s PRV111 Patch ................................................................................................. 24 
4.3 
Rationale for Use of the Product .................................................................................. 24 
4.4 
Rationale for Dose Selection ........................................................................................ 25 
5 
TRIAL OBJECTIVES ................................................................................................. 25 
5.1 
Primary Objective ........................................................................................................ 25 
5.2 
Secondary Objectives ................................................................................................... 25 
6 
INVESTIGATIONAL PLAN ...................................................................................... 25 
6.1 
Overall Trial Design and Plan: Description ................................................................. 25 
6.2 
Discussion of Trial Design ........................................................................................... 30 
7 
SELECTION OF SUBJECTS ...................................................................................... 31 
7.1 
Inclusion Criteria .......................................................................................................... 31 
7.2 
Exclusion Criteria......................................................................................................... 31 
7.3 
Criteria for Individual Subject Discontinuation of Protocol Therapy .......................... 32 
7.4 
Criteria for Individual Subject Discontinuation from the Trial ................................... 32 
7.5 
Handling of Subject Withdrawals or Subject Discontinuation of Study Intervention . 32 
7.6 
Premature Termination or Suspension of Study .......................................................... 33 
7.7 
Replacement of Subjects .............................................................................................. 33 
8 
TREATMENTS ........................................................................................................... 33 
8.1 
Treatments Administered ............................................................................................. 33 
8.1.1 
Description of Test Product ......................................................................................... 33 
8.1.2 
Packaging ..................................................................................................................... 33 
8.1.3 
Labeling........................................................................................................................ 34 


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8.1.4 
Preparation ................................................................................................................... 34 
8.1.5 
Dosing and Administration .......................................................................................... 34 
8.2 
Dose-limiting Toxicity (Stopping Rules for an Individual Subject) ............................ 34 
8.3 
Dose Modification ........................................................................................................ 35 
8.4 
Dose Interruption ......................................................................................................... 35 
8.5 
Study Drug Handling and Accountability .................................................................... 35 
8.6 
Study Drug Disposal .................................................................................................... 36 
8.7 
Concomitant Medications and Therapy ....................................................................... 36 
8.8 
Drugs Contraindicated with PRV111........................................................................... 37 
9 
VARIABLES ASSESSED ........................................................................................... 37 
9.1 
Eligibility Only Assessments ....................................................................................... 37 
9.1.1 
Confirmation of Squamous Cell Carcinoma ................................................................ 37 
9.1.2 
Tumor Staging .............................................................................................................. 37 
9.1.3 
Demographics, Medical and Medication History ........................................................ 37 
9.1.4 
Pregnancy Test ............................................................................................................. 38 
9.1.5 
Eastern Collaborative Oncology Group ....................................................................... 38 
9.2 
Efficacy Assessments ................................................................................................... 38 
9.2.1 
Tumor Photography and Measurements ...................................................................... 38 
9.2.2 
Response and Non-Response (Tumor Volume Change from Baseline Criteria) ......... 38 
9.2.3 
 ...... 39 
9.2.4 
 ....................................................................... 39 
9.2.5 
Loco-regional Control .................................................................................................. 40 
9.3 
Safety Assessments ...................................................................................................... 40 
9.3.1 
Physical Examination, Vital Signs, Weight ................................................................. 40 
9.3.2 
Oral Cavity Examination.............................................................................................. 40 
9.3.3 
Neck Lymph Nodes Examination ................................................................................ 40 
9.3.4 
Safety Laboratory Assessments ................................................................................... 40 
9.3.5 
Electrocardiograms ...................................................................................................... 41 
9.3.6 
Adverse Event Definitions/Reporting Requirements ................................................... 41 
9.3.6.1 
Expected Events ........................................................................................................... 41 
9.3.6.2 
Suspected Adverse Reaction ........................................................................................ 41 
9.3.6.3 
Adverse Reaction ......................................................................................................... 41 
9.3.6.4 
Adverse Device Effects ................................................................................................ 41 
9.3.6.5 
Serious Adverse Event Definitions / Reporting Requirements .................................... 42 


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9.3.6.5.1 Serious Adverse Event or Serious Suspected Adverse Reaction ................................. 42 
9.3.6.5.2 Pregnancy ..................................................................................................................... 43 
9.3.6.5.3 Serious Unexpected and Suspected Adverse Reaction ................................................ 43 
9.3.6.6 
Recording Adverse Events ........................................................................................... 43 
9.3.6.7 
Determining Relationship of Adverse Events to Study Drug ...................................... 44 
9.3.6.8 
Reporting Deaths and Other Serious Adverse Events .................................................. 44 
9.3.6.8.1 Events to Be Reported and Timeframe ........................................................................ 44 
9.3.6.8.2 Governing Regulatory Requirements ........................................................................... 44 
9.3.6.9 
Initial Information Provided by the Investigator .......................................................... 45 
9.3.6.10 Follow-up Information ................................................................................................. 46 
9.3.6.11 Serious Adverse Event that are Unexpected and related Serious Adverse Reaction 
Review that have a Potential Impact on Trial Conduct ................................................ 46 
9.4 
Pharmacokinetics Assessment ..................................................................................... 46 
9.5 
Technical Success Assessments ................................................................................... 47 
9.6 
Timing of Assessments ................................................................................................ 47 
9.6.1 
Screening (Visit 0) ....................................................................................................... 47 
9.6.2 
Baseline, Treatment (Visit 1) ....................................................................................... 47 
9.6.3 
Treatment (Visit 2) ....................................................................................................... 48 
9.6.4 
Treatment (Visit 3) ....................................................................................................... 49 
9.6.5 
Treatment (Visit 4) ....................................................................................................... 50 
9.6.6 
Post-Treatment/Pre-Op Visit (Visit 5) ......................................................................... 50 
9.6.7 
Surgery Day (Visit 6) ................................................................................................... 51 
9.6.8 
Post-Treatment Follow-Up (Visits 7, 8, & 9) .............................................................. 51 
10 
STATISTICAL METHODS AND PLANNED ANALYSES ..................................... 51 
10.1 
General Considerations ................................................................................................ 51 
10.2 
Sample Size Determination .......................................................................................... 51 
10.3 
Pharmacokinetics ......................................................................................................... 52 
10.4 
Study Populations ........................................................................................................ 52 
10.4.1 
Safety Population ......................................................................................................... 52 
10.4.2 
Evaluable Population ................................................................................................... 52 
10.5 
Statistical Analyses ...................................................................................................... 52 
10.5.1 
Analysis Timepoints .................................................................................................... 52 
10.5.2 
Subject Accountability, Demographics, and Baseline Characteristics ........................ 53 
10.5.3 
Primary Endpoints ........................................................................................................ 53 


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10.5.4 
Secondary Endpoints .................................................................................................... 53 
10.5.5 
Efficacy Data ................................................................................................................ 53 
10.5.6 
Safety Data ................................................................................................................... 54 
10.5.7 
Pharmacokinetics Data ................................................................................................. 54 
10.5.8 
Technical Data ............................................................................................................. 54 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 54 
12 
DOCUMENTATION AND INSPECTIONS .............................................................. 55 
12.1 
Study Monitoring ......................................................................................................... 55 
12.2 
Audits and Inspections ................................................................................................. 55 
13 
ETHICAL AND LEGAL ISSUES............................................................................... 56 
13.1 
Ethical Conduct/Good Clinical Practice ...................................................................... 56 
13.2 
Institutional Review Board .......................................................................................... 56 
13.3 
Written Informed Consent ........................................................................................... 56 
13.3.1 
Update of Informed Consent ........................................................................................ 57 
13.4 
Records and Case Report Forms .................................................................................. 57 
13.5 
Protocol Deviations ...................................................................................................... 57 
13.6 
Retention of Records .................................................................................................... 57 
14 
REFERENCES ............................................................................................................. 58 
 
2.1 
List of Tables 
Table 1. Schedule of Events.......................................................................................................... 13 
Table 2. Dosing Terminology ....................................................................................................... 34 
Table 3. Eastern Collaborative Oncology Group Performance Status ......................................... 38 
Table 4. Clinical Response to Treatment Based on Tumor Volume Change* ............................. 39 
Table 5. Pathological Response to Treatment............................................................................... 39 
Table 6. Clinical Laboratories ....................................................................................................... 40 
 
 
 


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2.2 
List of Figures 
Figure 1. PRV111 (Cisplatin Transmucosal System) ................................................................... 24 
Figure 2. Stage 1 dose determination scheme ............................................................................... 27 
Figure 3. Stage 2a safety scheme in case of escalated dose decision ........................................... 28 
Figure 4. Stage 2a safety scheme in case of de-escalated dose decision ...................................... 29 
Figure 5. Stage 2b safety and efficacy scheme ............................................................................. 30 


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3 
LIST OF ABBREVIATIONS AND TERMS 
Abbreviation 
Definition 
AE 
Adverse Event/Adverse Experience 
AUC 
Area under the curve 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CLP 
Cisplatin-Loaded 
 Particles 
Cmax 
Maximum concentration 
Cmin 
Minimum concentration 
CR 
Complete response 
CRF 
Case Report Form 
 
 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Collaborative Oncology Group Performance Status 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HPV 
Human papillomavirus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IRB 
Institutional Review Board 
IV 
Intravenous 
LFT 
Liver function test 
 
 
NCI 
National Cancer Institute 
PCFB 
Percent change from baseline 
PD 
Progressive disease 
PE 
Permeation enhancer 
PI 
Principal Investigator 


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Abbreviation 
Definition 
PK 
Pharmacokinetics  
PR 
Partial response 
PRMC 
Protocol Review and Monitoring Committee  
PRV111 
Cisplatin Transmucosal System 
QA 
Quality Assurance 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
t1/2 
Half life 
TEAE 
Treatment emergent adverse event 
 
 
ULN 
Upper limit of normal 
US 
United States 
VS 
Vital signs 
 


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4 
INTRODUCTION 
4.1 
Background of Disease 
Squamous cell carcinomas (SCC) of the head and neck include tumors that occur in the oral 
cavity (lips, buccal mucosa, anterior tongue, floor of the mouth, hard palate, upper gingiva, lower 
gingiva, buccal mucosa and retromolar trigone) (Brockstein, 2016). Most lip and oral cavity 
cancers originate in squamous cells, the thin flat cells that line the lips and oral cavity. Risk 
factors for oral cancer include chronic heavy use of alcohol and tobacco, long periods of 
exposure to natural or artificial sunlight, and exposure to human papillomavirus (HPV). Statistics 
also show that males and those of low socioeconomic background are at a higher risk of 
developing oral cancer than other demographics (Brockstein, 2016; da Silva, 2012).  
In 2017, an estimated 50,000 new cases of oral and pharynx cancer will be reported in the United 
States (US); approximately 11.1 adults per 100,000 will develop oral and pharynx cancer per 
year (National Cancer Institute, 2016). The median age of diagnosis is 62 years. The incidence 
of oral cancer increases with age (National Cancer Institute, 2016; National Institute of Dental 
and Craniofacial Research, 2016).  
The 5-year survival rate for oral cancer is approximately 60%; diagnosis at an early stage 
significantly increases the 5-year survival rate (83% for Stage I versus 10%–22% for Stage IV) 
(da Silva, 2012; National Cancer Institute, 2016; National Institute of Dental and 
Craniofacial Research, 2014). Approximately 30% of subjects have early (Stage I or II) 
localized disease, with most subjects diagnosed with advanced disease (Brockstein, 2016; da 
Silva, 2012; National Cancer Institute, 2016).  
Oral cancer has a high rate of recurrence (18%–76% for subjects who undergo standard 
treatment), and is considered the major cause of poor survival rates. Recurrence can vary by 
tumor location, with a median time to recurrence of 9.5 months (range 2–79 months) for tongue, 
8 months (range 2–120 months) for buccal tumor, and 5–8 months for lip tumors (da Silva, 
2012; Gurudutt, 2011; Kelner, 2014). The median time to recurrence across all oral cancer sites 
is 7.5 months, with most recurrences (86%) occurring within 24 months (da Silva, 2012). 
Approximately 1/3 of subjects treated with surgery and adjuvant therapy will experience local or 
regional recurrence and/or distant metastasis. Local and regional recurrences account for up to 
90% of treatment failures post-surgery and radiotherapy (da Silva, 2012). An estimated 9,700 
deaths will occur due to oral and pharynx cancer in the US in 2017 (National Cancer Institute, 
2016).  
The treatment and management of oral cancer is dependent upon the stage of disease. Standard 
treatment for localized early disease is surgery with or without radiation (Brockstein, 2016). For 
subjects with pathologically loco-regionally advanced disease (Stage III/IV), or for those treated 
with surgery for early stage disease identified to have close or positive margins, or positive 
lymph nodes, adjuvant postoperative radiotherapy with or without chemotherapy is 
recommended (Brockstein, 2016). Typical treatment approaches for loco-regionally advanced 
disease will include neoadjuvant chemotherapy or radiotherapy, primary surgery followed by 
adjuvant radiotherapy or chemoradiotherapy, or chemotherapy or chemoradiotherapy without 


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surgery (Brockstein, 2016; da Silva, 2012; Gregoire, 2010; Marta, 2015; Seiwert, 2007). 
Salvage surgery, adjuvant radiation, re-irradiation, and/or palliative chemotherapy is 
recommended for subjects with locally recurrent disease (Milano, 2015). For subjects with 
locally recurrent metastatic disease, palliative chemotherapy, immunotherapy, and/or supportive 
care are recommended (Brockstein, 2016). The most common chemotherapy drugs for advanced 
oral cancer includes cisplatin, methotrexate, carboplatin, 5-fluorouracil, paclitaxel, and 
docetaxel, which when administered alone or in combination have been shown to provide 
clinical benefit with demonstrated improvement in overall survival (da Silva, 2012; Gregoire, 
2010; Vermorken, 2010).  
4.2 
Privo’s PRV111 Patch 
PRV111 (Cisplatin Transmucosal System) is a thin, 2-layer, matrix-type, non-sterile 
transmucosal patch consisting of a 
 matrix layer embedded with cisplatin loaded 
 
particles (CLPs) and a non-woven fabric adhesive unidirectional backing, which is applied to the 
matrix layer during manufacturing (Figure 1). The patch is self-adhesive. 
  
Figure 1. PRV111 (Cisplatin Transmucosal System) 
In addition to the PRV111 drug product, a separately packaged Permeation Enhancer (PE) 
Powder for Reconstitution (a vial 
 
 to be reconstituted at the clinical site 
with 1 mL of Water for Injection) is used in conjunction with the PRV111 drug product. The 
reconstituted PE Solution is intended to improve the absorption of the cisplatin active ingredient 
and will be applied pre and post patch application (see Pharmacy Manual for details).  
4.3 
Rationale for Use of the Product 
Privo’s PRV111 is intended as a local induction chemotherapy, to improve the local control of 
the disease prior to surgery by shrinking the tumor size. Local cisplatin delivery may result in 
larger and more effective doses of cisplatin delivered to the tumor while significantly reducing or 
eliminating the systemic toxicities and side effects traditionally associated with intravenous (IV) 
cisplatin chemotherapy. If proven safe and effective for the treatment of SCC of the oral cavity, 
PRV111, in association with the standard care, may decrease the risk of local tumor recurrence.  
 


