Clinical trial NCT04574583
Conditions: Metastatic Cancer Solid Tumors
Keywords: Immunotherapy Checkpoint Inhibitor Vaccine Combination Therapy Metastatic Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2020-11-24; Completion date: 2023-05-19
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Background:

Combination immunotherapy techniques are being explored to improve responses and enhance benefits in people with cancer. Researchers want to see if this type of treatment can help people with advanced solid tumors.

Objective:

To find a safe dose of SX-682 in combined treatment with Bintrafusp alfa and BN-CV301 vaccines and to see if this treatment will cause tumors to shrink.

Eligibility:

Adults age 18 and older with metastatic cancer may be eligible for the first part of the trial. Adults age 18 and older with metastatic triple negative breast cancer or p16 negative head and neck squamous cell cancer, and who are not candidates for curative surgery may be eligible for the second part of the trial.

Design:

Participants will be screened under a separate protocol.

Participants may have tumor biopsies. They will have physical exams. Their symptoms and medicines will be reviewed. They will have blood tests. They will have electrocardiograms to evaluate their heart.

Participants will have imaging scans of the chest, abdomen, and pelvis. They may have a procedure where a small tube with a tiny video camera is put into the nose to look at the throat if they have head and neck cancers.

Participants will get bintrafusp alfa through an intravenous catheter. For this, a small tube is put into an arm vein. They will get BN-CV301 vaccines as injections in the arm or thigh. They will take SX-682 by mouth twice a day. They will take the study drugs up to 2 years. They will keep a medicine diary.

Participants will have study visits every 2 weeks. They will have 1 or 2 follow-up visits within 30 days after they stop treatment. Then they will be monitored by phone or email for 2 years.

Detailed description:
Background:

* Combination immunotherapy approaches are being actively explored to further improve responses, enhance clinical benefit, and overcome resistance to Programmed Cell Death Ligand 1 (PD(L)-1) agents in cancer participants.
* Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types. Overexpression of IL-8 and/or its receptors C-X-C motif chemokine receptor 1 (CXCR1) and C-X-C motif chemokine receptor 2 (CXCR2), is commonly seen in many human cancers including breast, cervical, melanoma and prostate.
* SX-682 is an oral, small molecule inhibitor of the CXCR1/2 chemokine receptors that are believed involved in myeloid-derived suppressor cells (MDSC)-recruitment to tumor and other pro-tumoral mechanisms.
* Bintrafusp alfa (M7824 or MSB0011359C) is a bifunctional protein composed of the extracellular domain of the Transforming Growth Factor Beta Receptor 2 (TGF-BetaRII) receptor (TGF-Beta 'trap') fused to a human immunoglobulin G1 (IgG1). Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking, antigen specific cluster of differentiation 8 (CD8+) T-cell lysis and natural killer (NK) cell activation.
* CV301 is a poxviral-based vaccine comprised of recombinant Modified vaccinia Ankara (MVA-BN-CV301, prime) and recombinant fowlpox (FPV-CV301, boost). CV301 contains transgenes encoding two (2) tumor-associated antigens (TAA), mucin 1 (MUC1) and carcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3), designated TRICOM). A recent phase 1 clinical trial demonstrated that antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, brachyury, were generated in most participants.
* Preclinical studies performed in LTIB with SX-682, M7824 and a CEA-based vaccine showed a significant reduction in tumor growth as well as a significant increase in tumor infiltration with cluster of differentiation 4 (CD4+) and CD8+ T cells.

Objectives:

* Arm 1 (Sequential Dose Escalation):

  * To evaluate the safety and tolerability of single agent SX-682 given for 2 weeks preceding M7824 and CV301.
  * To determine the maximum tolerated dose (MTD) of SX-682 given for 2 weeks preceding M7824 and the CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of SX-682 followed by M7824 and CV301 vaccines.
* Arm 2 (Combination Dose Escalation):

  --To determine the recommended phase 2 dose (RP2D) of SX-682 given concurrently with M7824 and the CV301 vaccines in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of the drug combination.
* Arm 3 (Expansion):

  * To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each disease separately in two cohorts: Triple Negative Breast Cancer (TNBC) and Human papilloma virus (HPV) negative head and neck squamous cell carcinoma (HNSCC).

Eligibility:

* Age \>= 18 years old
* Arms 1 and 2 (Dose-Escalation Cohort): Subjects with cytologically or histologically confirmed locally advanced or metastatic solid tumors.
* Arm 3 (Expansion Cohorts):

  * Triple Negative Breast Cancer (TNBC): Subjects with cytologically or histologically confirmed locally advanced or metastatic Triple Negative Breast Cancer that has progressed on at least one prior treatment in the advanced or in the metastatic setting.
  * Human papilloma virus (HPV) negative head and neck squamous cell carcinoma (HNSCC): Subjects with cytologically or histologically confirmed locally advanced or metastatic, HPV negative head and neck squamous cell cancer (p16 negative for oropharyngeal) that has progressed on at least one prior treatment involving a platinum drug or cetuximab in advanced or in the metastatic setting.
* Prior first line systemic therapy is required unless there is no standard treatment available, the participant cannot tolerate standard first line treatment, or the participant declines standard treatment after appropriate counseling has been provided.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Adequate renal, hepatic, and hematologic function
* Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by Response Evaluation Criteria in Solid Tumors (RECIST) but visible on computed tomography (CT) scan). Participants with third space fluid (for example pleural effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have measurable disease according to RECIST 1.1

Design:

* Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term, 2-week SX-682 monotherapy, sequentially followed by treatment with M7824 and the CV301 vaccine series in advanced solid tumors (every 2 weeks (Q2W) dosing schedule) for the duration of treatment.
* Arm 2 is a phase I, open-label, 3+3 combination dose escalation trial with concurrently administered SX-682, M7824 and CV301 in advanced solid tumors (Q2W dosing schedule).
* Arm 3 has two expansion cohorts. Following identification of the MTD or recommended phase 2 dose (R2PD) for the combination of SX-682, M7824 and CV301 vaccine given concurrently, disease-specific phase 2 expansion cohorts will open in 1) advanced/metastatic triple negative breast cancer and 2) advanced/metastatic, platinum-refractory HPV negative head and neck squamous cell carcinoma.

Arms: arm 1: Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301.

Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins arm 2: Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL2 50 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301.

Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrollment to the next dose level begins arm 3: Participants with any solid tumor will receive a 2- week monotherapy lead-in of SX-682 DL1 100 mg by mouth (PO) twice a day (BID) followed sequentially by treatment with a dual combination of + BinTrafusp Alfa (M7824) 1200 mg fixed dose intravenous (IV) + BN-CV301.

Participants will be evaluated for dose-limiting toxicities at the completion of the dose level before enrolling onto the next dose level.
Interventions: intervention 1: SX-682 intervention 2: M7824 intervention 3: MVA-BN-CV301 intervention 4: recombinant fowlpox viral (FPV)-CV301
Intervention descriptions: intervention 1: SX-682 will be given orally at designated dose twice a day every day intervention 2: Subjects will receive M7824 at a flat dose of 1,200 mg intravenously on Days 1 and 15 of each cycle. intervention 3: MVA-BN-CV301 will be given as four subcutaneous injections (4x10\^8 Inf.U/0.5ml twice during Cycle 1 (Days 1 and 15) intervention 4: FPV-CV301 will be given as one subcutaneous injection (1x10\^9 Inf.U/0.5ml) on Day 1 starting at cycle 2 through cycle 5 (every 4 weeks) then on Day 1 of every 3 cycles (Cycles 8 and Cycle 11).

Protocol documents:
ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
Page 1 of 23
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:
James Gulley, MD, PhD.
STUDY TITLE:
Phase I/II Trial Investigating the Safety, Tolerability, 
Pharmacokinetics, Immune and Clinical Activity of SX-
682 in Combination with BinTrafusp Alfa (M7824 or 
TGF- “Trap”/PD-L1) with CV301 TRICOM in 
Advanced Solid Tumors (STAT).
STUDY SITE:
NIH Clinical Center
Cohort: 
Affected patients  
Consent Version:
03/18/2022 
WHO DO YOU CONTACT ABOUT THIS STUDY? 
James Gulley, MD, PhD, 
 
 
KEY INFORMATION ABOUT THIS RESEARCH 
This consent form describes a research study and is designed to help you decide if you would 
like to be a part of the research study. 
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
This section provides the information we believe is most helpful and important to you in making 
your decision about participating in this study. Additional information that may help you decide 
can be found in other sections of the document. Taking part in research at the NIH is your choice.
You are being asked to take part in this study because you have been diagnosed with a metastatic 
cancer, which may be Triple Negative Breast Cancer (TNBC) or p16 negative Head and Neck 
Squamous Cell Cancer (HNSCC) and your doctor has found that you are not a candidate for 
curative surgery. You may also be asked to participate in the first part of the study only (see 
description below),if you have a solid tumor.
The purpose of this study is to find a safe dose of SX-682 in combined treatment with M7824 
and CV301 vaccines and to see if this combined treatment will cause your tumors to shrink. 
The use of SX-682, M7824 and CV301 vaccines in this study is considered investigational 
which means these drugs have not been approved by the U.S. Food and Drug Administration 
(FDA) to treat cancer. However, the FDA has given us permission to use these drugs in this 
study. 
SX-682 and M7824 are drugs that block the pathways that cancer cells use to prevent your 
immune system from fighting your cancer. M7824 has been tried in other types cancers. 
Recently, the manufacturer of the drug closed 3 large studies because the drug was not shown 
to help those patients more than standard therapies. In addition, in some cases it seemed like 
the drug might make the cancer grow faster. However, the type of cancer treated in those 
studies was not the same as your cancer.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
Page 2 of 23
CC ICF template v. 05.05.20
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CV301 vaccines (MVA-BN-CV301 and FPV-CV301) are designed to create immune cells that 
can recognize and kill certain types of cancer. 
There are other standard of care drugs and/or procedures that may be used to treat your disease, 
and these can be given to you by your regular cancer doctor if you are not in this study. For 
example: there is chemotherapy and radiation therapy. The treatment given in this study and the 
known possible side effects may or may not be significantly different than if you were to receive 
standard care or participate in another clinical trial. 
SX-682 and M7824 have been found to decrease blood counts (anemia), cause bleeding, 
problems with heart, kidney, the immune system and other organs. It is possible that the anemia 
and/or bleeding may be so severe that you require a blood transfusion. You cannot join this 
study if you are not willing to have a blood transfusion.  The CV301 vaccines may cause fever, 
flu-like symptoms, chills and nausea. 
If you decide to join this study, here are some of the most important things that you should know 
that will happen:

First, we will perform tests to find out if you fit the study requirements. We will do 
standard blood tests and scans to test your health and see the status of your disease.

The study is divided into 3 parts. In part 1 we will try to find the safe dose of SX-682 by 
itself and then followed by treatment with M7824 and CV301 vaccines. In part 2, we 
will try to find the safe dose of SX-682 combined with M7824 and CV301 vaccines. In 
part 3, we will try to find out if the safe dose of SX-682 in combined treatment with 
M7824 and CV301 vaccines from part 1 or 2 is effective in shrinking your tumor.

Depending on when you enter the study, you will have treatment with the following 
drugs for up to 2 years. 
o
SX-682 alone for 2 weeks followed by treatment with M7824 and CV301 
vaccines (group 1), 
o
SX-682 alone for 2 weeks followed by combination treatment with SX-682, 
M7824 and CV301 vaccines (group 2), 
o
SX-682, M7824 and CV301 vaccines in combination (group 3)
You cannot choose which part of the study to enroll in; enrollment will occur in 
sequential fashion, meaning that participants will enroll as they are screened and 
determined to be eligible. 

If you fit the study requirements and decide to take part, you will start your treatment 
with SX-682 tablets that are taken by mouth twice a day. We will then send you home 
with a supply of SX-682 that you will need to take. 

M7824 is given as an IV (intravenous) infusion. A small plastic tube is put into a vein in 
your arm and the medication is given once every two weeks. It could also be given 
through a central catheter (known as a port or mediport) if you already have one installed.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
Page 3 of 23
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

CV301 vaccines will be given as injections under the skin in the upper arms or thighs. 
This is similar to receiving a vaccine shot and will be done on day 1 and 15 of the first 
28-day cycle and on day 1 of each cycle for the following 4 cycles, then day 1 of every 
3 cycles.

You will not need to stay in the hospital for this study, though your doctor might decide 
to admit you for safety purposes. You have to come to the Clinical Center every 2 weeks 
while you are receiving treatment. Each visit should last no more than 8 hours. Combined 
treatment with three drugs will continue for one year, after that you will have treatment 
with M7824 and SX-682 only for another year. If you have unacceptable side effects 
(both drugs) or you are no longer benefiting from the study therapy, it can be stopped 
earlier. If you are tolerating and benefiting from the study drugs, treatment may continue 
after 2 years. 

At your visits, will have clinical, laboratory, and imaging tests to see how you are doing 
and to assess your disease. We will also collect required samples from you (such as:  
blood and tissue) for both clinical and research purposes.

As described above and later in more detail in this consent form, you may have side 
effects if you take part in this study. Some can be mild or very serious, temporary, long-
lasting, or permanent, and may include death. You will be seen regularly during the 
study. You will have clinical, laboratory, and imaging tests to see how you are doing and 
see how your disease is responding. We will also collect samples from you (such as 
blood and tumor tissues) for both clinical and research purposes. Some of the samples 
are required and some are optional.

After the study treatment has ended, we would like to see you in the Clinical Center once 
or twice for first month. If you stop treatment for reasons other than worsening of your 
disease, we will continue to invite you for imaging studies approximately every 3 months 
until your disease gets worse. You can also have these studies done locally and send us 
the results. If your disease gets worse, we will contact you by phone or e-mail every year 
for 2 years to check on your health. 

You will need to practice an effective form of birth control during the study treatment 
and for 6 months after you finish study treatment (the restricted period).

Some drugs and vaccines are not allowed during this study. Please let you doctor know 
about all medicines you are taking or planning to take.
This study may benefit you by shrinking of your tumor or lessening of your symptoms, such as 
pain, that are caused by the cancer. Even if you do not benefit from this study, the results from 
our research will help others in the future.
You are free to stop taking part in the trial at any time. If you decide to stop, the study doctor 
may ask you to agree to certain tests or have you follow up with your own doctor to make sure 
you are safe. 
The remaining document will now describe the research study in more detail. This information 
should be considered before you make your choice. Members of the study team will talk with you 
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
about the information in this document. Some people have personal, religious, or ethical beliefs 
that may limit the kinds of medical or research interventions in which they would want to 
participate. Take the time you need to ask any questions and discuss this study with NIH staff, and 
with your family, friends, and personal health care providers.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and, you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document. the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research. 
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to find a safe dose of SX-682 in combined treatment with M7824 and 
CV301 vaccines and to see if this combined treatment will cause your tumors to shrink.
We are asking you to join this research study because you have been diagnosed with a metastatic 
cancer, which may be Triple Negative Breast Cancer (TNBC) or p16 negative Head and Neck 
Squamous Cell Cancer (HNSCC) and your doctor has found that you are not a candidate for 
curative surgery. You may also be asked to participate in the first part of the study only if you have 
a solid tumor.
The use of SX-682, M7824 and CV301 vaccines in this study is considered investigational which 
means this combination has not been approved by the U.S. Food and Drug Administration (FDA) 
to treat cancer. However, the FDA has given us permission to use these drugs in this study.
SX-682 and M7824 are drugs that blocks pathways that cancer cells use to prevent your immune 
system from fighting your cancer.
CV301 vaccines (MVA-BN-CV301 and FPV-CV301) are designed to create immune cells that 
can recognize and kill certain types of cancer. 
The study is broken into 3 parts. In part 1 we will try to find the safe dose of SX-682 by itself and 
then followed by treatment with M7824 and CV301 vaccines. In part 2, we will try to find the safe 
dose of SX-682 combined with M7824 and CV301 vaccines. In part 3, we will try to find out if 
the safe dose of SX-682 in combined treatment with M7824 and CV301 vaccines from part 2 is 
effective in shrinking your tumor.
WHAT WILL HAPPEN DURING THE STUDY?
If you take part in parts 1 or 2 of the study, you will take SX-682 alone by mouth during first 2 
weeks. 
After that you will get combined treatment in cycles (1 Cycle = 28 days). 
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Depending on the time you enter the study, you will continue treatment with M7824 + CV301 
vaccines (group 1), or continue treatment with M7824 + CV301 vaccines + SX-682 (group 2).
If you are enrolled during part 3 of the study, you will receive a combination of SX-682, M7824 
and CV301 from the begining of study.
M7824 will be given to you through an IV (intravenous catheter, a small plastic tube that is put 
into a vein, usually in your arm) once every 2 weeks (on days 1 and 15 of every cycle). 
CV301 vaccines will be given as injections under the skin in the upper arms or thighs. This is 
similar to receiving a vaccine shot and will be done on day 1 and 15 of cycle 1, on day 1 of each 
cycle for the following 4 cycles and then on day 1 of every 3 cycles.
SX-682 should be taken by mouth 2 times a day. Try to space your doses out evenly throughout 
the day, so ideally, take a dose between 6-9 am and between 6-9 pm with approximately 1 cup 
(240 mL) of water. You should take tablets at least two hours after a solid meal and at least one 
hour before the next solid meal.  If you need to take your SX-682 earlier than scheduled or you 
missed a dose, you can take it up to 2 hours before or after the scheduled time. If you vomit after 
taking SX-682, please, do not immediately take another tablet unless the tablet is visible. You 
should simply proceed with next dose as scheduled.
You will be given a Medication Diary to complete for each cycle. In the diary, you will be asked 
to record the date and time of each dose of SX-682. You will also be asked to record missed doses. 
Please bring the diary with you to every study visit.
At each visit, please also bring all empty bottles and any unused medication you may have.
If your doctor is convinced that you have unacceptable side effects caused by one of the treatment 
drugs, this drug will be stopped, and you may continue treatment with the other drug(s) if your 
study doctor finds that it is in your interest.  
Combined treatment with all three (M7824, SX-682 and CV 301) drugs/vaccine will continue for 
one year, after that you will have treatment with M7824 and SX-682 only for another year. If you 
have unacceptable side effects (both drugs) or you are no longer benefiting from the study therapy, 
it can be stopped earlier. If you are tolerating and benefiting from the study drugs, treatment may 
continue after 2 years.
Before you begin the study
Before you begin this study, you will need to have standard clinical exams and tests to make sure 
you are eligible for this study. The exams and tests are part of regular cancer care. These tests will 
be done under a separate protocol. 
You will also be asked to provide documentation to confirm your diagnosis. If documentation is 
not available, we will perform a biopsy (collect a sample of your tumor) to confirm your diagnosis.
If treatment does not start within 28 days before initiation of study therapy, some tests may need 
to be repeated.
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IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
During the study
Ongoing procedures before treatment, and on days 1 and 15 of every cycle: 

Physical examination, including weight and vital signs.

Electrocardiogram (EKG – a record of your heartbeat) to evaluate your heart (up until cycle 
6).

Discussion of any symptoms you might be having and review of your medications.

Routine blood tests to find out if you are anemic, have low blood counts, and if your liver, 
kidneys, thyroid, clotting system and other organs are working well

Pregnancy test if you are a woman who can have children before taking the drug on days 
1 only.
Ongoing procedures before and during treatment:

Imaging assessments/scans – either a CT (a series of x-ray images taken of parts of your 
body) or if you cannot have a CT scan, MRI (magnetic testing, which does not involve any 
radiation) of chest, abdomen and pelvis at 6 weeks after starting treatment then every 8 
weeks after that (groups 1 and 2), or every 8 weeks (group 3). 
A computer tomography (CT) scan produces a series of x ray images taken of parts of 
your body.
Magnetic resonance imaging (MRI) uses a strong magnetic field and radio waves to 
take pictures of your body. The MRI scanner is a metal cylinder surrounded by a strong 
magnetic field. During the MRI, you will lie on a table that can slide in and out of the 
cylinder. We will place soft padding or a coil around your head. You will be in the 
scanner about 30 minutes. You may be asked to lie still for up to 30 minutes at a time. 
While in the scanner you will hear loud knocking noises, and you will be fitted with 
earplugs or earmuffs to muffle the sound. You will be able to communicate with the 
MRI staff at all times during your scan, and you may ask to be moved out of the 
machine at any time. 