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Cisplatin (cis-diamminedichloroplatinum) has been approved in the US for 38 years as an 
antineoplastic agent and is commonly administered systemically IV as a standard of care 
chemotherapy for the treatment of oral cancer, alone and in combination with other 
chemotherapies (da Silva, 2012; Vermorken, 2007; Vermorken, 2010). However, systemic 
treatment with cisplatin can lead to dose-limiting toxicities (DLTs) and significant side effects, 
including renal toxicity, ototoxicity, and myelosuppression, which can limit the extent and 
duration of treatment (WG Critical Care, 2015). These side effects of IV cisplatin 
administration can be dose-limiting, reducing the dosage and length of cisplatin treatment for 
subjects. Treatment with cisplatin which is targeted to the tumor site and not administered 
systemically may reduce the dose-limiting systemic toxicities that are observed with IV cisplatin 
administration.  
The antineoplastic activity of cisplatin can be primarily attributed to its ability to bind and 
modify nuclear and mitochondrial DNA, forming multiple intrastrand and interstrand DNA 
adducts, which leads to the activation of the p53 apoptotic pathway and subsequently cell death 
(Galluzzi, 2014; Johnstone, 2015). Cisplatin has also been linked to inducing chemokine and T-
cell infiltration of tumor sites, thereby impeding tumor growth (Hong, 2011). 
4.4 
Rationale for Dose Selection  
The maximum total planned PRV111 cisplatin dose if dose escalation proceeds as planned in 
Stage 2 (10 mg per treatment visit for 5 single patch applications, and 20 mg per treatment visit 
for 5 double patch applications) is approximately 9 to 18 times lower than the recommended 
dose of IV cisplatin (180 mg for an 80 kg person) (WG Critical Care, 2015). 
Version 10 of the drug product will be used for this clinical trial since it has shown good safety 
and efficacy in 4 nonclinical studies. This version has the optimal dose per patch as 2 mg 
(0.5 mg/cm2) that balances the quality, drug release and uniformity of the patch.  
5 
TRIAL OBJECTIVES 
5.1 
Primary Objective 
• Determine a safe and efficacious dose of PRV111 (Cisplatin Transmucosal System) 
(cisplatin drug-loaded patch + PE) under the conditions of the trial. 
5.2 
Secondary Objectives 
• Evaluate tumor response  
• Assess the safety and tolerability of the treatment 
• Evaluate systemic, tumor , and lymph nodes (if available) platinum levels following 
administration 
• Evaluate device technical success including the residual cisplatin level in the patch after 
the application period 
6 
INVESTIGATIONAL PLAN 
6.1 
Overall Trial Design and Plan: Description 


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Study Design: This is a 2-stage adaptive study. For Stage 1, up to 10 subjects will be enrolled for 
the purpose of 5 evaluable subjects for the 1st stage of the study to determine a safe and 
efficacious dose. For Stage 2, the target goal is 11 evaluable subjects for the efficacy analysis of 
the final dose. If the dose remains the same as Stage 1, Stage 2 will target 6 additional evaluable 
subjects but up to 21 subjects will be recruited if the dose is changed between Stage 1 and 2.  
For the purpose of dose selection, tolerable dose is defined as a dose where fewer than 33% of 
subjects being evaluated within the safety population present with DLTs. Effective dose is 
determined based on the evaluable population as described in the Section 10.2.  
The 2 stages of the study are described below:   
Stage 1: Up to 10 subjects will be enrolled for the purpose of 5 evaluable subjects and 
undergo 3 treatment applications at each of the 4 planned treatment visits. Each treatment 
visit will involve application of 1 ml of the permeation enhancer and will be applied pre and 
post patch application (see Pharmacy Manual for details) (One ml vial of PE per visit, see 
Pharmacy Manual). Starting approximately 5 minutes after application of the PE, 1 or 2 
patches (depending on tumor size) will be applied. A total of 3 treatment applications of 
patches will occur. These successive applications will span approximately 35 minutes. The 3 
applications provide a total of 6 mg of cisplatin per visit (12 mg if 2 patches are applied at 
the same time). The 4 treatment visits will be separated by 2 to 6 days (at least 48 hours 
apart).  
The following decisions will be made based on safety and efficacy of the dose: 
Dosing Rules for Stage 1: 
1) If fewer than 2 subjects experience DLTs, then the following scheme will be considered 
for Stage 2 dosing: 
a. If fewer than or equal to 2 of the evaluable subjects have a response (as tumor volume 
PCFB complete response [CR], strong response [SR] or partial response [PR])) the 
dose will be escalated from 3 to 5 treatment applications per treatment visit for Stage 
2. 
b. If 3 or more evaluable subjects have a response (as tumor volume PCFB complete 
response [CR], strong response [SR] or partial response [PR])), the dose will remain 
the same for Stage 2 (3 applications per treatment visit). 
2) If 2 or more subjects experience DLTs at any time during Stage 1, the following scheme 
will be considered for dose de-escalation in Stage 2: 
a. If there are 5 evaluable subjects in Stage 1: 
- 
If out of 5 evaluable subjects, 2 or more subjects have a response (as tumor 
volume PCFB complete response [CR], strong response [SR] or partial response 
[PR])), the dose will be de-escalated to 2 applications per treatment visit. 
- 
If out of 5 evaluable subjects, fewer than 2 have a response (as tumor volume 
PCFB complete response [CR], strong response [SR] or partial response [PR])), 
the dose will be considered intolerable and the study will be stopped. 
b. If Stage 1 dosing was stopped prior to having 5 evaluable subjects, the dose will be 
de-escalated from 3 applications to 2 applications per treatment visit. 


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c.  
Figure 2. Stage 1 dose determination scheme 
 
Stage 2: In case of dose escalation or de-escalation, Stage 2 will be conducted in 2 parts: 
Stage 2a and Stage 2b. 
Subjects will receive 2, 3, or 5 treatment applications at each of the 4 planned treatment 
visits, depending on the results of Stage 1. Up to 21 additional subjects will be enrolled in 
Stage 2 if necessary, for the purpose of 11 total evaluable subjects at the final dose for the 
efficacy analysis.  
Stage 2a: 
This stage will include 5 subjects (Stage 2a flowcharts). In this stage, only safety outcomes 
will be considered for determining the dosing regimen for the set of subjects to be enrolled in 
Stage 2b. All subjects enrolled in this stage will be monitored for possible DLTs.    
1) If fewer than 2 subjects with DLTs in Stage 2a, enrollment will continue for the 
remaining number of subjects required in Stage 2b at the same dose. 
2) If 2 subjects experience DLTs in Stage 2a, dosing will be re-considered. It may be 
stopped or, when possible, decreased for the remaining subjects enrolled in Stage 2b: 
a. If “Stage 2a - Escalated Dose”, the original dose will be used on the remaining 
patients.  


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b. If “Stage 2a - De-escalated Dose”, the study will stop, as no safe dose could be 
determined. 
 
Figure 3. Stage 2a safety scheme in case of escalated dose decision 
 


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Figure 4. Stage 2a safety scheme in case of de-escalated dose decision 
 
Stage 2b: In this stage both safety and efficacy will be evaluated.  All subjects will be monitored 
for possible DLTs (Stage 2b – All Doses flowchart).  
Stopping Rules at Stage 2b:   
If 3 subjects with DLTs, no additional subjects will be dosed.  
Efficacy Rules at Stage 2b: 
Efficacy rules are described in the statistical plans for this stage since it is end of the study. 
 


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Figure 5. Stage 2b safety and efficacy scheme 
Note: The surgery is to be performed no later than 42 days post Visit 1. 
All subjects will subsequently undergo standard of care, surgical ablation of the tumor and 
satellite nodes, and possibly additional radiotherapy and chemotherapy. All subjects will be 
followed for up to 6 months post-surgery at 3 visits: 1 month, 3 months, and 6 months post-
surgery for loco-regional response and safety. Follow-up visits may coincide with standard of 
care follow-up visits, if deemed appropriate by the Principal Investigator. 
6.2 
Discussion of Trial Design 
This study is intended to establish the first-in-human safety and efficacy observations and the 
optimal dose of the PRV111 (Cisplatin Transmucosal System) prior to the surgical removal of 
SCC tumors of the oral cavity. 
 
 


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7 
SELECTION OF SUBJECTS 
7.1 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible for the trial:  
1. Adult subjects, men and women, defined by age ≥18 years at the time of screening 
2. Pathologically proven and clinically confirmed T1 (≤2 cm) or T2 (≥2 cm but ≤4 cm) SCC 
of the lip or oral cavity (anterior 2/3 of the tongue, floor of mouth, lower and upper 
gingiva, salivary gland, hard palate, and buccal mucosa) 
3. Tumor must be easily accessible, with no evidence of infection or active bleeding, 
encroaching major vessels or clinical evidence of neural invasion. Tumor should not have 
been previously irradiated 
4. Tumor must be amenable to surgical resection no later than 42 days post Visit 1 
5. Clinically and/or radiologically measurable tumor 
6. Eastern Collaborative Oncology Group Performance Status (ECOG PS) of ≤2   
7. Adequate renal function as demonstrated by renal creatinine clearance >50 mL/min 
(calculated using the Cockcroft-Gault formula) 
8. Adequate organ function defined as: ANC ≥1000/µL, platelet ≥100,000/µL; 
Hb ≥9.0 g/dL; AST and ALT ≤2.5 times the upper limit of normal (ULN), serum 
bilirubin ≤1.5 times the ULN or direct bilirubin ≤ULN for subjects with total bilirubin 
>1.5 times the ULN 
9. Candidates for standard of care treatment consisting of surgery 
10. Male and female subjects of childbearing potential must agree to use 2 methods of 
effective contraception from Screening during the entire duration of the study and for at 
least 30 days after the final dose of investigational product. An appropriate birth control 
is defined as barrier methods with spermicides, oral or parenteral contraceptives and/or 
intrauterine devices, or naturally or surgically sterile (with documentation in the subject's 
medical records). Postmenopausal women are defined as presenting at least 12 months’ 
natural spontaneous amenorrhea, or at least 6 weeks following surgical menopause 
(bilateral oophorectomy). Females of childbearing potential must be non-lactating and 
have a negative serum hCG within 14 days of treatment initiation 
11. Absence of any serious underlying medical conditions which could impair the ability of 
the subject to participate in the study 
12. Have a life expectancy of >3 months 
13. Willing and able to provide written informed consent 
14. Able to return to study site for treatment and follow-up visits as defined in the Protocol 
7.2 
Exclusion Criteria 
Subjects meeting any of the following criteria are ineligible for the trial: 
1. Known distant metastasis of the SCC of the oral cavity 
2. Systemic chemotherapy for the treatment of SCC of the head and neck less than 2 years 
prior to Screening 
3. Concurrent documented malignancy, with the exception of localized SCC of the skin 
4. Exposure to any investigational agent within 3 months prior to Screening 


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5. Known allergy or hypersensitivity to platinum-containing agents, or known intolerance to 
a prior platinum-containing agent, or to any of the excipients, which, in the judgement of 
the physician will preclude re-exposure to platinum-containing agent 
6. Active, uncontrolled infection requiring systemic therapy, such as but not limited to HIV, 
Hepatitis B or C 
7. Uncontrolled intercurrent illness that would risk subject safety, interfere with the 
objectives of the Protocol, or limit subject compliance with study requirements, as 
determined by the Investigator 
8. Known or suspected pregnancy, planned pregnancy, or lactation 
9. Any medical or psychiatric condition that may compromise the ability to give written 
informed consent 
7.3 
Criteria for Individual Subject Discontinuation of Protocol Therapy 
Subjects should be discontinued from protocol therapy, while follow-up as per protocol, for the 
following reasons: 
• 
Completion of the scheduled PRV111 therapy 
• 
Meets 1 of the stopping rules for an individual subject (Section 8.2) 
• 
Pregnancy 
• 
Noncompliance with trial or follow-up procedures 
• 
Withdrawal at the Investigator’s request for any reason that the Investigator believes 
continuation of study drug therapy would not be in the subject’s best interest 
• 
Subjects may be withdrawn at any time for drug intolerability, disease progression, 
availability of other therapeutic options, or subject judgment 
7.4 
Criteria for Individual Subject Discontinuation from the Trial 
Subjects may withdraw from further participation in the study at any time and for any reason 
without prejudice. The degree to which a subject withdraws can vary and efforts will be made to 
collect important safety data if feasible and the subject agrees. A subject will be considered to be 
withdrawn from the trial for the following reasons: 
• 
Withdrawn consent from all treatment and follow-up 
• 
Death 
• 
Lost to follow-up 
• 
Termination of the trial by the Sponsor 
7.5 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
If a subject withdraws consent for the treatment, the Investigator will make every effort to 
complete all final evaluations and procedures required by the Protocol. The subject will be asked 
to return to the clinic for a follow-up visit to assess overall safety prior to study completion. In 
the event a subject withdraws for safety reasons (adverse event/serious adverse event [AE/SAE], 
National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events [CTCAE] 


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toxicity related events, etc.), every effort will be made to continue to follow-up with the subject 
until the documented condition resolves to protocol-established grades. 
The reasons for discontinuation of dosing must be clearly documented on the case report form 
(CRF). 
7.6 
Premature Termination or Suspension of Study 
The study may be suspended or prematurely terminated if there is sufficient reasonable cause. 
Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to Privo, Institutional Review Board (IRB), US 
FDA, and appropriate committees. If the study is prematurely terminated or suspended, the 
Principle Investigator (PI) will be required to promptly inform the IRB and provide the reason(s) 
for the termination or suspension.  
Circumstances that may warrant termination include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to subjects 
• 
Determination of futility 
• 
Excessive study treatment toxicity leading to delays in the scheduled surgery 
7.7 
Replacement of Subjects 
Subjects will not be replaced. 
8 
TREATMENTS 
Study treatment is to be administered only to subjects who have provided informed consent and 
have met the criteria outlined in Sections 7.1 and 7.2. 
8.1 
Treatments Administered 
8.1.1 
Description of Test Product 
PRV111 (Cisplatin Transmucosal System) (referred to as PRV111) consists of: 
• 
PRV111 4 cm2 patch containing 2 mg of cisplatin (0.5 mg/cm2) backed with a pressure 
sensitive acrylic adhesive non-woven fabric backing. 
• 
PE Powder for Reconstitution 
 
 
 
 
 
8.1.2 
Packaging 
The PRV111 4 cm2 patch and PE Powder for Reconstitution is packaged in a self-sealing pouch, 
2.25” x 4.0” (constructed of medical grade paper). The primary pouch is enclosed in a secondary 
heat sealed triple laminated Mylar foil pouch (to protect the patch from light and moisture).  


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All components are packaged in a quaternary cardboard carton which is labeled appropriately.  
8.1.3 
Labeling 
The proposed labeling of the PRV111 patch (Cisplatin Transmucosal System) study drug is 
described in the Pharmacy Manual. 
8.1.4 
Preparation 
Refer to the Pharmacy Manual for a complete description of preparation. Each investigational 
site, and all site personnel handing the PRV111 patch, will be trained on application and 
handling. 
8.1.5 
Dosing and Administration 
Each treatment visit will include 1 mL application of the PE. Starting 5 minutes after application 
of the PE, 1 or 2 patches (depending on tumor size) will be applied. For Stage 1, a total of 
3 treatment applications of patches will occur. These successive applications will span 
approximately 35 minutes. The 3 applications provide a total of 6 mg of cisplatin per visit 
(12 mg if 2 patches are applied at the same time).  
In Stage 2 (Stage 2a and Stage 2b), subjects will receive 2, 3, or 5 treatment applications at each 
of the 4 planned treatment visits, depending on the results of Stage 1. 
Refer to the Pharmacy Manual for detailed instructions on applying the PRV111 patches. 
Table 2 presents definition used for dosing and treatment in this study. Treatment is expected to 
be approximately 35 minutes for each treatment visit. 
Table 2. Dosing Terminology 
Term 
Definition 
Treatment visit 
Two to 6 days apart, during which PRV111 patches will be administered. 
Treatment application 
Three patch applications will occur during each treatment visit in Stage 1.  
Two, 3, or 5 patch applications will occur during each treatment visit in Stage 2. 
 
8.2 
Dose-limiting Toxicity (Stopping Rules for an Individual Subject) 
Toxicity will be graded and recorded according to the NCI CTCAE version 4.03 (US 
Department of Health and Human Services, 2010), which are considered at least possibly 
related to PRV111 Patch. A DLT is defined as a clinically significant Treatment-Emergent AE 
(TEAE) or laboratory abnormality unrelated to disease progression, concurrent illness, or 
concomitant therapy and that meets any of the following criteria: 
• 
Grade 3 or 4 non-hematologic toxicity excluding alopecia  


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• 
Grade 3 or 4 nausea, vomiting, or diarrhea, lasting >48 hours, despite standard 
prophylaxis and/or treatment (refer to Section 8.7 for a list of suggested anti-emetic 
medications) 
• 
Grade 4 neutropenia lasting >5 days. 
• 
Febrile neutropenia, defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for more 
than 1 hour. 
• 
Grade 4 thrombocytopenia or thrombocytopenia with clinically significant bleeding (ie, 
bleeding that requires blood or platelet transfusion or other medical intervention, or that 
may cause disability or death, such as cerebral hemorrhage). 
• 
Any toxicity that precludes administration of at least 3 of the 4 planned applications.  
• 
Grade 4 local toxicity- oral mucositis according to World Health Organization scale: 
o Grade 0 - No oral mucositis 
o Grade 1 - Erythema and soreness 
o Grade 2 - Ulcer, able to eat solids 
o Grade 3 - Ulcers, requires liquid diet (due to mucositis) 
o Grade 4 - Ulcers, alimentation not possible (due to mucositis) 
• 
Any related AE leading to surgery delay for more than 96 hours is a DLT 
8.3 
Dose Modification 
If in the clinical judgment of the Medical Monitor and the PIs, clinically relevant safety issues 
are identified, the dose regimen (number of patches/visit and/or number of visits) may be 
reduced at any time during the conduct of the study. 
8.4 
Dose Interruption 
At the Investigator’s discretion, study drug may be interrupted, for reasons not related to toxicity 
(eg, intercurrent illness, subject scheduling conflict). Such interruption may not last more than 
144 hours and may not occur more than 1 time during the subject’s treatment schedule. 
Subjects who experience an AE(s) requiring interruption of study drug for ≥144 hours will be 
removed from treatment. 
Subjects who experience a DLT will be terminated from dosing, but will remain in the study for 
the purpose of data collection. The DLT period will be defined as the start of treatment to 
14 days after the last treatment application or the time of surgery, whichever is first. 
8.5 
Study Drug Handling and Accountability 
The Investigator (or designee, ie, study pharmacist) at the site will be responsible for handling all 
study drug supplies and maintaining required documentation. The Investigator must maintain 
complete and current inventory and dispensing records.  


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The Investigator (or designee) will:   
• 
Ensure study drug supplies (PRV111 study kits) are stored between 2º and 8º C (in an 
appropriately controlled limited-access room in a secure location.  
• 
Dispense the appropriate number of study patches. 
• 
Record pertinent information regarding the number of study kits used (eg, subject 
identification code, date of use, number of patches used, etc.) on the Drug Dispensing 
Log, or other appropriate inventory form. This inventory will be maintained throughout 
the trial and will be periodically reviewed by a Sponsor representative.  
• 
All used and unused patches during a treatment visit must be sent to the pharmacokinetics 
(PK) lab. They should be separated into properly labeled sealing plastic bags. The used 
patches will be processed by the PK lab to assess the residual levels of cisplatin of each 
application. Preparation for shipping and shipping logistics will be found in the 
Laboratory Manual. 
8.6 
Study Drug Disposal 
Periodically throughout and at the conclusion of the trial, an inventory of unused study drug kits 
will be conducted by a Sponsor representative. All unused study drug materials during a 
treatment visits must be sent to the PK lab in labelled, sealing plastic bags and they will be 
disposed in an appropriate manner according to the laboratory policy.  
At the treatment completion, any remaining unopened and unused study drug in the kit will be 
sent back to the Sponsor. Preparation for shipping and shipping logistics will be found in the 
Pharmacy Manual. At the termination of the trial, a final drug accountability review and 
reconciliation must be completed and any discrepancies must be investigated and their resolution 
documented. 
8.7 
Concomitant Medications and Therapy 
Concomitant medications and therapies include other prescription medications, over-the-counter 
drugs, or dietary supplements that a study participant takes in addition to the investigational 
product. Based on FDA’s recommendation, anti-emetic prophylaxis will be mandatory. 
Symptomatic anti-emetics will be used during the study.  
All subjects will receive emesis prophylaxis, administered approximately 30 minutes before 
PRV111 treatment. The drug used may be either ondansetron or promethazine, the dose to be 
determined at the discretion of the PI. After treatment, subjects may self-administer orally or via 
feeding tube approximately every 12 hours for 24 to 48 hours for persistent nausea. 
Alternatively, subjects may receive promethazine 12.5 mg orally approximately 60 minutes 
before administration of the PRV111 treatment. After treatment, subjects may self-administer 
promethazine 12.5 mg approximately every 4 to 6 hours for 24 to 48 hours for persistent nausea.  
Subjects with diarrhea will receive appropriate interventions/medications at the discretion of the 
treating physician consistent with current clinical practice. 


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Based upon the Investigator’s judgment, the subject might need topical anesthetic (ie, lidocaine, 
Magic Mouthwash) to ameliorate discomfort or prevent accidental touching and removal of the 
patch. 
8.8 
Drugs Contraindicated with PRV111 
Refer to the package insert for Platinol-AQ Injection for a list of drugs that interact with 
cisplatin. 
Plasma levels of anticonvulsant agents may become subtherapeutic during cisplatin therapy. 
9 
VARIABLES ASSESSED 
Refer to Table 1for scheduling of study assessments.  
9.1 
Eligibility Only Assessments 
Refer to Table 1for for timing of assessments. 
9.1.1 
Confirmation of Squamous Cell Carcinoma 
Subjects eligible for enrollment must have histological confirmation of SCC. 
HPV, the possible etiology of SCC, will be ascertained using immunohistochemistry for p16 
overexpression per institutional standards. Results are not an eligibility requirement, but should 
be available at some point during the subject’s participation in the study. 
9.1.2 
Tumor Staging 
The size or direct extent of the primary tumor intended for surgical resection will be assessed for 
eligibility (National Cancer Institute, 2015): 
• 
Tx: tumour cannot be assessed 
• 
Tis: carcinoma in situ 
• 
T0: no evidence of tumour 
• 
T1, T2, T3, T4: size and/or extension of the primary tumour 
9.1.3 
Demographics, Medical and Medication History 
Demographic information, including age, sex, race, history of tobacco and alcohol use, and 
medical history will be obtained by interviewing the subject. 
Baseline characteristics consist of a complete medical history and detailed disease history. 
Medical history includes prior and ongoing medical diagnoses and conditions, surgical 
procedures not related to the primary diagnosis, and medications taken within the previous 
28 days. Disease history is a history of the primary diagnosis and should include the date of 
initial oral SCC diagnosis and staging; for recurrent cases- date of most recent relapse and/or re-
staging; histologic diagnosis; prior treatments (eg, chemotherapy, radiotherapy); and any current 
signs and symptoms related to the primary diagnosis. 


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9.1.4 
Pregnancy Test 
A serum pregnancy test to establish eligibility for female subjects of childbearing potential will 
be performed. In addition, a negative urine pregnancy test must be documented within 7 days 
prior to the first treatment visit, and at Visit 5. 
9.1.5 
Eastern Collaborative Oncology Group 
Performance status will be assessed using ECOG PS criteria (Table 3). 
Table 3. Eastern Collaborative Oncology Group Performance Status 
Grade 
ECOG PS 
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, eg, 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 
Abbreviations: ECOG PS=Eastern Collaborative Oncology Group Performance Status. 
 
9.2 
Efficacy Assessments 
Refer to Table 1for timing of assessments. 
9.2.1 
Tumor Photography and Measurements 
The primary lesion will be photographed before PRV111 treatment. This will be done to allow 
for a clinical assessment of response to treatment. For details refer to Study Manual for 
instructions.  
The tumor will be measured in cm to 1 digit to the right of the decimal point using a disposable 
plastic ruler or caliper. Three dimensions must be recorded (Length x Width x Height).  
Note: If tumor or cancerous lesion is flat, a small number (0.05 cm) will be recorded for the 
Height. If the tumor is a concave, a negative Height is recorded. If the height is an unmeasurable 
dent, it can be recorded as (-0.05 cm). 
The following formula will be used to calculate tumor volume (cm3) 
𝐿 𝑥 𝑊 𝑥 𝐻 𝑥 𝜋/6 
9.2.2 
Response and Non-Response (Tumor Volume Change from Baseline Criteria) 
The terms “response” and “non-response” will be defined according to the tumor volume change 
from baseline (CFB) criteria: 


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PCFB  = % tumor volume change from the baseline  
Response will be defined as CR, PR or SR. Non-Response will be defined as SD or PD (Table 
4). 
Table 4. Clinical Response to Treatment Based on Tumor Volume Change* 
Complete 
Response 
(CR)  
Disappearance of primary lesion. 
Partial Response (PR) 
PCFB: ≥30% to 69% decrease in the total tumor volume shrinkage (as determined by 
clinical measurement, taking as reference the baseline volume.  
Strong Response (SR) 
PCFB: ≥70% to 99% decrease in the total tumor volume shrinkage (as determined by 
clinical measurement, taking as reference the baseline volume. 
Progressive 
Disease 
(PD) 
PCFB: At least a 20% increase tumor volume as determined by clinical measurement 
taking as reference the baseline volume (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the volume determined by clinical measurement at baseline 
* Necrosis/inflammation will not be included towards clinical tumor measurements. 
9.2.3 
 
 
 
 
9.2.4 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


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9.2.5 
Loco-regional Control 
Subjects will be followed for up to 6 months, and the incidence of local and regional (nodes) 
tumor recurrence will be recorded. 
9.3 
Safety Assessments 
Refer to Table 1for timing of assessments. 
9.3.1 
Physical Examination, Vital Signs, Weight 
A complete physical examination will be performed by the Investigator or Sub-investigator. The 
physical examination will include a review of all body systems (head, eyes, nose and throat, 
cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, lymph nodes, 
dermatological, extremities/joints), and weight. 
Seated blood pressure (mmHg), pulse (beats per minute) and temperature (degrees Celsius) will 
be measured after the subject has been sitting for at least 3 minutes. 
Neuropathy and ototoxicity will be assessed via clinical examination since cisplatin can potentially 
cause neurotoxicity and ototoxicity. Questions will be asked to document symptoms such as tinnitus, 
pain in the extremities, or loss of sensation in the eCRFs.   
9.3.2 
Oral Cavity Examination 
A systematic and thorough visual and manual oral examination will be performed. This will 
include a visual examination of all the soft tissues of the mouth, including manual extension of 
the tongue to examine its base, a bi-manual palpation of the floor of the mouth, and a digital 
examination of the borders of the tongue. 
Special attention must be given to the application site and the tumor, with documentation of any 
local adverse reactions, including documentation with photographs if warranted. 
9.3.3 
Neck Lymph Nodes Examination 
A cervical and local lymph nodes examination will be performed.  
9.3.4 
Safety Laboratory Assessments 
Clinical laboratories to be assessed will be as in Table 6. 
Table 6. Clinical Laboratories 
COMPLETE BLOOD COUNT 
CHEMISTRY PANEL 
• hematocrit 
• hemoglobin 
• platelet count 
• red blood cell count 
• white blood cell count and differential (absolute and 
percentage); neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and reticulocyte count 
• alanine aminotransferase  
• albumin 
• alkaline phosphatase 
• aspartate aminotransferase 
• bilirubin (direct and total) 
• blood urea nitrogen 
• calcium 
• chloride 
• creatininea 
• gamma glutamyl 
transferase 
• glucose 
• magnesium 
• potassium 


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URINALYSIS 
• CO2 
• sodium 
• total protein 
• urinalysis dipstick with reflex microscopic 
examination for abnormalities 
a Creatinine Clearance will be used to assess renal function using Cockcroft-Gault Equation  
9.3.5 
Electrocardiograms 
Electrocardiograms (ECGs) will be evaluated for clinically relevant changes from Baseline. 
9.3.6 
Adverse Event Definitions/Reporting Requirements 
An AE (also known as an “adverse experience”) is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related (US Code of 
Federal Regulations [CFR] 312.32).  
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the drug, without any 
judgment about causality.  
All clinical AEs noted during the study will be reported on the appropriate AE page of the CRF. 
AEs that are serious, unexpected, and at least possibly related to study participation will be 
reported to the IRB and to the US FDA within the timelines described below. All other AEs, 
such as those that are expected, or definitely not related to the study participation, are to be 
reported per the IRB’s policy and to FDA as part of regular data submission at the time of annual 
Investigational New Drug report.  
9.3.6.1 
Expected Events 
Expected events are those that have been previously identified as resulting from administration 
of the study drug. An AE is considered unexpected, for expedited reporting purposes only, when 
either the type of event or the severity of the event is not listed in the current Investigator’s 
Brochure (IB). 
9.3.6.2 
Suspected Adverse Reaction 
A suspected adverse reaction is a subset of all AEs for which there is a reasonable possibility (ie, 
evidence to suggest a causal relationship between the drug and the AE) that the drug caused the 
event. Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction.  
9.3.6.3 
Adverse Reaction 
An adverse reaction is a subset of all suspected adverse reactions, and is defined as any AE 
caused by a drug.  
9.3.6.4 
Adverse Device Effects 


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Adverse device effects are those AEs thought to be related to the use of an investigational 
medical device. This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. This definition also includes any event resulting from use 
error or from intentional misuse of the investigational medical device.  
An Unanticipated Adverse Device Effect is an adverse device effect, which by its nature, 
incidence, severity or outcome has not been identified in available information on the device.  
Additional device issues, malfunctions or misuse will be documented in the electronic CRF.  
9.3.6.5 
Serious Adverse Event Definitions / Reporting Requirements 
9.3.6.5.1 Serious Adverse Event or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
• 
Death. This includes any death that occurs while the subject is on study and/or within 
30 days after the last dose of study drug. An autopsy will be requested, and if performed, 
results will be submitted to the Sponsor.  
• 
A life-threatening AE. An AE or suspected adverse reaction is considered life-threatening 
if, in the view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death. It does not include a reaction that had it occurred in a more 
severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization. In the absence of an 
AE, hospitalization or prolongation of hospitalization should not be reported as a serious 
AE (SAE) in the following situations: 
o Hospitalization or prolongation of hospitalization is needed for a procedure required 
by the Protocol. 
o Hospitalization or prolongation of hospitalization is part of routine procedure 
followed by study center. 
o Hospitalization for survey visits or annual physicals. 
o For a hospitalization planned (and documented) before the start of the study for a pre-
existing condition which has not worsened.  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 


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9.3.6.5.2 Pregnancy 
For safety reporting purposes, any pregnancy occurring during the study will be considered an 
“important medical event” (Section 9.3.6.5.1). If a study subject becomes pregnant while 
participating in the study, the study drug will be discontinued immediately and the pregnancy 
will be reported to the Sponsor. The Investigator will then report follow-up information to the 
Sponsor regarding the course of the pregnancy, including perinatal and neonatal outcome, 
regardless of the fact that the subject has discontinued the study. Once the newborn is determined 
to be healthy, as defined by and agreed upon by the Sponsor and Investigator, additional follow-
up will no longer be required. 
9.3.6.5.3 Serious Unexpected and Suspected Adverse Reaction 
An unexpected AE (or serious and unexpected suspected adverse reaction [SUSAR]) is any AE 
or suspected adverse reaction that is not listed in the IB or is not listed at the specificity or 
severity that has been observed, if an IB is not required/available, is not consistent with the risk 
information described in the general investigational plan. This also refers to AEs or suspected 
adverse reactions mentioned in the IB as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug but are not specifically mentioned as occurring with 
the study drug. A SUSAR requires mandatory expedited reporting to the applicable regulatory 
authority(ies) (Section 9.3.6.8). The Sponsor will forward the formal notification describing the 
SUSAR to Investigators. Each Investigator must then notify his/her IRB of the SUSAR, in 
accordance with the IRB’s policy. 
The Sponsor should be notified within 24 hours of the Investigator becoming aware of a SUSAR 
and the event documented on the CRF. 
9.3.6.6 
Recording Adverse Events 
All AEs (including SAEs) within the 5 pre-surgery visits are to be accurately recorded on the 
AE/SAE page(s) of the CRF. In addition, any SAEs within 30 days of visit 5 will need to be 
recorded. The Investigator will carefully evaluate each AE to determine: 
• 
Duration (start and end dates) 
• 
Severity (grade) 
• 
Seriousness 
• 
Relationship to study drug (Not Related, Possible, Definite) 
• 
Action taken (none, study drug modification, medical intervention) 
• 
Outcome (resolved without sequelae, resolved with sequelae, ongoing) 
 
The Investigator will evaluate the recorded AEs and SAEs with regard to maximum intensity and 
relationship to study drug. Maximum intensity should be assigned using one of the severity 
grades as outlined in the NCI CTCAE v4.0. If the AE is not specifically listed in CTCAE v4.0, 
the following grades will be used: 
• 
Grade 1: mild 
• 
Grade 2: moderate 


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• 
Grade 3: severe 
• 
Grade 4: life-threatening or disabling 
• 
Grade 5: death 
9.3.6.7 
Determining Relationship of Adverse Events to Study Drug  
The Investigator must attempt to determine if an AE or SAE is related to the use of the study 
drug. This relationship should be described as follows: 
Possible 
The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug 
BUT the event could have been produced by an intercurrent medical condition 
which, based on the pathophysiology of the condition and the pharmacology of 
the study drug, would be unlikely to be related to the use of the study drug OR 
the event could be the effect of a concomitant therapy. 
Definite 
The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug and 
based on the known pharmacology of the study drug, the event is clearly related 
to the effect of the study drug. 
Not Related Based on the evidence available, causality is not possible. 
9.3.6.8 
Reporting Deaths and Other Serious Adverse Events 
9.3.6.8.1 Events to Be Reported and Timeframe  
Any death or other SAE experienced by the subject during treatment or within 30 days of 
receiving study drug, regardless of expectedness, relationship to study drug, or any death that 
occurs more than 30 days after receiving study drug and is believed to be study drug-related, 
must be promptly reported to the Sponsor (within 24 hours (of a working day) of the Investigator 
becoming aware of the event) by telephone or email transmission. 
9.3.6.8.2 Governing Regulatory Requirements 
Compliance with this request for prompt reporting is essential in that the Sponsor is responsible 
for informing the FDA and other regulatory authorities as well as all other participating 
Investigators of the event.  
Under FDA ruling (US CFR, Title 21 CFR Part 312.32) and the International Council on 
Harmonisation (ICH) Guidelines for Clinical Safety Data Management Definitions and 
Standards for Expedited Reporting, the Sponsor is required to submit written documentation, in 
the form of an IND Safety Report, on the following: 
• 
SUSARs 
• 
Unexpected fatal or life-threatening suspected adverse reactions 
• 
Findings from other studies that suggest a significant risk to humans exposed to drug 