Flexible pharyngolaryngoscopy – procedure to look into your throat and larynx, or voice 
box using laryngoscope, a small plastic tube with tiny video camera, that put into your nose 
(before treatment and during treatment if you have head or neck cancer and your doctor 
thinks it is necessary).

Each visit should last no more than 8 hours. 
When you are finished taking the drugs (treatment)
Within 30 days after you have finished taking the study drug, you will be asked to return to the 
Clinical Center once or twice for end of treatment and/or safety follow up visits. At these visits, 
you will be asked questions about your health, get a physical exam and undergo blood tests. 
If you have been taken off treatment for reasons other than worsening of your disease, you will 
continue to have imaging studies approximately every 3 months until your disease worsens. You 
can have these studies at home institution and send us results.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
If you are unable to return for these visits, we will obtain the information from you by telephone 
or e-mail.
Once you stop coming to Clinical Center for safety visits and your scans, we will call or e-mail 
you every year for 2 years to check on your health. 
Each visit should last no more than 8 hours.
Additional research testing
In addition to the tests that we will conduct to determine whether you are having side effects or if 
you are responding to the study therapy, we will also collect samples from you and perform tests 
for purposes of research only. Tumor and blood samples may be used to look at the effects of 
therapy on your immune system, markers of tumor activity, how well tumor genes are working, to 
check drug level in the blood and free tumor DNA and tumor cells circulating in the blood.
Blood samples 
Blood samples around 0.5 cup (~130 ml) total will be collected including all days as indicated 
below. This amount of blood is within the blood collection total limit (550 ml) that could be drawn 
from adult participants within any 8-week period. 

on first day of treatment before taking drug (groups 1 and 2)

on first day of treatment every few hours after taking drug for up to 6 hours (group 1 only)

on day 7 of treatment before and approximately 30 minutes after taking drug (group 1 only) 

on day 1 of cycle 1 before treatment 

on day 1 of cycle 1 at the end of M7824 infusion (group 1 and 2 only)

on day 15 of cycle 1 

on day 1 of cycles 2 and 3 before treatment 
Tumor samples 
We will ask you to provide samples of your tumors from previous surgeries or biopsies if available. 
We also may perform three optional tumor biopsies: before therapy, at the time of first imaging 
study and at the time of worsening of the disease. Please see Risks from Biopsy for the risks of 
biopsy. You can participate in this study even if you decide not to undergo the biopsy procedures. 
You will be asked to sign a separate consent each time you agree to have an optional biopsy.
Tumor and blood samples collected for research purposes on this study may be used to look for 
specific changes in the DNA in tumors that could be used to develop new ways of diagnosing and 
treating cancer. DNA (also called deoxyribonucleic acid) in the cells carries genetic information 
and passes it from one generation of cells to the next – like an instruction manual. Normal tissue 
contains the DNA (instructions) that you were born with, DNA in tumor cells has changed – or 
mutated – and we think that change in the DNA is what causes tumors to form and to grow. RNA 
(also called ribonucleic acid) carries the instructions from the DNA to the parts of your cells that 
make proteins. 
IRB NUMBER: 20C0155
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To look at your RNA, we may use do what is called “RNA sequencing.” This is where we will do 
special tests in the lab to look at the sequence, or order, of how your RNA are put together. 
To determine which parts of the RNA have mutated, we will compare the RNA in your tumor cells 
to RNA from normal cells. We will then analyze the results from similar tumors to see if there are 
any changes in the RNA that are common to a particular type of tumor.
HOW LONG WILL THE STUDY TAKE?
You will come to the NIH Clinical Center to get treatment and check status of your health every 
two weeks for 2 years or until your disease gets worse or you have unacceptable side effects at 
which time, we will stop treatment. If you are tolerating and benefiting from the study drugs, 
treatment may continue after 2 years.
Visits will range from 4-8 hours in length.
Some of these visits may be done with your local provider if you are unable to return to the NIH.   
After stopping treatment, we would like to see you regularly in the NIH Clinical until your disease 
worsens. If your disease gets worse, we will contact you during the following 2 years to check on 
your health.
HOW MANY PEOPLE WILL PARTICIPATE IN THIS STUDY?
We plan to have up to 105 people take part in this study.
WHAT ARE THE RISKS AND DISCOMFORTS OF BEING IN THE STUDY?
The drug used in this study may affect how different parts of your body work such as your liver, 
kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if 
changes occur that may affect your health.
Here are important points about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last longer.

Some side effects may be serious and may even result in death.
Here are important points about how you and the study doctor can make side effects less of a 
problem:

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.

The study doctor may adjust the study drugs to try to reduce side effects.
SX-682

Low blood cell counts, which may lead to anemia, bleeding, or infection.

Problems with your heart noted on electrocardiogram (EKG – a record of your heartbeat) 
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
Widespread immune activation known as “cytokine storm”, which may include fever, 
muscle aches, confusion, drop in blood pressure, difficulty breathing, or kidney failure.

Tumor lysis syndrome (TLS) is caused by the sudden, rapid death of cancer cells in 
response to treatment. When cancer cells die, they may spill their inner (intracellular) 
contents, which accumulate faster than they can be eliminated. This debris from the cancer 
cells can change the balance of the chemistry of the body, which can be dangerous. 
Symptoms of tumor lysis syndrome include severe nausea and vomiting, shortness of 
breath, an irregular heartbeat, kidney failure, urine abnormalities, severe fatigue and/or 
joint pain.

Immune suppression, which may lead to infection.

Increase in frequency and/or severity of immune-related adverse events of M7824 and/or 
CV301, which may make worse the side effects of the other drugs you will take (see under 
M7824 and CV301).
M7824
Common (occurring in more than 5 % of patients)

Tiredness 

Nausea 

Diarrhea

Constipation

Vomiting

Swelling of your lower legs or hands

Fever

Decreased appetite

Loss of body fluids (dehydration)

Skin growths called keratoacanthomas that resemble skin cancer. These usually go away 
after treatment and can leave a scar.

Rash, blisters, skin discoloration and other skin abnormalities

Bleeding has been frequently observed in patients receiving M7824. Patients may 
experience bleeding in different sites such as gums, nose, ears, eyes, vagina, breast); have 
blood in the urine or stool; cough up or vomit blood; or have bleeding in internal organs, 
including within the lungs and gastrointestinal tract, the brain or head. . Occasionally, this 
bleeding can be serious and potentially life threatening or fatal. If the bleeding is severe 
you may require a blood transfusion. If you experience any bleeding on this trial, please 
tell the study team immediately. Tell your doctor if you've had a life-long problem of 
frequent or excessive bleeding or bruising, or if you take aspirin or prescription medication 
to thin your blood.
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
Shortness of breath

Cough

Anemia - low number of red blood cells that can cause tiredness and shortness of breath.  
This may require a blood transfusion.

Abdominal pain

Headache

Itching
Occasional (occurring in less than 5% of patients)

Chills (feeling cold)

Shortness of breath

Blood clots that form throughout the body, blocking small blood vessels. Symptoms may 
include chest pain, shortness of breath, leg pain, problems speaking, or problems moving 
parts of the body

Easy bruising

Reaction to other drugs such as rash, anaphylaxis, and changes in blood

Infusion-related reaction, including dizziness or fainting (low blood pressure), flushing, 
rash, fever, shortness of breath or sick to your stomach, or pain at the site of infusion. 
Although usually reversible with treatment, it can be severe or life threatening

Back pain

Cancerous growth on the skin that can be removed

Stroke

Slow wound healing. If you are having surgery please discuss with your doctor. 

Thickening of the skin, nails
In addition to the above, we have seen a few cases of nodular regenerative hyperplasia.  This is 
when small growths, or nodules, occur in the liver.  These usually do not cause symptoms, but can 
occasionally be associated with high blood pressure in the vein to the liver which could over time 
lead to liver damage.
Allergic reactions or reactions related to the infusions might occur during treatment. 
Although M7824 is a fully human protein the risk cannot be completely excluded. Usually, these 
reactions are mild to moderate and can be treated with drugs, but in very rare cases they can also 
be severe, life-threatening which require advanced cardiac life support, or fatal. 
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For the prevention of infusion-related side effects and possible allergic reactions you may receive 
a premedication of an antihistamine drug (Benadryl® or similar) and acetaminophen (Tylenol®) 30 
to 60 minutes before the infusion.
There is a risk for keratoacanthomas, a type of skin lesion. These appear as small bumps and have 
the potential to turn into squamous cell carcinoma skin cancer gradually over time. We work with 
a dermatologist at the NIH. If you develop a keratoacanthoma while on this study, we will make 
every attempt to prevent progression to skin cancer. The dermatologist will monitor you regularly 
and can remove these lesions if indicated. 
In addition, immune-related side effects might be possible. These adverse events are caused by 
over activity of your body’s immune system. The immune system normally protects you from 
infections and foreign substances, and sometimes from cancer. If the immune system is overactive, 
it may think that parts of the body are foreign substances and attack them.
Examples of these are listed below. In rare cases, immune-related side effects can be life-
threatening or fatal.
Types of immune-related side effects:

joint pain

arthritis (inflammatory disease of the joint)

pneumonitis (inflammatory disease of the lung): symptoms may include but are not limited 
to a new or worsening cough, shortness of breath possibly with fever. Preliminary data 
suggested that there may be the tendency of higher frequency and severity in Japanese 
patients compared with non-Japanese patients: tell your study doctor right away if you have 
any of these symptoms as it may need to be treated urgently

hypothyroidism (decreased function of the thyroid gland)

hyperthyroidism (increased function of thyroid gland)

thyroiditis (inflammatory disease of the thyroid gland)

autoimmune hepatitis (inflammatory disease of the liver caused by the body’s immune 
system): Signs and symptoms of this include yellowing of the skin or whites of the eyes, 
dark urine, severe nausea and vomiting, pain in the upper right side of your abdomen, skin 
itchiness, not feeling hungry and bleeding or bruising more easily than normal

thrombocytopenia (decrease of the blood platelets)

dry eyes

inflammatory eye disease 

diabetes mellitus (high blood sugar levels)

Problems with your adrenal glands (Adrenal Insufficiency): may cause stomach pains, 
vomiting, muscle weakness and fatigue, depression, low blood pressure, weight loss, 
kidney problems, and changes in mood and personality. These complications may be 
permanent and may require hormone replacement
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
inflammatory disease of muscles characterized by pain and tenderness

colitis (inflammatory disease of the large intestine): It may cause abdominal pain and 
diarrhea with or without blood. Fever may be present. It may require you to receive 
additional fluids. If left untreated, in rare occasions this may lead to a tear in the wall of 
the intestine which can be serious and life threatening

Autoimmune encephalitis is a type of brain inflammation where the body's immune system 
attacks healthy cells and tissues in the brain or spinal cord

psoriasis 

autoimmune disorder (body’s immune system attacks its own cells) potentially affecting 
any area of the body and can result in swelling, pain, and/or organ dysfunction

myocarditis (inflammation of the heart muscle)

skin rash with blisters that can be itchy 

Kidney problems: you may have an increase of creatinine levels in a blood test (creatinine 
is a protein marker that measures kidney function) but not have any symptoms or feel 
unwell. Uncommonly a patient may experience nephritis which is an inflammation of the 
kidneys that stops the kidneys from working properly

Problems with the pituitary gland (hypopituitarism): Hypopituitarism refers to decreased 
output of hormones from the pituitary gland in the brain and may be caused by 
inflammation of the pituitary gland (hypophysitis). Symptoms may include headaches, 
thirstiness, and trouble seeing or double vision, leakage of breast milk or irregular periods 
in women. These complications may be permanent and may require hormone replacement

Pancreatitis (inflammation of the pancreas)

Liver problems: Increases in the blood level of substances called enzymes found within 
your liver cells. The enzyme changes are unlikely to make you feel unwell, however, if 
these blood enzyme levels become very high, your study doctor may need to stop the study 
medication

Nervous system problems: symptoms can include unusual weakness of legs, arms, or face, 
numbness, or tingling in hands or feet. In rare situations, there is the potential for the 
inflammation of the nervous system to be severe.
CV301 vaccines
Likely 

Injection-site reaction (pain or discomfort, itching, redness, firmness, swelling, skin 
thickening, or bumps)

Flu-like symptoms (fatigue, soreness, general body pain, abdominal pain, cough, fever, 
headache) 
Less Likely 
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
Acute fever 

Chills 

Chest tightness 

Shortness of breath 

Arm or leg pain and/or swelling 

Headache 

Loss of appetite 

Weight loss 

Diarrhea 

Constipation 

Rash 

Nausea 

Dizziness 

Mild inflammation of tissue lining the lungs 

Chronic inflammation of the skin 

Difficulty sleeping

Open sores (ulcers) at the injection site

Bruising at the injection site

Warmth at the injection site 

Enlarged lymph nodes 

Low blood levels of sodium 

Inflammation of the testicles

Inflammation of thyroid tissue

Joint pain
Rare but Serious
•
Difficulty breathing 
•
Low blood pressure 
•
Wheezing 
•
Clots in the lung 
•
Clots in the leg 
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•
Kidney damage
•
Decreased blood oxygen levels
•
Fluid around the lining of the lungs
•
Fluid around the lining of the heart
Risks from Biopsy 
This procedure usually causes only brief discomfort at the site from which the biopsy is taken. 
Rarely, infection or bleeding may occur at the needle site.
Risks from Blood Collection 
Side effects of blood draws include pain and bruising in the area where the needle was placed, 
lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, 
low red blood cell count (anemia) can develop.
Risks from Contrast dye used in CT scans
If contrast dye is used, there is a risk for allergic reaction to the dye. If you are allergic to or 
sensitive to medications, contrast dye, iodine, or shellfish, you should notify it to the Study team. 
If you have had kidney problems/failure in the past, please notify it to your study doctor. 
What are the risks related to pregnancy?
If you are able to become pregnant, we will ask you to have a pregnancy test before starting this 
study.You will need to practice an effective form of birth control before starting study treatment, 
during study treatment, and for 6 months after you finish study treatment (the restricted period). If 
you become pregnant, there may be unknown risks to the fetus or unborn child, or risks that we 
did not anticipate. There may be long-term effects of the treatment being studied that could 
increase the risk of harm to a fetus. You must tell the study doctor if your birth control method 
fails during the restricted period, please contact the study team as soon as possible. If you think or 
know you have become pregnant during the restricted period, please contact the research team 
member identified at the top of this document as soon as possible.
If you are a sexually active person with a partner able to become pregnant, it is important that your 
partner not become pregnant during the restricted period. There may be unknown risks to a fetus 
or risks we did not anticipate. You and your partner must agree to use birth control if you want to 
take part in this study. If you think your partner has become pregnant during the restricted period, 
please contact the study team as soon as possible. If you and your partner plan for your partner to 
become pregnant after the restricted period, please discuss this with the study team.
What are the risks of radiation from being in the study?
During your participation in this research study, you will be exposed to radiation from up to 9 CT 
scans (chest/abdomen/pelvis) and up to 3 CT-guided biopsies (optional).  The amount of radiation 
exposure you will receive from these procedures is equal to approximately 12.3 rem. A rem is a 
unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
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of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans that you get in this study will expose you to the roughly the same amount of radiation 
as 41 years of background radiation. Being exposed to too much radiation can cause harmful side 
effects such as an increase in the risk of cancer. The risk depends on how much radiation you are 
exposed to. Please be aware that about 40 out of 100 people (40%) will get cancer during their 
lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer from the radiation 
exposure in this study is 1.2 out of 100 (1.2%) and of getting a fatal cancer is 0.6 out of 100 (0.6 
%).
Risks of MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. 
Welders and metal workers may have small metal fragments in the eye. You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff. You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss. Everyone 
having a research MRI scan will be fitted with hearing protection. If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans
Risks of gadolinium enhanced MRI
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, hives, 
and lowering of blood pressure. You should not receive gadolinium if you previously had an 
allergic reaction to it.  You will be asked about such allergic reactions before gadolinium is given.   
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of deaths.  
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A blood test of your kidney function may be done within the month before an MRI scan with 
gadolinium contrast. You will not receive gadolinium for a research MRI scan if your kidney 
function is below the safe level. 
Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to years.  
The long-term effects of the retained gadolinium are unknown.  Some types of gadolinium contrast 
drugs are less likely to remain in the body than others.  In this study, we will use the gadolinium 
contrast drugs that are less likely to remain in the body.
WHAT ARE THE BENEFITS OF BEING IN THE STUDY?
You might not benefit from being in this study. 
However, the potential benefit to you might include shrinking of your tumor or lessening of your 
symptoms, such as pain, that are caused by the cancer.
Are there any potential benefits to others that might result from the study?
In the future, other people might benefit from this study because what we learn in this study may 
eventually be used to treat others with your disease. 
WHAT OTHER OPTIONS ARE THERE FOR YOU?
Before you decide whether or not to be in this study, we will discuss other options that are 
available to you. Instead of being in this study, you could: 

choose to be treated with surgery, radiation or with drugs already approved by the FDA for 
your disease

choose to take part in a different study, if one is available

choose not to be treated for cancer but you may want to receive comfort care to relieve 
symptoms.
DISCUSSION OF FINDINGS
New information about the study
If we find out any new information that may affect your choice to participate in this study, we 
will get in touch with you to explain what we have learned. This may be information we have 
learned while doing this study here at the NIH or information we have learned from other 
scientists doing similar research in other places.
Return of research results
Results of research studies performed on this study will not be shared with you.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if your disease worsens or comes back during treatment

if you become pregnant

if you have side effects from the treatment that your doctor thinks are too severe

if you need treatment that is not allowed on this study
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
if study drugs become unavailable

if new information shows that another treatment would be better for you

if the study is stopped for any reason
In this case, you will be informed of the reason therapy is being stopped. 
After therapy is stopped, we would like to see you for a safety visit 30 days after your last dose.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to EMD Serono, Bavarian 
Nordic, Syntrix or designated representatives.
STORAGE, SHARING AND FUTURE RESEARCH USING YOUR SPECIMENS AND 
DATA
Will Your Specimens or Data Be Saved for Use in Other Research Studies?
As part of this study, we are obtaining specimens and data from you. We will remove all the 
identifiers, such as your name, date of birth, address, or medical record number and label your 
specimens and data with a code so that you cannot easily be identified. However, the code will 
be linked through a key to information that can identify you. We plan to store and use these 
specimens and data for studies other than the ones described in this consent form that are going 
on right now, as well as studies that may be conducted in the future. These studies may provide 
additional information that will be helpful in understanding colorectal cancer, or other diseases 
or conditions. This could include studies to develop other research tests, treatments, drugs, or 
devices, that may lead to the development of a commercial product by the NIH and/or its research 
or commercial partners. There are no plans to provide financial compensation to you if this 
happens. Also, it is unlikely that we will learn anything from these studies that may directly 
benefit you.
I give permission for my coded specimens and data to be stored and used for future research as 
described above.
_____ Yes
_____ No
Initials
Initials
Will Your Specimens or Data Be Shared for Use in Other Research Studies?
We may share your coded specimens and data with other researchers. If we do, while we will 
maintain the code key, we will not share it, so the other researchers will not be able to identify 
you. They may be doing research in areas that are similar to this study or in other unrelated areas. 
These researchers may be at NIH, other research centers and institutions, or commercial entities. 
I give permission for my coded specimens and data to be shared with other researchers and used 
by these researchers for future research as described above.
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_____ Yes 
_____ No
Initials
Initials
If you change your mind and do not want us to store and use your specimens and data for future 
research, you should contact the research team member identified at the top of this document. 
We will do our best to comply with your request but cannot guarantee that we will always be 
able to destroy your specimens and data. For example, if some research with your specimens and 
data has already been completed, the information from that research may still be used. Also, for 
example, if the specimens and data have been shared already with other researchers, it might not 
be possible to withdraw them. 
In addition to the planned use and sharing described above, we might remove all identifiers and 
codes from your specimens and data and use or share them with other researchers for future 
research at the NIH or other places. When we or the other researchers access your anonymized 
data, there will be no way to link the specimens or data back to you. We will not contact you to 
ask your permission or otherwise inform you before we do this. We might do this even if you 
answered "no" to the above questions. If we do this, we would not be able to remove your 
specimens or data to prevent their use in future research studies, even if you asked, because we 
will not be able to tell which are your specimens or data.
NIH policies require that your clinical and other study data be placed in an internal NIH database 
that is accessible to other NIH researchers for future research. These researchers will not have 
access to any of your identifiers, such as your name, date of birth, address, or medical record 
number; and your data will be labeled with only a code. We cannot offer you a choice of whether 
your data to be placed in this database or not. If you do not wish to have your data placed in this 
database, you should not enroll in this study. 
Will Your Genomic Data Be Shared Outside of This Study?
As part of this research study, we will put your genomic data in a large database for broad sharing 
with the research community. These databases are commonly called data repositories. The 
information in this database will include but is not limited to genetic information, race and 
ethnicity, and sex. If your individual data are placed in one of these repositories, they will be 
labeled with a code and not with your name or other information that could be used to easily 
identify you, and only qualified researchers will be able to access them. These researchers must 
receive prior approval from individuals or committees with authority to determine whether these 
researchers can access the data.
Summary information about all of the participants included in this study (including you) is being 
placed in a database and will be available through open access. That means that researchers and 
non-researchers will be able to access summary information about all the participants included in 
the study, or summary information combined from multiple studies, without applying for 
permission. The risk of anyone identifying you with this information is very low.
NIH policies require that genomic data be placed in a repository for sharing. Therefore, we 
cannot offer you a choice of whether your data will be shared. If you do not wish to have your 
data placed in a repository, you should not enroll in this study. 
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
How Long Will Your Specimens and Data be Stored by the NIH?
Your specimens and data may be stored by the NIH indefinitely. 
Risks of Storage and Sharing of Specimens and Data
When we store your specimens and data, we take precautions to protect your information from 
others that should not have access to it. When we share your specimens and data, we will do 
everything we can to protect your identity, for example, when appropriate, we remove information 
that can identify you. Even with the safeguards we put in place, we cannot guarantee that your 
identity will never become known or someone may gain unauthorized access to your information. 
New methods may be created in the future that could make it possible to re-identify your specimens 
and data.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses. Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.  You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

If some tests and procedures are performed outside the NIH Clinical Center, 
you may have to pay for these costs if they are not covered by your insurance 
company.

Medicines that are not part of the study treatment will not be provided or paid 
for by the NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be 
provided by the NIH Clinical Center.
CONFLICT OF INTEREST (COI) 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest. This process is detailed in a COI Guide. You may ask your research team for a copy of 
the COI Guide or for more information. Members of the research team who do not work for NIH 
are expected to follow these guidelines or the guidelines of their home institution, but they do not 
need to report their personal finances to the NIH.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
The National Institutes of Health and the research team for this study have developed CV301 being 
used in this study. This means it is possible that the results of this study could lead to payments to 
NIH. By law, the government is required to share such payments with the employee inventors. 
You will not receive any money from the development of CV301.
The NIH and the research team for this study are using SX-682, M7824 and CV301 vaccines 
developed by Syntrix, EMD Serono and Bavarian Nordic through a joint study with your study 
team and the company. These companies also provide financial support for this study. 
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING 
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY 
Some of your health information, and/or information about your specimen, from this study will 
be kept in a central database for research. Your name or contact information will not be put in 
the database. Your test results will be identified by a unique code and the list that links the code 
to your name will be kept separate from your sample and health information. Your information 
may be given out if required by law. For example, certain states require doctors to report to health 
boards if they find a disease like tuberculosis. However, the researchers will do their best to 
make sure that any information that is released will not identify you.
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private. However, we cannot guarantee total privacy. Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor Center for Cancer Research of National Cancer Institute.

Qualified representatives from Syntrix, EMD Serono or Bavarian Nordic, the 
pharmaceutical companies who provides SX-682, M7824 and CV301 vaccines.
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances. 
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court. 
The Certificate does not protect your information when it: 
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical information 
that we collect under the authority of the Public Health Service Act. In some cases, the Privacy 
Act protections differ from the Certificate of Confidentiality. For example, sometimes the Privacy 
Act allows release of information from your record without your permission, for example, if it is 
requested by Congress. Information may also be released for certain research purposes with due 
consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit. However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES 
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022




PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2022
Page 23 of 23
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness should sign below if either:
1. A short form consent process has been used to enroll a non-English speaking subject or
2. An oral presentation of the full consent has been used to enroll a blind or illiterate subject
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not also 
serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 20C0155
IRB APPROVAL DATE: 04/05/2022

Prot_SAP_002.pdf: 
Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
1 
Abbreviated Title: STAT Trial 
NIH Protocol # 20C0155 
Version Date: 08/17/2022 
NCT # NCT04574583 
IBC # RD-20-IV-09  
Title: Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and 
Clinical Activity of SX-682 in Combination with BinTrafusp Alfa (M7824 or TGF-β 
“Trap”/PD-L1) with CV301 TRICOM in Advanced Solid Tumors (STAT). 
 
NIH Principal Investigator: 
 
James Gulley, MD, PhD  
Genitourinary Malignancies Branch (GMB)  
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
 
 
 
 
  
 
 
Drug Name: 
SX-682 
Bintrafusp alfa 
(M7824) 
 
MVA-BN-
CV301 
FPV-CV301 
IND Number: 
21166  
Sponsor: 
CCR, NCI 
 
Manufacturer: 
Syntrix 
EMD Serono 
Bavarian 
Nordic 
Bavarian 
Nordic 
Supplier: 
Syntrix 
EMD Serono 
Bavarian 
Nordic 
Bavarian 
Nordic 
 
Commercial Agents: None 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
2 
 
PRÉCIS  
Background: 
• Combination immunotherapy approaches are being actively explored to further improve 
responses, enhance clinical benefit, and overcome resistance to PD(L)-1 agents in cancer 
participants.  
• Interleukin-8 (IL-8) is a pro-inflammatory chemokine produced by various cell types. 
Overexpression of IL-8 and/or its receptors CXCR1 and CXCR2, is commonly seen in 
many human cancers including breast, cervical, melanoma and prostate.  
• SX-682 is an oral, small molecule inhibitor of the CXCR1/2 chemokine receptors that are 
believed involved in MDSC-recruitment to tumor and other pro-tumoral mechanisms.  
• Bintrafusp alfa (M7824 or MSB0011359C) is a bifunctional protein composed of the 
extracellular domain of the TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1. 
Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking, antigen-
specific CD8+ T-cell lysis and NK cell activation. 
• CV301 is a poxviral-based vaccine comprised of recombinant Modified vaccinia Ankara 
(MVA-BN-CV301, prime) and recombinant fowlpox (FPV-CV301, boost). CV301 
contains transgenes encoding two (2) tumor-associated antigens (TAA), mucin 1 (MUC1) 
and carcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, 
ICAM-1 and LFA-3, designated TRICOM). A recent phase 1 clinical trial demonstrated 
that antigen-specific T cells to MUC1 and CEA, as well as to a cascade antigen, 
brachyury, were generated in most participants.  
• Preclinical studies performed in LTIB with SX-682, M7824 and a CEA-based vaccine 
showed a significant reduction in tumor growth as well as a significant increase in tumor 
infiltration with CD4+ and CD8+ T cells. 
Objectives: 
• Arm 1 (Sequential Dose Escalation):  
 To evaluate the safety and tolerability of single agent SX-682. 
 To determine the MTD of SX-682 followed by M7824 and CV301 vaccines in 
participants with advanced or metastatic solid tumors. If the MTD is not reached 
the study will be focused to describe the safety and tolerability of SX-682 
followed by M7824 and CV301 vaccines. 
• Arm 2 (Combination Dose Escalation):  
 To determine the recommended phase 2 dose (RP2D) of SX-682 with M7824 and 
CV301 vaccines in participants with advanced or metastatic solid tumors. If the 
MTD is not reached the study will be focused to describe the safety and 
tolerability of the drug combination. 
• Arm 3 (Expansion): 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
3 
 To evaluate preliminary efficacy based on Objective Response Rate (ORR), in 
each disease cohort separately. 
Eligibility: 
• Age > 18 years old 
• Arms 1 and 2 (Dose-Escalation Cohort): Subjects with cytologically or histologically 
confirmed locally advanced or metastatic solid tumors.  
• Arm 3 (Expansion Cohorts): 
o TNBC: Subjects with cytologically or histologically confirmed locally advanced 
or metastatic Triple Negative Breast Cancer that has progressed on at least one 
prior treatment in the advanced or in the metastatic setting.  
o HPV negative HNSCC: Subjects with cytologically or histologically confirmed 
locally advanced or metastatic, HPV negative head and neck squamous cell 
cancer (p16 negative for oropharyngeal) that has progressed on at least one prior 
treatment involving a platinum drug or cetuximab in advanced or in the metastatic 
setting.  
• Prior first line systemic therapy is required unless there is no standard treatment 
available, the participant cannot tolerate standard first line treatment, or the participant 
declines standard treatment after appropriate counseling has been provided.  
• ECOG performance status of 0 to 1 
• Adequate renal, hepatic, and hematologic function 
• Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but 
evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by 
RECIST but visible on CT scan). Participants with third space fluid (for example pleural 
effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have 
measurable disease according to RECIST 1.1 
Design: 
• Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term, 2-
week SX-682 monotherapy lead-in followed by treatment with M7824 and CV301 
vaccine series in advanced solid tumors (Q2W dosing schedule) for the duration of 
treatment. 
• Arm 2 is a phase I, open-label, 3+3 combination dose escalation trial with short term SX-
682 monotherapy lead in followed by SX-682 combination with M7824 and CV301 
vaccine series in advanced solid tumors (Q2W dosing schedule). Each enrolled 
participant will receive SX-682 as monotherapy for 2 weeks then will receive SX-682, 
M7824 and CV301 for the duration of treatment 
• Arm 3 has two expansion cohorts. Following identification of the MTD or R2PD for the 
combination of SX-682, M7824 and CV301 vaccine, disease-specific phase 2 expansion 
cohorts will open in 1) advanced/metastatic triple negative breast cancer and 2) 
advanced/metastatic, platinum-refractory HPV negative head and neck squamous cell 
carcinoma. 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
4 
 
TABLE OF CONTENTS  
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
STATEMENT OF COMPLIANCE ................................................................................................ 7 
1. 
INTRODUCTION .................................................................................................................. 8 
1.1 
Study Objectives .............................................................................................................. 8 
1.2 
Background and Rationale ............................................................................................... 9 
2 
ELIGBILITY ASSESSMENT AND ENROLLMENT ........................................................ 39 
2.1 
Eligibility Criteria .......................................................................................................... 39 
2.2 
Screening Evaluation ...................................................................................................... 42 
2.3 
Participant Registration And Status Update Procedures ................................................ 44 
2.4 
Baseline Evaluation ........................................................................................................ 45 
3 
STUDY IMPLEMENTATION ............................................................................................ 45 
3.1 
Study Design .................................................................................................................. 45 
3.2 
Study Stopping rules ...................................................................................................... 52 
3.3 
Drug Administration ...................................................................................................... 53 
3.4 
Dose Modifications ........................................................................................................ 54 
3.5 
Study Calendar ............................................................................................................... 68 
3.6 
Cost and Compensation .................................................................................................. 77 
3.7 
Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 77 
4 
Concomitant Therapy............................................................................................................ 78 
4.1 
The Following Treatments Should not be Administered During the Trial: ................... 78 
5 
CORRELATIVE STUDIES FOR RESEARCH ................................................................... 79 
5.1 
Samples .......................................................................................................................... 79 
5.2 
Correlative Studies for Research/Pharmacokinetic Studies ........................................... 80 
5.3 
Samples for Genetic/Genomic Analysis ........................................................................ 83 
5.4 
Sample Storage, Tracking and Disposition .................................................................... 84 
6 
DATA COLLECTION AND EVALUATION ..................................................................... 88 
6.1 
Data Collection ............................................................................................................... 88 
6.2 
Data Sharing Plans ......................................................................................................... 89 
6.3 
Response Criteria ........................................................................................................... 89 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 96 


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5 
7.1 
Definitions ...................................................................................................................... 96 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ....................................... 96 
7.3 
NCI Clinical Director Reporting .................................................................................... 96 
7.4 
Institutional Biosafety Committee (IBC) Reporting Criteria ......................................... 96 
7.5 
NIH Required Data and Safety Monitoring Plan ........................................................... 98 
8 
SPONSOR PROTOCOL/SAFETY REPORTING ............................................................... 98 
8.1 
Definitions ...................................................................................................................... 98 
8.2 
Assessment of Safety Events ........................................................................................ 100 
8.3 
Reporting of Serious Adverse Events .......................................................................... 100 
8.4 
Waiver of expedited reporting to CCR ........................................................................ 101 
8.5 
Safety Reporting Criteria to the Pharmaceutical Collaborators ................................... 101 
8.6 
Reporting Pregnancy .................................................................................................... 101 
8.7 
Regulatory Reporting for Studies Conducted Under CCR-Sponsored IND ................ 102 
8.8 
Sponsor Protocol Non-Adherence Reporting ............................................................... 102 
9 
CLINICAL MONITORING ............................................................................................... 102 
10 STATISTICAL CONSIDERATIONS................................................................................ 103 
10.1 
Statistical Hypothesis ............................................................................................... 103 
10.2 
Sample Size Determination ...................................................................................... 104 
10.3 
Populations for Analyses .......................................................................................... 105 
10.4 
Statistical Analyses ................................................................................................... 106 
11 Collaborative Agreements .................................................................................................. 107 
11.1 
Cooperative Research and Development Agreement (CRADA) ............................. 107 
12 HUMAN SUBJECTS PROTECTIONS ............................................................................. 108 
12.1 
Rationale for Subject Selection ................................................................................ 108 
12.2 
Participation of Children .......................................................................................... 108 
12.3 
Participation of Subjects Unable to Give Consent ................................................... 108 
12.4 
Risk/Benefit Assessment for All Participants .......................................................... 108 
12.5 
Consent Process and Documentation ....................................................................... 111 
13 REGULATORY AND OPERATIONAL CONSIDERATIONS ....................................... 112 
13.1 
Study Discontinuation and Closure .......................................................................... 112 
13.2 
Quality Assurance and Quality Control.................................................................... 112 
13.3 
Conflict of Interest Policy......................................................................................... 112 
13.4 
Confidentiality and Privacy ...................................................................................... 113 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
6 
14 PHARMACEUTICAL INFORMATION ........................................................................... 113 
14.1 
SX-682 (IND#21166) ............................................................................................... 113 
14.2 
M7824 (IND#21166) ................................................................................................ 114 
14.3 
CV301 (IND#21166) ................................................................................................ 115 
15 REFERENCES ................................................................................................................... 117 
16 Appendices .......................................................................................................................... 124 
16.1 
Appendix A-Performance Status Criteria ................................................................. 124 
16.2 
Appendix B: Drugs Known to Significantly Prolong the Qtc* ................................ 125 
16.3 
Appendix C Participant’s Medication Diary ________________________ ........... 127 
 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
7 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 


Abbreviated Title: STAT Trial 
Version Date: 08/17/2022 
 
8 
 
1. INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objectives: 
• Arm 1 (Sequential Dose Escalation):  
 To evaluate the safety and tolerability of single agent SX-682. 
 To determine the MTD of SX-682 followed by M7824 and CV301 vaccines in 
participants with advanced or metastatic solid tumors. If the MTD is not reached 
the study will be focused to describe the safety and tolerability of SX-682 
followed by M7824 and CV301 vaccines. 
• Arm 2 (Combination Dose Escalation):  
 To determine the RP2D of SX-682 with M7824 and CV301 vaccines in 
participants with advanced or metastatic solid tumors. If the MTD is not reached 
the study will be focused to describe the safety and tolerability of the drug 
combination. 
• Arm 3 (Expansion): 
 To evaluate preliminary efficacy based on objective response rate (ORR), in each 
disease cohort separately. 
1.1.2 Secondary Objectives: 
• Arms 1 and 2 (Dose Escalations):  
 To characterize the PK/PD profile of SX-682 as a single agent and in 
combination. 
• All Arms:  
 To evaluate preliminary efficacy: disease control rate (DCR; CR+PR+SD) and 
progression-free survival (PFS) using RECIST1.1. 
1.1.3 Exploratory Objectives (may be performed on selected participants if there are adequate 
samples.): 
• All Arms: 
 To evaluate the effect on immune cell subsets and soluble factors in peripheral 
blood. 
 To evaluate the effect on cytokine levels (IL-8, IL-6 and others) in peripheral 
blood. 
 To evaluate the effect on T cell clonality in peripheral blood and tumor samples. 
 To evaluate the effect on antigen-specific T cells responses to CEA, MUC1 and 
the cascade antigen brachyury in peripheral blood. 
 To evaluate the effect on antigen-specific T cell responses to CEA, MUC1 and the 
cascade antigen brachyury in tumor biopsies. 








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2 
ELIGBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria  
• Participants must have histologically or cytologically confirmed: 
 Metastatic or locally advanced, Solid tumor (Cohort 1) 
OR 
 Metastatic or locally recurrent, non-resectable Triple Negative Breast Cancer (TNBC), 
defined as ER < 10%, PR < 10% per immunohistochemistry (IHC) and HER 2 negative. 
HER2 negative or unamplified breast cancer is defined as IHC 0 or 1+ or IHC 2+ with 
FISH average HER2 copy number < 4.0 signals per cell or HER2/CEP17 < 2.0 with 
average HER2 copy number < 4.0 signals per cell.[89] HER2 testing must have been 
performed in a laboratory accredited by the College of American Pathology (CAP) or 
another accrediting entity (Cohort 2). 
OR 
 Metastatic or locally recurrent, non-resectable p16 negative Head and Neck Squamous 
Cell Cancer (HNSCC). Oropharyngeal tumors must be negative for p16 overexpression 
by IHC per ASCO/CAP guidelines and in a CAP accredited lab.[90] All other head and 
neck malignancies do not require p16 testing (Cohort 3). 
• Participants must have histologically or cytologically confirmed metastatic or locally 
advanced disease. Historical reports from a CAP accredited lab are acceptable.  
• Subjects in Arms 1 and 2 may have disease that is measurable or non-measurable but 
evaluable disease (e.g. present on bone scan, rising tumor markers, non-measurable by 
RECIST but visible on CT scan). Participants with third space fluid (for example pleural 
effusions) as only site of disease will not be eligible. Subjects in Arm 3 must have 
measurable disease according to RECIST 1.1See Section 6.3.1 for the evaluation of 
measurable disease.  
• Participants must  
 have received at least one prior systemic therapy for metastatic or locally advanced 
disease, unless there is no standard treatment available, 
OR 
 not tolerate standard first line treatment,  
OR 
 decline standard treatment after appropriate counseling has been provided.  
Note: Participants in Arm 3, Cohort 3 who have PD-L1 positive TNBC must have progressed on 
atezolizumab + nab-paclitaxel. Participants in Arm 3, Cohort 3 (p16 negative HNSCC) must 
have progressed on or been intolerant to a regimen involving a platinum drug or cetuximab 
monotherapy.  
• Age >18 years. 


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40 
• ECOG performance status 0 or 1 (Appendix A). 
• Participants must have adequate organ and marrow function as defined below:  
 Absolute neutrophil count (ANC) >1,500/mcL 
 Platelets >100,000/mcL 
 Hemoglobin > 9 g/dL without a blood transfusion in the 14 days prior to enrollment.  
 Total bilirubin < 1.5X upper limit of normal (ULN) OR in subjects with Gilbert’s 
Syndrome, a total bilirubin < 3.0 x ULN  
 AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal OR in subjects with 
known liver metastasis, AST/ALT < 3.0 X ULN 
 An estimated creatinine clearance (CrCl) > 60 mL/min/1.73 m2 using the Cockroft-Gault 
calculation (https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc). 
• The effects of immunotherapies on the developing human fetus are unknown. For this reason 
and because immunotherapy agents as well as other therapeutic agents used in this trial are 
known to be teratogenic, women of child-bearing potential and men must agree to use 
adequate contraception (hormonal or barrier method of birth control; abstinence) at the time 
of study entry, for the duration of study treatment and up to 6 months after the last dose of 
the study drug (s). Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician 
immediately.  
• Participants with well-controlled HIV infection are eligible for trial as long as: 
 On an effective anti-retroviral therapy (ART) > 4 weeks and with evidence of viral 
suppression defined as HIV viral load < 400 copies/mL at enrollment  
 CD4+ count > 200 cells/µL at enrollment  
• No reported opportunistic infections within 6 months prior to enrollment except for the 
following which will be allowed: 
o Esophageal candidiasis treated within last 6 months or currently improving with 
antifungal treatment 
o Oral and/or genital HSV treated within last 6 months or currently improving with 
antiviral treatment  
o Mycobacterium avium infection in last 6 months or that has been treated for at least 1 
month. 
• Immunomodulating drugs must be discontinued at least 1 weeks prior to enrollment for 
recent short course use (≤ 14 days) or discontinued at least 4 weeks prior to enrollment for 
long term use (> 14 days). 
• Participants must have a received their last treatment > 4 weeks or 5 half-lives of the last 
treatment drug, whichever is shorter before starting on trial. 
• Participants with known history of hepatitis B (HBV) infection are eligible for trial as long as 
the HBV viral load is undetectable.  