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• 
Findings from animal or in vitro testing that suggest a significant risk to humans exposed 
to drug 
• 
Increased rate of occurrence of serious suspected adverse reactions from what is reported 
in the IB or the Protocol 
Written submission must be made by the Sponsor to the FDA/other regulatory authorities (and 
by the Investigator to the IRB) as soon as possible, and in no event later than 15 calendar days 
after the Sponsor determines that the information qualifies for reporting. The Sponsor shall also 
inform all Investigators. 
In addition, the Sponsor is further required to report, by either telephone or facsimile 
transmission or in writing to the FDA/other regulatory authorities the occurrence of any 
unexpected fatal or life-threatening event associated with the use of the drug (SUSARs) no later 
than 7 calendar days after notification of the event, followed by a written report no later than 
15 calendar days after the initial report receipt date. The Sponsor shall also inform all 
Investigators. 
The Sponsor will provide expedited reports of the following SUSARs to the Investigators for 
reporting to their IRB: 
• 
SUSARs that have arisen in the clinical trial that was assessed by the IRB. 
• 
SUSARs that have arisen in other clinical trials of the same Sponsor and with the same 
medicinal product, and that could have consequences for the safety of the subjects 
involved in the clinical trial that was assessed by the IRB. 
Investigators are required to promptly report to the IRB all unanticipated problems involving risk 
to human subjects, including AEs that should be considered unanticipated problems (21 CFR 
312.53(c)(1)(vii), 312.66, and 21 CFR 56.108(b)(1)). 
9.3.6.9 
Initial Information Provided by the Investigator 
The Investigator must transmit sufficient initial information to the Sponsor (or designee) should 
an SAE report meet the criteria for completion of an IND Safety Report. As much of the 
following information about the subject and the event will be requested: 
• 
Subject identification code, gender, and age or date of birth 
• 
Underlying diagnosis and extent of disease 
• 
Lot number and expiration date of study drug (if available) 
• 
Dose, route, frequency, and duration of study drug administered 
• 
Date of last study drug administration 
• 
Description of event, including date of onset and duration 
• 
Date of death (if applicable) 
• 
Intervention(s) required 
• 
Concomitant therapy (including regimens and indications) 
• 
Pertinent laboratory data/diagnostic study (including dates) 
• 
Pertinent medical history 
• 
Study drug status (dose interrupted, discontinued) 


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• 
Did event abate after interruption of study drug administration (if applicable)? 
• 
Did event recur after study drug was reintroduced (if applicable)? 
• 
Severity of the AE 
• 
Relationship of the AE to study treatment 
• 
Outcome of the AE 
9.3.6.10 Follow-up Information  
Follow-up data concerning the SAE (eg, diagnostic test reports, physician's summaries, etc.) 
must also be submitted to the Sponsor as they become available by email as soon as they become 
available, and until the event resolves or stabilizes. 
9.3.6.11 Serious Adverse Event that are Unexpected and related Serious Adverse 
Reaction Review that have a Potential Impact on Trial Conduct 
The Investigator will review each SAE report and evaluate further the relationship of the SAE to 
study drug and to the subject’s underlying disease. 
Based on the Investigator’s and Sponsor’s assessment of causality of the AE and discussions 
with the Medical Monitor, a decision will be made by the Sponsor concerning the need for 
further action with respect to the future conduct of the study. The primary consideration 
governing further action is whether new findings affect the safety of other subjects participating 
in the clinical study. If the discovery of a new SAE related to study drug raises concern over the 
safety of its continued administration to subjects, the Sponsor will take immediate steps to notify 
FDA, other regulatory authorities, and all Investigators participating in clinical studies with the 
study drug. 
Further action required may include any of the following: 
• 
Alteration of the existing research program by modification of the Protocol 
• 
Discontinuation or suspension of the study 
• 
Alteration of the informed consent process by modification of the existing consent form 
and informing current study participants of new findings 
• 
Modification of previously identified expected suspected adverse reaction lists to include 
SAEs newly identified as study drug-related 
9.4 
Pharmacokinetics Assessment 
 
 
 
 
 


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9.5 
Technical Success Assessments 
Technical assessment data will include: 
• 
Taste of the PE solution 
• 
Taste of the PRV111 patch 
• 
Adhesion, including the time of adhesion of PRV111 patch 
• 
PRV111 patch peel-off 
• 
Residual cisplatin level in the patch after the application period. All PRV111 patches will 
be assessed for the amount of residual cisplatin in each patch after each application 
period. If the product detaches prematurely, the residual cisplatin will be assessed and the 
time of detachment will be noted. 
9.6 
Timing of Assessments 
Refer to Table 1for a schedule of events. 
9.6.1 
Screening (Visit 0)  
• 
Visit and all historical exams/tests must occur within 28 days prior to initial treatment 
(Visit 1). Confirmed SCC 
• 
Obtain and document consent from potential subject on Informed Consent Form (ICF) 
• 
Review inclusion/exclusion criteria to determine eligibility 
• 
Review demographics, medical and medications history to determine eligibility based on 
inclusion/exclusion criteria 
• 
Obtain or perform a general physical examination (must be within 14 days of first dose) 
and check VS  
• 
 
• 
Perform a systematic and thorough visual and manual examination of the oral cavity 
mouth and cervical and local lymph nodes examination 
• 
Obtain historical or perform an ECG 
• 
 
 
• 
Perform clinical labs: blood draw for complete blood count (CBC), chemistry panel 
(creatinine for determining creatinine clearance, blood urea nitrogen (BUN), liver 
function test (LFT), electrolytes [potassium, magnesium, calcium, and sodium], hCG 
[serum]) for females of childbearing potential and perform urinalysis. 
• 
AE documentation begins after subject signs the ICF 
• 
Schedule study visits 
• 
Obtain historical or test tissue for HPV 
9.6.2 
Baseline, Treatment (Visit 1) 
Occurs within 28 days following Screening visit (Visit 0).Predose Assessments (Baseline): 
• 
Verify inclusion/exclusion criteria 
• 
Perform and record result of physical examination and VS 


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• 
Perform and record visual oral cavity examination and neck lymph node examination 
• 
Perform and document baseline clinical tumor measurement  
• 
Collect clinical labs: blood draw for CBC, chemistry panel (creatinine for determining 
creatinine clearance, BUN, LFT, electrolytes [potassium, magnesium, calcium, and 
sodium], hCG [urine] for females of childbearing potential), and perform urinalysis.  
• 
Administer oral anti-emetics (ondansetron or promethazine, the dose to be determined at 
the discretion of the PI) before the start of PRV111 treatment 
• 
Photograph the tumor  
• 
Draw blood for PK (-15 to 0 minutes predose)  
• 
Administer PE (refer to Pharmacy Manual for administration instructions)  
▪ document time of application 
▪ ask for taste of PE solution 
• 
Administer PRV111 patch(es) and document time of each application and removal. Ask 
for taste of patch. 
Postdose Assessments: 
• 
Draw blood for PK 30±5 minutes, 60±5 minutes and 120 ±5 minutes following 
application of the last patch at that treatment visit.  
• 
VS shall be monitored at 30±5 minutes, 60±5 minutes and 120 ±5 minutes following 
application of the last patch applied. 
• 
Collect all used patches (include the ones that detached prematurely), record the time of 
the detachment of each patch, store the patches in the plastic bags supplied by the 
Sponsor (refer to Laboratory Manual for instructions). 
• 
Record AEs as reported by subject or observed by Investigator 
• 
Review any concomitant therapy 
• 
Schedule study visits 
9.6.3 
Treatment (Visit 2)  
Occurs at least 48 hours, up to 144 hours, after previous visit. 
Predose Assessments: 
• 
Perform and document physical examination and VS 
• 
Perform and document visual oral examination and neck lymph node examination 
• 
Perform and document clinical tumor measurement and Tumor volume CFB criteria  
• 
Administer oral anti-emetics (ondansetron or promethazine, the dose to be determined at 
the discretion of the PI) before the start of PRV111 treatment 
• 
Photograph the tumor  
• 
Draw blood for PK (-15 to 0 minutes predose)  
• 
Administer PE (refer to Pharmacy Manual for administration instructions) 
▪  document time of application 
• 
Administer PRV111 patch(es) and document time of each application and removal 
▪ Document adherence of each patch 


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Postdose Assessments: 
• 
Draw blood for PK 30±5 minutes following application of the last patch applied at that 
treatment visit. VS shall be monitored at 30±5 minutes following application of the last 
patch at that treatment visit.  
• 
Collect all used patches (include the ones that detached prematurely), record the time of 
the detachment of each patch, store the patches in the plastic bags supplied by the 
Sponsor (refer to Laboratory Manual for instructions) 
• 
Record AEs as reported by subject or observed by Investigator 
• 
Review any concomitant therapy 
• 
Schedule study visits  
9.6.4 
Treatment (Visit 3)  
Occurs at least 48 hours , up to 144 hours, after previous visit. 
Predose Assessments: 
• 
Perform and document physical examination and VS 
• 
Perform and document visual oral examination and neck lymph node examination 
• 
Perform and document clinical tumor measurement and Tumor volume change from 
baseline 
• 
Collect clinical labs: blood draw for CBC, chemistry panel (creatinine for determining 
creatinine clearance, BUN, LFT, electrolytes [potassium, magnesium, calcium, and 
sodium], and perform urinalysis.  
• 
Administer oral anti-emetics (ondansetron or promethazine, the dose to be determined at 
the discretion of the PI) before the start of PRV111 treatment 
• 
Photograph the tumor  
• 
Draw blood for PK (-15 to 0 minutes predose)  
• 
Administer PE (refer to Pharmacy Manual for administration instructions) 
▪ Document time of application 
• 
Administer PRV111 patch(es) and document time of each application and removal 
▪ Document adherence of each patch 
Postdose Assessments: 
• 
Draw  blood for PK 30±5 minutes 
• 
VS shall be monitored for 30±5 minutes following application of the last patch applied at 
that treatment visit 
• 
Collect all used patches (include the ones that detached prematurely), record the time of 
the detachment of each patch, store the patches in the plastic bags supplied by the 
Sponsor (refer to Laboratory Manual for instructions). 
• 
Record AEs as reported by subject or observed by Investigator 
• 
Review any concomitant therapy 
• 
Schedule study visits for subjects 


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9.6.5 
Treatment (Visit 4) 
Occurs at least 48 hours, up to 144 hours, after previous visit. 
Predose Assessments: 
• 
Perform and document physical examination and VS 
• 
hCG [urine] for females of childbearing potential 
• 
Perform and document clinical tumor measurement and tumor volume change from 
baseline criteria  
• 
Perform and document visual oral examination and neck lymph node examination  
• 
Administer oral anti-emetics (ondansetron or promethazine, the dose to be determined at 
the discretion of the PI) before the start of PRV111 treatment 
• 
Photograph the tumor  
• 
Draw blood for PK (-15 to 0 minutes predose)  
• 
Administer PE (refer to Pharmacy Manual for administration instructions) 
▪  document time of application 
• 
Administer PRV111 patch(es) and document time of each application and removal 
▪ Document adherence of each patch 
Postdose Assessments: 
• 
Draw blood for PK 30±5 minutes, 60±5 minutes and 120±5 minutes 
• 
VS shall be monitored at 30±5 minutes, 60±5 minutes and 120±5 minutes following 
application of the last patch applied. 
• 
Collect all used patches (include the ones that detached prematurely), record the time of 
the detachment of each patch, store the patches in the plastic bags supplied by the 
Sponsor (refer to Laboratory Manual for instructions). 
• 
Record AEs as reported by subject or observed by Investigator 
• 
Review any concomitant therapy 
• 
Schedule study visits  
9.6.6 
Post-Treatment/Pre-Op Visit (Visit 5) 
• 
Occurs a minimum of 72 hours after the last visit and prior to surgery. Perform and 
document physical examination and VS 
• 
Perform and document visual oral examination and neck lymph node examination 
• 
 
  
• 
Perform and document clinical tumor measurement and Tumor volume CFB criteria  
• 
ECG 
• 
Collect clinical labs: blood draw for CBC, chemistry panel (creatinine, BUN, LFT, 
electrolytes [potassium, magnesium, calcium, and sodium], and perform urinalysis  
• 
Photograph the tumor  
• 
Record AEs as reported by subject or observed by Investigator 
• 
Review any concomitant therapy 


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9.6.7 
Surgery Day (Visit 6) 
• 
Tumor resection as per the standard of care 
• 
 
 
 
 
 
• 
Post-Surgery, collect clinical labs. Draw blood for CBC, chemistry panel (creatinine, 
BUN, LFT, electrolytes [potassium, magnesium, calcium, and sodium], and perform 
urinalysis. Post-surgical labs may be used, if deemed appropriate by the Principal 
Investigator 
 
9.6.8 
Post-Treatment Follow-Up (Visits 7, 8, & 9) 
All subjects will be followed for up to 6 months post-surgery at 3 visits: 1, 3, and 6 months post-
surgery for loco-regional response and safety. Follow-up visits may coincide with standard of 
care follow-up visits, if deemed appropriate by the Principal Investigator. 
• 
Perform and record results of physical examination and VS 
• 
Perform visual oral examination and neck lymph node examination to assess for signs of 
loco-regional recurrence 
• 
Review any concomitant therapy 
10 
STATISTICAL METHODS AND PLANNED ANALYSES 
10.1 
General Considerations 
Clinical response to treatment will be evaluated according to Table 4. 
10.2 
Sample Size Determination 
Safety outcomes resulting in DLT will be used during the conduct of this study to select doses 
being tested according to pre-defined thresholds of toxicity. 
• 
Local and systemic safety and tolerability will be summarized using descriptive statistics.   
• 
The number of subjects with DLTs will be capped to be fewer than 2 subjects with DLTs 
out of 5 new subjects enrolled.  
• 
The treatment regimen will be deemed tolerable if fewer than a third of the subjects 
exposed to it present DLTs. 
• 
Efficacy based on Tumor volume CFB criteria will be summarized, and the null 
hypothesis that the probability of response is at most 30%, where a response is the 
occurrence of CR or PR will be tested using a one-sided test exact binomial test at level 
0.018. 
• 
 
 
• 
Variables measuring technical success (including residual cisplatin level in the patch) 
will be summarized using descriptive statistics. 


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At the end of Stage 2, the following is a statistical analysis of the sample size as it pertains to 
efficacy:  
Power and Sample Size 
  
Based on Simon's 2-stage procedure, the null hypothesis that the true response rate is 0.30 will 
be tested against a 1-sided alternative. In the first stage, 5 evaluable subjects will be accrued. If 
there are 2 or fewer responses in these 5 subjects, the dose will be escalated. Otherwise, the dose 
will remain the same or de-escalated based on safety data. Additional subjects will be accrued for 
a total of 11 evaluable subjects at the final dose. The null hypothesis will be rejected if 7 or more 
responses are observed at the final dose. This design yields a type I error rate of 0.018 and power 
of 96.44% when the true response rate is 0.85. 
Null response rate: P0 
Alt. response rate: P1 
Alpha one-tailed 
Power 
n1 
r1 
N 
R 
 0.30 
0.85 
0.018 
96.44% 
5 
2 
11 
6 
N is the total number of evaluable subjects at the final dose 
n1 is the number of evaluable subjects accrued during Stage 1 
r1, if r1 or fewer responses are observed during stage 1, escalate the dose if safety requirements are met  
R, if R or fewer responses are observed by the end of Stage 2 in N subjects, then an effective dose is not found 
10.3 
Note: If the dose is not increased after Stage 1, the test will be performed using 
all evaluable subjects from Stage 1 and 2. If the dose is adjusted after Stage 1, the 
test will be performed using all evaluable subjects from Stage 
2.Pharmacokinetics 
 
 
10.4 
Study Populations 
10.4.1 
Safety Population 
All subjects who have at least 1 PRV111 patch applied will be included in the Safety Population. 
10.4.2 
Evaluable Population 
All subjects who have met the inclusion and exclusion criteria, and have completed at least 75% 
of the total dose required for that stage will be included in the Evaluable Population. This 
population will be used for the efficacy analysis. 
10.5 
Statistical Analyses 
 
 
 
 
 
 


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10.5.2 
Subject Accountability, Demographics, and Baseline Characteristics 
Subject completion status, dose modification, and study terminations will be summarized for 
each of the study stages and for the study overall. Subjects with major protocol violations will be 
listed. Demographics will be summarized along with baseline characteristics such as medical 
history, and baseline physical examination, weight, VS, ECOG PS, and concomitant therapy.  
10.5.3 
Primary Endpoints 
The primary endpoints for the study involve determination of a safe and efficacious dose of 
PRV111 (Cisplatin Transmucosal System) (cisplatin drug-loaded patch + PE) under the 
conditions of the trial. 
Therefore, the primary endpoint is based on the incidence of DLTs and tumor volume CFB. 
10.5.4 
Secondary Endpoints 
Based on secondary objectives, the secondary endpoints are: 
• 
Evaluate tumor response  
o 
 
o 
  
• 
Assess short and long-term safety of the treatment 
o Loco-regional control: subjects will be followed-up for disease recurrence and safety 
following surgery 
o Incidence of recurrence at 6 months 
• 
Total platinum assessment in blood, tumor and lymph nodes (if available) 
• 
Technical success: 
o Successful adhesion of the patch to the target lesion 
o Successful delivery (including release and permeation) of the drug to the target 
lesion, without getting to surrounding oral surfaces 
o Successful peel of the used patch after 10 minutes without damaging the target lesion 
underneath  
o Adhesion of the backing to the polymeric matrix embedded CLPs 
o Taste of the PE solution 
o Taste of the PRV111 patch 
o Residual cisplatin level in the patch after the application period 
10.5.5 
Efficacy Data 
Efficacy outcomes include: 
• 
Response to treatment evaluated by Tumor volume change from baseline (CFB) 
• 
 
• 
Incidence of recurrence at 6 months 
• 
 


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10.5.6 
Safety Data 
Safety observations and measurements including study drug exposure, AEs, laboratory data, 
physical examination findings, VS, weight, and concomitant therapy will be summarized and 
presented in tables and listings. 
Laboratory parameters will be summarized using descriptive statistics and data listings. The 
incidence of clinically significant abnormalities will be summarized. Physical examinations, VS, 
and weight will be summarized by changes from baseline values using descriptive statistics. 
AEs occurring after the start of treatment are TEAEs. The severity of the TEAEs will be graded 
according to the CTCAE criteria, version 4.03. The severity of oral mucositis will be graded 
according to the WHO grade (Section 8.2).  
The number and percentages of subjects experiencing TEAEs will be tabulated by system organ 
class and preferred term. Assessments of TEAEs will include characterization of the type, 
incidence, severity, seriousness, and relationship to treatment. Summary subject listings will be 
provided for subjects with dose modification, SAEs, TEAEs resulting in study discontinuation, 
and deaths. The rates of local tolerability and oral mucositis will be reported. 
10.5.7 
Pharmacokinetics Data 
 
10.5.8 
Technical Data 
Technical success is defined as: 
• 
Successful adhesion of the patch to the target lesion. 
• 
Successful delivery (including release and permeation) of the drug to the target lesion, 
without getting to surrounding oral surfaces. 
• 
Successful peel of the used patch after 10 minutes without damaging the target lesion 
underneath. 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality Assurance (QA) and Quality Control systems will be implemented and maintained with 
Standard Operating Procedures by Privo Technologies, as appropriate, to ensure that this clinical 
study is conducted and data are generated, documented and reported in compliance with the 
Protocol, ICH E6 GCP and applicable regulatory requirements. 
Before enrolling any subjects in this study, a Sponsor representative and the Investigator will 
review the Protocol, IB, CRFs and instructions for their completion, as well as the procedures for 
obtaining informed consent and for reporting TEAEs and SAEs. A qualified representative of the 
Sponsor will monitor the conduct of the study by visiting the site and by contacting the site by 
telephone and email. During site visits, the study Monitor will assure accurate and reliable data 
collection by verifying the information recorded on the CRFs against source documents and 
medical records (ie, source document verification).  


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Measures will be undertaken to protect the confidentiality of records that could identify subjects 
respecting the privacy and confidentiality rules in accordance with applicable regulatory 
requirements. 
12 
DOCUMENTATION AND INSPECTIONS  
12.1 
Study Monitoring 
The Sponsor has responsibility to governing regulatory authorities to take all reasonable steps to 
ensure the proper conduct of the study with respect to trial ethics, Protocol adherence, and data 
integrity and validity. 
This trial will be closely monitored by Sponsor representatives throughout its duration. 
Monitoring will be in the form of personal visits with the Investigator and staff as well as any 
appropriate communications by telephone, mail, or email transmission.  
The personal visits and monitoring are conducted to the extent possible however under certain 
circumstances such as COVID-19 pandemic, to minimize or eliminate immediate hazards or to 
protect the life and well-being of research staff and participants, discussions, monitoring and site 
closures will be performed remotely via technologies including but not limited to phone calls, 
email, eCRF, eTMF and file sharing on video conferencing for source documents.  Sponsor and 
sites can utilize video and teleconferencing such as ZOOM to remotely discuss, review and 
approve documents. The PI sign off can be obtained and saved electronically for all eCRFs at the 
site. 
The purpose of these contacts is to review trial progress, Investigator and subject adherence to 
the protocol, and to determine if there are any problems associated with the conduct of the study. 
The following may be assessed during site monitoring visits: 
• 
Required regulatory documentation 
• 
Signed ICFs 
• 
Subject accrual and follow-up 
• 
Study drug inventory records 
• 
Investigator and subject compliance to the study Protocol 
• 
Concomitant therapy uses 
• 
AE documentation 
• 
Protocol deviation documentation 
• 
Data are accurate, complete, and verifiable when compared to source documents 
The Investigator and study staff are expected to cooperate with monitors during such visits and 
provide all relevant study documents. 
12.2 
Audits and Inspections 
All documentation pertaining to this clinical trial may be subject to a QA audit by the Sponsor, 
or the FDA. Upon request, the auditor will have access to inspect, copy, review, and audit all 
source documents, CRFs, medical records, correspondence, and ICFs pertaining to the subjects 
in the trial. The Investigator agrees to promptly take any reasonable steps that are requested by 


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the Sponsor as a result of an audit to cure deficiencies in the study documents and CRFs. Other 
documentation subject to QA audit includes the IRB files, certification and quality control of 
supporting laboratories, and records relevant to the trial in any supporting pharmacy facilities. 
Conditions of storage of study materials are also subject to inspection. Sponsor representatives 
may observe the conduct of any aspect of the clinical trial or its supporting activities both within 
and outside of the Investigator's institution. 
13 
ETHICAL AND LEGAL ISSUES 
13.1 
Ethical Conduct/Good Clinical Practice  
This study will be conducted in accordance with the ethical principles that have their origin in 
the current Declaration of Helsinki and will be consistent with ICH GCP and applicable 
regulatory requirements.  
13.2 
Institutional Review Board 
This study must be reviewed and approved by the IRB representing the institution prior to 
enrolling subjects. The IRB must be appropriately constituted and meet all requirements as 
described in Part 56, Title 21 of the US CFR. The review must include both the Protocol and the 
ICF for the trial. A copy of the Letter or Notice of Approval from the IRB must be received by 
the Sponsor prior to shipment of drug supplies to the Investigator. The IRB membership list must 
be submitted to the Sponsor with the written IRB approval and updated lists, if applicable. 
The Investigator must promptly report all changes in the research activity and all unanticipated 
problems involving risk to the subjects or others to their IRB. The Investigator will provide 
progress reports as required by the IRB. The Investigator is responsible for assuring continuing 
review and approval of the clinical study on an annual basis and submitting documentation of 
renewal to the Sponsor. The Investigator will give notice to the IRB when participation in the 
study has been completed. 
13.3 
Written Informed Consent 
The Investigator agrees to protect the rights, safety, and welfare of the subjects entered into the 
study, including obtaining written informed consent prior to performing any study-related 
procedures and informing each subject that the study drug is being used for investigational 
purposes. A copy of the IRB-approved ICF to be used during the study must be submitted for 
Sponsor review prior to study initiation. 
Prior to entry into the study, the purpose and nature of the study and possible AEs must be 
explained to each patient. All questions about the study should be answered to the patient’s 
satisfaction or the patient’s legal representative. It is the responsibility of the Investigator or 
designee to obtain written informed consent from each patient, thereby attesting that consent was 
freely given. A copy of the signed and dated ICF will be given to the patient. Documentation of 
the informed consent process must be evident in the patient’s clinical files, and the original 
executed ICF must be available for review by the study Monitor. 


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13.3.1 
Update of Informed Consent 
In the event that modifications in the experimental design, dosages, parameters, subject selection, 
etc., of the Protocol are indicated or required, and in the event that such modifications 
substantially alter the study design or increase the potential risk to subjects, revisions to the 
existing ICF will be made. Such a revision will be reviewed and approved by the appropriate 
IRB, and documentation of this approval will be forwarded to the Sponsor for submission to the 
appropriate regulatory body.  
In addition, all current study participants, as well as subsequent study candidates, will be 
informed of the study design modification or increase in potential risk, and written informed 
consent will be obtained as outlined in Section 13.3. 
13.4 
Records and Case Report Forms 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the investigation on each 
individual treated with the study drug. Data reported on the CRF that are derived from source 
documents must be consistent with the source documents or the discrepancies must be explained. 
All requested information must be entered on the CRF in the spaces provided.  
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirements.  
The completed CRF must be promptly reviewed, signed, and dated by a qualified physician who 
is an Investigator or Sub-Investigator. The Investigator must retain a copy of the CRFs including 
records of the changes and corrections.  
13.5 
Protocol Deviations 
The study is to be conducted as described in this Protocol without deviation unless there is a 
safety concern. The Protocol should not be modified for any subject without the prior consent of 
the Sponsor and, if necessary, the IRB responsible at the investigative site. 
In the event of an important deviation, a report will be submitted to the IRB (as applicable) and 
site explaining the circumstances. 
13.6 
Retention of Records 
US federal law requires that the Investigator retain copies of all files pertaining to the trial (ie, 
medical records, laboratory reports, drug inventory/disposition records, signed ICFs, CRFs, all 
correspondence, dates and reports of monitoring visits) for a period of 2 years following the date 
of marketing application approval of the drug for the indication investigated in the study, and 
until there is no pending or contemplated marketing application, or for 2 years following the 
Sponsor’s discontinuing worldwide clinical development of the study drug, as notified by the 
Sponsor, whichever is longer.  
If the Investigator relocates, retires, or withdraws for any reason from the study, trial records 
may be transferred to an acceptable designee, such as another Investigator within the institution. 


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Prior notice of such transfer will be provided in writing to the Sponsor. The Investigator must 
obtain written permission from the Sponsor prior to disposing of any records.  
 
14 
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cancer. Ann Oncol 2010; 21 Suppl 7:vii252-vii261. 
WG Critical Care, LLC. Cisplatin Injection (NDA 018057), product labeling. 2015. 
Paramus, NJ, WG Critical Care, LLC. 

SAP_001.pdf: 
Privo Technologies 
Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
PROTOCOL CLN-001 Amendment 5
Phase 2, Open-Label, Single-Arm Safety, Tolerability, Anti-Tumor Effects, 
Systemic Exposure, and Device Technical Effects of PRV111 (Cisplatin 
Transmucosal System) in Subjects with Oral Squamous Cell Carcinoma 
STATISTICAL ANALYSIS PLAN 
March 2020 
CONFIDENTIAL 
 
 
 
 
 
Privo Technologies, Inc. 
200 Corporate Place, Suite 6B 
Peabody, MA 01960 
Page 1 of 51 




Privo Technologies 
Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
Page 3 of 51 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
Abbreviation 
Definition 
AE(s) 
Adverse Event(s)/Adverse Experience(s) 
ANCOVA 
Analysis of Covariance 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count 
CFB(s) 
Change(s) from Baseline 
CFR 
Code of Federal Regulations 
CLP 
Cisplatin-Loaded 
 Particles 
CR 
Complete response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Collaborative Oncology Group Performance Status 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IV 
Intravenous 
LFT 
Liver function test 
LOCF 
Last Observation Carried Forward 
NRI 
Non-responder Imputation 
ORR 
 
PCFB 
Objective Response Rate (Tumor volume change from baseline 
assessment of CR or PR) 
Percent change from baseline  
PD 
Progressive disease 
PE 
Permeation enhancer 
PI 
Principal Investigator 
PK 
Pharmacokinetics  
PR 
Partial response 
PRV111 
Cisplatin Transmucosal System 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCC 
Squamous cell carcinoma 
SD 
Stable disease/ Standard deviation for statistical summaries 
SOC 
Standard of care /  
MedDRA System Organ Class for AE assessment 
TEAE 
Treatment Emergent Adverse Events 
VAS 
Visual analog scale 


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
Page 4 of 51 
 
 
TABLE OF CONTENTS 
                                    Page 
 
 
1 
Introduction 
6 
1.1 
Background 
6 
2 
Trial Design 
7 
2.1 
Study Objectives 
7 
2.2 
Study Design 
7 
2.3 
Sample Size 
9 
2.4 
Selection and Withdrawal of Subjects 
9 
2.4.1 
Inclusion Criteria 
9 
2.4.2 
Exclusion Criteria 
10 
2.5 
Criteria for Individual Subject Discontinuation of Protocol Therapy 
10 
2.6 
Criteria for Individual Subject Discontinuation from the Trial 
10 
2.7 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 11 
2.8 
Replacement of subjects 
11 
2.9 
Treatments Administered 
11 
a. 
Description of Test Product 
11 
b. 
Dosing and Administration 
11 
2.10 
Dose-limiting Toxicity (Stopping Rules for an Individual Subject) 
12 
2.11 
Schedule of Events 
13 
2.12 
Study Endpoints 
16 
2.12.1 
Primary Endpoints 
16 
2.12.2 
Secondary Endpoints 
16 
3 
Efficacy Assessments 
16 
3.1 
PRIMARY: Tumor Photography and Measurements 
17 
3.1.1 PRIMARY: Response and Non-Response (Tumor Volume Change from Baseline 
Criteria) 
17 
3.1.2 Primary Efficacy Analysis 
18 
 
 
 
19 
 
 
19 
3.2.2 SECONDARY: Loco-regional Control 
21 
3.2.3 SECONDARY: Technical Success 
22 
3.2.4 Secondary Analysis 
23 
4 
Safety Assessments 
23 
4.1.1 Physical Examinations Analysis: 
24 
4.2.1 Oral Cavity Examination Analysis: 
26 
4.3.1 Neck Lymph Nodes Analysis 
26 
4.4.1 Laboratory Tests Analysis: 
27 
4.5.1 ECG Parameters Analysis: 
29 
4.7 Adverse Events Analysis: 
33 


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
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4.7.1 Deaths, Other Serious Adverse Events (SAEs), and Other Significant AEs 
Analysis: 
34 
4.8 
Pharmacokinetics and Biodistribution Assessment 
34 
4.8.1 Pharmacokinetics Analysis: 
34 
5 
Data Analysis and Statistical Considerations 
34 
5.1 
Statistical Analysis 
35 
5.2 
Treatment Analysis Guidelines 
36 
5.2.1 
Efficacy Analyses 
36 
5.2.2 Evaluable Population 
36 
5.2.3 
Baseline Values for Tumor Measurement 
36 
5.2.4 
Change from Baseline (CFB) and Percent Change from Baseline (PCFB) 
37 
5.2.5 
Descriptive Summary Statistics 
37 
5.3 
Safety Analyses 
37 
5.3.1 Safety Population 
37 
5.3.2 Concomitant Medication and Therapy 
37 
5.3.3 Medical History, Medication History and Baseline Disease Characteristics 
37 
5.3.4 Subject Accountability, Demographics, and Baseline Characteristics 
38 
6 
Data Handling 
38 
6.1 
Pooling of Centers 
38 
6.2 
Handling of Missing Data 
38 
6.3 
Drop-outs, Withdrawals, Replacement Policy 
38 
7 
Changes from the Protocol 
38 
8 
Appendices 
39 
8.1 
 
39 
8.2 
Appendix 2: ECOG Performance Status (ECOG PS) 
51 
8.3 
Appendix 3: Common Terminology Criteria for Adverse Events (CTCAE) 
51 
 
 


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
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1 
Introduction 
This Statistical Analysis Plan (SAP) is based on study procedures and analyses described in the 
protocol (Amendment 5 dated 25 MAR 2020). Table shells and mock listings corresponding to 
the contents of this document will be included with the final version.  
1.1 
Background 
Squamous cell carcinomas (SCC) of the head and neck include tumors that occur in the oral 
cavity. Most lip and oral cavity cancers originate in squamous cells, the thin flat cells that line 
the lips and oral cavity. Risk factors for oral cancer include chronic heavy use of alcohol and 
tobacco, long periods of exposure to natural or artificial sunlight, and exposure to human 
papillomavirus. The 5-year survival rate for oral cancer is approximately 60%; diagnosis at an 
early stage significantly increases the 5-year survival rate. Oral cancer has a high rate of 
recurrence (18%–76% for subjects who undergo standard treatment). Approximately 1/3 of 
subjects treated with surgery and adjuvant therapy will experience local or regional recurrence 
and/or distant metastasis.  
 