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• Participants with known history of hepatitis C (HCV) infection must have been treated and 
cured (viral load is undetectable). For participants with HCV infection who are currently on 
treatment, they are eligible if they have an undetectable or unquantifiable HCV RNA 12 
weeks or longer after definitive treatment completion. 
• Subjects must be able to understand and be willing to sign a written informed consent 
document. 
2.1.2 Exclusion Criteria 
• Participants who are receiving any other investigational agents. 
• Participants with active brain metastases or central nervous system metastasis (less than 28 
days out from definitive radiotherapy or surgery of brain metastasis) are excluded from this 
clinical trial. However, participants with treated brain metastasis are eligible if there is no 
magnetic resonance imaging (MRI) evidence of progression for 6 weeks after treatment is 
complete and the MRI within 28 days prior to enrollment. Participants requiring 
immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone equivalent) 
for palliation are excluded. Participants with evidence of intratumoral or peritumoral brain 
metastasis hemorrhage on screening imaging are also excluded unless the hemorrhage of 
brain metastases is grade < 1 and has been stable on two consecutive imaging scans.  
• History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to any of study drugs 
• Steroid use or active autoimmune disease that might deteriorate when receiving an 
immunostimulatory agent with the exception of:  
 Diabetes type I, eczema, vitiligo, alopecia, psoriasis, hypo- or hyperthyroid disease or 
other mild autoimmune disorder not requiring immunosuppressive treatment; 
 Participants requiring hormone replacement with corticosteroid are eligible if the 
steroids are administered only for the purpose of adrenal insufficiency and at doses of 
<10 mg of prednisone or equivalent per day; 
 Administration of steroids for other conditions through a route known to result in a 
minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is 
acceptable; 
 Participants on physiologic doses of systemic intravenous or oral corticosteroid 
therapy (≤ the equivalent of prednisone 10 mg/day.  
 The use of corticosteroids as premedication for contrast-enhanced studies which is 
allowed prior to enrollment. 
• Participants with a history of serious intercurrent chronic or acute illness, such as cardiac or 
pulmonary disease, hepatic disease, bleeding diathesis or recent (within 3 months) clinically 
significant bleeding events or other illness considered by the Investigator as high risk for 
investigational drug treatment. 
• History of second malignancy within 3 years of enrollment except for the following: 
adequately treated localized skin cancer, ductal carcinoma in situ, cervical carcinoma in situ, 
superficial bladder cancer or other localized malignancy which has been adequately treated.  


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• Receipt of any organ transplantation requiring ongoing immunosuppression including 
allogenic stem-cell transplant.  
• Participants with bone metastases who have initiated denosumab or a bisphosphonate therapy 
within 28 days prior to enrollment. Continuation of prior therapy is allowed.  
• Participants who have a QTcf interval > 475 msec or > 480 msec with a BBB on screening 
electrocardiogram.  
• Participants with a personal or family history of long-QT syndrome or are on a concomitant 
drug that is known to cause significant QTc prolongation within 2 weeks or 5 half-lives 
(whichever is shorter) of enrollment (see Appendix B for list of drugs) 
• Participants with heart failure (New York Heart Association [NYHA] class III or IV) or 
cerebrovascular accident within one year or acute myocardial infarction within one year. 
• Participants unwilling to accept blood products or blood transfusions as medically indicated. 
As there is a risk of severe bleeding with M7824, participants must be willing to receive 
blood transfusions if medically necessary for their own safety 
• Any other condition, which would, in the opinion of the Principal Investigator indicated the 
subject is a poor candidate for the clinical trial or would jeopardize the subject or the 
integrity of the data obtained. 
• Pregnant women are excluded from this study because study drugs potential for teratogenic 
or abortifacient effects are unknown. Because there is an unknown but potential risk for 
adverse events in nursing infants secondary to treatment of the mother with study drugs, 
breastfeeding should be discontinued if the mother is treated with study drugs. 
2.1.3 Recruitment Strategies 
This protocol may be abstracted into a plain language announcement posted on NIH websites, 
including www.clinicaltrials.gov and the CCR website, and on NIH social media forums. 
Outside providers and colleagues may directly refer participants for screening into this study. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.  
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videosReview of existing pathology specimens/reports 
from a specimen obtained for diagnostic purposes. 
2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study #01-C-0129 (provided the procedure is permitted on the study) on which 
screening activities will be performed. Assessments performed at outside facilities or on another 


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NIH protocol within the timeframes below may also be used to determine eligibility once a 
participant has signed the consent. 
All screening tests and procedures must be performed within 28 days prior to initiation of study 
therapy, unless otherwise specified:  
• Complete medical history and physical examination (including weight, height, vital 
signs, and ECOG performance status). 
• CT of chest, abdomen and pelvis with contrast (preferred)  
• A brain CT  
• Clinical laboratory tests (within 16 days prior to enrollment) 
− Biochemical Profile: sodium, potassium, chloride magnesium, phosphorus,  
bicarbonate, calcium, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, 
total protein, albumin, and total and direct bilirubin,. 
− Hematology: complete blood count (CBC) with differential and platelets 
− CD4 (if clinically indicated) 
− TSH, free T4, lipase, amylase 
− Lymphocyte panel (TBNK) 
− Coagulation panel: PT, INR, PTT 
− Urinalysis 
− Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of menopause (within 7 days prior to enrollment).  
− HBV, HCV (or HCV viral load if recently completed treatment for HCV), HIV 
viral load by PCR (within 3 months prior to enrollment). 
• Electrocardiogram (EKG) in triplicate 
• Histologic or cytologic confirmation of tumor disease (at any time point prior to 
enrollment). Confirmation of tumor histology in NCI Laboratory of Pathology 
(archival tumor samples will be requested; if unavailable, the subject may choose to 
undergo fresh biopsy). Pathological confirmation of diagnosis of cancer in the 
Laboratory of Pathology at NIH Clinical Center or Walter Reed National Military 
Medical Center at Bethesda. However, if no pathologic specimen is available or if 
participants arrived with a diagnosis from Walter Reed National Military Medical 
Center at Bethesda, patients may enroll with a pathologist’s report showing a 
histologic diagnosis of metastatic cancer, TNBC or HPV negative HNSCC in a 
College of American Pathologists (CAP) accredited laboratory and a clinical course 
consistent with the disease. If there is no available tumor sample or pathology report 
from a CAP accredited lab, a biopsy will be performed to confirm the diagnosis in a 
CAP accredited lab. 
• Documentation of Immunohistochemistry (IHC) confirmation of Triple Negative 
Breast Cancer (TNBC), defined as ER < 10%, PR < 10% and HER2 negative. HER2 


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negative or unamplified breast cancer is defined by IHC and FISH HER2 testing. 
FISH must have been performed in a laboratory accredited by the College of 
American Pathology (CAP) or another accrediting entity (Arm 3, Cohort 2 only) (at 
any time point prior to initiation of study therapy) 
• Documentation of IHC confirmation of HPV negative, oropharyngeal tumor is 
defined by negative p16 overexpression in the tumor (Arm 3, Cohort 3 only) (at any 
time point prior to initiation of study therapy). Other head and neck malignancies do 
not require p16 testing. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found  at: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
2.3.1 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a 
lab abnormality or temporary condition may be rescreened.. 
2.3.2 Treatment Assignment Procedures (for registration purpose only): 
Cohorts 
Number Name 
Description 
1 
Phase 1: Solid Tumor  
Participants with any solid tumor enrolled to SX-682 
escalation dose levels 
2 
Phase 2: TNBC Expansion 
Participants with Triple Negative Breast Cancer 
enrolled at the RP2D of SX-682 in combination with 
M7824 and CV301 
3 
Phase 2: HPV-HNSCC 
Expansion 
Participants with HPV negative Head and Neck 
Cancer enrolled at the RP2D of SX-682 in 
combination with M7824 and CV301 
Arms 
Number Name 
Description 
1 
Sequential Dose Escalation 
Escalating doses of SX-682 for 2 weeks THEN 
M7824 + CV301  


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Number Name 
Description 
2 
Combination Dose 
Escalation  
Escalating doses of SX-682 for 2 weeks THEN 
Escalating doses of SX-682 + M7824 + CV301  
3 
Disease-Specific Expansion  RP2D of SX-682 + M7824 + CV301  
Participants in Cohort 1 will be sequentially assigned to Arms 1 and 2.  
Participants in Cohorts 2 and 3 will be assigned to Arm 3. 
2.4 
BASELINE EVALUATION 
Tests done at screening do not need to be repeated on baseline if performed in designated time 
frame prior to start of study treatment 
Within 7 days prior to first dose of any study drug: 
• Physical exam including height, weight, ECOG performance status and vital signs.  
• Concomitant Medications and Baseline Signs and Symptoms evaluation. 
• EKG 
• Serum pregnancy test (β-HCG) for females of childbearing-potential and women 
< 12 months since the onset of natural menopause (i.e., amenorrhea not induced by 
chemotherapy or other medication). 
• Biochemical Profile: sodium, potassium, chloride, magnesium, phosphorus,  
bicarbonate, calcium, glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, 
total protein, albumin, and total and direct bilirubin. 
• TSH, free T4, lipase, amylase 
• Hematology: CBC with differential and platelets. Lymphocyte panel (TBNK)  
• Coagulation panel: PT, INR, and PTT 
• Urinalysis 
• Flexible clinic-based pharyngolaryngoscopy to evaluate the airway for safety and for 
mucosal involvement (if clinically indicated in participants with head and neck 
cancers) 
• Collection of archival tumor samples for research if available (any time prior to 
treatment). 
• Optional tumor biopsy for research purposes. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN  
This is an open label Phase I/II trial, consisting of a safety run-in phase I (Arms 1 and 2) and an 
expansion phase II, disease-specific cohorts (Arm 3). 
In Arm 1 the safety and MTD dose of short term (2 weeks) SX-682 monotherapy lead-in 
following by treatment with M7824 and CV301 will be determined in participants with solid 


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tumors (Schema 1). An evaluation of DLTs (eDLTs) will occur at the completion of each dose 
level and will be done prior to enrolling on the next dose level.  
In Arm 2 the safety, MTD/RP2D of continuing treatment of SX-682 in combination with M7824 
and CV301 will be determined in participants with solid tumors (Schema 2). An evaluation of 
DLTs (eDLTs) will occur at the completion of each dose level and will be done prior to enrolling 
on the next dose level. 
During Arm 3 expansion cohorts, when RP2D of SX-682 in combination with M7824 and 
CV301 is estimated, we will proceed with enrollment to Cohorts 2 (participants with triple 
negative breast cancer) and Cohort 3 (participants with HPV negative head and neck cancer) to 
evaluate efficacy of the SX-682 in combination with M7824 and CV301 (Schema 3).  
SX-682 will be self-administered by the participant orally twice daily according to designated 
Dose Level ( Table 4). 
Administration of M7824 will be at a flat dose of 1,200 mg every 2 weeks by IV. Participants 
will receive M7824 treatment every 14 (-1/+3) days. 
CV301 will be administered at a flat dose for both the prime and booster vaccines. The priming 
MVA-BN-CV301 is delivered as four subcutaneous injections of 4x108 infectious units 
(Inf.U)/0.5 mL every 14 days for 2 doses (Cycle 1, Day 1 and Cycle 1, Day 15). FPV-CV301 is 
given subcutaneously at 1×109Inf.U/0.5 mL every 4 weeks starting on Cycle 2 Day 1 x 4 cycles 
then on Day 1 of every 3 cycles (every 12 weeks) for up to 1 year on trial. Participants will 
receive CV301 as scheduled (-1/+3) days. 
Subjects on all arms will receive combined treatment with study drugs for up to 2 years (BN-
CV301 will be administered for up to 1 year on trial; M7824 and SX-682 will be administered 
for up to 2 years on trial). Furthermore, after 2 years on treatment with M7824 and/or SX-682, 
the PI can discuss an additional treatment period with CRADA partners as long as in the opinion 
of the PI the participant continues to gain clinic benefit and is tolerating the drug regimen. 
Disease progression should be confirmed with a subsequent scan 4 to 8 weeks later prior to 
removing a participant from study therapy, unless the participant is clinically progressing or is no 
longer gaining benefit in the opinion of the investigator. Subjects with evidence of disease 
progression can remain on treatment beyond radiographic progression if in the opinion of the 
investigator the subject is benefiting from treatment. For complete list of off treatment criteria, 
see Section 3.7.2. 
Patients may undergo up to three optional biopsies for research purposes only: at baseline, at first 
restaging (+/- 1 week) and at time of progression. 
 


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Schema 1. Cohort 1, Arm 1 
 


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Schema 2. Cohort 1, Arm 2. Combination Dose Escalation Cohort. 
 
3.1.1 Dose Limiting Toxicity 
Dose-limiting toxicity (DLT) will be defined as any one of the following adverse events (AEs), 
as defined by CTCAE v5.0, possibly attributable to study drugs by the Investigator, that occur 
within 28 days after the start of study therapy: 
• Any Grade 4 AEs, except for: 
o  laboratory values that are determined to not be clinically significant or single 
laboratory valued that resolve to Grade ≤ 1 or baseline grade within 7 days with 
adequate medical management. 
o adverse drug reaction which in the opinion of the investigator is not clinically 
relevant or can be medically managed with minimal risk to the participant (e.g. 
placement of a pleural catheter for recurrent inflammatory pleural effusions) 
• Average QTcf ≥ 501 msec or > 60 msec change from baseline (Grade 3) 
• Any Grade 3 AEs except for any of the following: 
o Grade 3 flu-like symptoms or fever, as well as associated symptoms of fatigue, 
headaches, nausea, emesis which can be controlled with conservative medical 
management.  
o Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites 
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o Any Grade ≥ 3 drug-related amylase or lipase abnormality that is not associated 
with symptoms or clinical manifestations of pancreatitis.  
o Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood 
transfusions or erythroid growth factor use does not require treatment 
discontinuation.  
o Keratoacanthoma and squamous cell carcinoma of the skin.  
o Any endocrinopathy that can be medically managed with hormone replacement 
o Grade 3 neutropenia without fever 
o Since the safety profile of M7824 is well characterized (see IB), a single grade 3 
adverse event known to be associated with M7824, as per IB section 6.2.6 will not 
be considered a DLT. 
 Additionally, M7824 has a known potential to cause bleeding, with a rate 
of grade 3 bleeding events as high as 15.3% [92].  Therefore a grade 3 
bleeding event will not be considered a DLT. 
o Any grade 3 adverse drug reaction which in the opinion of the investigator is not 
clinically relevant or can be medically managed with minimal risk to the 
participant (e.g. placement of a pleural catheter for recurrent inflammatory pleural 
effusions) 
• Any grade 3 or higher adverse event or unexpected toxicities due to the combination of 
therapies that would not be expected with individual agents alone, will be considered a 
DLT. 
3.1.2 Dose Escalation Common Rules 
Starting dose of SX-682 will be 25 mg by mouth twice daily (50 mg total daily dose). 
The first 3 participants enrolled on a given dose level of Arms 1 and 2 will be observed for DLT. 
If no DLT in those 3 participants, the next dose level will open. If DLT(s) occur, seeTable 5. 
There will be an interval of at least 28 days between enrolling the last participant on a given dose 
level and enrolling a participant on the next dose level in Arms 1 and 2, in order to assess for 
DLTs.  
Subjects who do not complete the DLT observation period for reasons other than a DLT will be 
replaced and not included in the evaluation. 
Participants will be eligible for the DLT evaluation if at least ≥85 percent of SX-682 scheduled 
doses were taken and 100% of scheduled doses of M7824 or CV301 were administered within 
the DLT period. 
In case of DLT, DLT will be documented and participant, per PI discretion, may continue study 
treatment if toxicity could be managed by interruption of the dose of study treatment or dose 
reductions (See section 3.4). Participant, once having DLT, will not be used for DLT evaluation 
on another dose level if treated on a lower dose level.  
Any of the trial drugs may be discontinued for toxicity per the discretion of the primary 
investigator if is it felt that the toxicity can be directly linked to a specific drug or drugs. Per PI 


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discretion participant can continue treatment with 2 other drugs. However, if 2 drugs or more 
must be discontinued, the participant will be taken off treatment. 
3.1.3 Sequential Dose Escalation (Arm 1) 
In Arm 1 participants will receive SX-682 as monotherapy for 2 weeks during the lead-in (Days -
14L to -1L) and then continue treatment with M7824 and CV301 starting Cycle 1, Day 1.  
The dose escalation will start from dose level 1 and continue until dose level 3 (Table 4) in 
sequential order using a standard 3+3 design (Table 5). Aside from looking at DLTs within a 
given dose level, the total number of DLTs will also be evaluated among the initial 3DLs in Arm 
1 to guide further safety assessments.  If there are 0 DLTs reported in the initial 3 DLs 
(minimum of 12 participants) in Arm 1, then Arm 2 can open as depicted in Schema 2 with 
starting at DL2. If there is 1 or more DLTs identified among all the participants in the first 3 
DLs, enrollment in Arm 1 will continue with the next participants being enrolled on DL4 then 
DL5, using a 3+3 design in order to determine the maximally tolerated dose (MTD) before 
proceeding to Arm 2, DL 1.  
Dose escalation will proceed in groups of 3–6 participants. The MTD is the dose level at which 
no more than 1 of up to 6 participants experience DLT during 28 days of treatment, and the dose 
below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. 
 
Table 4: Dose levels of SX-682 
 
 
Dose Escalation Schedule 
 
Dose Level 
Dose of SX-682  
Total SX-682 daily 
dose 
Level 1 
25 mg by mouth twice daily  
50 mg 
Level 2 
50 mg by mouth twice daily 
100 mg 
Level 3 
100 mg by mouth twice daily 
200 mg 
Level 4 
200 mg by mouth twice daily 
400 mg 
Level 5 
400 mg by mouth twice daily 
800 mg 
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Table 5. Escalation Decision Rules 
 
Number of Participants 
with DLT 
at a Given Dose Level 
Escalation Decision Rule* 
0 out of 3 
Enter up to 3 participants at the next dose level 
> 2 
Dose escalation will be stopped. This dose level will 
be declared the maximally administered dose 
(highest dose administered). Up to three (3) 
additional participants will be entered at the next 
lowest dose level if only 3 participants were treated 
previously at that dose. 
1 out of 3 
Enter up to 3 more participants at this dose level. 
• If 0 of these 3 participants experience DLT, 
proceed to the next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared 
the maximally administered dose. UP to three (3) 
additional participants will be entered at the next 
lowest dose level if only 3 participants were 
treated previously at that dose. 
<1 out of 6 at highest dose 
level below the maximally 
administered dose 
This is the MTD and is generally the recommended 
phase 2 dose. At least 6 participants must be entered 
at the recommended phase 2 dose. 
 
3.1.4 Combination Dose Escalation (Arm 2) 
In Arm 2 participants will receive SX-682 as monotherapy for the lead-in (Days -14L to -1L) and 
then will continue treatment with SX-682 combined with M7824 and CV301 starting on Cycle 1 
Day 1. 
If 6 participants have been treated in Arm 1 at dose level 3 without DLT during DLT period, the 
dose escalation of SX-682 will start from dose level 2 and continue until dose level 5 (Table 4) 
in sequential order using a standard 3+3 design (Table 5). 
If there was 1 or more DLT in Arm 1 at dose level 1 through 3 during DLT period, the dose 
escalation of SX-682 will start from dose level 1 and continue until dose level 5 (Table 4) in 
sequential order using a standard 3+3 design (Table 5). 
If in Arm 1 dose level 1 or 2 are estimated as MTD, we will submit an amendment with 
justification for study continuation.  
Dose escalation will proceed in groups of 3–6 participants. The MTD is the dose level at which 
no more than 1 of up to 6 participants experience DLT during 28 days of treatment, and the dose 
below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. The RP2D 
may not necessarily be the same as the MTD.  