The most common chemotherapy drugs for advanced oral cancer includes cisplatin, 
methotrexate, carboplatin, 5-fluorouracil, paclitaxel, and docetaxel, which when administered 
alone or in combination have been shown to provide clinical benefit with demonstrated 
improvement in overall survival. 
 
PRV111 (Cisplatin Transmucosal System) is a thin, 2-layer, self-adhesive transmucosal patch 
embedded with cisplatin and a non-woven fabric adhesive backing. In addition to the PRV111 
drug product, a separately packaged Permeation Enhancer Powder for Reconstitution is used in 
conjunction with the PRV111 drug product. The reconstituted Permeation Enhancer Solution is 
applied prior to the administration of PRV111 to improve the absorption of the cisplatin active 
ingredient.  
 
Privo’s PRV111 is intended as a local induction chemotherapy, to improve the local control of 
the disease prior to surgery by shrinking the tumor size. Local cisplatin delivery may result in 
larger and more effective doses of cisplatin delivered to the tumor while significantly reducing 
or eliminating the systemic toxicities and side effects traditionally associated with intravenous 
(IV) cisplatin chemotherapy. Treatment with cisplatin which is targeted to the tumor site and 
not administered systemically may reduce the dose-limiting systemic toxicities that are 
observed with IV cisplatin administration.  If proven safe and effective for the treatment of 
SCC of the oral cavity, PRV111, in association with the standard care, may decrease the risk of 
local tumor recurrence.  
 
 


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
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2 
Trial Design  
2.1 
Study Objectives  
Primary Objectives 
• Determine a safe and efficacious dose of PRV111 (Cisplatin Transmucosal System) 
(cisplatin drug-loaded patch + permeation enhancer [PE]) under the conditions of the trial. 
 
Secondary Objectives 
• Evaluate tumor volume shrinkage  
• Assess long-term safety of the treatment 
• Evaluate device technical success including the residual cisplatin level in the patch after the 
application period 
• Evaluate systemic, tumor and lymph node (if available) platinum levels following 
administration 
 
2.2 
Study Design 
This is a two-stage adaptive design. The First stage with 6 patients focuses on determining a 
safe dose, while stage 2 expands the study at the previously determined dose.  See the Protocol 
section on synopsis. 
 
Methodology: This is a Phase 1/2, open-label, prospective, single-arm study of the safety and 
efficacy dose-finding, systemic exposure, and device technical success of PRV111 (Cisplatin 
Transmucosal System) (cisplatin drug-loaded patch+PE) in subjects with oral squamous cell 
carcinoma (SCC) amenable to surgery.  
 
Study Design: This is a 2-stage adaptive study. For Stage 1, up to 10 subjects will be enrolled 
for the purpose of 5 evaluable subjects for the 1st stage of the study to determine a safe and 
efficacious dose. For Stage 2, the target goal is up to 11 evaluable subjects for the efficacy 
analysis of the final dose. If the dose remains the same as Stage 1, Stage 2 will target 6 
additional evaluable subjects but up to 21 subjects will be recruited if the dose is changed 
between Stage 1 and 2.  
For the purpose of dose selection, tolerable dose is defined as a dose where fewer than 33% of 
subjects being evaluated within the safety population present with dose-limiting toxicities 
(DLTs). Effective dose is determined based on the evaluable population as described in the 
Statistical Methods section.  
The 2 stages of the study are described below:   
 
Stage 1: Up to 10 subjects will be enrolled for the purpose of 5 evaluable subjects and 
undergo 3 treatment applications at each of the 4 planned treatment visits. Each treatment 
visit will include 1 application of the PE. Starting approximately 5 minutes after application 


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
Page 8 of 51 
 
of the PE, 1 or 2 patches (depending on tumor size) will be applied. A total of 3 treatment 
applications of patches will occur. These successive applications will span approximately 
35 minutes. The 3 applications provide a total of 6 mg of cisplatin per visit (12 mg if 2 
patches are applied at the same time). The 4 treatment visits will be separated by 2 to 4 days 
(at least 48 hours).  
The following decisions will be made based on safety and efficacy of the dose: 
Dosing Rules for Stage 1: 
1) If fewer than 2 subjects experience DLTs, then the following scheme will be considered 
for stage 2 dosing: 
a. If fewer than or equal to 2 of the evaluable subjects have a response (Defined in the 
efficacy table) the dose will be escalated from 3 to 5 treatment applications per 
treatment visit for Stage 2. 
b. If 3 or more evaluable subjects have a response (CR or PR), the dose will remain the 
same for Stage 2 (3 applications per treatment visit). 
2) If 2 or more subjects experience DLTs at any time during Stage 1, the following scheme 
will be considered for dose de-escalation in Stage 2: 
a. If there are 6 evaluable subjects in Stage 1: 
- If out of 6 evaluable subjects, 2 or more subjects have a response (CR or PR), the 
dose will be de-escalated to 2 applications per treatment visit. 
- If out of 6 evaluable subjects, fewer than 2 have a response (CR or PR), the dose will 
be considered intolerable and the study will be stopped. 
b. If Stage 1 dosing was stopped prior to having 6 evaluable subjects, the dose will be de-
escalated from 3 applications to 2 applications per treatment visit. 
Stage 2: In case of dose escalation or de-escalation, Stage 2 will be conducted in 2 parts: 
Stage 2a and Stage 2b. 
Subjects will receive 2, 3, or 5 treatment applications at each of the 4 planned treatment 
visits, depending on the results of Stage 1. Up to 21 additional subjects will be enrolled in 
Stage 2 if necessary, for the purpose of 16 total evaluable subjects at the final dose for the 
efficacy analysis.  
 
Stage 2a: This stage will include 6 subjects (Stage 2a flowcharts). In this stage, only safety 
outcomes will be considered for determining the dosing regimen for the set of subjects to be 
enrolled in Stage 2b. All subjects enrolled in this stage will be monitored for possible DLTs.    
1) If fewer than 2 subjects with DLTs in Stage 2a, enrollment will continue for the 
remaining number of subjects required in Stage 2b at the same dose. 
2) If 2 subjects experience DLTs in Stage 2a, dosing will be re-considered. It may be 
stopped or, when possible, decreased for the remaining subjects enrolled in Stage 2b: 
a. If “Stage 2a - Escalated Dose”, the original dose will be used for up to 10 additional 
evaluable subjects enrolled for Stage 2b.  
b. If “Stage 2a - Same Dose”, dosing will be stopped. Additional subjects, for up to 10 
evaluable subjects, will be enrolled for Stage 2b at a lower dose, consisting of 2 
applications per treatment visit.  


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Protocol CLN-001 Amendment 5 
Statistical Analysis Plan 
 
Page 9 of 51 
 
c. If “Stage 2a – De-escalated Dose”, the study will stop, as no safe dose could be 
determined. 
 
2.3 
Sample Size 
 
 
 
 
 
2.4 
Selection and Withdrawal of Subjects 
2.4.1 Inclusion Criteria 
Subjects must meet the following inclusion criteria:  
1. Adult subjects, men and women, defined by age ≥18 years at the time of screening. 
2. Pathologically proven and clinically confirmed T1 (<2 cm) or T2 (>2 cm but ≤4 cm) 
SCC of the lip or oral cavity (anterior 2/3 of the tongue, floor of mouth, lower and 
upper gingiva, salivary gland, hard palate, and buccal mucosa). 
3. Tumor must be easily accessible, with no evidence of infection or active bleeding, 
encroaching major vessels or clinical evidence of neural invasion. Tumors should not 
have been previously irradiated. 
4. Tumor must be amenable to surgical resection no later than 42 days post Visit 1. 
5. Clinically and/or radiologically measurable tumor. 
6. Eastern Collaborative Oncology Group Performance Status of ≤2. 
7. Adequate renal function as demonstrated by renal creatinine clearance ≥50 mL/min 
(calculated using the Cockcroft-Gault formula). 
8. Adequate organ function defined as: ANC ≥1000/µL, platelet ≥100,000/µL; 
hemoglobin ≥9.0 g/dL; AST and ALT ≤2.5 times the upper limit of normal (ULN), 
serum bilirubin ≤1.5 times the ULN or direct bilirubin ≤ULN for subjects with total 
bilirubin >1.5 times the ULN. 
9. Candidates for standard of care treatment consisting of surgery. 
10. Male and female subjects of childbearing potential must agree to use 2 methods of 
effective contraception from screening and for at least 30 days after the final dose of 
investigational product. Appropriate birth control is defined as barrier methods with 
spermicides, oral or parenteral contraceptives and/or intrauterine devices, or naturally 
or surgically sterile (with documentation in the subject's medical records). 
Postmenopausal women are defined as presenting at least 12 months’ natural 
spontaneous amenorrhea, or at least 6 weeks following surgical menopause (bilateral 
oophorectomy). Females of childbearing potential must be non-lactating and have a 
negative serum hCG within 14 days of treatment initiation. 
11. Absence of any serious underlying medical conditions which could impair the ability of 
the subject to participate in the study. 


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Statistical Analysis Plan 
 
Page 10 of 51 
 
12. Have a life expectancy of ≥3 months. 
13. Willing and able to provide written informed consent. 
14. Able to return to study site for treatment and follow-up visits as defined in the Protocol. 
 
2.4.2 Exclusion Criteria  
Subjects meeting any of the following criteria will be excluded from the study:  
1. Known distant metastasis of the SCC of the oral cavity 
2. Prior radiation and/or systemic chemotherapy for the treatment of SCC of the head and 
neck less than 2 years prior to screening 
3. Concurrent malignancy, with the exception of localized squamous cell carcinomas of 
the skin 
4. Exposure to any investigational agent within 3 months prior to screening 
5. Known allergy or hypersensitivity to platinum-containing agents, or known intolerance 
to a prior platinum-containing agent, or to any of the excipients, which, in the 
judgement of the physician will preclude re-exposure to platinum-containing agent 
6. Active, uncontrolled infection requiring systemic therapy, such as but not limited to 
HIV, Hepatitis B or C 
7. Uncontrolled intercurrent illness that would risk subject safety, interfere with the 
objectives of the protocol, or limit subject compliance with study requirements, as 
determined by the Investigator 
8. Known or suspected pregnancy, planned pregnancy, or lactation  
9. Any medical or psychiatric condition that may compromise the ability to give written 
informed consent 
2.5    Criteria for Individual Subject Discontinuation of Protocol Therapy 
Subjects should be discontinued from protocol therapy, while follow-up as per protocol, for the 
following reasons: 
• 
Completion of the scheduled PRV111 therapy 
• 
Meets 1 of the stopping rules for an individual subject  
• 
Pregnancy 
• 
Noncompliance with trial or follow-up procedures 
• 
Withdrawal at the Investigator’s request for any reason that the Investigator believes 
continuation of study drug therapy would not be in the subject’s best interest 
• 
Subjects may be withdrawn at any time for drug intolerability, disease progression, 
availability of other therapeutic options, or subject judgment 
2.6 
Criteria for Individual Subject Discontinuation from the Trial 
Subjects may withdraw from further participation in the study at any time and for any reason 
without prejudice. The degree to which a subject withdraws can vary and efforts will be made 
to collect important safety data if feasible and the subject agrees. A subject will be considered 
to be withdrawn from the trial for the following reasons: 
• 
Withdrawn consent from all treatment and follow-up 


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Statistical Analysis Plan 
 
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• 
Death 
• 
Lost to follow-up 
• 
Termination of the trial by the Sponsor 
2.7 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
If a subject withdraws consent for the treatment, the Investigator will make every effort to 
complete all final evaluations and procedures required by the Protocol. The subject will be 
asked to return to the clinic for a follow-up visit to assess overall safety prior to study 
completion. In the event a subject withdraws for safety reasons (adverse event/serious adverse 
event [AE/SAE], National Cancer Institute’s (NCI) Common Terminology Criteria for 
Adverse Events [CTCAE] toxicity related events, etc.), every effort will be made to continue to 
follow-up with the subject until the documented condition resolves to protocol-established 
grades. 
The reasons for discontinuation of dosing must be clearly documented on the case report form 
(CRF). 
2.8 
Replacement of subjects  
 
Subjects will not be replaced. 
 
2.9 
 Treatments Administered 
a. Description of Test Product 
 
PRV111 (Cisplatin Transmucosal System) (referred to as PRV111) consists of: 
• 
PRV111 4 cm2 patch containing 2 mg of cisplatin (0.5 mg/cm2) backed with a pressure 
sensitive acrylic adhesive non-woven fabric backing. 
• 
PE Powder for Reconstitution 
 
 
 
 
  
b. Dosing and Administration 
Each treatment visit will include 1 mL application of the PE. Starting 5 minutes after 
application of the PE, 1 or 2 patches (depending on tumor size) will be applied. For Stage 1, a 
total of 3 treatment applications of patches will occur. These successive applications will span 
approximately 35 minutes. The 3 applications provide a total of 6 mg of cisplatin per visit 
(12 mg if 2 patches are applied at the same time).  


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Statistical Analysis Plan 
 
Page 12 of 51 
 
In Stage 2 (Stage 2a and Stage 2b), subjects will receive 2, 3, or 5 treatment applications at 
each of the 4 planned treatment visits, depending on the results of Stage 1. 
Refer to the Pharmacy Manual for detailed instructions on applying the PRV111 patches. 
Table 1 presents definition used for dosing and treatment in this study. Treatment is expected 
to be approximately 35 minutes for each treatment visit. 
Table 1. Dosing Terminology 
Term 
Definition 
Treatment visit 
Two to 6 days apart, during which PRV111 patches will be administered. 
Treatment application 
Three patch applications will occur during each treatment visit in Stage 1.  
Two, 3, or 5 patch applications will occur during each treatment visit in Stage 2. 
 
 
2.10 Dose-limiting Toxicity (Stopping Rules for an Individual Subject) 
Toxicity will be graded and recorded according to the NCI CTCAE version 4.03 (US 
Department of Health and Human Services, 2010), which are considered at least possibly 
related to PRV111 Patch. A DLT is defined as a clinically significant Treatment-Emergent AE 
(TEAE) or laboratory abnormality unrelated to disease progression, concurrent illness, or 
concomitant therapy and that meets any of the following criteria: 
• 
Grade 3 or 4 non-hematologic toxicity excluding alopecia  
• 
Grade 3 or 4 nausea, vomiting, or diarrhea, lasting >48 hours, despite standard 
prophylaxis and/or treatment  
• 
Grade 4 neutropenia lasting >5 days. 
• 
Febrile neutropenia, defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) for 
more than 1 hour. 
• 
Grade 4 thrombocytopenia or thrombocytopenia with clinically significant 
bleeding (ie, bleeding that requires blood or platelet transfusion or other medical 
intervention, or that may cause disability or death, such as cerebral hemorrhage). 
• 
Any grade 3 or 4 toxicity related to the study drug that precludes administration of 
at least 3 of the 4 planned applications.  
• 
Grade 4 local toxicity- oral mucositis according to World Health Organization 
scale: 
o Grade 0 - No oral mucositis 
o Grade 1 - Erythema and soreness 
o Grade 2 - Ulcer, able to eat solids 
o Grade 3 - Ulcers, requires liquid diet (due to mucositis) 
o Grade 4 - Ulcers, alimentation not possible (due to mucositis) 
• 
Any treatment related AE leading to surgery delay for more than 96 hours is a DLT 
 
 
 


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Protocol CLN-001 Amendment 5  
 
Page 13 of 51 
 
 
2.11 Schedule of Events 
Table 2. Schedule of Events 
 
Screening 
Within 
28 
Days Prior 
to Visit 1 
Days 
Surgery 
Months Post Surgery 
Treatment Visits 
Post Treatment 
Pre-Op 
Standard 
of 
Care 
(SOC) Follow-up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7, 8, 9 
0 
1 
≥48 and ≤ 144 hours, post 
previous visit 
≥72 hours post 
last treatment 
≤42 
days 
post Visit 1 
1, 3, & 6 months (all 
can be +/-3 weeks) SOC 
visits 
Confirmed SCC 
X 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xa 
 
 
 
 
 
 
Schedule study visits 
X 
X 
X 
X 
X 
X 
 
 
Demographic, 
medical/history 
X 
 
 
 
 
 
 
 
Physical examination,b,s 
 
 VSc 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
Anti-emetics 
 
Xa 
Xa 
Xa 
Xa 
 
 
 
  
X 
 
 
 
 
 
 
 
Oral cavity examinationd 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
Neck lymph nodes exam 
X 
Xa 
Xa 
Xa 
Xa 
X 
 
X 
ECG s 
X 
 
 
 
 
X 
 
 
  X 
 
 
 
 
X 
 
 
Clinical labsf 
X 
Xa 
 
Xa 
 
X 
Xo 
 
HPV s 
Xg 
 
 
 
 
 
 
 
Pregnancy test 
Xh 
Xa 
 
 
X 
 
 
 
PK sampling 
 
Xi 
Xj 
Xj 
Xi 
 
 
 
Tumor resection 
 
 
 
 
 
 
Xk 
 


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Protocol CLN-001 Amendment 5  
 
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Screening 
Within 
28 
Days Prior 
to Visit 1 
Days 
Surgery 
Months Post Surgery 
Treatment Visits 
Post Treatment 
Pre-Op 
Standard 
of 
Care 
(SOC) Follow-up 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visits 7, 8, 9 
0 
1 
≥48 and ≤ 144 hours, post 
previous visit 
≥72 hours post 
last treatment 
≤42 
days 
post Visit 1 
1, 3, & 6 months (all 
can be +/-3 weeks) SOC 
visits 
PRV111 patch treatment 
 
Xp 
Xp 
Xp 
Xp 
 
 
 
Tumor measurementsq 
 
Xa 
Xa 
Xa 
Xa 
X 
 
 
Tumor 
Volume 
change 
from baseline (CFB) criteria 
 
 
Xa 
Xa 
Xa 
X 
 
 
Tumor photographs 
 
Xl 
Xl 
Xl 
Xl 
X 
 
 
Loco-regional recurrence 
 
 
 
 
 
 
 
X 
Histologys 
Xm 
 
 
 
 
 
Xm 
 
Technical successn 
 
X 
X 
X 
X 
 
 
 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
 
X 
AE assessment 
X 
X 
X 
X 
X 
Xr 
 
 
Abbreviations: AE=adverse event; 
; ECG=electrocardiogram; HPV=human papilloma virus; 
 
; PE=permeation enhancer; PK=pharmacokinetics; SCC=squamous cell carcinoma; VS=vital signs.  
 
a Performed prior to dosing. 
b  If a physical exam was performed within 14 days prior to the screening visit, it does not need to be repeated at the screening. 
c VS: seated blood pressure and pulse will be measured after the subject has been sitting for at least 3 minutes, respiration, temperature, height and weight will be recorded 
at every visit. VS will be obtained pre-dose at all visits and subject will also be monitored at 30+5 minutes, 60+5 minutes and 120+5 minutes following application of the last 
patch applied at Visits 1 and 4 and at 30+5 minutes post last patch application at Visits 2 and 3. 
d  Take photos of the tumor region for further assessment of tumor shrinkage. 
e Every attempt should be made to use the same test for each subject for both timepoints. 
f     CBC and chemistry panel (creatinine to determine the creatinine clearance, BUN, LFT, electrolytes (potassium, magnesium, calcium, and sodium), urinalysis. 
g  Tissue will be collected at Screening but the HPV status will be ascertained at any time during the study using immunohistochemistry for p16 according to institutional 
clinical protocols. 
h  Serum pregnancy test to establish eligibility for female subjects of childbearing potential. A negative urine pregnancy test must be documented within 7 days prior to the 
first treatment visit, and at Visit 5. 
i  Visit 1 & 4: PK blood samples for total platinum collected pre- treatment (time -15 to 0 minutes), and 30±5 minutes, 60±5 minutes and 120±5 minutes post removal of 
last patch. 
j     Visit 2 & 3: PK blood samples for total platinum collected pre- treatment (time -15 to 0 minutes), and 30±5 minutes, post removal of last patch and PE application. 
k    Sampling for tumor and lymph nodes (if available) platinum levels. 


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l      Photos need to be taken prior to patch application. 
      m   Confirmation of tumor histology by a clinical pathologist is required prior to enrollment. A final pathology report, issued by a clinical pathologist is required following 
surgical resection of the tumor specimen. 
n Taste of the PE solution and patch, adhesion, peel-off, residual cisplatin level in the patch.  
o  Performed after surgery if possible  
p PE should be applied to the tumor area prior to first patch and allow to stay for 5 minutes. Then applied again to the tumor area for 1 minute. Note that the mouth should 
be kept open for the saliva not wash off the PE.  
q Use “0.05” cm for the “Height” of a flat tumor. If a concave tumor, the “Height” can be shown as a negative number. If a non-measurable dent, use “-0.05” cm. 
 
r Only SAEs within 30 days post visit 5 need to be recorded.  
s. May use historical SOC information prior to consent if collected within 28 days prior to first treatment. 


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2.12 Study Endpoints 
2.12.1 Primary Endpoints 
The primary endpoints for the study involve determination of a safe and efficacious dose of 
PRV111 (Cisplatin Transmucosal System) (cisplatin drug-loaded patch + PE) under the 
conditions of the trial. Therefore, the primary endpoint is based on the incidence of DLTs and  
tumor volume change from baseline (CFB). 
 
 
 
2.12.2 Secondary Endpoints 
Based on secondary objectives, the secondary endpoints are:  
 
• 
Evaluate tumor response  
 
  
 
 
• 
Assess short and long-term safety of the treatment  
▪  Loco-regional control: subjects will be followed-up for disease recurrence 
and safety following surgery  
▪ Incidence of recurrence at 6 months  
• 
Total platinum assessment in blood, tumor and lymph nodes (if available)  
• 
Technical Success 
▪ Successful adhesion of the patch to the target lesion  
▪ Successful delivery (including release and permeation) of the drug to the 
target lesion, without getting to surrounding oral surfaces  
▪ Successful peel of the used patch after 10 minutes without damaging the 
target lesion underneath  
▪ Adhesion of the backing to the polymeric matrix embedded CLPs  
▪ Taste of the PE solution  
▪ Taste of the PRV111 patch  
▪ Residual cisplatin level in the patch after the application period  
 
 
 
3 
Efficacy Assessments  
 
Efficacy outcomes include: 
• 
Response to treatment evaluated by Tumor volume change from baseline (CFB) 
• 
 
• 
Incidence of recurrence at 6 months 
• 
Histological effect of PRV111 on the tumor tissue 


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3.1 
PRIMARY: Tumor Photography and Measurements  
 
The primary lesion will be photographed before PRV111 treatment. This will be done to allow 
for a clinical assessment of response to treatment. For details refer to Study Manual for 
instructions.  
The tumor will be measured in cm to 1 digit to the right of the decimal point using a disposable 
plastic ruler or caliper. Three dimensions must be recorded (Length x Width x Height).  
 
Note: If tumor or cancerous lesion is flat, a small number (0.05 cm) will be recorded for the 
Height. If the tumor is a concave, a negative Height is recorded. If the height is an 
unmeasurable dent, it can be recorded as (-0.05 cm). The volume calculations use the heights 
absolute value. The following formula will be used to calculate tumor volume (cm3) 
 
L x W x H x π/6 
 
 
3.1.1 PRIMARY: Response and Non-Response (Tumor Volume Change from 
Baseline Criteria) 
 
The terms “response” and “non-response” will be defined according to the tumor volume 
change from baseline (CFB) criteria: 
 
PCFB  = % tumor volume change from the baseline  
 
Response will be defined as CR, SR, or PR. Non-Response will be defined as SD or PD.  
Clinical Response to Treatment  
Table 2. The Efficacy Criteria  
Complete 
Response 
(CR) 
Disappearance of primary lesion.  
Partial Response (PR) 
PCFB: ≥30% to 69% decrease in the total tumor volume shrinkage (as determined by 
clinical measurement, taking as reference the baseline volume.  
Strong Response (SR) 
PCFB: ≥70% to 99% decrease in the total tumor volume shrinkage (as determined by 
clinical measurement, taking as reference the baseline volume. 
Progressive 
Disease 
(PD) 
PCFB: At least a 20% increase tumor volume as determined by clinical measurement 
taking as reference the baseline volume (Note: the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD, taking as reference the volume determined by clinical measurement at baseline 
 


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3.1.2 Primary Efficacy Analysis  
 
The primary efficacy variable is response according to the Tumor Volume criteria per 
agreement from the FDA. (Section 7.3.1), where a response is CR, SR or PR (ORR; Objective 
Response Rate) and a non-response is SD or PD (See Efficacy Criteria table). The primary 
analysis is the analysis using the Efficacy Population and tumor volume change from baseline 
(CFB). Include 95% CI for CFB tumor size. The study will be deemed a success if at least 7 of 
the up to 11 evaluable subjects achieve a minimum of a PR.  
 
Change of tumor volume will be summarized for each visit, however the final efficacy 
determination will be based on CFB from V1 to V5.   
 
A frequency distribution of efficacy based on overall response rate (ORR) at each visit will be 
provided evaluable population.  A one-sided test of response (CR, PR, SR) rate less than 30% 
will be calculated at each visit.  
 
Photographs from V1 vs V5 will be presented 
 
 
 
 
 
 


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3.2.2 SECONDARY: Loco-regional Control 
Subjects will be followed-up for 6 months, and the incidence of local and regional (nodes) 
tumor recurrence will be recorded.  
 
 
A summary table will show if any tumor recurred in the evaluable patients at 1,3, and 6 month 
follow up visits. The final analysis will include the summary of the incidence of tumor 
recurrence and survival status for the Efficacy of Evaluable Population.  
 


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Time to recurrence and time to death will be summarized, with Kaplan-Meier curves will be 
described in the CSR and corresponding summary statistics at months 1, 3 and 6. 
 
3.2.3 SECONDARY: Technical Success 
 
Technical assessment data will include: 
 
• 
Taste of the PE solution 
• 
Taste of the PRV111 patch 
• 
Adhesion, including the time of adhesion of PRV111 patch 
• 
PRV111 patch peel-off 
• 
Residual cisplatin level in the patch after the application period. All PRV111 patches 
will be assessed for the amount of residual cisplatin in each patch after each application 
period. If the product detaches prematurely, the residual cisplatin will be assessed and 
the time of detachment will be noted. 
 
Results will be summarized using descriptive statistics.  
 


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4 
Safety Assessments  
Safety observations and measurements including study drug exposure, AEs, laboratory data, 
physical examination findings, VS, weight, and concomitant therapy will be summarized and 
presented in tables and listings SAEs will be collected within 30 days post-surgery. Certain key 
parameters such as “Expected” and “Related to treatment” will be recorded. AEs that occur 
from visit 1 to visit 5 are documented. AEs (not SAEs) during or after surgery are not 
documented since the oral tumor and reconstructive surgeries can result in many AEs. The list 
of expected SAEs due to oral cancer surgery and reconstructive surgery is included in the 
Investigator Brochure. Laboratory parameters will be summarized using descriptive statistics 
and data listings. The incidence of clinically significant abnormalities will be summarized. 
Physical examinations, VS, and weight will be summarized by changes from baseline values 
using descriptive statistics. 
 
AEs occurring after the start of treatment are TEAEs. The severity of the TEAEs will be 
graded according to the CTCAE criteria, version 4.0. The severity of oral mucositis will be 
graded according to the WHO grade. The number and percentages of subjects experiencing 
TEAEs will be tabulated by system organ class and preferred term. Assessments of TEAEs 
will include characterization of the type, incidence, severity, seriousness, and relationship to 
treatment. Summary subject listings will be provided for subjects with dose modification, 
SAEs, TEAEs resulting in study discontinuation, and deaths. The rates of local tolerability and 
oral mucositis will be reported. 
 
Safety assessments include: 
• 
Physical Examination, Vital Signs, Weight 
• 
Oral Cavity Examination 
• 
Neck Lymph Nodes Examination 
• 
Safety Laboratory Assessments 
• 
Electrocardiograms 
• 
Adverse events  
 
4.1 
Physical Examination, Vital Signs, Weight 
 
A complete physical examination will be performed by the Investigator or Sub-investigator.  
 


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The physical examination will include a review of all body systems (head, eyes, nose and 
throat, cardiovascular, respiratory, gastrointestinal, musculoskeletal, neurological, lymph 
nodes, dermatological, extremities/joints), and weight. 
 
Seated blood pressure (mmHg), pulse (beats per minute) and temperature (degrees Celsius) 
will be measured after the subject has been sitting for at least 3 minutes. 
 
Neuropathy and ototoxicity will be assessed via clinical examination since cisplatin can potentially 
cause neurotoxicity and ototoxicity. Questions will be asked to document symptoms such as 
tinnitus, pain in the extremities, or loss of sensation in the eCRFs.  
 
 
4.1.1 Physical Examinations Analysis: 
 
A complete general physical examination, including height and weight and vital signs (VS), 
will be assessed and recorded. Seated blood pressure (mmHg), pulse (beats per minute) and 
temperature (degrees Celsius) will be measured after the subject has been sitting for at least 3 
minutes. Measured values of all vital signs and the corresponding CFBs (Change from 
baseline) will be summarized with descriptive statistics by visit. All observed vital signs and 
corresponding CFB will be presented in a listing. All abnormal physical examination findings 
will be included in the adverse events listings and summary tables. 
 
Height is measured only at the screening visit and will not be included in the vital signs 
summary table but will be included in the listing. 
 


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4.2 
Oral Cavity Examination 
A systematic and thorough visual and manual oral examination will be performed. This will 
include a visual examination of all the soft tissues of the mouth, including manual extension of 


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the tongue to examine its base, a bi-manual palpation of the floor of the mouth, and a digital 
examination of the borders of the tongue. 
Special attention must be given to the application site and the tumor, with documentation of 
any local adverse reactions, including documentation with photographs if warranted. 
4.2.1 Oral Cavity Examination Analysis: 
 
A systematic and thorough visual and manual oral examination will be performed. This will 
include a visual examination of all the soft tissues of the mouth, including manual extension of 
the tongue to examine its base, a bi-manual palpation of the floor of the mouth, and a digital 
examination of the borders of the tongue. Results will be summarized using descriptive 
statistics 
4.3 
Neck Lymph Nodes Examination 
A cervical and local lymph nodes examination will be performed.  
4.3.1 Neck Lymph Nodes Analysis 
A cervical and local lymph nodes’ examination will be performed. Results will be summarized 
using descriptive statistics.  


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4.4 
Safety Laboratory Assessments 
Clinical laboratories to be assessed will be as in Table 3. 
Table 3. Clinical Laboratories 
COMPLETE BLOOD COUNT 
CHEMISTRY PANEL 
• hematocrit 
• hemoglobin 
• platelet count 
• red blood cell count 
• white blood cell count and differential (absolute and 
percentage); neutrophils, lymphocytes, monocytes, 
eosinophils, basophils, and reticulocyte count 
• alanine aminotransferase  
• albumin 
• alkaline phosphatase 
• aspartate aminotransferase 
• bilirubin (direct and total) 
• blood urea nitrogen 
• calcium 
• CO2 
• chloride 
• creatininea 
• gamma 
glutamyl 
transferase 
• glucose 
• magnesium 
• potassium 
• sodium 
• total protein 
URINALYSIS 
• urinalysis 
dipstick 
with 
reflex 
microscopic 
examination for abnormalities 
a Creatinine Clearance will be used to assess renal function using Cockcroft-Gault Equation  
 
4.4.1 Laboratory Tests Analysis: 
Laboratory values such as routine blood chemistry, hematology, and urinalysis will be 
measured for each subject. Summary statistics will be provided by visit for blood chemistry 
and hematology and the corresponding CFBs. The calculation for CFB is described in 
Section9.5. If the value at Baseline is missing, then CFB will be defined as the change from the 
value recorded at Screening. Urinalysis results and serum and urine pregnancy test results will 
be included in the listings of laboratory parameters but not in the summary tables. Laboratory 
ranges displayed and used for normal values will be per site. If a laboratory is missing ranges, 
the next most-similar lab will be used. For example, if Site 001 is missing a normal range, 
another lab from the same site will be used as reference (i.e. Baylor HHS is missing red blood 
cells, the value from Baylor Austin will be used). Data will be displayed per lab and per 
patient.  