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3.1.5 Expansion Cohorts (Arm 3, Cohorts 2 and 3) 
The safety, tolerability and efficacy evaluation of combination will continue with the RP2D of 
SX-682, M7824 and CV301 found during the dose escalation cohort (Arms 1 and 2). The dose of 
SX-682 used in combination with M7824 and CV301 in Arm 3 cannot exceed the highest 
tolerable dose for SX-682 monotherapy as determined in Arms 1 and 2. 
Enrollment into the expansion cohorts can commence after the RP2D has been determined (after 
the 6th participant on relevant dose level completes the DLT evaluation period). For performance 
of the expansion cohorts, see Schema 3 
Schema 3 Expansion Cohorts in Triple Negative Breast Cancer and HPV negative HNSCC 
  
 
3.2 
STUDY STOPPING RULES 
For safety reasons, enrollment will be temporarily halted until an expedited safety report has 
been evaluated by the investigators, IND sponsor, and submitted to the FDA for either of the 
following events attributable to treatment regimen occurring within 30 days of receiving 
investigational agent:  
• One occurrence of grade 5 toxicity  
• Two occurrences of grade 4 toxicity 
• Grade 3 or higher toxicities that occur at a higher rate than expected for each individual 
agent in the combination.  


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3.3 
DRUG ADMINISTRATION 
3.3.1 General Dosing Rules: 
Except where stated otherwise in the study calendar a window of -1/+ 3 days for every two 
weeks M7824 dosing and/or study calendar a window of -1/+ 3 days for the scheduled CV301 
dosing is allowed in the event of scheduling issues (i.e. holiday, bad weather or other scheduling 
issues). Any dose that cannot be accommodated within this window will be skipped and the dose 
not made up. Similar drug administrations should not be given less than 11 days from one 
another.  
The preferred order of drug administration in the day hospital is CV301, then M7824 
administration; when possible, administer the vaccine within 60 minutes prior to the M7824 
administration; however, the exact timing of vaccine administration is flexible. 
3.3.2 SX-682  
SX-682 will be given orally at designated dose twice a day every day. SX-682 is available as a 
25 mg and a 100 mg tablet. If necessary, the 100 mg tablets can be cut in half using a pill splitter; 
the tablets are pre-scored for this purpose. The tablets are not to be crushed, chewed, or dissolved 
before swallowing.  
SX-682 should be taken at approximately the same times each day. Participants should take SX-
682 with water once in the morning (suggested between 6-9 am) and once in the evening 
(suggested between 6-9 pm). For two hours before and one hour after the dose, the participant’s 
diet should be limited to clear liquids only (no solid foods). Doses should be taken within 2 hours 
of the scheduled time.  
In case of a missed dose (more than 2 hours late) or vomiting after taking SX-682, participants 
will be instructed not to make up the missed dose. 
Up to 15% of scheduled doses of SX-682 can be missed per cycle unless directed by PI/AI to 
hold additional doses of SX-682 during a planned cycle.  
Participants will complete and return Participant’s Diary (Appendix C), which will be reviewed 
by research staff at the end of each cycle. 
3.3.3 CV301 Vaccines  
Participants will be primed with MVA-BN-CV301 twice during Cycle 1 (Days 1 and 15), 
followed by booster vaccines with FPV-CV301 on Day 1 of subsequent cycles (every 4 weeks) x 
4 cycles  (Cycle 2 through Cycle 5) then on Day 1 of every 3 cycles (Cycles 8 and Cycle 11).  
A single dose of MVA-BN-CV301 is given as four subcutaneous injections with each of these 
injections containing 4x108 Inf.U/0.5ml. Each injection will be given in a different arm or leg. 
A dose of FPV-CV301 is given as one subcutaneous injection with each injection containing 
1x109 Inf.U/0.5ml. For participant comfort, it is generally preferred if FPV-CV301 is 
administered in the upper arm; however, the vaccine can be given in any extremity. 
3.3.4 M7824  
Subjects will be scheduled to receive M7824 at a flat dose of 1,200 mg IV on Days 1 and 15 of 
each cycle.  


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Subjects will receive M7824 via IV infusion over 1 hour (-10 minutes / +20 minutes, that is, over 
50 to 80 minutes) once every 2 weeks. Infusion rate may be adjusted in the event of certain 
adverse events as described in section 3.4.4. M7824 can be administered through a central line 
(preexisting) or a peripheral IV. A 0.2 micron in-line filter is required for administration of 
M7824. The preference is for M7824 to be given via peripheral line. However, if the research 
team documents that the main material of the port is titanium, M7824 can be administered via 
mediport. It is the responsibility of the research team to confirm and document this in CRIS. 
Once documented, the ordering physician can change the route of administration to mediport. 
Please refer to the pharmacy manual for a list of acceptable materials known to be compatible 
with M7824. 
In order to mitigate potential infusion-related reactions, premedication with an antihistamine and 
with acetaminophen (for example, 25-50 mg diphenhydramine and 500-650 mg acetaminophen) 
within approximately 30 to 60 minutes prior to dosing of M7824 is optional and at the discretion 
of the Investigator. Steroids as premedication are not permitted. 
3.4 
DOSE MODIFICATIONS 
3.4.1 General Rules  
When, at the beginning of a treatment week, treatment delay related to one of study drugs is 
indicated, treatment with other drugs should not be delayed.  
If, in the opinion of the investigator, a toxicity is considered to be due solely to one drug, the 
dose of other drugs does not require modification. 
Any of the trial drugs may be held for toxicity per the discretion of the primary investigator if is 
it felt that the toxicity can be directly linked to a specific drug. For AEs that are attributed to a 
study drug, a study drug may be held or reduced (only SX-682 can be reduced) when in the 
opinion of the investigator doing so will minimize the risks to the participant and maximize 
clinic benefit (e.g., in the event of observed tumor reduction but also intolerable ADRs at the full 
dose).  
If one drug is discontinued during first year of treatment, a participant may per PI discretion 
continue treatment with 2 other drugs. However, if 2 drugs must be discontinued, the participant 
will be taken off treatment. If one drug is discontinued during second year of treatment, a 
participant may per PI discretion continue treatment with the other drug. 
For non-medical logistical reasons, unrelated acute illnesses, or palliative radiation, dosing with 
any drug can be delayed up to 2 months. Where at all possible, dosing should be restarted to keep 
in line with the original treatment schedule. 
For AEs that are unrelated to the study drugs, study drug(s) may be held for up to 2 months at the 
discretion of the PI. 
Any dose that would have occurred within this window will be skipped and the dose not made 
up. 
If a participant on trial continues to gain benefit from treatment with one or more of the trial 
drugs at the two-year mark, the investigator can discuss with the CRADA partners the possibility 
of continuing the participant on treatment with the assigned trial drugs for an additional specified 
period of time. 


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In case of Grade 3 and Grade 4 AEs not study drug related, the study treatment may be 
interrupted based on the Investigator assessment and the subject will be medically treated for the 
event. 
If the AE reduces to a lower tolerable grade the study treatment might be resumed in the 
subsequent week. If the AE remains the same despite the medical treatment until the next 
treatment (second cycle after the AE occurred) a consideration of a possible extension of the 
dose interruption for up to 1 additional cycle or a permanent withdrawal from the study treatment 
should be considered. 
If upon the resumed study treatment, the subject experiences the same AE, permanent 
withdrawal from the study treatment should be considered. 
Grade 3 and 4 laboratory abnormalities that do not have clinical significance and are not related 
to study drugs do not require dose interruption. 
3.4.2 SX-682 
If any SX-682 related AE observed is grade > 2 (except for electrolyte abnormalities that can be 
easily replenished or other lab abnormalities that have no clinical consequence or can be easily 
medically managed with minimal risk to the participant), treatment should be delayed by 1 week 
(except for hyperbilirubinemia where drug will be held for grade 2) – and up to 4 consecutive 
weeks. If, with a delay of up to 4 weeks, the treatment related AE resolves, then SX-682 can be 
resumed at the same dose level or at a lower dose level per the PI discretion. 
If, after 4 weeks of delay, all treatment related AEs have still not resolved (to grade ≤ 1), then 
any further treatment with SX-682 should be delayed until AEs are resolved (to grade ≤ 1), and 
then reduced by one dose level at the time of reinitiating.  
3.4.3 CV301 
Dose delays or dose omissions of CV301 vaccines are allowed per PI discretion. There are no 
dose reductions for the CV301 vaccines.  
3.4.4 M7824 
Dose delays or dose omissions of M7824 are allowed per PI discretion. There are no dose 
reductions for M7824.  
3.4.4.1 Adverse Drug Reactions (ADRs) Requiring Treatment Discontinuation  
All adverse events in this trial will be graded using the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
Any Grade 4 ADRs require permanent treatment discontinuation except for any of the 
following: 
• Single laboratory values out of normal range that do not have any clinical correlate and 
resolve to Grade ≤ 1 or Baseline grade within 7 days with adequate medical management.  
• Grade 4 symptomatic endocrinopathies (e.g., thyroiditis or hypophysitis), treatment 
should be delayed, and treatment started according to best medical judgement based on 
the most updated professional guidelines (NCCN, EMSO, SITC, etc.). Following the 
initiation of appropriate medical therapy for the endocrinopathy, treatment can be 
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• Asymptomatic lab abnormalities (Grade 3 or 4) as described below in the Grade 3 ADR 
section.  
• Grade 4 non-tumor bleeding will not require permanent treatment discontinuation if an 
alternative explanation for the bleeding is identified. If no alternative explanation is 
identified, treatment must be permanently discontinued.  
Any Grade 3 ADRs require treatment temporary discontinuation except for any of the 
following:  
• Transient (≤ 48 hours) Grade 3 flu-like symptoms or fever, which is controlled with medical 
management. 
• Transient (≤ 48 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that is 
controlled with medical management.  
• Tumor flare phenomenon defined as local pain, irritation, or rash localized at sites of known 
or suspected tumor. 
• Any single Grade ≥ 3 drug-related transaminase, alkaline phosphatase, or bilirubin 
abnormality with no other associated laboratory (or other) abnormality that is not associated 
with symptoms or clinical manifestations of hepatitis. If the liver function abnormality not 
associated with symptoms or clinical manifestations of hepatitis has not resolved to Grade ≤ 1 
within the subsequent 2 cycles (56 days), the subject should permanently discontinue 
treatment with M7824.  
• Any single Grade ≥ 3 drug-related amylase or lipase abnormality with no other associated 
laboratory (or other) abnormality that is not associated with symptoms or clinical 
manifestations of pancreatitis. If the amylase or lipase abnormality not associated with 
symptoms or clinical manifestations of pancreatitis has not resolved to Grade ≤ 1 within the 
subsequent 2 cycles (56 days), the subject should permanently discontinue treatment with 
M7824.  
• Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or 
erythroid growth factor use does not require treatment discontinuation.  
• Increases in Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 3 that 
resolves to ≤ 2 by Day 1 of the next cycle (infusions should not be given if the ECOG PS is 
≥ 3 on the day of M7824 administration and should be delayed until ECOG PS ≤ 2). 
• Keratoacanthoma and squamous cell carcinoma of the skin. Any suspicious skin lesion should 
be biopsied for confirmation of diagnosis and be surgically removed as indicated by 
dermatologist and a dermatological consult obtained.  
• Grade 3 non-tumor bleeding requiring intervention or hospitalization. Study treatment must 
be permanently discontinued unless an alternative explanation can be identified. In the case of 
alternative explanations for the Grade 3 bleeding event, study treatment should be held until 
recovery to at least Grade 1.  
• Other infusion reactions and immune-related ADRs, see NCCN guidelines for the 
management of immune related adverse events (Table 6). NCCN guidelines are merely 


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suggestions based on current knowledge; however, given this is an evolving field, 
investigators are encouraged to consult professional guidelines.  
o In addition to NCCN guidelines, the following recommendations should be 
considered when managing irAEs: 
• Permanent treatment discontinuation is required in case of immune-related 
Grade 4 rash/inflammatory dermatitis, nephritis, autoimmune hemolytic 
anemia, 
hemolytic 
uremic 
syndrome, 
aplastic 
anemia, 
immune 
thrombocytopenia, 
acquired 
thrombotic 
thrombocytopenic 
purpura 
inflammatory arthritis, myositis and polymyalgia-like syndrome.  
 
• For Grade 4 immune-related lymphopenia, permanent treatment 
discontinuation will be required, if lymphopenia is considered immune-
related in nature, no clear alternative explanation exists for the event, and 
it does not resolve within 14 days. Permanent treatment discontinuation is 
not required when the AE is manifested by a single laboratory value out of 
normal range without any clinical correlates. In this case, treatment should 
be held until the etiology is determined. If the event is not considered 
immune-related and resolves to Grade ≤ 1, restarting treatment may be 
considered.  
 
• For Grade 1 immune-related pneumonitis: continue treatment. If clinically 
indicated, monitor participants weekly or more frequently as needed with 
history, physical examination and pulse oximetry. If symptoms appear 
and/or changes in the physical exam are noted, treat as Grade 2.  
 
•  For myositis requiring management with rituximab, treatment should be 
discontinued.  
 
• For Grade 3 or 4 endocrinopathies: withhold until clinically stable or 
permanently discontinue depending on severity.  
 
• For hepatitis with no tumor involvement of the liver: withhold if total 
bilirubin increases to more than 1.5 and up to 3 times ULN, permanently 
discontinue if more than 3 times ULN  
 
• Hepatitis with tumor involvement of the liver: permanently discontinue if 
total bilirubin increases to more than 3 times ULN.  
3.4.4.2 Infusion-related Reactions 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 48 hours after completion of infusion. These possible IRR are identified based 
on a list of MedDRA PTs and divided into reactions versus signs and symptoms. 


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• An IRR should be considered when onset is on the day of infusion (during or after the 
infusion) or the day after the infusion (irrespective of resolution date) for any infusion related 
reaction, drug hypersensitivity, anaphylactic reaction, hypersensitivity and/or Type 1 
hypersensitivity. 
• Signs and symptoms of infusion related reactions and hypersensitivity/allergic reactions 
should be considered when onset is on the day of infusion (during or after the infusion) and 
resolved completely with the end date within 2 days after onset. Signs and symptoms may 
include but not limited to: fever, chills or shaking, rigors, flushing, hypotension, wheezing, 
pruritus, rash and hypoxemia, shortness of breath, back or neck pain, facial swelling, 
dizziness, feeling of passing out. 
Infusion-related reactions and hypersensitivity reactions (Grades 1 to 4) should be handled 
according to the best medical judgement based on the most updated professional guidelines 
(NCCN, ESMO, SITC, etc.). Guidelines provided in Table 6 are merely suggestions based on 
current knowledge; however, given this is an evolving field, investigators are encouraged to 
consult the most updated professional guidelines. 
Table 6: Treatment Modifications for Symptoms of Infusion-related Reactions  
NCI-CTCAE Grade 
Treatment Modification for M7824 
Grade 1 – mild 
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated. 
Consider decreasing the infusion rate of the 
particular agent by 50% and monitoring 
closely for any worsening. 
 
Grade 2 – moderate 
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDs, narcotics, i.e. 
fluids); prophylactic medications indicated for 
≤ 24 hours. 
Consider temporarily discontinuing infusion 
of the particular agent. 
Consider resuming infusion of the particular 
agent at 50% of previous rate once infusion 
related reaction has resolved or decreased to 
at least Grade 1 in severity and monitor 
closely for any worsening. 
Grade 3 or Grade 4 – severe or life-
threatening 
Grade 3: Prolonged (e.g., not rapidly 
responsive to symptomatic medication and/or 
brief interruption of infusion); hospitalization 
indicated for clinical sequelae. 
Grade 4: Life-threatening consequences; 
urgent intervention indicated. 
Stop the infusion immediately and disconnect 
infusion tubing from the subject. 
For grade 3 events: Consider withdrawing 
immediately 
from 
treatment 
with 
that 
particular agent and not offering any further 
treatment with that agent based upon if the 
clinical condition can be safely managed. 
For grade 4 events: Withdraw immediately 
from treatment and do not offer further 
treatment with that agent.  
 
If the infusion rate of M7824 has been decreased by 50% or interrupted due to an infusion 
reaction, keep it decreased for the next scheduled infusion. If no infusion reaction is observed in 
the next scheduled infusion, the infusion rate may be returned to baseline at the subsequent 
infusions based on investigator’s medical judgment.  
















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condition can be safely managed; 
Consider 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent 
Consider adding prophylactic 
antibiotics for opportunistic infections  
Specialty consult as appropriate 
month. 
Grade 4  
 
Permanently discontinue M7824; 
Consider 
1.0 to 2.0 mg/kg/day 
prednisone or equivalent and/or other 
immunosuppressant as needed 
Consider adding prophylactic 
antibiotics for opportunistic infections  
Consider specialty consult as 
appropriate 
If improves to Grade ≤ 1:  
Consider tapering steroids over at least 1 month 
Requirement for 10 mg per day 
or greater prednisone or 
equivalent for more than 12 
weeks for reasons other than 
hormonal replacement for 
adrenal insufficiency 
 
Persistent Grade 2 or 3 irAE 
lasting 12 weeks or longer 
Consider permanently discontinuing 
M7824  
Consider specialty consult as 
appropriate  
 
 
3.4.4.4.1 Rash with Hyperkeratosis / Keratoacanthoma / Squamous Cell Carcinoma of the Skin 
Dermatological consults will be requested on a case-by-case basis as needed with potential 
biopsy of suspicious skin lesions.  
3.4.4.4.2 Suggested Evaluation of Suspected Bleeding or Hemorrhage Events and Treatment 
Modification  
For anemia or hemorrhage events assessed as treatment-related, items queried may include but 
are not limited to detailed relevant past medical and treatment history, bruising tendency, history 
of blood transfusions and/or dependency, and a request for an updated participant history 
including details such as concomitant medications, all laboratory data, updated dosing 
information and recent tumor evaluation scans.  
In this protocol, anemia may be due to M7824 (documented in 29% of patients based on pooled 
safety analysis set from a total of 765 participants, refer to IBv7) and/or SX-682. For M7824 
anemia is an AESI and important identified risk (see Investigators’ Brochure). Notably, there are 
many reasons for hemorrhage and/or anemia in patients with advanced cancer, and Hb level of at 
least 9 g/dL is required for this study. A thorough investigation of new anemia cases of 
unspecified etiology is recommended: 
• Participants must enter the study with Hgb values at least 9 g/dL and baseline anemia 
evaluation is conducted per recommendations below.  
• Consider hematology consult for severe and or refractory anemias.  


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• All relevant hematologic testing for treatment related anemias should be done prior to blood 
transfusion, if clinically feasible. 
• Transfusion should be performed at the discretion of the investigator, based on clinical 
assessment and considered when participant experiences significant anemia.  
• Guidance for evaluation of baseline anemia or suspected treatment-related anemias is 
provided below. Investigators may consider the following laboratory evaluations in 
participants with anemia.  
o Hb and CBC with differential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes 
counts) 
o Peripheral blood smear for cell morphological assessment 
o Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, 
and serum folate, B12 values and other chemistries 
o Coagulation factors (PT, PTT, INR) 
o Urinalysis including culture 
o Iron panel (TIBC, ferritin, Fe) 
• Discuss further management with Principal Investigator for clinically significant treatment 
related anemias.  
Multiple protocols using M7824, several mucosal bleeding events ranging from low grade 
gingival bleeding and epistaxis to more serious hemoptysis, GI bleeding and hematuria have 
been observed. Some of these events can be attributed to bleeding events related to cancer 
directly and others bleeding events can be attributed to an inflammatory process (e.g. colitis) 
which is a known toxicity of anti-PD-L1 agents including M7824. However, there remains the 
possibility that M7824 may increase the overall risk of bleeding in ways that may not be directly 
related to direct tumor bleeding or inflammatory bleeding events described with checkpoint 
inhibitors like M7824. However, there is no evidence of a negative effect on coagulation or 
platelet number or function. It is hypothesized that this possible increased mucosal bleeding risk 
may be due to the known mucoprotective effects of TGFβ. Accordingly, participants will be 
closely monitored for mucosal bleeding (e.g., gum bleeding, nose bleeds, coughing up blood, 
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5 MVA-BN-CV301 will be given on days 1 and 15 of Cycle 1. FPV-CV301 will be given Day 1 of Cycles 2 through 5 then Day 1 of 
Cycle 8 and Cycle 11. Can be -1/+3 days due to holidays, inclement weather, conflicts, or similar reasons except where explicitly 
noted elsewhere. CV301 administrations should not be given less than 11 days apart. See Table 8  
 
6 EOT – End of treatment visit: Where feasible, on the day of or within 30 days of the decision to discontinue treatment prematurely 
before completion of one year of treatment. Does not need to be completed if drug is withheld after one year of treatment. Research 
labs will be collected if feasible. Participants continuing to experience toxicity at the off-treatment visit will be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. Participants must remain on the study to have 
additional assessments completed 
7 30 days (+/- 7 days) after last treatment. If subjects are not willing to come to NIH to FU visit, they will be contacted by phone to 
assess adverse events. Does not need to be repeated if EOT performed within this time frame.  
8 Participants who are taken off treatment for reasons other than disease progression, will be invited for optional imaging studies every 
3 months (+/- 2 weeks) until they experience PD in order to assess PFS. If participants unable to come, participants will be followed 
by phone or email and outside images will be requested. Participants who opt out of these scans will have their data censored in data 
analysis at the time they become unfollowable for PFS. After progression and 30 days Safety Follow up visit, participants will be 
followed by phone or email for long-term clinical outcomes, and further tumor therapy every year for 2 years.  
9 EKGs will be done in triplicate on screening, before SX-682 administration at baseline and then every two weeks until cycle 6, at 
EOT and at the safety FU visit.  
10 Biochemical profile: sodium, potassium, magnesium, phosphorus, chloride, bicarbonate, calcium, glucose, BUN, creatinine, ALT, 
AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin.  
11 Performed every 8 weeks: Lymphocyte panel (TBNK), TSH, Free T4, lipase, amylase, urinalysis, PT/PTT/INR, unless there is a 
clinical concern that warrants evaluation on a more frequent basis 
12 For women of childbearing potential at screening and baseline serum pregnancy test must be performed, but on day 1 of each cycle 
and EOT, urine pregnancy test can also be used. 
13 In Arms 1 and 2, the first restaging will occur 6 weeks after starting treatment (+/- 1 week) and then every eight weeks (+/- 1 week). 
In Arm 3, restaging will occur every eight weeks (+/- 1 week). In the event of a PR or CR tumor imaging assessments may be 
performed every 3 months (+/- 2 weeks) at the discretion of the investigator. Tumor assessment should be continued beyond end of 
treatment in participants who have not experienced PD until they experience PD in order to assess PFS. In addition to a baseline scan, 
confirmatory scans can also be obtained 4 to 8 weeks following initial documentation of objective response per the discretion of the 
primary investigator. MRI of chest, abdomen and pelvis (if participant has contradiction to CT). 
14 Brain CT/MRI if there is a history of prior CNS metastasis or there is a concern for CNS involvement. 
15 Optional biopsies at baseline and as close as logistically feasible to first imaging restaging (+/- 1 week if possible). Optional biopsy 
also at time of progression. In addition, tissue collected during unscheduled procedures may also be collected for research purposes. 






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Cycle 
(Day)  
Time 
SX-682 
M7824 
Immune and Other Analyses 
  
  
PK 
PK 
ADA Soluble Factors 
Immune phenotyping/ 
RNA analysis, 
Antigen-specific 
response, T-cell 
clonality 
CTCs 
 
30 
minutes 
X 
 
 
Cycle 1 (1) predose 
X 
X 
X 
X 
X 
X 
  
End 
of 
Infusion 
(EOI) 
X 
X 
 
 
 
Cycle 
1 
(15) 
 
X 
 
 
X 
X 
Cycle 2 (1) predose 
X 
 
 
X 
X 
X 
Cycle 
3 
(1)** 
predose 
X 
X** X** X 
X 
EOT 
 
X 
X 
X 
X 
 
*Lead-In, Day -14L labs only for Cohort 1, Arm 1 (Sequential Dose Escalation).  
**The last M7824 PK/ADA timepoint should be Cycle 3, Day 1 predose or EOT, whichever comes first.  
 
Table 10: Arm 2 Research Blood Draws 
Cycle 
(Day)  
Time 
SX-682 
M7824 
Immune and Other Analyses 
  
  
PK 
PK 
ADA 
Soluble Factors 
Immune phenotyping/ RNA 
analysis, Antigen-specific 
response, T-cell clonality 
CTCs 




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Cycle (Day) Time 
Immune and Other Analyses 
  
  
Soluble 
Factors 
Immune 
phenotyping/ RNA 
analysis, Antigen-
specific response,        
T-cell clonality 
CfDNA 
CTCs 
Cycle 1 (1) 
predose 
X 
X 
X 
X 
Cycle 1 (15) predose 
X 
X 
X 
Cycle 2 (1) 
predose 
X 
X 
X 
X 
Cycle 3 (1) 
predose 
X 
X 
X 
EOT 
 
X 
X 
X 
 


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3.6 
COST AND COMPENSATION 
3.6.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center. If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not 
covered by insurance company. Medicines that are not part of the study treatment will not be 
provided or paid for by the NIH Clinical Center. 
3.6.2 Compensation 
There will no compensation provided in this study.  
3.6.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy. 
3.7 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA 
Prior to removal from study, efforts must be made to have all subjects complete a safety visit 
approximately 30 days (+/- 7 days) following the last dose of study therapy. 
3.7.1 Criteria for Removal from Protocol Therapy 
• Participant request to be withdrawn from active therapy 
• Confirmed clinical or radiographic progression of disease except when the investigator 
feels the subject is still benefiting from treatment. NOTE: treatment may be continued 
despite progression according to RECIST 1.1 at any time if: 
 There are no new or concerning symptoms. 
 There is no decrease in ECOG PS. 
 The Investigator does not consider it necessary to administer a salvage therapy. 
• Unacceptable Toxicity as described in sections 3.3  
• Investigator discretion 
• Positive pregnancy test 
• Need to use restricted medication, section 4.1 
• Completion of 2 years of therapy unless the PI feels that the participant continues to gain 
benefit from two or more of the trial drugs and discusses continuing on trial with the 
CRADA partners for an additional specified period of time.  
3.7.2 Off -Study Criteria 
• Completion of 2 years follow-up period after confirmed disease progression  
• PI decision to end the study 
• Participant lost to follow up 


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• Investigator discretion 
• Death 
• Participant request to be withdrawn from the study 
• Screen Failure 
3.7.3 Lost to Follow-up 
A participant will be considered lost to follow-up if he or she fails to return for 3 consecutive 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit and 
counsel the participant on the importance of maintaining the assigned visit schedule and 
ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, an IRB approved certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in 
the participant’s medical record or study file.  
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
4 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only 
by a properly authorized/licensed clinician. Medications to be reported in the Case Report Form 
(CRF) are concomitant prescription medications, over-the-counter medications and supplements. 
Any medications (other than those excluded by the clinical trial protocol) that are considered 
necessary to protect subject welfare or alleviate symptoms and will not interfere with the trial 
medications may be given at the Investigator’s discretion. 
Palliative radiotherapy delivered in a normal organ-spearing technique may be administered 
during the trial. The assessment of PD will not be based on the necessity for palliative 
radiotherapy.  
4.1 
THE FOLLOWING TREATMENTS SHOULD NOT BE ADMINISTERED DURING THE TRIAL: 
• Other immunotherapies or immunosuppressive drugs for example, chemotherapy or 
systemic corticosteroids except for prophylaxis or treatment of allergic reactions, 
endocrine replacement therapy at low dose prednisone [≤ 10 mg daily] or equivalent, for 
the treatment of irAEs, or for short courses (≤ 14 days) as appropriate medical therapy for 
unrelated medical conditions (e.g. asthma). Steroids with no or minimal systemic effect 
(topical, inhalation) are allowed. 
• Prophylactic use of corticosteroids for infusion related reactions. Corticosteroid 
administration prior to CT scans in participants with intravenous contrast allergy is 
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• QTc prolonging drugs: The drug-drug interactions of SX-682 in humans have not yet 
been determined. However, due to its in vitro inhibition of hERG, concomitant dosing of 
SX0682 with drugs known to have a clinically significant prolongation the QT interval 
(See Appendix B), such as pimozide and thioridazine, should be avoided until further 
human EKG data is gathered. Drugs that may conditionally prolong QTc that are not 
included in Appendix B, maybe be used with caution after reviewing the risks/benefits 
and potential alternative options. QTc prolonging agents are not prohibited in participants 
no longer receiving SX-682. 
• In vitro studies indicate SX-682 inhibits CYP2C8. Medications that are substrates of this 
enzyme may have altered metabolism when administered concurrently with SX-682. 
CYP2C8 substrates will be evaluated on a case-by-case basis prior to concurrent use with 
SX-682. Updated drug-information resources should be consulted   
(e.g. https://drug-interactions.medicine.iu.edu/MainTable.aspx). 
• Any live vaccine therapies for the prevention of infectious disease. Administration of 
inactivated vaccines is allowed (for example, inactivated influenza vaccines). Locally 
approved COVID vaccines are permitted.  
• Systemic anticancer treatment other than the investigational agents in this trial except for 
disease specific appropriate hormonal therapies (e.g., ADT for prostate cancer, anti-
estrogen for breast cancer, somatostatin analogue for neuroendocrine cancer). 
• All anticoagulation drugs will be reviewed by the investigator to determine the potential 
for interactions or potential safety concerns with the investigational agents. Any 
anticoagulation agent deemed to have a potentially clinically significant interaction with 
the investigational agent(s) by the investigator should not be administered while on the 
clinical trial.  
• All herbal supplements will be reviewed by the investigator to determine the potential for 
herbal interactions or potential safety concerns with the investigational agents. Any 
herbal supplement deemed to have a potentially clinically significant interaction with the 
investigational agent(s) by the investigator should not be administered while on the 
clinical trial. 
5 
CORRELATIVE STUDIES FOR RESEARCH 
Biospecimens will be evaluated to help identify the effect of the study dugs on the immune 
response before and after treatment, to gain insight into potential biomarkers, and help improve 
the administered therapy. 
5.1 
SAMPLES 
5.1.1 Tumor Samples 
Where available, archival tumor samples will be requested. 
Optional biopsies may be performed as per Study Calendar 3.5. Attempts will be made to obtain 
up to six cores (18G or 20G preferred) or direct biopsies with biopsy forceps if safe and feasible. 
These tumor core biopsies will be obtained percutaneously by interventional radiology as long as 
considered minimal procedural risk. Direct biopsies with biopsy forceps will be obtained by 
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5.2.4 ADA 
Serum samples may be analyzed by a validated electrochemiluminescence immunoassay 
(ECLA) to detect the presence of anti-M7824. Samples that screen positive will be subsequently 
tested in a confirmatory assay. Those confirmed positive will be titered for a quasi-quantitative 
result. Samples may be further tested in qualified or validated immunogenicity characterization 
methods. The investigation will be done by Syntrix and EMD Serono for analysis under existing 
CRADAs with these companies. 
5.2.5 Analyses of Tumor Tissue for Immune Markers  
Biopsy samples may be used to study immune infiltration as well as PD-L1 status within the 
tumor microenvironment pre vs. post treatment by IHC and/or multiplex immunofluorescence. 
Biopsies may be subjected to dissociation and analysis by flow cytometry to determine immune 
infiltration. Tumor infiltrating lymphocytes may be cultured from biopsies for assessment of T 
cell clonality and antigen specificity. 
Tumor samples will be sent to the Laboratory of Pathology at NIH for disease evaluation; 
remaining samples will be used for research. 
5.2.5.1 Antigen-specific T cell responses to CEA, MUC1 and the cascade antigen brachyury in 
tumor biopsies. 
Tumor infiltrating lymphocytes (TIL) may be cultured from tumor fragments in standard T cell 
media with high dose recombinant human IL-2 (6000 U/mL). CD8 and CD4 TIL will be purified 
from cultured TIL using pan T cell negative magnetic selection. B cells will be sorted from 
PBMC using negative magnetic isolation and will be expanded using flt3-expressing 3T3 cells 
and IL-7. Expanded B cells will serve as autologous antigen presenting cells for coincubation 
assays. B cells will be electroporated with full length capped and tailed mRNA encoding for 
MUC1, CEA or the cascade antigen brachyury. Autologous B cells loaded with mRNA will be 
co-incubated with TIL cultured from tumor fragments (2:1 APC: T cell ratio) and IFNg 
production will be measured by ELISA. 
5.3 
SAMPLES FOR GENETIC/GENOMIC ANALYSIS 
5.3.1 RNA and T-cell Receptor Clonality Analysis of Blood and Tumor Tissue 
RNA expression and T-cell receptor clonality analysis may be done on the peripheral blood as 
well as archived tumor tissue or optional biopsies to help further evaluate changes in immune 
response and RNA expression levels with treatment as well as to determine tumor and infiltrating 
lymphocyte characteristics which may be predictive of response to treatment. In addition, these 
analyses will also be used to gauge resistance mechanisms and additional targets for future 
therapy. Digital Spatial Profiling (DSP) including RNA in situ hybridization may also be 
performed on tissue for spatially resolved high plex profiling of RNA and protein targets. De-
identified, coded samples may be analyzed for RNA expression levels and DSP using the 
Nanostring platform and T-cell receptor clonality using the ImmunoSeq platform (LTIB and NCI 
Frederick Genomic Core Facility).  
NCI Fredrick Genomic Core Facility:  
Leidos Biomedical Research, Inc:  
  










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participant confidentiality. Using a computerized inventory system and a backup hardcopy 
process, all specimen collection and processing steps will be documented, and the specific 
location of each specimen will be tracked. Each new specimen collected will be assigned a 
unique barcode identifier that can be linked to the original specimen collected and other relevant 
information within the inventory system. Specimen labels will indicate protocol number, order in 
which the participant enrolled on the trial, type of sample, as appropriate. The inventory process 
contains other security provisions sufficient to safeguard participant privacy and confidentiality. 
Access to the inventory system and associated documents is restricted to appropriate individuals. 
Requests to use specimens stored in the repository must be approved by the trial Principal 
Investigator. SOPs ensure that any changes in informed consent made by a participant and 
relayed to the trial Principal Investigator will be reflected in the inventory system to ensure that 
specimens are destroyed as appropriate. All laboratory personnel are trained to adhere to SOPs 
and are monitored for high-quality performance. Samples are stored in labeled boxes in secured 
freezers (i.e., -80°C, liquid nitrogen or other, as appropriate) according to stability requirements. 
These freezers are located in the 
 
5.4.6 Protocol Completion/Sample Destruction 
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described in 
sections above. The study will remain open so long as sample or data analysis continues. 
Samples from consenting subjects will be stored until they are no longer of scientific value or if a 
subject withdraws consent for their continued use, at which time they will be destroyed.  
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will 
be per the requirements of section 7.2. 
If the participant withdraws consent the participant’s data will be excluded from future 
distributions, but data that have already been distributed for approved research use will not be 
able to be retrieved. 
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The principal investigator, associate investigators/research nurses and/or a contracted 
data manager will assist with the data management efforts. Primary and final analyzed data will 
have identifiers so that research data can be attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. 
Document AEs from the administration of the first study intervention through 30 after the study 
agent (s) was/were last administered. Beyond 30 days after the last intervention, only adverse 
events which are serious and related to the study intervention need to be recorded. 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
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• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the participant’s outcome. 
Adverse Events of grade 1 will not be collected. 
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
subject confidentiality and trial data has occurred, his will be reported expeditiously per 
requirements in section 7.2.1 
6.2 
DATA SHARING PLANS 
6.2.1 Human Data Sharing Plan 
The PI will share coded linked human data generated in this research for future research  
− in a NIH-funded or approved public repository clinicaltrials.gov and dbGaP 
− in BTRIS  
− in publication and/or public presentations 
− with approved outside collaborators under appropriate agreements 
− at the time of publication or shortly thereafter. 
6.2.2 Genomic Data Sharing Plan 
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy. 
6.3 
RESPONSE CRITERIA  
For the purposes of this study, participants should be re-evaluated for response according to 
schedule in the Study Calendar, section 3.5.  
In the event of a PR or CR tumor imaging assessments may be performed every 3 months (+/- 2 
weeks) at the discretion of the investigator. In addition to a baseline scan, confirmatory scans can 
also be obtained 4 to 8 weeks following initial documentation of objective response per the 
discretion of the primary investigator. 
The preferred method of disease assessment is CT with contrast. If CT with contrast is 
contraindicated, CT of the chest without contrast and MRI scan of the abdomen/pelvis is 
preferred. Additional assessment of tumor response may include the following evaluations; 
nuclear bone scan for subjects with known/suspected bone lesions; and CT or MRI scan of the 
brain (only as clinically warranted based on symptoms/findings). 
Brain CT / MRI scan should be performed, if clinically indicated by development of new specific 
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designate 1 or more of the following measures of tumor status to follow for determining response: 
CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, 
and the results of other assessments. All available images collected during the trial period will be 
considered. The most appropriate measures to evaluate the tumor status of a subject should be 
used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to 
the measures used to document the progressive tumor status that qualifies the subject for 
enrollment. 
Progressive disease should be confirmed by imaging 4 to 8 weeks (preferably at 4 weeks, but not 
more than 8 weeks) after progression has been diagnosed according to RECIST 1.1. before the 
participant is removed from treatment [93]. If progression is based on the occurrence of a new 
lesion in an area not scanned at Baseline, a further on-study scan 4 to 8 weeks later should be 
considered before performing the 28-Day Safety Follow-up visit. 
Tumor responses to treatment will be assigned based on the evaluation of the response of target, 
non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in 
metric notation). 
To assess objective response, the tumor burden at baseline will be estimated and used for 
comparison with subsequent measurements. At baseline, tumor lesions will be categorized in 
target and non-target lesions according to RECIST 1.1. 
Results for these evaluations will be recorded with as much specificity as possible so that pre and 
post-treatment results will provide the best opportunity for evaluating tumor response. 
The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if 
the Investigator suspects PD. 
iRECIST will also be used for exploratory endpoints (See section 6.3.3) 
For the primary endpoint antitumor activity will be evaluated with target and/or non-target 
lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. [93]. 
Palliative radiotherapy delivered in a normal organ-spearing technique may be administered 
during this trial. The assessment of PD will not be based on the necessity for palliative 
radiotherapy. 
If a target lesion is radiated during the course of treatment, this target lesion will no longer be 
considered a measurable lesion and will be removed from the target lesion sum moving forward 
as is recommended in RECISTv1.1.  
6.3.1 Disease Parameters 
Measurable disease: Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as:  
• By chest x-ray: >20 mm;  
• By CT scan:  
o Scan slice thickness 5 mm or under: as >10 mm 
o Scan slice thickness >5 mm: double the slice thickness  
• With calipers on clinical exam: >10 mm. 


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All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). 
Tumor lesions that are situated in a previously irradiated area may be considered measurable if 
there is demonstrated progression in the radiated lesion prior to starting on the trial.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node 
must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended 
to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured 
and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered 
non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same participant, these are preferred for selection as target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over 
and above the 5 target lesions should be identified as non-target lesions and should also be 
recorded at baseline. Measurements of these lesions are not required, but the presence, absence, 
or in rare cases unequivocal progression of each should be noted throughout follow-up.  
6.3.2 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
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Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray: Lesions on chest x-ray are not acceptable as measurable lesions.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI 
is variable globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease. 
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements. However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following complete 
response (CR) or surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially 
above the upper normal limit, they must normalize for a participant to be considered in complete 
clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published. [94-96] In addition, the 


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Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[97]  
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
FDG-PET: While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study. 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Note: If tumor markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not a single lesion 
increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). The participant's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 
Table 12. Response Criteria for Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
> 4 to 8 wks. Confirmation** 
CR 
Non-
CR/Non-PD 
No 
PR 
>4 to 8 wks. Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-
CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 


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Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a 
new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target 
lesions may be accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring 
discontinuation of treatment without objective evidence of disease progression at 
that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of 
treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials 
so to assign this category when no lesions can be measured is not advised 
 
6.3.3 iRECIST 
As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST.[98] 
Using iRECIST criteria the following will be incorporated into the assessment: 
• An increase in the sum of target lesions of more than 20%, unequivocal increase in the 
non-target lesions or new lesions result in iUPD (unconfirmed progression disease); 
iUPD can be assigned multiple ties as long as iCPD (confirmed progressive disease) is 
not confirmed at the next assessment.  
•  Progression is confirmed in the target lesion category if the next imaging assessment 
after iUPD (4-8 weeks later) confirms a further increase in sum of measures of target 
disease from iUPD, with an increase of at least 5mm. Progression is confirmed in the 
non-target lesion category if subsequent imaging, done every 4-8 weeks after iUPD 
shows a further unequivocal increase in non-target lesions. Progression is confirmed in 
the new lesions category if at next assessment additional new lesions appear or an 
increase in the size of previously seen new lesions is seen (>5 mm for sum of new target 
lesion).  
However, the criteria for iCPD (after iUPD) are not considered to have been met if complete 
response, partial response or stable disease criteria (compared with baseline and as defined by 
RECIST 1.1) are met at the next assessment after iUPD. The status is reset (unlike RECIST 1.1, 
in which any progression precludes later complete response, partial response, or stable disease). 
iCR, iPR, or iSD should then be assigned; and if no change is detected, then the timepoint 
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6.3.4 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented. 
Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met.  
6.3.5 Progression-Free Survival (PFS)  
PFS is defined as the duration of time from start of treatment to time of progression or death, 
whichever occurs first 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting 
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.  
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to 
be reported per these policies. 
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.   
To report these deaths, please send an email describing the circumstances of the death t  
 
7.4 
INSTITUTIONAL BIOSAFETY COMMITTEE (IBC) REPORTING CRITERIA 
7.4.1 Serious Adverse Event Reports to IBC 
The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life-
threatening experience associated with the use of CV301 vaccines as soon as possible but in no 


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event later than 7 calendar days of initial receipt of the information. Serious adverse events that 
are unexpected and associated with the use of the CV301 vaccines, but are not fatal or life-
threatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar 
days after the investigator’s initial receipt of the information. Adverse events may be reported by 
using the FDA Form 3500a. 
7.4.2 Annual Reports to IBC 
Within 60 days after the one-year anniversary of the date on which the IBC approved the initial 
protocol, and after each subsequent anniversary until the trial is completed, the Principal 
Investigator (or delegate) shall submit the information described below. Alternatively, the IRB 
continuing review report can be sent to the IBC in lieu of a separate report. Please include the 
IBC protocol number on the report. 
7.4.3 Clinical Trial Information  
A brief summary of the status of the trial in progress or completed during the previous year. The 
summary is required to include the following information:  
• the title and purpose of the trial  
• clinical site 
• the Principal Investigator 
• clinical protocol identifiers;  
• participant population (such as disease indication and general age group, e.g., adult or 
pediatric);  
• the total number of participants planned for inclusion in the trial; the number entered into 
the trial to date whose participation in the trial was completed; and the number who 
dropped out of the trial with a brief description of the reasons  
• the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, 
or fully completed,  
• if the trial has been completed, a brief description of any study results.  
7.4.4 Progress Report and Data Analysis  
Information obtained during the previous year's clinical and non-clinical investigations, 
including:  
• a narrative or tabular summary showing the most frequent and most serious adverse 
experiences by body system 
• a summary of all serious adverse events submitted during the past year 
• a summary of serious adverse events that were expected or considered to have causes not 
associated with the use of the gene transfer product such as disease progression or 
concurrent medications 
• if any deaths have occurred, the number of participants who died during participation in 
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a brief description of any information obtained that is pertinent to an understanding of the gene 
transfer product’s actions, including, for example, information about dose-response, information 
from controlled trials, and information about bioavailability. 
7.5 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.5.1 Principal Investigator/Research Team  
The clinical research team will meet on a weekly basis when participants are being actively 
treated on the trial to discuss each participant. Decisions about dose level enrollment and dose 
escalation will be made based on the toxicity data from prior participants. Evaluation of DLTs 
(eDLTs; Schema 1 and 2) will occur after all participants are enrolled on a given dose level.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each participant to 
ensure safety and data accuracy. The principal investigator will personally conduct or supervise 
the investigation and provide appropriate delegation of responsibilities to other members of the 
research staff. 
7.5.2 Data Safety Monitoring Board (DSMB) 
The DSMB is an independent group of at least 3 experts that monitors participant safety and 
advises The Sponsor. DSMB members will be separate and independent of study staff 
participating in this trial and should not have scientific, financial, or other conflicts of interest 
related to this trial. The DSMB will consist of members with appropriate expertise to contribute 
to the interpretation of data from this trial. A quorum will consist of a simple majority. 
The DSMB will review cumulative safety data from this trial at least annually. 
The DSMB will meet when trial halting criteria (see Section 3.2) are met, or as requested by the 
sponsor or PI. 
The DSMB will have a final review meeting at the end of the study. 
Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will 
review applicable data, including, but not limited to, enrollment, demographics, dosing data, 
clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the 
DSMB charter. The DSMB will review blinded aggregate data in the open session of the DSMB 
meetings. 
Additional data may be requested by the DSMB, and interim statistical reports may be generated 
as deemed necessary and appropriate by the Sponsor. As an outcome of each review/meeting, the 
DSMB will make a recommendation as to the advisability of proceeding with study product 
administration, and to continue, modify, or terminate this trial.  
 
8 
SPONSOR PROTOCOL/SAFETY REPORTING 
8.1 
DEFINITIONS 
8.1.1 Adverse Event  
Any untoward medical occurrence in a participant or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign 


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(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product (ICH E6 (R2)) 
8.1.2 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• 
Death, 
• 
A life-threatening adverse event (see section 8.1.3) 
• 
Inpatient hospitalization or prolongation of existing hospitalization: 
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing 
condition, or a procedure required by the protocol, without a serious deterioration in 
health, is not considered a serious adverse event. 
o A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for participant convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to 
the hospital would not be considered a serious adverse event. The reason for seeking 
medical care should be evaluated for meeting one of the other serious criteria 
• 
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 a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Life-threatening  
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32) 
8.1.4 Severity 
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 
8.1.5 Relationship to Study Product 
All AEs will have their relationship to study product assessed using the terms: related or not 
related.  
• Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 


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• Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 
8.1.6 Adverse Events of Special Interest (AESI) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the Investigational Product(s) and may require close monitoring and rapid 
communication by the investigator to the sponsor. An AESI may be serious or non-serious. The 
rapid reporting of AESIs assessed as severe allows ongoing surveillance of these events to 
characterize and understand them in association with the use of these investigational products.  
Only AESIs that match the definition of SAE will be reported within 7 days from the knowledge 
of event. Other non-SAE AESIs do not need to be reported to OSRO but only collected in the 
clinical database. 
The adverse events related to mucosal bleeding, regardless of site, will be collected as an AESI 
to enable evaluation of potential risk factors, such as site/past radiation/associated infection at 
site/recent instrumentation and other variables such as time to onset, exposure history, grade of 
bleeding, anatomical sites, etc. can be collected. 
 
8.2 
ASSESSMENT OF SAFETY EVENTS 
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship. AEs will be followed through resolution. 
SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator. 
• 
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database. 
• 
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator. 
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
Sponsor with the exception of any listed in section 8.4. 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS 
Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event 
of Special Interest that require expedited reporting must be submitted immediately (within 24 
hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the 
expedited reporting requirements are found in section 8.4 
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Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies occurring from the date of the first dose until 6 months after the last dose should, 
if possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes. 
8.7 
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR-SPONSORED IND 
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected 
adverse reaction only if there is evidence to suggest a causal relationship between the study 
product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all 
investigators to whom the sponsor is providing drug under its INDs or under any investigator’s 
IND) in an IND safety report of potential serious risks from clinical trials or any other source, as 
soon as possible, in accordance to 21 CFR Part 312.32.  
All serious events will be reported to the FDA at least annually in a summary format. 
8.8 
SPONSOR PROTOCOL DEVIATION REPORTING 
A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual 
of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or 
protocol-specific procedural requirements on the part of the participant, the Investigator, or the 
study site staff inclusive of site personnel performing procedures or providing services in support 
of the clinical trial. 
It is the responsibility of the study Staff to document any protocol deviation identified by the 
Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online 
application. The entries into the PDTS online application should be timely, complete, and 
maintained per CCR PDTS user requirements.   
In addition, any deviation to the protocol should be documented in the participant’s source 
records and reported to the reviewing IRB per their guidelines. OSRO required protocol 
deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 
Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol 
deviations. 
9 
CLINICAL MONITORING  
Clinical site monitoring is conducted to ensure: 
• that the rights of the participants are protected; 
• that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and 
• the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
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Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 
expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates. 
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV). 
Some monitoring activities may be performed remotely, while others will occur at the study 
site(s). Monitoring visit reports will describe visit activities, observations, and associated action 
items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring 
reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, 
coordinating center (if applicable), and the Sponsor regulatory file. 
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR 
Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as 
applicable per institutional and IRB guidance. 
. 
10 STATISTICAL CONSIDERATIONS 
10.1 STATISTICAL HYPOTHESIS 
Primary Objectives: 
• Arm 1 (Sequential Dose Escalation):  
 To evaluate the safety and tolerability of single agent SX-682. 
 To determine the MTD of SX-682 followed by M7824 and CV301 in participants 
with advanced or metastatic solid tumors. If the MTD is not reached the study 
will be focused to describe the safety and tolerability of SX-682 followed by 
M7824 and CV301. 
• Arm 2 (Combination Dose Escalation):  
 To determine the RP2D of SX-682 with M7824 and CV301 in participants with 
advanced or metastatic solid tumors. If the MTD is not reached the study will be 
focused to describe the safety and tolerability of the drug combination. 
• Arm 3 (Expansion): 
 To evaluate preliminary efficacy based on Objective Response Rate (ORR), in 
each disease cohort separately. 
Secondary Objectives: 


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• Arms 1 and 2 (Dose Escalations):  
 To characterize the PK/PD profile of SX-682 as a single agent and in 
combination. 
• All Arms:  
 To evaluate preliminary efficacy: Disease control rate (DCR) and Progression-
free survival (PFS) using RECIST1.1 
10.2 SAMPLE SIZE DETERMINATION 
The trial will begin with two phase I evaluations (Cohort 1, Arms 1 and 2; Dose Escalation) as 
follows: initially participants will be enrolled in Arm 1 involving monotherapy with SX-682 
followed by M7824 + CV301. This will initially include up to 3 dose levels, with 3 participants 
per dose level if no DLTs are experienced. However, if in any of the dose levels, a DLT is 
identified in the 3 participants, 3 more participants will be enrolled in that dose level, with 
subsequent escalation only if there are <=1 DLTs in 6 participants. Thus, up to 18 participants 
may be enrolled in these first 3 dose levels. If there is one or more DLTs identified in in the first 
3 dose levels, escalation will continue to DL4 and 5 using the above 3+3 design. If there are no 
DLTs in the first 3 dose levels, then participants will be enrolled to Arm 2. As a result, 
depending on toxicities identified, between 9 and 30 participants may be treated within this 
sequential dose escalation arm.  
In Arm 2, a combination arm with SX-682 followed by the triplet combination (SX-682, M7824, 
CV301), up to 5 dose levels may be explored. Using a standard 3+3 design, up to 5x6=30 
participants may be included in this arm. Thus, up to 30+30=60 total participants may be treated 
in the phase I portion (Cohort 1, Arms 1 and 2) of the trial. 
The phase II evaluation (Arm 3) will take place separately in two cohorts: 
TNBC: 
Based on prior studies [70-72], the clinical response rate for similar participants with advanced 
disease receiving a single agent checkpoint inhibitor is expected to be 8-10%. Thus, an observed 
response rate of approximately 15% or higher would be desirable. 
In Arm 3, Cohort 2 (TNBC), the trial will be conducted using a Simon minimax two-stage phase 
II trial design [99] to rule out an unacceptably low response rate (CR+PR) of 5% (p0=0.05) in 
favor of an improved response rate of 20% (p1=0.20). With alfa=0.10 (probability of accepting a 
poor treatment=0.10) and beta = 0.20 (probability of rejecting a good treatment=0.20), the first 
stage will enroll 12 evaluable participants, and if 0 of the 12 has a response, then no further 
participants will be accrued in that cohort. If 1 or more of the first 12 participants has a response, 
then accrual would continue until a total of 21 evaluable participants have been treated in that 
cohort. As it may take up to several months to determine if a participant has experienced a 
response, a temporary pause in the accrual may be necessary to ensure that enrollment to the 
second stage is warranted. If there are 1-2 participants with a response out of 21 participants in 
this cohort, this would be an uninterestingly low response rate. If there were 3 or more of 21 
(14.3%) who experienced a response, this would be sufficiently interesting to warrant further 
study in later trials. Under the null hypothesis (5% response rate), the probability of early 
termination is 54.0%. 
HPV negative HNSCC: 


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Based on prior studies [82, 87, 88], the clinical response rate for similar participants with this 
disease is expected to be 13-18%. Thus, an observed response rate of greater than 25% would be 
desirable. 
In Arm 3, Cohort 3 (HPV negative HNSCC), the trial will be conducted using a Simon minimax 
two-stage phase II trial design[99] to rule out an unacceptably low response rate (CR+PR) of 
15% (p0=0.15) in favor of an improved response rate of 40% (p1=0.40). With 
alfa=0.10(probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of 
rejecting a good treatment=0.20), the first stage will enroll 9 evaluable participants, and if 0 to 1 
of the 9 have a response, then no further participants will be accrued in that cohort. If 2 or more 
of the first 9 participants have a response, then accrual would continue until a total of 16 
evaluable participants have been treated in that cohort. As it may take up to several months to 
determine if a participant has experienced a response, a temporary pause in the accrual may be 
necessary to ensure that enrollment to the second stage is warranted. If there are 2-4 participants 
with a response out of 16 participants in this cohort, this would be an uninterestingly low 
response rate. If there were 5 or more of 16 (31.3%) who experienced a response, this would be 
sufficiently interesting to warrant further study in later trials. Under the null hypothesis (15% 
response rate), the probability of early termination is 60.0%. 
It is expected that up to 1.5 years may be required to enroll up to 60 participants in Arms 1 and 2. 
It is then expected that 2-3 years may be required to complete accrual to Arm 3. Thus, accrual is 
expected to be completed in 4-5 years. The total number of evaluable participants is no more 
than 60+21+16=97. To allow for a small number of inevaluable participants, the accrual ceiling 
for treated participants in the dose escalation and expansion cohorts combined will be set at 105 
participants 
10.3 POPULATIONS FOR ANALYSES 
Intention to treat: any subjects who enroll onto the trial and provide consent and who receive at 
least 1 dose of SX-682, will be included in safety analyses in Arms 1 and 2.  
In Arm 3, any participants who receive at least one cycle (defined as 28 days) of SX-682, 
M7824, and CV301 will be included in safety evaluations as well as efficacy evaluations for the 
appropriate cohort. 
10.3.1 Evaluable for toxicity  
All participants will be evaluable for toxicity from the time of their first treatment with SX-682. 
Participant will be eligible for the DLT evaluation if at least ≥85 percent of SX-682 scheduled 
doses were taken and 100% of scheduled doses of M7824 or CV301 were administered within 
the DLT period. 
10.3.2 Evaluable for objective response  
Only those participants who have measurable disease present at baseline, have received at least 
one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for 
response. These participants will have their response classified according to the definitions in 
section 6.3). (Note: Participants who receive at least treatment cycle and exhibit objective 
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10.3.3 Evaluable Non-Target Disease Response 
Participants who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for non-target disease. The response 
assessment is based on the presence, absence, or unequivocal progression of the lesions.  
10.4 STATISTICAL ANALYSES 
10.4.1 General Approach 
Following a determination of safety, tolerability, and the MTD in Arms 1 and 2, the fraction of 
participants who experience a response in each disease-specific cohort of Arm 3 will be reported 
along with confidence intervals. 
10.4.2 Analysis of the Primary Endpoints 
The toxicity grades per participant will be tabulated and reported by dose level during dose 
escalation (Arms 1 and 2). This will also include separate evaluations for the initial monotherapy 
evaluations preceding the evaluation of the combination at each dose level.  
In Arm 3, the fraction of participants who experience a response in each disease-specific cohort 
will be reported along with 95% two-sided confidence intervals. 
10.4.3 Analysis of the Secondary Endpoint(s) 
10.4.4 PK evaluations will be performed on participants in both dose escalation Arms (both for 
single agent SX-682 and the combination of agents); results will be reported using 
standard descriptive statistics. In Arm 3, separately by cohort, the disease control rate 
(DCR; CR+PR+SD) will be reported as the fraction of participants who experience this 
outcome, along with a 95% two-sided confidence interval for each fraction. Progression 
free survival (PFS) will be calculated using the Kaplan-Meier method, including 
progressions or death without progression as events. Participants who come off study for 
reasons other than progression and choose not to participate in optional imaging will be 
censored in data analysis at the time when they become unfollowable for PFS.  
 
10.4.5 Safety Analyses 
The fraction of participants who experience a toxicity, by grade and type of toxicity, will be 
tabulated per dose level (both single agent and combination of agents) during the Arms 1 and 2 
portion of the trial. Participants who take one dose or more of SX-682 will be evaluable for 
safety.  
10.4.6 Baseline Descriptive Statistics 
Baseline demographic characteristics will be reported. 
10.4.7 Planned Interim Analyses 
As indicated in the two-stage designs, the number of responses after 9 or 12 evaluable 
participants have been treated in the appropriate cohort will be noted and will be used to 
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10.4.8 Sub-Group Analyses 
In Arm 3, analyses will be performed separately by histology. 
10.4.9 Tabulation of individual Participant Data 
None 
10.4.10 
Exploratory Analyses 
All Arms: 
 To evaluate response via iRECIST 
 To evaluate the effect on immune cell subsets and soluble factors in peripheral blood. 
 To evaluate the effect on serum cytokine levels (IL-8, IL-6 and others) in peripheral 
blood. 
 To evaluate the effect on T cell clonality in peripheral blood and tumor samples. 
 To evaluate the effect on antigen-specific T cells responses to CEA, MUC1 and the 
cascade antigen brachyury in peripheral blood. 
 To evaluate the effect on antigen-specific T cell responses to CEA, MUC1 and the 
cascade antigen brachyury in the tumor biopsies.  
 To evaluate the presence of lymphocytic infiltrates and other tumor markers as well as to 
evaluate RNA in situ hybridization for IL-8, TGF-β and other soluble factors in tumor 
biopsies. 
 To evaluate M7824 PK profile in this drug combination  
 To evaluate ADA in this drug combination 
 To evaluate long term (2 years after completion of treatment) clinical outcomes 
 To evaluate CTCs  
In Arms 1 and 2 (Dose-Escalations), the following are the parameters will be evaluated, 
separately per dose level: 
 To evaluate ORR per RECISTv1.1 
In Arm 3 (Expansions) the following are the parameters will be evaluated, separately per cohort. 
  To evaluate changes in circulating free DNA.  
Any exploratory evaluations which generate quantitative measures will be done using descriptive 
statistics including confidence intervals when appropriate. Any statistical tests performed for 
evaluation of exploratory objectives will be done without formal adjustment for multiple 
comparisons, but in the context of the number of tests performed. 
11 COLLABORATIVE AGREEMENTS  
11.1  COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) 
A CRADA (03153) is in place with Syntrix for the supply of SX-682. 
A CRADA (02666) is in place with EMD Serono for the supply of M7824. 


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A CRADA (02561) is in place with Bavarian Nordic for the supply of CV301. 
12 HUMAN SUBJECTS PROTECTIONS  
12.1 RATIONALE FOR SUBJECT SELECTION 
No individual who meets the criteria for eligibility will be excluded from participation based on 
their race, ethnicity, gender, or socioeconomic status. Particular attention will be made to acquire 
a broad and diversified population. 
12.2 PARTICIPATION OF CHILDREN 
Children (younger than 18 years) will not be included in this protocol due to the limited data on 
study drugs in children and the different biology of childhood malignancy. 
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 12.4.2), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the 
subjects and to identify an LAR as needed.  . 
Please see section 12.5.1 for consent procedure.   
 
12.4 RISK/BENEFIT ASSESSMENT FOR ALL PARTICIPANTS  
12.4.1 Known Potential Risks  
12.4.1.1 Study Drug Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or sections 1.2.2.2, 1.2.3.1, 1.2.4.1 of this protocol document. Frequent 
monitoring for adverse effects will help to minimize the risks associated with administration of 
the study agents. 
12.4.1.2 Risk of Biopsy 
All care will be taken to minimize risks that may be incurred by tumor sampling. However, there 
are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained 
fully during informed consent. 
12.4.1.3 Risks of local anesthesia and/or light sedation. 
Biopsies will be done under local anesthesia and/or light sedation. Potential side effects 
of sedation include headache, nausea and drowsiness. These side effects usually go away 
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12.4.1.4 Risks of contrast dye used in CT scans  
There is a chance of developing an allergic reaction from the contrast material, which may cause 
symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, 
death.  The contrast material may also cause kidney problems. 
For IV contrast: Potential side effects include discomfort when the contrast material is injected, 
feeling warm, flushed, a metallic taste, or rarely vomiting or nausea.  
For oral contrast:  Potential side effects include vomiting, nausea, cramping, bloating, 
constipation or diarrhea after drinking the contrast. 
 
12.4.1.5 Risks of exposure to Ionizing Radiation  
This research study involves up to nine (9) CT scans (C/A/P) and up to three (3) CT guided 
biopsies (optional) collected for research purposes only. Subjects undergoing these scans and  
optional biopsies collection will be exposed up to 12.3 rem.  
The CT scans that participant will get in this study will expose them to the roughly the same 
amount of radiation as 41 years of background radiation. The risk of getting cancer from the 
radiation exposure in this study is 1.2 out of 100 (1.2 %) and of getting a fatal cancer is 0.6 out of 
100 (0.6 %)  
 
12.4.1.6 Risks of MRI 
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  
It may be unsafe to have an MRI scan for participants with pacemakers or other implanted 
electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips 
on the wall of a large artery), metal prostheses (including metal pins and rods, heart valves, and 
cochlear implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel 
fragments. Welders and metal workers may have small metal fragments in the eye.  
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the 
scanner is loud enough to damage hearing, especially in people who already have hearing loss.  
There are no known long-term risks of MRI scans. 
 
12.4.1.7 Risks of Gadolinium 
The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.   
Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and 
usually go away quickly.  Mild symptoms may include coldness in the arm during the injection, a 
metallic taste, headache, and nausea.  In an extremely small number, fewer than one in 300,000 
people, more severe symptoms have been reported including shortness of breath, wheezing, 
hives, and lowering of blood pressure.  
People with kidney disease are at risk for a serious reaction to gadolinium contrast called 
“nephrogenic systemic fibrosis (NSF)”.  This condition always involves the skin and can also 
involve the muscles, joints and internal organs.  NSF has resulted in a very small number of 
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Most of the gadolinium contrast leaves the body in the urine.  However, the FDA has issued a 
safety alert that indicates small amounts of gadolinium may remain in the body for months to 
years.  The long-term effects of the retained gadolinium are not known.  Some types of 
gadolinium contrast drugs are less likely to remain in the body than others. The gadolinium 
contrast drugs that are less likely to remain in the body will be used on this study. 
 
12.4.1.8 Research Blood Collection Risks 
Risks of blood draws include pain and bruising in the area where the needle is placed, 
lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, 
low red blood cell count (anemia) can develop.  
12.4.1.9 Risk of Rapid Progression 
Three large studies of bintrafusp alfa were recently stopped when the drug 
manufacturer reviewed data that suggested that the studies would not be likely to prove the study 
treatment better than standard treatments. This data also suggested that there may be a portion of 
patients that have either no benefit from bintrafusp alfa, or that bintrafusp alfa will make the 
tumor grow faster. This has been described with other immunotherapy approaches also with 
studies suggesting this happens in about 15% of cases. 
 
12.4.1.10 
Other Risks 
Risks include the possible occurrence of any of a range of side effects which are listed in the 
Consent Document or this protocol document. Frequent monitoring for adverse effects will help 
to minimize the risks associated with administration of the study agents. 
12.4.2 Known Potential Benefits 
The study drugs may help to control the disease. The results may help the investigators learn 
more about the disease and develop new treatments for participants with this disease. 
12.4.3 Assessment of Potential Risks and Benefits 
Solid tumors treatment needs improved therapy options. Current studies suggest that study 
therapy may have tremendous anti-tumor efficacy.  
A number of clinically appropriate strategies to minimize risks to participants have been built 
into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and 
management guidelines. Overall, the potential benefit of the study therapy in subjects with solid 
tumors outweigh the risks associated with this drug. 
The potential benefit to a participant that participates in this study is better control of their tumor 
growth and disease recurrence which may or may not have a favorable impact on symptoms 
and/or survival. 
Potential adverse reactions attributable to the administration of the study drug utilized in this trial 
are discussed in Sections 1.2.2.2, 1.2.3.1, 1.2.4.1. All care will be taken to minimize side effects, 
but they can be unpredictable in nature and severity 


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12.5 CONSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee(s) for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with 
policy including HRPP policy 303) per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed. 
 
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant) or as described below, with a manual 
(non-electronic) signature on the electronic document. When required, witness signature will be 
obtained similarly as described for the investigator and participant.  
 
Manual (non-electronic) signature on electronic document: 
When a manual signature on an electronic document is used for the documentation of consent 
at the NIH Clinical Center, this study will use the following to obtain the required signatures: 
• 
Adobe platform (which is not 21 CFR Part 11 compliant); or,   
• 
iMedConsent platform (which is 21 CFR Part 11 compliant) 
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations (if remote consent); the 
same screen may be used when in the same location but is not required.   
Both the investigator and the participant will sign the document using a finger, stylus or 
mouse.  
Note: Refer to the CCR SOP PM-2, Obtaining and Documenting the Informed Consent 
Process for additional information (e.g., verification of participant identity when obtaining 
consent 
remotely) 
found 
 
at:   
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 
 
12.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 12.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 12.5 
 


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13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily 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 study participants, 
investigators, and regulatory authorities. If the study is prematurely terminated or suspended, the 
Principal Investigator (PI) will promptly inform study participants and the Institutional Review 
Board (IRB) and will provide the reason(s) for the termination or suspension. Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping  
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and Food and Drug Administration (FDA). 
13.2 QUALITY ASSURANCE AND QUALITY CONTROL 
Clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities. 
13.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed 
and managed. Furthermore, persons who have a perceived conflict of interest will be required to 
have such conflicts managed in a way that is appropriate to their participation in the design and 


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conduct of this trial. The study leadership in conjunction with the NCI has established policies 
and procedures for all study group members to disclose all conflicts of interest and will establish 
a mechanism for the management of all reported dualities of interest. 
13.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be stored at NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems 
used by clinical sites and by NCI CCR research staff will be secured and password protected. At 
the end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants. 
14 PHARMACEUTICAL INFORMATION 
14.1 SX-682 (IND#21166) 
14.1.1 Acquisition and Accountability 
Investigational SX-682 is manufactured and supplied for the trial by Syntrix. Drug will be 
delivered directly to the NIH Pharmacy. Individual bottles with tablets will be prepared for each 
study participant according to assigned dose by NIH Pharmacy personnel. Participants will pick 


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up bottles at NIH Pharmacy and will return bottles and not-used tablets after completion of every 
cycle together with Medication Diary to Study Coordinator. After review of leftover tablets and 
Medication Diary, unused tablets will be returned to pharmacy and disposed by pharmacy 
personnel 
14.1.2 Formulation, Appearance, Packaging, and Labeling 
SX-682 is dispensed as either 25 mg or 100 mg tablets for oral administration.  
SX-682 exhibits 99.4% protein binding.  
The anticipated half-life of the drug varies by dose administered with a 25mg flat dose resulting 
in a half-life of 2.6 hours and a 200 mg flat dose resulting in a half-life is 14 hours.  
14.1.3 Product Storage and Stability 
Store SX-682 between 15 to 30°C. On the basis of available stability data for the API and a drug 
product demonstration batch, SX-682 is projected stable for at least 2 years when stored as 
above. 
14.1.4 Preparation 
SX-682 is dispensed as 25 mg or 100 mg tablets for oral administration. If necessary, the 100 mg 
tablets can be cut in half using a pill splitter; the tablets are pre-scored for this purpose. The 
tablets should not be crushed, chewed, or dissolved before being swallowed.  
14.1.5 Administration 
Please see Section 3.3.2  
14.2 M7824 (IND#21166) 
14.2.1 Acquisition and Accountability 
M7824 is manufactured and supplied for the trial by EMD Serono Research and Development 
Institute. Drug will be delivered directly to the NIH Pharmacy. Individual IV bags will be 
prepared for each study participant according to assigned dose by NIH Pharmacy personnel. IV 
bags will be delivered from NIH Pharmacy to participant unit where drug will be infused to the 
participant. 
14.2.2 Formulation, Appearance, Packaging, and Labeling 
M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in 
USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable 
volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format 
complying with USP and Ph Eur with an aluminum crimp seal closure. Each single-use vial 
contains 600mg of M7824, formulated as 10mg/mL of active, 6% (w/v) Trehalose, 40 mM NaCl, 
5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM LHistidine at pH 5.5.  
The liquid formulation is diluted directly with 0.9% sodium chloride solution for injection. The 
estimated volumes of delivery are anticipated to be no more than 250mL. The verified 
concentration range in the infusion solution is 0.16 mg/mL to 9.6 mg/mL.  
14.2.3 Product Storage and Stability 
M7824 drug product must be stored at 2°C to 8°C until use. The storage condition is based on 
data from ongoing longterm stability studies with M7824. M7824 drug product stored at room 


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(23°C to 27°C) or higher temperatures for extended periods of time might be subject to 
degradation. 
The chemical and physical in-use stability for the infusion solution of M7824 in 0.9% saline 
solution has been demonstrated for a total of 72 hours at room temperature. However, from a 
microbiological point of view, the diluted solution should be used immediately and is not 
intended to be stored unless dilution has taken place in controlled and validated aseptic 
conditions. If not used immediately, in-use storage times and conditions prior to administration 
are the responsibility of the user. Do not freeze or shake the diluted solution. 
No other drugs should be added to the infusion containers containing M7824. 
14.2.4 Preparation 
Preparation is described in pharmacy manual. 
14.2.5 Administration 
Please see Section 3.3.4 
14.3 CV301 (IND#21166) 
14.3.1 Acquisition and Accountability 
Investigational CV301 vaccines (MVA-BN-CV301 and FPV-CV301) will be supplied by the 
manufacturer, Bavarian Nordic. Drug will be delivered directly to the NIH Pharmacy. Individual 
syringes with the drugs will be prepared for each study participant by NIH Pharmacy personnel. 
Syringes will be delivered from NIH Pharmacy to participant unit where drug will be injected to 
the participant. 
14.3.2 Formulation, Appearance, Packaging, and Labeling 
The manufacturing department of Bavarian Nordic will supply MVA-BN-CV301 and FPV-CV301, 
with each vaccine provided in 2 mL type I borosilicate glass vials closed with sterile bromobutyl 
rubber stoppers, crimped with aluminum caps and covered with polypropylene closures.  
14.3.3 Product Storage and Stability 
Supplies of both the MVA-BN-CV301 and the FPV-CV301 vaccines will be shipped 
temperature controlled and monitored to the clinical trial site. Once at the site, the package 
should be handed over to personnel in charge of vaccine preparation (e.g., the pharmacist or 
representative). Site personnel are responsible for proper storage of vaccine upon receipt.  
Both the MVA-BN-CV301 and the FPV-CV301 vaccines must be shipped to site and stored at a 
minimum temperature of -4°F +/- 9°F (-20°C +/- 5°C) or -80ºC ± 10ºC, avoiding direct light. A 
vial must not be re-frozen once it has been thawed. A provisional shelf life of 2 years at -80°C ± 
10°C has been given. Expiry date may be extended due to real time stability data. Storage at -
20°C ± 5°C is limited to 12 months after moving from -80°C ± 10°C to -20°C ± 5°C. 
14.3.4 Preparation 
MVA-BN-CV301 and FPV-CV301 encode the human MUC-1 and the human CEA gene in 
combination with human TRICOM. No marker gene is present in both recombinant viruses.  


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MVA-BN-CV301 is a liquid-frozen, highly attenuated, live recombinant virus based on the viral 
vector MVA-BN. It is administered as s.c. injection. Packaging and vials will be labeled 
according to the respective product specifications.  
One MVA-BN-CV301 vaccine vial has a nominal titer of 4 x 108 infectious units (Inf.U) in 0.5 
mL of the drug product. 
FPV-CV301 is a liquid-frozen, highly attenuated, live recombinant virus. It is administered as 
s.c. injection. The packages and vials will be labeled according to the respective product 
specifications.  
One FPV-CV301 vaccine vial has a nominal virus titer of 1 x 109 Inf.U in 0.5 mL of the drug 
product. 
14.3.5 Administration 
Please see Section 3.3.3. 


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Simon, R., Controlled Clinical Trials. 1989. p. 1-10. 
16 APPENDICES 
16.1 APPENDIX A-PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
 


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16.2 APPENDIX B: DRUGS KNOWN TO SIGNIFICANTLY PROLONG THE QTC* 
Generic Name* 
 
 
 
Brand Name* 
Aclarubicin 
 
 
 
 
Aclacin and others 
Amiodarone  
 
 
 
Cordarone and others 
Anagrelide 
 
 
 
 
Agrylin and others 
Arsenic trioxide 
 
 
 
Trisenox 
Astemizole 
 
 
 
 
Hismanal 
Azithromycin  
 
 
 
Zithromax and others 
Bepridil 
 
 
 
 
Vascor 
Chloroquine  
 
 
 
Aralen 
Chlorpromazine 
 
 
 
Thorazine and others 
Cilostazol 
 
 
 
 
Pletal 
Ciprofloxacin  
 
 
 
Cipro and others 
Cisapride 
 
 
 
 
Propulsid 
Citalopram 
 
 
 
 
Celexa and others 
Clarithromycin 
 
 
 
Biaxin and others 
Cocaine 
 
 
 
 
Cocaine 
Disopyramide  
 
 
 
Norpace 
Dofetilide 
 
 
 
 
Tikosyn 
Domperidone  
 
 
 
Motilium and others 
Donepezil 
 
 
 
 
Aricept 
Dronedarone  
 
 
 
Multaq 
Droperidol 
 
 
 
 
Inapsine and others 
Erythromycin  
 
 
 
E.E.S. and others  
Escitalopram  
 
 
 
Cipralex and others 
Flecainide 
 
 
 
 
Tambocor and others 
Fluconazole 
 
 
 
 
Diflucan and others 
Gatifloxacin  
 
 
 
Tequin 
Grepafloxacin  
 
 
 
Raxar 
Halofantrine  
 
 
 
Halfan 
Generic Name* 
 
 
 
Brand Name* 
Haloperidol 
 
 
 
 
Haldol (US & UK) and others 
Ibogaine 
 
 
 
 
None 
Ibutilide 
 
 
 
 
Corvert 
Levofloxacin  
 
 
 
Levaquin and others 
Levomepromazine (methotrimeprazine) 
Nosinan and others 
Levomethadyl acetate  
 
 
Orlaam 
Levosulpiride  
 
 
 
Lesuride and others 
Mesoridazine  
 
 
 
Serentil 
Methadone 
 
 
 
 
Dolophine and others 
Moxifloxacin  
 
 
 
Avelox and others 
Ondansetron  
 
 
 
Zofran and others 
Oxaliplatin 
 
 
 
 
Eloxatin 
Papaverine HCl (Intracoronary) 
 
None 
Pentamidine (systemic) 
 
 
Pentam 
  


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Pimozide 
 
 
 
 
Orap 
Probucol 
 
 
 
 
Lorelco 
Procainamide  
 
 
 
Pronestyl and others 
Propofol 
 
 
 
 
Diprivan and others 
Quinidine 
 
 
 
 
Quinaglute and others 
Roxithromycin 
 
 
 
Rulide and others 
Sevoflurane 
 
 
 
 
Ultane and others 
Sotalol  
 
 
 
 
Betapace and others 
Sparfloxacin  
 
 
 
Zagam 
Sulpiride 
 
 
 
 
Dogmatil and others 
Sultopride 
 
 
 
 
Barnetil and others 
Terfenadine 
 
 
 
 
Seldane 
Terlipressin 
 
 
 
 
Teripress and others 
Terodiline 
 
 
 
 
Micturin and others  
Thioridazine  
 
 
 
Mellaril and others 
Vandetanib 
  
 
 
 
Caprelsa 
* CredibleMeds.org 


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16.3 APPENDIX C PARTICIPANT’S MEDICATION DIARY ________________________ 
16.3.1 Lead In 
Participant’s ID _________________________ Treatment LEAD IN:_____________________ 
Participant SX-682 Dose:__________________ Treatment Dates:______________________  
INSTRUCTIONS TO THE PARTICIPANT: 
1. Complete this form for two-week period on the trial.  
2. You will take SX-682 twice a day for every day of two-week period. This drug should be 
taken in a fasting state, meaning no food 2 hours prior to taking the drug and no food 1 
hour after taking the drug.  
3. Record the date, the number of tablets that you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the 
comment’s column. 
5. Please bring this form and your bottles (even it is empty) when you come for your clinic 
visit. 
Day 
Date 
Oral SX-682 (every 12 hours) 
Comments 
(Side effects, reason for missing  
dose, etc) 
Morning Dose 
Evening Dose 
Time 
# Tablets Time 
# Tablets  
-14L  
 
 
 
 
 
-13L  
 
 
 
 
 
-12L  
 
 
 
 
 
-11L  
 
 
 
 
 
-10L  
 
 
 
 
 
-9L 
 
 
 
 
 
 
-8L 
 
 
 
 
 
 
-7L 
 
 
 
 
 
 
-6L 
 
 
 
 
 
 
-5L 
 
 
 
 
 
 
-4L 
 
 
 
 
 
 
-3L 
 
 
 
 
 
 
-2L 
 
 
 
 
 
 
-1L 
 
 
 
 
 
 
Participant’s signature:  ___________________________________________________ 


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16.3.2 Cycles 
Participant’s ID _________________________ Treatment Cycle:_____________________ 
Participant SX-682 Dose:__________________ Treatment Dates:______________________  
INSTRUCTIONS TO THE PARTICIPANT: 
1. Complete one form for each cycle on the trial.  
2. You will take SX-682 twice a day for every day of the cycle. This drug should be taken 
in a fasting state, meaning no food 2 hours prior to taking the drug and no food 1 hour 
after taking the drug.  
3. Record the date, the number of tablets that you took, and when you took them. 
4. If you have any comments or notice any side effects, please record them in the 
comment’s column. 
5. Please bring this form and your bottles (even it is empty) when you come for your clinic 
visit. 
Day 
Date 
Oral SX-682 (every 12 hours) 
Comments 
(Side effects, reason for missing  
dose, etc) 
Morning Dose 
Evening Dose 
Time 
# Tablets 
Time 
# Tablets 
 
1 
 
 
 
 
 
 
2 
 
 
 
 
 
 
3 
 
 
 
 
 
 
4 
 
 
 
 
 
 
5 
 
 
 
 
 
 
6 
 
 
 
 
 
 
7 
 
 
 
 
 
 
8 
 
 
 
 
 
 
9 
 
 
 
 
 
 
10 
 
 
 
 
 
 
11 
 
 
 
 
 
 
12 
 
 
 
 
 
 
13 
 
 
 
 
 
 
14 
 
 
 
 
 
 
15 
 
 
 
 
 
 
16 
 
 
 
 
 
 
17 
 
 
 
 
 
 
18 
 
 
 
 
 
 
19 
 
 
 
 
 
 
20 
 
 
 
 
 
 
21 
 
 
 
 
 
 
22 
 
 
 
 
 
 
23 
 
 
 
 
 
 
24 
 
 
 
 
 
 


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Day 
Date 
Oral SX-682 (every 12 hours) 
Comments 
(Side effects, reason for missing  
dose, etc) 
Morning Dose 
Evening Dose 
Time 
# Tablets 
Time 
# Tablets 
 
25 
 
 
 
 
 
 
26 
 
 
 
 
 
 
27 
 
 
 
 
 
 
28 
 
 
 
 
 
 
Participant’s signature: ___________________________________________________