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4.5 
Electrocardiograms 
Electrocardiograms (ECGs) will be evaluated for clinically relevant changes from Baseline. 
4.5.1 ECG Parameters Analysis: 
 
ECG parameters will be reported as normal or abnormal per subject and per visit.  
 
4.6 
Adverse Event Definitions/Reporting Requirements 
An AE (also known as an “adverse experience”) is defined as any untoward medical 
occurrence associated with the use of a drug in humans, whether or not considered drug related 
(US Code of Federal Regulations [CFR] 312.32).  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of the drug, 
without any judgment about causality. A TEAE, treatment emergent adverse event is an AE 
that occurred on or after the start of treatment. 


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All clinical AEs noted during the study will be reported on the appropriate AE page of the 
CRF. 
AEs that are serious, unexpected, and at least possibly related to study participation will be 
reported to the IRB and to the US FDA within the timelines described below. All other AEs, 
such as those that are expected, or definitely not related to the study participation, are to be 
reported per the IRB’s policy and to FDA as part of regular data submission at the time of 
annual Investigational New Drug report.  
4.6.1 Expected Events 
Expected events are those that have been previously identified as resulting from administration 
of the study drug. An AE is considered unexpected, for expedited reporting purposes only, 
when either the type of event or the severity of the event is not listed in the current 
Investigator’s Brochure (IB). 
4.6.2 Suspected Adverse Reaction 
A suspected adverse reaction is a subset of all AEs for which there is a reasonable possibility 
(ie, evidence to suggest a causal relationship between the drug and the AE) that the drug 
caused the event. Suspected adverse reaction implies a lesser degree of certainty about 
causality than adverse reaction.  
4.6.3 Adverse Reaction 
An adverse reaction is a subset of all suspected adverse reactions and is defined as any AE 
caused by a drug.  
4.6.4 Adverse Device Effects 
Adverse device effects are those AEs thought to be related to the use of an investigational 
medical device. This definition includes AEs resulting from insufficient or inadequate 
instructions for use, deployment, implantation, installation, or operation, or any malfunction of 
the investigational medical device. This definition also includes any event resulting from use 
error or from intentional misuse of the investigational medical device.  
An Unanticipated Adverse Device Effect is an adverse device effect, which by its nature, 
incidence, severity or outcome has not been identified in available information on the device.  
Additional device issues, malfunctions or misuse will be documented in the electronic CRF.  
4.6.5 Serious Adverse Event Definitions / Reporting Requirements 
4.6.6 Serious Adverse Event or Serious Suspected Adverse Reaction 
An AE or suspected adverse reaction is considered serious if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  


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Death. This includes any death that occurs while the subject is on study and/or within 
30 days after the last dose of study drug. An autopsy will be requested, and if 
performed, results will be submitted to the Sponsor.  
A life-threatening AE. An AE or suspected adverse reaction is considered life-threatening 
if, in the view of either the Investigator or Sponsor, its occurrence places the subject at 
immediate risk of death. It does not include a reaction that had it occurred in a more 
severe form, might have caused death. 
Inpatient hospitalization or prolongation of existing hospitalization. In the absence of an 
AE, hospitalization or prolongation of hospitalization should not be reported as an 
serious AE (SAE) in the following situations: 
Hospitalization or prolongation of hospitalization is needed for a procedure required by 
the Protocol. 
Hospitalization or prolongation of hospitalization is part of routine procedure followed 
by study center. 
Hospitalization for survey visits or annual physicals. 
For a hospitalization planned (and documented) before the start of the study for a pre-
existing condition which has not worsened.  
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples 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. 
4.6.7 Pregnancy 
For safety reporting purposes, any pregnancy occurring during the study will be considered an 
“important medical event”. If a study subject becomes pregnant while participating in the 
study, the study drug will be discontinued immediately and the pregnancy will be reported to 
the Sponsor. The Investigator will then report follow-up information to the Sponsor regarding 
the course of the pregnancy, including perinatal and neonatal outcome, regardless of the fact 
that the subject has discontinued the study. Once the newborn is determined to be healthy, as 
defined by and agreed upon by the Sponsor and Investigator, additional follow-up will no 
longer be required. 
4.6.8  Serious Unexpected and Suspected Adverse Reaction 
An unexpected AE (or serious and unexpected suspected adverse reaction [SUSAR]) is any AE 
or suspected adverse reaction that is not listed in the IB or is not listed at the specificity or 
severity that has been observed, if an IB is not required/available, is not consistent with the risk 
information described in the general investigational plan. This also refers to AEs or suspected 


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adverse reactions mentioned in the IB as occurring with a class of drugs or as anticipated from 
the pharmacological properties of the drug but are not specifically mentioned as occurring with 
the study drug. A SUSAR requires mandatory expedited reporting to the applicable regulatory 
authority(ies). The Sponsor will forward the formal notification describing the SUSAR to 
Investigators. Each Investigator must then notify his/her IRB of the SUSAR, in accordance 
with the IRB’s policy. 
The Sponsor should be notified within 24 hours of the Investigator becoming aware of a 
SUSAR and the event documented on the CRF. 
4.6.9 Recording Adverse Events 
All AEs (including SAEs) within the 5 pre-surgery visits are to be accurately recorded on the 
AE/SAE page(s) of the CRF. In addition, any SAEs within 30 days of visit 5 will need to be 
recorded. The Investigator will carefully evaluate each AE to determine: 
Duration (start and end dates) 
Severity (grade) 
Seriousness 
Relationship to study drug (Not Related, Possible, Definite) 
Action taken (none, study drug modification, medical intervention) 
Outcome (resolved without sequelae, resolved with sequelae, ongoing) 
The Investigator will evaluate all AEs and SAEs with regard to maximum intensity and 
relationship to study drug. Maximum intensity should be assigned using one of the severity 
grades as outlined in the NCI CTCAE v4.0. If the AE is not specifically listed in CTCAE v4.0, 
the following grades will be used: 
Grade 1: mild 
Grade 2: moderate 
Grade 3: severe 
Grade 4: life-threatening or disabling 
Grade 5: death 
4.6.10 Determining Relationship of Adverse Events to Study Drug  
The Investigator must attempt to determine if an AE or SAE is related to the use of the study 
drug. This relationship should be described as follows: 
Possible 
The event follows a reasonable temporal sequence from administration of the 
study drug and the event follows a known response pattern to the study drug 
BUT the event could have been produced by an intercurrent medical condition 
which, based on the pathophysiology of the condition and the pharmacology 
of the study drug, would be unlikely to be related to the use of the study drug 
OR the event could be the effect of a concomitant therapy. 
Definite 
The event follows a reasonable temporal sequence from administration of the 
study drug, the event follows a known response pattern to the study drug and 


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based on the known pharmacology of the study drug, the event is clearly 
related to the effect of the study drug. 
Not Related Based on the evidence available, causality is not possible. 
 
4.7 Adverse Events Analysis: 
All treatment-emergent adverse events (TEAE) will be summarized. Counts and percents of 
each observed system organ class (SOC) and preferred term as defined in the Medical 
Dictionary for Regulatory Activities (MedDRA) version 9.0 or later will be presented. The 
preferred terms will be summarized in the following sets of tables: 
• Baseline AEs, occurring after enrolment and prior to treatment; 
• All TEAEs;  
• All serious TEAEs; 
• All TEAE leading to discontinuation from study 
• All TEAEs by closest relationship (related or not related). Relationship will be 
recorded as definitely related, probably related, possibly related, or not related to the 
study medication; the recorded relationship will be included in listings. 
 
Reported severity (mild, moderate or severe) will be included in the listing. The severity 
of the TEAEs will be graded according to the CTCAE criteria, version 4.0 (Appendix 3), 
A separate table for AE of CTCAE grade greater than 2 (moderate) will be generated. The 
severity of oral mucositis will be graded according to the WHO grade. 
 
A subject having the same TEAE (preferred term) more than once over the course of the study 
will be counted only once in the incidence calculation for that preferred term.  Similarly, if a 
subject had more than one TEAE in a single SOC, the subject will be counted only once in the 
incidence calculation for that SOC.  If a subject had a TEAE more than once in the study, the 
occurrence with the maximum severity will be used in the calculation of the incidence of 
individual TEAE by severity. If a subject had a TEAE more than once in the study, the 
occurrence with the highest relationship to treatment will be used in the calculation of the 
incidence of individual TEAE by relationship. 
 


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4.7.1 Deaths, Other Serious Adverse Events (SAEs), and Other Significant AEs 
Analysis:  
Listings will be provided for  
• Deaths,  
• SAEs,  
• Discontinuations due to TEAEs,  
• Grade 4 AEs, and  
• Related AEs. 
 
4.8 Pharmacokinetics and Biodistribution Assessment 
 
4.8.1 Pharmacokinetics Analysis: 
 
 
Whole blood samples will be assessed for PK parameters and maximum concentration (Cmax) 
during treatment period will be determined.   PK parameters will be derived from the platinum 
concentrations obtained from Excite Pharma Services. Tumor and lymph node cis platinum 
content will be provided as well.  
 
 Summary statistics for PK data will be displayed for the following category:  : 
1. Tumor tissue 
2. Lymph nodes  
3. Blood 
4. Residual Patch 
 
Cmax based on blood concentrations across patch treatment period as well as other summary 
statistics for each patient will be listed.  
 
 
 
 
Systemic, tumor and lymph node (if available) platinum levels will be summarized using 
descriptive statistics. Analysis will be adjusted based on the number of patches applied per 
application (1 or 2) and total number of treatment visits. 
 
 
 
5 
Data Analysis and Statistical Considerations 
Statistical analyses and summaries will be provided when all corresponding data is collected 
and processed, and the corresponding database portions are locked through this stage of the 


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study. All available data from post-operative visits for other subjects, if any, will be included. 
The final analysis including all available post-operative data will be performed when the last 
subject has reached the 6-month post-operative follow-up visit and the final database is locked. 
 
Statistical tables, data listings and graphs will be prepared using SAS Version 9.1 or higher 
(SAS Institute, Cary, North Carolina, USA).  
 
 
5.1 Statistical Analysis 
Safety outcomes resulting in DLTs will be used during the conduct of this study to select doses 
being tested according to pre-defined thresholds of toxicity. 
 
• 
Local and systemic safety and tolerability will be summarized using descriptive 
statistics.  
• 
The number of subjects with DLTs will be capped to be fewer than 2 subjects with 
DLTs out of 5 new subjects enrolled.  
• 
The treatment regimen will be deemed tolerable if fewer than a third of the subjects 
exposed to it present DLTs. 
• 
Efficacy based on Tumor volume CFB criteria will be summarized, and the null 
hypothesis that the probability of response is at most 30%, where a response is the 
occurrence of CR or PR will be tested using a one-sided test exact binomial test at level 
0.018. 
• 
Other efficacy assessments such as change in tumor volume or tumor histology will be 
summarized using descriptive statistics. 
• 
Variables measuring technical success (including residual cisplatin level in the patch) 
will be summarized using descriptive statistics. 
 
At the end of Stage 2, the following is a statistical analysis of the sample size as it pertains to 
efficacy:  
 
Power and Sample Size 
  
Based on Simon's 2-stage procedure, the null hypothesis that the true response rate is 0.30 will 
be tested against a 1-sided alternative. In the first stage, 5 evaluable subjects will be accrued. If 
there are 2 or fewer responses in these 5 subjects, the dose will be escalated. Otherwise, the 
dose will remain the same or de-escalated based on safety data. 
 
 
 
This 
design yields a type I error rate of 0.018 and power of 96.44% when the true response rate is 
0.65. 
Null response rate: P0 
Alt. response rate: P1 
Alpha one-tailed 
Power 
n1 
r1 
N 
R 
 0.30 
0.85 
0.018 
96.44% 
5 
2 
11 
6 


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N is the total number of evaluable subjects at the final dose 
n1 is the number of evaluable subjects accrued during Stage 1 
r1, if r1 or fewer responses are observed during stage 1, escalate the dose if safety requirements are met  
R, if R or fewer responses are observed by the end of Stage 2 in N subjects, then an effective dose is not 
found 
 
Note: If the dose is not increased after Stage 1, the test will be performed using all evaluable 
subjects from Stage 1 and 2. If the dose is adjusted after Stage 1, the test will be performed 
using all evaluable subjects from Stage 2. 
 
 
5.2 Treatment Analysis Guidelines 
 
5.2.1 Efficacy Analyses  
The primary efficacy analysis will be conducted after all evaluable subjects will have 
undergone their surgical ablation of the oral tumor, in addition to the interim analysis described 
below. 
Note:  All hypothesis tests will be performed at a 0.018 level. 
 
5.2.2 Evaluable Population 
 
All subjects who have met the inclusion and exclusion criteria, and have completed at least 75% 
of the total dose required for that stage will be included in the Evaluable Population*. This 
population will be used for the efficacy analysis. Only subjects in the evaluable population will 
be assessed for tumor response.  
 
* 75% is defined as at least 3/4 patch application visits completed  
 
 
5.2.3 Baseline Values for Tumor Measurement  
The baseline values for each subject will be those recorded at Visit 1. If the value at the 
Baseline visit is missing, then the value from the earliest available visit will be used. For tumor 
measurements, if the Visit 1 measurement is missing, then the measurements from the 
screening CT scan will be used as baseline values.  
 


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5.2.4 Change from Baseline (CFB) and Percent Change from Baseline 
(PCFB)   
CFB will be calculated at each post-baseline visit for all evaluable subjects as: 
CFB = Post-Baseline value – Baseline value. 
CFB will be reported to the same number of decimal places as the variable. 
 
PCFB will be calculated at each post-baseline visit for all evaluable subjects as: 
PCFB  = 100*CFB/ Baseline value  
= 100*(Post-Baseline value – Baseline value) /Baseline value. 
PCFB will be reported to same number of decimal places as the variable.  
 
5.2.5 Descriptive Summary Statistics 
The following standards will be applied for each analysis unless otherwise specified. Simple 
summary statistics for continuous data are defined as: n (number of non-missing observations), 
mean, standard deviation, maximum, median, minimum. The number and percentage of 
subjects will be used to summarize categorical data. All data will be listed and sorted by 
investigator number, variable, subject number, and visit, if appropriate.  
 
 
5.3 Safety Analyses 
The Safety Population will be used for all summaries of safety data.  
will be used in the calculation of the incidence of individual TEAE by relationship. 
 
5.3.1 Safety Population 
All subjects who have at least 1 PRV111 patch applied will be included in the Safety 
Population. 
 
 
5.3.2 Concomitant Medication and Therapy 
A listing of concomitant medications and therapy will be provided for the Safety Population. 
 
5.3.3 Medical History, Medication History and Baseline Disease Characteristics 
Medical history and baseline disease characteristics will be listed for the Safety Population.  
ECOG PS (Appendix 2) will be included. 
 


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5.3.4 Subject Accountability, Demographics, and Baseline Characteristics  
 
Subject completion status, dose modification, and study terminations will be summarized for 
each of the study stages and for the study overall. Subjects with major protocol violations will 
be listed. Demographics will be summarized along with baseline characteristics such as 
medical history, and baseline physical examination, weight, VS, ECOG PS, and concomitant 
therapy.  
 
 
6  Data Handling   
 
6.1 Pooling of Centers 
This is a multi-center study. The data from all sites will be pooled for all analyses.  
6.2 Handling of Missing Data 
All missing data will be queried. Missing efficacy data which are not retrievable through 
queries will be imputed. Missing safety data will not be imputed. If the value of a vital sign 
assessment, ECG variable, laboratory value, or clinical tumor measurement is missing at 
Baseline, then CFB will be defined as the change from the value recorded at the next earliest 
available data point.  
  
Non-Responder Imputation (NRI) 
 
No missing values imputation will be applied.  
 
6.3 Drop-outs, Withdrawals, Replacement Policy  
If a subject withdraws from the study at any time, either at his or her request or at the 
Investigator’s discretion, the reason(s) for withdrawal will be recorded on the relevant page of 
the CRF. Subjects withdrawn due to AEs will be monitored until resolution of all AEs. 
Subjects who withdraw from dosing will be not replaced. However, their data will still be used 
if they are considered part of the evaluable population, unless they state otherwise.  
 
 
7 Changes from the Protocol 
No changes from the protocol are planned. 
 


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8.2 Appendix 2: ECOG Performance Status (ECOG PS) 
Performance status will be assessed using ECOG PS at Baseline for inclusion criterion. 
 
Grade 
ECOG PS 
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 
 
 
8.3 Appendix 3: Common Terminology Criteria for Adverse Events 
(CTCAE) 
CTCAE Grade refers to the 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: 
 
Grade 
Severity Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not 
indicated. 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental 
ADL*. 
3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of 
hospitalization indicated; disabling; limiting self-care ADL**. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden.