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Abbreviated Title: STAT Trial NIH Protocol \# 20C0155 Version Date: 03/18/2022 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-
"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)   
| Investigational Agents:   | Bintrafusp alfa   |            |                  |
|---------------------------|-------------------|------------|------------------|
| Drug Name:                | SX-682            |            |                  |
| IND Number:               | 21166             |            |                  |
| Sponsor:                  | CCR, NCI          |            |                  |
| Manufacturer:             | Syntrix           | EMD Serono | Bavarian  Nordic |
| Supplier:                 | Syntrix           | EMD Serono | Bavarian  Nordic |  
Commercial Agents: None
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precis

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-RII receptor (TGF- "trap") fused to a human IgG1.  
Preclinical data shows bintrafusp alfa treatment increases T-cell trafficking, antigenspecific 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):  
To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each disease cohort separately.
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eligibility age > 18 years

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
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design

Arm 1 is a phase I, open-label, 3+3 sequential dose escalation trial with short term, 2week 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 SX682 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.  
| TABLE OF CONTENTS                                                                                                                                             |                                                                                                                                                                 |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PRÉCIS                                                                                                                                                        |                                                                                                                                                                 |
| TABLE OF CONTENTS ..............................................................................................................................4             |                                                                                                                                                                 |
| STATEMENT OF COMPLIANCE                                                                                                                                       |                                                                                                                                                                 |
| INTRODUCTION ...............................................................................................................................................8 |                                                                                                                                                                 |
| 1.                                                                                                                                                            | Study Objectives ....................................................................................................................................8          |
| 1.1                                                                                                                                                           |                                                                                                                                                                 |
| 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                                                                                                           |
| Baseline Evaluation                                                                                                                                           |                                                                                                                                                                 |
| 2.4                                                                                                                                                           |                                                                                                                                                                 |
| 3                                                                                                                                                             | STUDY IMPLEMENTATION .............................................................................................................45                            |
| Study Design                                                                                                                                                  |                                                                                                                                                                 |
| 3.1                                                                                                                                                           |                                                                                                                                                                 |
| 3.2                                                                                                                                                           | Study Stopping rules .                                                                                                                                          |
| 3.3                                                                                                                                                           | Drug Administration                                                                                                                                             |
| 3.4                                                                                                                                                           | Dose Modifications                                                                                                                                              |
| 3.5                                                                                                                                                           | Study Calendar ..................................................................................................................................68             |
| Cost and Compensation                                                                                                                                         |                                                                                                                                                                 |
| 3.6                                                                                                                                                           |                                                                                                                                                                 |
| 3.7                                                                                                                                                           | Criteria for Removal from Protocol Therapy and Off Study Criteria..................................77                                                           |
| 4                                                                                                                                                             | Concomitant Therapy                                                                                                                                             |
| The Following Treatments Should not be Administered During the Trial: ......................78                                                                |                                                                                                                                                                 |
| 4.1                                                                                                                                                           |                                                                                                                                                                 |
| S                                                                                                                                                             | CORRELATIVE STUDIES FOR RESEARCH ...................................................................................79                                          |
| 5.1                                                                                                                                                           | SAMPLES                                                                                                                                                         |
| 5.2                                                                                                                                                           | Correlative Studies for Research/Pharmacokinetic Studies                                                                                                        |
| Samples for Genetic/Genomic Analysis ..........................................................................................83                             |                                                                                                                                                                 |
| 5.3                                                                                                                                                           |                                                                                                                                                                 |
| 5.4                                                                                                                                                           | Sample Storage, Tracking and Disposition                                                                                                                        |
| 6                                                                                                                                                             | DATA COLLECTION AND EVALUATION ...............................................................................88                                                |
| 6.1                                                                                                                                                           | DATA COLLECTION .............................................................................................................................................88 |
| DATA SHARING Plans                                                                                                                                            |                                                                                                                                                                 |
| 6.2                                                                                                                                                           |                                                                                                                                                                 |
| 6.3                                                                                                                                                           | Response Criteria ................................................................................................................................89            |
| 7                                                                                                                                                             | NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN...96                                                                                               |
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design

| Version Date: 03/18/2022 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 103 10.3 Populations for Analyses 105 10.4 Statistical Analyses 105 11 Collaborative Agreements 107 11.1 Cooperative Research and Development Agreement (CRADA) 107 12 HUMAN SUBJECTS PROTECTIONS 107 12.1 Rationale for Subject Selection 107 12.2 Participation of Children 107 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 110 13 REGULATORY AND OPERATIONAL CONSIDERATIONS 111 13.1 Study Discontinuation and Closure 111 13.2 Quality Assurance and Quality Control 112 13.3 Conflict of Interest Policy 112 13.4 Confidentiality and Privacy 1125   |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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abbreviated title stat trial version

| 14   PHARMACEUTICAL INFORMATION ...............................................................................................113   |                                                                                                                                                              |
|--------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|
| SX-682 (IND#21166)                                                                                                                   |                                                                                                                                                              |
| 14.1                                                                                                                                 |                                                                                                                                                              |
| 14.2                                                                                                                                 | M7824 (IND#21166)                                                                                                                                            |
| 14.3                                                                                                                                 | CV301 (IND#21166)                                                                                                                                            |
| REFERENCES .                                                                                                                         |                                                                                                                                                              |
| 15                                                                                                                                   | Appendices ..............................................................................................................................................123 |
| 16                                                                                                                                   | Appendix A-Performance Status Criteria........................................................................123                                            |
| 16.1                                                                                                                                 |                                                                                                                                                              |
| 16.2                                                                                                                                 | Appendix B: Drugs Known to Significantly Prolong the Qtc*..................................124                                                               |
| 16.3                                                                                                                                 | Appendix C Participant's Medication Diary                                                                                                                    |
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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.  
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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.  
. To evaluate the presence of lymphocytic and myeloid cell infiltrates and other tumor markers as well as to evaluate RNA expression for IL-8, TGF-β and other soluble factors in tumor biopsies.  
. To evaluate clinical responses (ORR, and DCR) per iRECIST
➤ 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 circulating tumor cells (CTCs)
.  
In Arms 1 and 2 (Dose-Escalation Cohort), the following are the parameters will be evaluated, separately per dose level:
✦ To evaluate ORR per RECISTv1.1
.  
In Arm 3 (Expansion Cohorts) the following are the parameters which will be evaluated, separately per disease-specific cohort
. To evaluate changes in circulating free DNA (cfDNA)  
1.2  
  
BACKGROUND AND RATIONALE
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2 eligbility assessment and enrollment

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.  
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/L 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.  
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.  
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.
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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 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).  
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 CT of chest, abdomen and pelvis with contrast (preferred)
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.
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2.3 participant registration and status

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 here.
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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..  
| 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                                                         | Participants with HPV negative Head and Neck                                                                         |
| Expansion   | 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                                                           |
| 2           | Combination Dose                                                           | Escalating doses of SX-682 for 2 weeks THEN                                                                          |  
2.3.2 Treatment Assignment Procedures (for registration purpose only):  
| Number                                                                  | Name                                       | Description                    |
|-------------------------------------------------------------------------|--------------------------------------------|--------------------------------|
| Escalation                                                              | 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.
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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.
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3 study implementation 3.1 study

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 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 (BNCV301 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.  
Cohort 1, Arm 1: Sequential Dose Escalation Cohort  
  
DLT observation period - first 4 weeks  
  
Proceed to Cohort 1, Arm 2
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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 of known or suspected tumor.  
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, see**Table 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 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.  
| 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 |
| SX-682 is dispensed as a 25mg tablet. M7824 and CV301 will be given at fixed doses. |                             |        |
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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. 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
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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

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.
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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 SX682 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.
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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. 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.
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3.4 dose modifications 3.4.1 general

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. 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.
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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.
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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.
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any grade 4 adrs require

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 resumed per PI discretion.  
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.
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any grade 3 adrs require

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
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 immunerelated 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.  
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 lifethreatening 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. If hypersensitivity reaction occurs, the subject should be treated according to the best available medical practice. 3.4.4.3 Severe Hypersensitivity Reactions and Flu-like Symptoms If a hypersensitivity reaction occurs, the subject must be treated according to the best available medical practice including ACLS guidelines. Subjects should be instructed to report any delayed reactions to the Investigator immediately. A. Symptoms  
Impaired airway Decreased oxygen saturation (< 92%)
Confusion Lethargy Hypotension Pale / clammy skin Cyanosis B. Management Epinephrine injection and IV dexamethasone Participant should be placed on cardiac, blood pressure, heart rate, and oxygen saturation monitor immediately Alert intensive care unit for possible transfer if required
For prophylaxis of flu-like symptoms, a NSAID, for example, ibuprofen 400 mg or comparable NSAID dose, may be administered 2 hours before and 8 hours after the start of each dose of M7824 IV infusion. 3.4.4.4 Immune-Related Adverse Events Guidelines below are merely suggestions. If an immune-mediated reaction occurs, the subject should be treated according to the best available medical practice.
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table 7. management of immune

| Gastrointestinal irAEs                                                |                                                                     |                                                                                                                                                    |
|-----------------------------------------------------------------------|---------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------|
| Severity of Diarrhea/Colitis (NCI-CTCAE v5)                           | Initial Management                                                  | Follow-up Management                                                                                                                               |
| Grade 1 Diarrhea: < 4 stools/day over  Baseline Colitis: asymptomatic | Consider continuing M7824  Symptomatic treatment (e.g.  loperamide) | Consider close monitoring for worsening symptoms Consider educating subject to report worsening  immediately If worsens: Treat as Grade 2, 3 or 4. |  
| Version Date: 03/18/2022 Grade 2  Diarrhea: 4 to 6 stools per day over  Baseline; IV fluids indicated < 24  hours; not interfering with ADL Colitis: abdominal pain; blood in  stool                                                                           | Consider withholding M7824                                                                                                                                                                                                                                                                               | If improves to Grade ≤ 1:                                                                                                                                                                                                                                                                                                                                                       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Symptomatic treatment                                                                                                                                                                                                                                          | Consider resuming therapy If persists > 7 days or recurs: Consider treating as Grade 3 or 4.                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 3 to 4 Diarrhea (Grade 3): ≥ 7 stools per  day over Baseline; incontinence; IV  fluids ≥ 24 h; interfering with ADL Colitis (Grade 3): severe abdominal  pain, medical intervention indicated,  peritoneal signs Grade 4: life-threatening,  perforation | Consider withholding or  permanently discontinuing  M7824 for Grade 3 events  based upon if the clinical  condition can be safely  managed. For grade 4 events  permanently discontinue  treatment.                                                                                                      | If improves:  Consider continuing steroids until Grade ≤ 1, then  tapering over at least 1 month; consider resuming therapy  following steroids taper (for initial Grade 3).  If worsens, persists > 7 days, or recurs after  improvement: Consider adding infliximab 5mg/kg (if no  contraindication). Note: infliximab should not be used in  cases of perforation or sepsis. |
| Consider 1.0 to 2.0  mg/kg/day prednisone IV or  equivalent Consider adding prophylactic  antibiotics for opportunistic  infections  Consider lower endoscopy  Dermatological irAEs                                                                            |                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade of Rash                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                 |
| (NCI-CTCAE v5)                                                                                                                                                                                                                                                 | Initial Management                                                                                                                                                                                                                                                                                       | Follow-up Management                                                                                                                                                                                                                                                                                                                                                            |
| Grade 1 to 2                                                                                                                                                                                                                                                   | Consider continuing M7824                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                 |
| Covering ≤ 30% body surface area                                                                                                                                                                                                                               | If persists > 1 to 2 weeks or recurs:  Consider withholding M7824 and OX40 therapy  Consider skin biopsy                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                 |
| Consider symptomatic  therapy (for example,  antihistamines, topical  steroids)                                                                                                                                                                                | Consider 0.5-1.0 mg/kg/day prednisone or equivalent.  Once improving, consider tapering steroids over at least 1  month, consider prophylactic antibiotics for opportunistic  infections, and consider resuming M7824 therapy  following steroids taper. If worsens:  Consider treating as Grade 3 to 4. |                                                                                                                                                                                                                                                                                                                                                                                 |
| Grade 3 to 4 Grade 3: Covering > 30% body  surface area;  Grade 4: Life threatening  consequences                                                                                                                                                              | Consider withholding or  permanently discontinuing  M7824 for Grade 3 events  based upon if the clinical  condition can be safely  managed. For grade 4 events                                                                                                                                           | If improves to Grade ≤ 1:  Consider tapering steroids over at least 1 month; consider  resuming therapy following steroids taper (for initial  Grade 3).                                                                                                                                                                                                                        |  
| Version Date: 03/18/2022                                                                     | permanently discontinue  treatment. Consider skin biopsy  Consider dermatology  consult  Consider 1.0 to 2.0  mg/kg/day prednisone or  equivalent Consider adding prophylactic  antibiotics for opportunistic  infections  Pulmonary irAEs                                                                                                                                |                                                                                                                                                                                                                                                                     |
|----------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade of Pneumonitis (NCI-CTCAE v5)                                                          | Initial Management                                                                                                                                                                                                                                                                                                                                                        | Follow-up Management                                                                                                                                                                                                                                                |
| Grade 1                                                                                      | Consider withholding M7824                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                     |
| Radiographic changes only                                                                    | Consider Pulmonary and  Infectious Disease consults                                                                                                                                                                                                                                                                                                                       | Consider re-assessing at least every 3 weeks If worsens:  Consider treating as Grade 2 or Grade 3 to 4.                                                                                                                                                             |
| Grade 2                                                                                      | Consider withhold M7824                                                                                                                                                                                                                                                                                                                                                   |                                                                                                                                                                                                                                                                     |
| Mild to moderate new symptoms                                                                | Consider pulmonary and  Infectious Disease consults Consider monitoring  symptoms daily; consider  hospitalization  Consider 1.0 to 2.0  mg/kg/day prednisone or  equivalent Consider adding prophylactic  antibiotics for opportunistic  infections  Consider bronchoscopy, lung  biopsy                                                                                 | If improves:  When symptoms return to Grade ≤ 1, consider tapering  steroids over at least 1 month, and then consider  resuming therapy following steroids taper  If not improving after 2 weeks or worsening:  Consider treating as Grade 3 to 4.                  |
| Grade 3 to 4 Grade 3: Severe new symptoms;  New/worsening hypoxia; Grade 4: Life-threatening | Consider withholding or  permanently discontinuing  M7824 for Grade 3 events  based upon if the clinical  condition can be safely  managed. For grade 4 events  permanently discontinue  treatment. Consider hospitalization. Consider pulmonary and  Infectious Disease consults. Consider 1.0 to 2.0  mg/kg/day prednisone or  equivalent  Consider adding prophylactic | If improves to Grade ≤ 1:  Consider tapering steroids over at least 1 month  If not improving after 48 hours or worsening:  Consider adding additional immunosuppression (for  example, infliximab, cyclophosphamide, IV  immunoglobulin, or mycophenolate mofetil) |  
| Version Date: 03/18/2022                                                                  | antibiotics for opportunistic  infections  Consider bronchoscopy, lung  biopsy  Hepatic irAEs                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                        |
|-------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade of Liver Test Elevation (NCI-CTCAE v5)                                              | Initial Management                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Follow-up Management                                                                                                                                                                                                                                                                                   |
| Grade 1 Grade 1 AST or ALT > ULN to 3.0  x ULN and/or Total bilirubin >  ULN to 1.5 x ULN | Consider continuing M7824                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Consider continued liver function monitoring  If worsens:   Consider treating as Grade 2 or 3 to 4.                                                                                                                                                                                                    |
| Grade 2 AST or ALT > 3.0 to ≤ 5 x ULN  and/or total bilirubin > 1.5 to ≤ 3 x  ULN         | Consider withhold M7824                                                                                                                                                                                                                                                                                                                                                                                                                                                          | If returns to Grade ≤ 1: Consider resuming therapy. If elevation persists > 7 days or worsens:  Consider treating as Grade 3 to 4.                                                                                                                                                                     |
| Grade 3 to 4 AST or ALT > 5 x ULN and/or total  bilirubin > 3 x ULN                       | Consider withholding or  permanently discontinuing  M7824 for Grade 3 events  based upon if the clinical  condition can be safely  managed. For grade 4 events  permanently discontinue  treatment.  Consider 1.0 to 2.0  mg/kg/day prednisone or  equivalent Consider adding prophylactic  antibiotics for opportunistic  infections  Consider consulting  gastroenterologist/  hepatologist Consider obtaining MRI/CT  scan of liver and liver biopsy  if clinically warranted | If returns to Grade ≤ 1:  Consider tapering steroids over at least 1 month  If does not improve in > 7 days, worsens or rebounds:  Consider adding mycophenolate mofetil 1 gram (g) twice  daily  If no response within an additional 7 days, consider other  immunosuppressants per local guidelines. |
| Renal irAEs                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                        |
| Grade of Creatinine Increased  (NCI-CTCAE v5)                                             | Initial Management                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Follow-up Management                                                                                                                                                                                                                                                                                   |
| Continue renal function monitoring If worsens: Consider treating as Grade 2 to 3 or 4.    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                        |
| Grade 1 Creatinine increased > ULN to 1.5 x  ULN                                          | Consider continuing M7824                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                                                                                                                        |
| Grade 2                                                                                   | Consider withholding M7824                                                                                                                                                                                                                                                                                                                                                                                                                                                       | If returns to Grade ≤1:                                                                                                                                                                                                                                                                                |
| Creatinine increased > 1.5 and ≤ 6 x                                                      | Consider 1.0 to 2.0 mg/kg/day                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Consider tapering steroids over at least 1 month                                                                                                                                                                                                                                                       |  
| Version Date: 03/18/2022 ULN                                                                                                                                                             | prednisone or equivalent. Consider adding prophylactic  antibiotics for opportunistic infections Consider renal biopsy and consider resuming therapy following steroids  taper. If worsens:  Treat as Grade 4. Consider withholding or permanently  discontinuing M7824 for Grade 3  events based upon if the clinical  condition can be safely managed. For  grade 4 events permanently  discontinue treatment. Consider 1.0 to 2.0 mg/kg/day  prednisone or equivalent. Consider adding prophylactic  antibiotics for opportunistic infections Consider renal biopsy Consider Nephrology consult   |                                                                                                                                                                                                                                                                                                             |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 3-4 Creatinine increased > 6 x ULN                                                                                                                                                 | If returns to Grade ≤1: Consider tapering steroids over at least 1 month.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                             |
| Cardiac irAEs                                                                                                                                                                            |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                             |
| Myocarditis                                                                                                                                                                              | Initial Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Follow-up Management                                                                                                                                                                                                                                                                                        |
| New onset of cardiac signs or  symptoms and / or new laboratory  cardiac biomarker elevations (e.g.  troponin, CK-MB, BNP) or cardiac  imaging abnormalities suggestive  of myocarditis. | Consider withholding or permanently  discontinuing M7824 based upon if the  clinical condition can be safely managed. Consider hospitalization In the presence of life-threatening  cardiac decompensation, consider  transfer to a facility experienced in  advanced heart failure and arrhythmia  management. Consider cardiology consult to establish  etiology and rule-out immune-mediated  myocarditis.  Consider myocardial biopsy if  recommended per cardiology consult.                                                                                                                    | If symptoms improve and immune-mediated  etiology is ruled out, consider re-starting  therapy. If symptoms do not improve/worsen, viral  myocarditis is excluded, and immune-mediated  etiology is suspected or confirmed following  cardiology consult, consider managing as  immune-mediated myocarditis. |
| Immune-mediated myocarditis                                                                                                                                                              | Consider withholding or permanently  discontinuing M7824 based upon if the  clinical condition can be safely managed. Consider guideline based supportive  treatment as appropriate as per  cardiology consult. Consider 1.0 to 2.0 mg/kg/day  prednisone or equivalent Consider adding prophylactic antibiotics  for opportunistic infections.                                                                                                                                                                                                                                                      | Once improving, consider tapering steroids  over at least 1 month. If no improvement or worsening, consider  additional immunosuppressants (e.g.  azathioprine, cyclosporine A).                                                                                                                            |  
1 *Local guidelines, or e.g. ESC or AHA guidelines 2 ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines 3 AHA guidelines website: http://professional heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001  
| Endocrine irAEs                                                                                                                                                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                              |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Endocrine Disorder                                                                                                                                                                                                                                                                                                                                                      | Initial Management                                                                                                                                                                                                                                        | Follow-up Management                                                                                                                                                                                                                                                         |
| Grade 1 or Grade 2  endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus)                                                                                                                                                                                                                                             | Consider continuing M7824                                                                                                                                                                                                                                 | Consider continuing hormone  replacement/suppression and monitoring of  endocrine function as appropriate.                                                                                                                                                                   |
| Consider endocrinology consult if  needed Consider starting thyroid hormone  replacement therapy (for  hypothyroidism), anti-thyroid  treatment (for hyperthyroidism),  corticosteroids (for adrenal  insufficiency) or insulin (for Type I  diabetes mellitus) as appropriate.  Consider ruling-out secondary  endocrinopathies (i.e. hypopituitarism  / hypophysitis) |                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                              |
| Grade 3 or Grade 4  endocrinopathies  (hypothyroidism,  hyperthyroidism, adrenal  insufficiency, type I diabetes  mellitus)                                                                                                                                                                                                                                             | Consider withholding or permanently  discontinuing M7824 for Grade 3  events based upon if the clinical  condition can be safely managed. For  grade 4 events permanently  discontinue treatment  Consider hospitalization Consider endocrinology consult | Consider resuming therapy once symptoms  and/or laboratory tests improve to Grade ≤ 1  (with or without hormone  replacement/suppression). Consider continuing hormone  replacement/suppression and monitoring of  endocrine function as appropriate.                        |
| Consider starting thyroid hormone  replacement therapy (for  hypothyroidism), anti-thyroid  treatment (for hyperthyroidism),  corticosteroids (for adrenal  insufficiency) or insulin (for type I  diabetes mellitus) as appropriate.  Consider ruling-out secondary  endocrinopathies (i.e. hypopituitarism  / hypophysitis)                                           |                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                                                                              |
| Hypopituitarism/Hypophysitis                                                                                                                                                                                                                                                                                                                                            | If secondary thyroid and/or adrenal                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                              |
| (secondary endocrinopathies)                                                                                                                                                                                                                                                                                                                                            | insufficiency is confirmed (i.e.  subnormal serum FT4 with  inappropriately low TSH and/or low  serum cortisol with inappropriately  low ACTH):  Consider referring to  endocrinologist for dynamic  testing as indicated and                            | Consider resuming therapy once symptoms and  hormone tests improve to Grade ≤ 1 (with or  without hormone replacement). In addition, for hypophysitis with abnormal  MRI, consider resuming M7824 only once  shrinkage of the pituitary gland on MRI/CT  scan is documented. |  
| Version Date: 03/18/2022                                                       | measurement of other  hormones (FSH, LH,  GH/IGF-1, PRL, testosterone  in men, estrogens in women)                                                                                                                       |                                                                                                                             |
|--------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------|
|                                                                               | Consider hormone  replacement/suppressive  therapy as appropriate                                                                                                                                                        |                                                                                                                             |
|                                                                               | Consider performing pituitary  MRI and visual field  examination as indicated                                                                                                                                            | Consider continuing hormone  replacement/suppression therapy as  appropriate.                                               |
| If hypophysitis confirmed:  Continue M7824 if mild  symptoms   Consider withholding M7824 if  moderate, severe or lifethreatening symptoms of  hypophysitis. Consider  hospitalization. Consider  initiating corticosteroids (1 to 2  mg/kg/day prednisone or  equivalent) followed by  corticosteroids taper during at  least 1 month.  Consider adding prophylactic  antibiotics for opportunistic  infections. Other irAEs (not described above)                                                                                |                                                                                                                                                                                                                          |                                                                                                                             |
| Grade of other irAEs                                                           | Initial Management                                                                                                                                                                                                       | Follow-up Management                                                                                                        |
| (NCI-CTCAE v5)                                                                 |                                                                                                                                                                                                                          |                                                                                                                             |
| Grade 2 or Grade 3 clinical signs  or symptoms suggestive of a  potential irAE | Consider withholding M7824 pending                                                                                                                                                                                       | If irAE is ruled out, consider managing as                                                                                  |
| clinical investigation                                                         | appropriate according to the diagnosis and  consider re-starting therapy If irAE is confirmed, consider treating as Grade  2 or 3 irAE.                                                                                  |                                                                                                                             |
| Grade 2 irAE or first occurrence                                               | Consider withholding M7824 based                                                                                                                                                                                         |                                                                                                                             |
| of Grade 3 irAE                                                                | upon if the clinical 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 | If improves to Grade ≤ 1:  Consider tapering steroids over at least 1 month  and resuming therapy following steroids taper. |
| Recurrence of same Grade 3                                                     | Consider permanently discontinuing                                                                                                                                                                                       | If improves to Grade ≤ 1:                                                                                                   |
| irAEs                                                                          | M7824 based upon if the clinical                                                                                                                                                                                         | Consider tapering steroids over at least 1                                                                                  |  
| 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                                 | Consider permanently discontinuing  M7824  Consider specialty consult as  appropriate                                                                                                                                                               |                                                                             |
| Persistent Grade 2 or 3 irAE  lasting 12 weeks or longer                                                                                                                                            |                                                                                                                                                                                                                                                     |                                                                             |  
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.  
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 TGF. Accordingly, participants will be closely monitored for mucosal bleeding (e.g., gum bleeding, nose bleeds, coughing up blood, blood in their urine, or blood in the stool).
untitled h1
3.5 study calendar

| Cycles 2                                                      | EOT6      | Safety  FU 7   | Long  Term  FU 8   |    |    |    |
|---------------------------------------------------------------|-----------|----------------|--------------------|----|----|----|
| Screening                                                     | Baseline1 | Lead-In        | Cycle=28 (-1/+ 3)  |    |    |    |
| (Days -14L                                                    | days      |                |                    |    |    |    |
| to -1L)                                                       | Day 1     | Day 15         |                    |    |    |    |
| SX-6823                                                       | X         | X              | X                  |    |    |    |
| M78244                                                        | X         | X              |                    |    |    |    |
| MVA-BN-CV301 (Cycle 1  only)5                                 | X         | X              |                    |    |    |    |
| FPV-CV301(Cycle 2  onward)5                                   | X         |                |                    |    |    |    |
| Medical History                                               | X         |                |                    |    |    |    |
| Height                                                        | X         | X              |                    |    |    |    |
| ECOG                                                          | X         | X              | X                  |    |    |    |
| Clinical Assessment -  physical exam, vital signs18 ,  weight | X         | X              | X                  | X  | X  | X  |
| HIV, HCV, HBV viral load  by PCR                              | X         |                |                    |    |    |    |
| CD4                                                           | X         |                |                    |    |    |    |
| EKG 9                                                         | X         | X              | X                  | X  | X  | X  |
| CBC w/differential with  platelets                            | X         | X              | X                  | X  | X  | X  |  
| Cycles 2                                                                           | EOT6      | Safety  FU 7   | Long  Term  FU 8   |    |    |    |
|------------------------------------------------------------------------------------|-----------|----------------|--------------------|----|----|----|
| Screening                                                                          | Baseline1 | Lead-In        | Cycle=28 (-1/+ 3)  |    |    |    |
| (Days -14L                                                                         | days      |                |                    |    |    |    |
| to -1L)                                                                            | Day 1     | Day 15         |                    |    |    |    |
| Biochemical profile10                                                              | X         | X              | X                  | X  | X  | X  |
| Lymphocyte profiling  (TBNK), TSH, Free T4,  lipase, amylase, urinalysis11         | X         | X              | X                  |    |    |    |
| Pregnancy testing in women  of childbearing potential12                            | X         | X              | X                  | X  |    |    |
| PT/PTT/INR11                                                                       | X         | X              | X                  |    |    |    |
| Flexible clinic-based  pharyngolaryngoscopy  (HNSCC only) if clinically  indicated | as        |                |                    |    |    |    |
| X                                                                                  | X         | needed         |                    |    |    |    |
| Tumor evaluation (CT Scan  / MRI, if clinically  indicated)13                      | X         | X              | X                  |    |    |    |
| A brain CT / MRI scan (if  clinically indicated) 14                                | X         |                |                    |    |    |    |
| Nuclear bone scan (if  clinically indicated)                                       | X         |                |                    |    |    |    |
| Concomitant medications                                                            | X         | X              | X                  | X  | X  | X  |
| Adverse event evaluation                                                           | X         | X              | X                  | X  |    |    |
| Baseline signs and  symptoms                                                       | X         |                |                    |    |    |    |  
| Cycles 2                                                            | EOT6                                                         | Safety  FU 7   | Long  Term  FU 8           |
|---------------------------------------------------------------------|--------------------------------------------------------------|----------------|----------------------------|
| Screening                                                           | Baseline1                                                    | Lead-In        | Cycle=28 (-1/+ 3)          |
| (Days -14L                                                          | days                                                         |                |                            |
| to -1L)                                                             | Day 1                                                        | Day 15         |                            |
| Tumor biopsy (optional)15                                           | X                                                            | X              | X (at disease progression) |
| Research blood 16                                                   | See Table 9 (Arm 1), Table 10 (Arm 2), and Table 11  (Arm 3) |                |                            |
| Telephone or E-mail  Follow Up                                      | X                                                            |                |                            |
| Collection of archival  tumor samples for research  if available    | X                                                            |                |                            |
| Diet Order (may be  ordered during visits if  clinically indicated) | X                                                            | X              | X                          |
| Confirmation of disease 17                                          | X                                                            |                |                            |  
1Baseline evaluations do not need to be repeated if performed at screening within 7 days of any first drug administration. If treatment does not start within 28 days after enrollment (or if specific longer), screening evaluations will be repeated.  
2 Participants will be seen in clinic every 2 weeks while on treatment. If treatment is being held, clinic visits may be missed and the associated labs will be deferred per the discretion of the PI. Due to COVID-19 pandemic, outside of the DLT period, if the participant is not able to return to the NIH CC for treatment/follow-up, remote visits will be conducted in compliance with NIH guidelines and FDA regulations. A participant may be referred to their local provider or asked to come to the NIH CC for an in-person assessment, if clinically indicated, and at the discretion of the PI. In the case of any visits with participants' local providers, records will be obtained.  
3 Arm 1: during Lead-In only. Arms 2 and 3: during Lead-In (Arm 2 only) and every day of every cycle. See **Table 8**
4 On days 1 and 15 of every cycle. Can be -1/+3 days due to holidays, inclement weather, conflicts, or similar reasons except where explicitly noted elsewhere. M7824 drug administrations should not be given less than 11 days apart. See Table 8 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.  
16 Where feasible, research blood for all study assessments will be collected as per **Table 9, Table 10,** and **Table 11** below. The exact collection time for PK samples will be recorded 17 See Section 2.2.2 18 Arms 1 & 2: Day -14, SX-682 oral administration; collect full set of vital signs pre dose and (180 minutes) 3 hours post dose at the time of last PK blood collection. All 3 Arms: All cycles with CV301 & M7824 administration; collect a full set of vital signs pre CV301 vaccine administration and prior to start of M7824 infusion. During the M7824 infusion, collect a full set of vital signs every 30 minutes and at the end of the 60 minute observation period, for C1D1 and C1D15 doses. For the 3rd M7824 dose, C2D1 and all subsequent M7824 doses, the observation period is 30 minutes, a full set of vital signs will be collected at that time.
untitled h1
table 8 study drug administration

| Lead-In (days)   | Cycle 1      | Cycle 2 until Progression   |       |       |
|------------------|--------------|-----------------------------|-------|-------|
| Days -14L to -1L | C1D1         | C1D15                       | CxD1  | CxD15 |
| SX-682           | M7824        | M7824                       | M7824 | M7824 |
| MVA-BN-CV301     | MVA-BN-CV301 | FPV-CV301*                  |       |       |  
*Given every cycle for 4 cycles, then every 3 cycles for 2 additional doses (total of 1 year of vaccines).  
Arm 2:  
| Arm 2:  Lead-In (days)                                                                                     | Cycle 1      | Cycle 2 until Progression   |       |       |    |    |    |    |    |    |    |    |    |    |    |
|------------------------------------------------------------------------------------------------------------|--------------|-----------------------------|-------|-------|----|----|----|----|----|----|----|----|----|----|----|
| Days -14L to -1L                                                                                           | C1D1         | C1D15                       | CxD1  | CxD15 |    |    |    |    |    |    |    |    |    |    |    |
| SX-682                                                                                                     | SX-682      |                            |      |      |   |   |   |   |   |   |   |   |   |   |   |
| M7824                                                                                                      | M7824        | M7824                       | M7824 |       |    |    |    |    |    |    |    |    |    |    |    |
| MVA-BN-CV301                                                                                               | MVA-BN-CV301 | FPV-CV301*                  |       |       |    |    |    |    |    |    |    |    |    |    |    |
| *Given every cycle for 4 cycles, then every 3 cycles for 2 additional doses (total of 1 year of vaccines). |              |                             |       |       |    |    |    |    |    |    |    |    |    |    |    |  
| Cycle 1                                                                                                    | Cycle 2 until Progression   |            |       |
|------------------------------------------------------------------------------------------------------------|-----------------------------|------------|-------|
| C1D1                                                                                                       | C1D15                       | CxD1       | CxD15 |
| SX-682 Continuous                                                                                          |                             |            |       |
| M7824                                                                                                      | M7824                       | M7824      | M7824 |
| MVA-BN-CV301                                                                                               | MVA-BN-CV301                | FPV-CV301* |       |
| *Given every cycle for 4 cycles, then every 3 cycles for 2 additional doses (total of 1 year of vaccines). |                             |            |       |
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table 9 arm 1 research

| Cycle  (Day)             | Time         | SX-682              | M7824                | Immune and Other Analyses Immune phenotyping/  RNA analysis,  Antigen-specific  response, T-cell  clonality CTCs   |
|--------------------------|--------------|---------------------|----------------------|--------------------------------------------------------------------------------------------------------------------|
| PK                       | PK           | ADA Soluble Factors |                      |                                                                                                                    |
| Lead-In                  | X            | X                   | X                    |                                                                                                                    |
| (-14L)                   | predose      | X                   |                      |                                                                                                                    |
| 30  minutes              | X            |                     |                      |                                                                                                                    |
| 60  minutes              | X            |                     |                      |                                                                                                                    |
| 120  minutes             | X            |                     |                      |                                                                                                                    |
| (-7L) *                  | predose      | X                   | Not given until C1D1 | Not given until C1D1                                                                                               |
| Lead-In                  | 180  minutes | X                   |                      |                                                                                                                    |
| < 6 hours  X of 2nd dose |              |                     |                      |                                                                                                                    |  
| Cycle  (Day)    | Time    | SX-682              | M7824   | Immune and Other Analyses Immune phenotyping/  RNA analysis,  Antigen-specific  response, T-cell  clonality CTCs   |    |    |    |
|-----------------|---------|---------------------|---------|--------------------------------------------------------------------------------------------------------------------|----|----|----|
| PK              | PK      | ADA Soluble Factors |         |                                                                                                                    |    |    |    |
| 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.
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table 10 arm 2 research

| Cycle  (Day)   | Time   | SX-682   | M7824                                                                  | Immune and Other Analyses Immune phenotyping/ RNA   |
|----------------|--------|----------|------------------------------------------------------------------------|-----------------------------------------------------|
| PK             | PK     | ADA      | Soluble Factors analysis, Antigen-specific  response, T-cell clonality | CTCs                                                |  
| Cycle  (Day)    | Time                  | SX-682                  | M7824                                                                  | Immune and Other Analyses Immune phenotyping/ RNA   |    |    |    |
|-----------------|-----------------------|-------------------------|------------------------------------------------------------------------|-----------------------------------------------------|----|----|----|
| PK              | PK                    | ADA                     | Soluble Factors analysis, Antigen-specific  response, T-cell clonality | CTCs                                                |    |    |    |
| X               | Not given  until C1D1 | Not given  until C1D1 X | X                                                                      | X                                                   |    |    |    |
| Lead-In  (-14L) | predose               |                         |                                                                        |                                                     |    |    |    |
| Cycle 1 (1)     | predose               | X                       | X                                                                      | X                                                   | X  | X  | X  |
| EOI             | X                     | X                       |                                                                        |                                                     |    |    |    |
| Cycle           | 1                     |                         |                                                                        |                                                     |    |    |    |
| (15)            | X                     | X                       | X                                                                      |                                                     |    |    |    |
| Cycle 2 (1)     | predose               | X                       | X                                                                      | X                                                   | X  | X  | X  |
| Cycle           | 3                     |                         |                                                                        |                                                     |    |    |    |
| (1)*            | predose               | X                       | X*                                                                     | X*                                                  | X  | X  |    |
| EOT             | X                     | X                       | X                                                                      | X                                                   | X  |    |    |  
*The last M7824 PK/ADA timepoint should be Cycle 3, Day 1 predose or EOT, whichever comes first.  
| Cycle (Day)   | Time   | Immune and Other Analyses Immune  phenotyping/ RNA  analysis, Antigenspecific response,  T-cell clonality Soluble  Factors   | CfDNA   | CTCs   |
|---------------|--------|---|---------|--------|  
| Cycle (Day)   | Time    | Immune and Other Analyses Immune  phenotyping/ RNA  analysis, Antigenspecific response,  T-cell clonality Soluble  Factors   | 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

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.
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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.
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3.7 criteria for removal from

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
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.
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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.
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4.1 the following treatments should

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 allowed.
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, antiestrogen 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.
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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.
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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 Otolaryngology as long as considered minimal procedural risk. Two 3-millimeter punch biopsies of skin will be acceptable in lieu of 18-gauge core biopsies for participants with skin involvement.  
.  
Cores/biopsies 1 and 2: Formalin-Fixed Paraffin-Embedded (FFPE)
.  
Cores/biopsies 3 and 4: Fresh frozen
.  
Cores/biopsies 5 and 6: Fresh for flow cytometry or TIL culture
Tissue samples will be sent to Laboratory of Pathology for disease evaluation first, remaining samples will be processed and stored for research. If fresh-frozen cores are obtained, they will be processed and stored in CSP. Samples will be picked up and delivered for processing and storage by:
If fresh tissue to be used for flow cytometry or TIL culture are obtained, they will be processed and stored in the Translational Tumor Immunology Program (TTIP) Laboratory
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5.1.2 blood samples

The amount of blood that may be drawn from adult participants (i.e., those persons 18 years of age or older) for research purposes will not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any eight-week period. Please, see Study Calendar 3.5 for collection time points.
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5.2 correlative studies for research/pharmacokinetic

The following tests may be performed on selected participants' peripheral blood samples if there are adequate samples. If collected samples are not sufficient, the correlative studies will be performed in the order of priority as detailed below in the table. These correlative studies will be done in an exploratory fashion.  
Research samples will be sent either to Blood Processing Core (BPC), or Clinical Services Program - Leidos Biomedical Research, Inc. (CSP) or the TTIP Laboratory for barcoding, initial processing and storage. From these facilities samples will be sent to the designated places for analysis in batch shipments or upon request.  
All samples collected for correlative studies will be stored in locked rooms with limited access to study personnel.  
| Test/assay             | Volume   | Type   | of       | Collection   | Location   | of   |
|------------------------|----------|--------|----------|--------------|------------|------|
| (pprox.)               | tubea    | point  | specimen | analysis     |            |      |
| (processing/storage    |          |        |          |              |            |      |
| location)              |          |        |          |              |            |      |
| Functional Analysis of | 60-80    | mL     | Sodium   | Study        | LTIB, TTIP |      |
| immune cell subsets by | blood    | for    | heparin  | Calendar     | (CSP)      |      |
| FACS                   | PBMCs    | (green | 3.5      |              |            |      |  
| Version Date: 03/18/2022 Test/assay                  | Volume                | Type           | of               | Collection   | Location   | of        |
|------------------------------------------------------|-----------------------|----------------|------------------|--------------|------------|-----------|
| (approx.)                                            | tubea                 | point          | specimen         | analysis     |            |           |
| (processing/storage  location)                       |                       |                |                  |              |            |           |
| Antigen                                              | Specific              |                |                  |              |            |           |
| Immune                                               | Response              | by             |                  |              |            |           |
| cytokine staining assay                              | top) tubes            | LTIB  (CSP)    |                  |              |            |           |
| T                                                    | cell                  | clonality      | by               |              |            |           |
| immunoSeq platform                                   | NCI                   | Frederick      |                  |              |            |           |
| Genomic                                              | Core                  |                |                  |              |            |           |
| Facility  (CSP)                                      |                       |                |                  |              |            |           |
| RNA                                                  | expression,           | NCI            | Frederick        |              |            |           |
| Nanostring                                           | Genomic               | Core           |                  |              |            |           |
| Facility, Nanostring  (CSP)                          |                       |                |                  |              |            |           |
| Soluble                                              | Factors               | by             | 8 mL blood       | SST          | LTIB (CSP) |           |
| ELISA                                                | for serum             |                |                  |              |            |           |
| SX-682                                               | 3-6                   | mL             |                  |              |            |           |
| Pharmacokinetics                                     | blood                 | for            |                  |              |            |           |
| plasma                                               | EDTA                  | Syntrix, (BPC) |                  |              |            |           |
| M7824                                                | 4 mL blood            | SST            | EMD Serono (BPC) |              |            |           |
| Pharmacokinetics                                     | for serum             |                |                  |              |            |           |
| ADA                                                  | 4 mL blood            | SST            | EMD Serono (BPC) |              |            |           |
| for serum                                            |                       |                |                  |              |            |           |
| cfDNA                                                | 10                    | mL             | EDTA             |              |            |           |
| blood                                                | (lavender  top) tubes | (CSP)          |                  |              |            |           |
| CTCs                                                 | 10 ml blood           | CellSave       |                  |              |            |           |
| Analyses                                             | of                    | Immune         |                  |              |            |           |
| Markers by IHC and/or  multiplex  immunofluorescence | Tumor                 | LTIB           |                  |              |            |           |
| samples                                              | (LP, CSP)             |                |                  |              |            |           |
| T                                                    | cell                  | clonality      | by               | Tumor        | NCI        | Frederick |
| immunoSeq platform                                   | samples               | Genomic        | Core             |              |            |           |
| Facility (LP, CSP)                                   |                       |                |                  |              |            |           |
| RNA                                                  | expression,           | Tumor          | NCI              | Frederick    |            |           |
| Nanostring                                           | samples               | Genomic        | Core             |              |            |           |
| Facility, Nanostring  (LP, CSP)                      |                       |                |                  |              |            |           |
| Analysis                                             | of                    | immune         | Tumor            | TTIP (TTIP)  |            |           |  
| Test/assay                                                                                                                                              | Volume   | Type   | of       | Collection   | Location   | of   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|----------|--------|----------|--------------|------------|------|
| (approx.)                                                                                                                                               | tubea    | point  | specimen | analysis     |            |      |
| (processing/storage  location)                                                                                                                          |          |        |          |              |            |      |
| infiltration                                                                                                                                            | by       | flow   | samples  |              |            |      |
| cytometry/ELISA a. Please note that tubes and media may be substituted based on availability with the  permission of the PI or laboratory investigator. |          |        |          |              |            |      |
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5.2.1 immune phenotyping

Exploratory immunologic studies will be conducted to evaluate the study drug's effect on the immune response before and after treatment, to gain insight into potential biomarkers, and help improve the administered therapy. The following immune assays may be performed:  
1. PBMCs may be analyzed for changes in standard immune cell types (CD4 and CD8 T
cells, natural killer [NK] cells, regulatory T cells [Tregs], myeloid-derived suppressor cells [MDSCs], and dendritic cells) as well as 123 immune cell subsets, using multi-color flow cytometry.  
2. PBMCs from selected subjects may be analyzed for function of specific immune cell subsets, including CD4 and CD8 T cells, NK cells, Tregs, and MDSCs using flow-based assays.  
3. PBMCs may be analyzed for tumor antigen-specific immune responses using an intracellular cytokine staining assay. PBMCs will be stimulated in vitro with overlapping 15-mer peptide pools encoding the tumor-associated antigens such as CEA, MUC-1 and Brachyury; control peptide pools will involve the use of human leukocyte antigen peptide as a negative control and CEFT peptide mix as a positive control. CEFT is a mixture of peptides of CMV, Epstein-Barr virus, influenza, and tetanus toxin. Post-stimulation analyses of CD4 and CD8 T cells will involve the production of IFN-γ, IL-2, TNF, and the degranulation marker CD107a. If sufficient PBMCs are available, assays may also be performed for the development of T cells to other tumor-associated antigens.  
5.2.2 Soluble Factors
-Sera and/or plasma may be analyzed pre- and post-therapy for the following soluble factors: sCD27, sCD40 ligand using commercial ELISA kits. -Sera and/or plasma may be analyzed for changes in cytokines (IFN-γ, IL-8, IL-6, IL-10, IL-12, IL-2, IL-4, etc.), chemokines, antibodies, tumor-associated antigens, and/or other markers using ELISA or multiplexed assays (e.g. Mesoscale, Luminex, cytokine bead array).
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5.2.3 pharmacokinetics

Plasma and Serum samples may be analyzed by a validated immunoassay to quantitate SX-682 and M7824 concentration, respectively. Samples may be further tested in qualified or validated PK characterization assays. Coded, linked samples will be shipped to Syntrix and EMD Serono for analysis under existing CRADAs with these companies.
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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.
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5.2.5 analyses of tumor tissue

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.
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5.3 samples for genetic/genomic analysis

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. Deidentified, 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:  
  
5.3.2 Plasma analysis for circulating free DNA (cfDNA):
for circulating free tumor Plasma may be analyzed pre- and post-therapy in DNA using PCR-based techniques.  
5.3.3 Analysis for Circulating Tumor Cells (CTCs)
Plasma may be analyzed pre- and post-therapy in for circulating tumor  
  
cells. TCs enumeration will be investigated using ferrofluidic enrichment and multi-parameter flow cytometric detection. CTCs are identified by positive expression of epithelial markers and a viability marker and negative expression of hematopoietic markers.
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sample storage tracking and disposition

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  
Samples will not be sent outside the National Institutes for Health (NIH) without appropriate approvals and/or agreements, if required.  
Sample Management and Storage at Clinical Services Program - Leidos Biomedical 5.4.1 Research, Inc. (CSP)
Clinical Services Program - Leidos Biomedical Research, Inc.  
  
All data associated with the participant samples is protected by using a secure database. All samples drawn at the NIH Clinical Center will be transported to the Clinical Support Laboratory at the Frederick National Laboratory for Cancer Research by couriers.  
Samples will be tracked and managed by Central Repository database, where there is no link to personal identifiable information. All samples will be stored in either a -80°C freezer or vapor phase liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, Maryland.  
NCI Frederick Central Repositories (managed under a subcontract) store, among other things, biological specimens in support of NIH clinical studies. All specimens are stored in secure, limited-access facilities with sufficient security, backup, and emergency support capability and monitoring to ensure long-term integrity of the specimens for research. Specimens are stored in accordance with applicable HHS and FDA Protection of Human Subjects Regulations in accordance with the subcontractor's Federal-wide Assurance. The subcontractor's role limited to clinical research databases and repositories containing participant specimens. The subcontractor does not conduct or have any vested interest in research on human subjects but does provide services and support the efforts of its customers, many of which are involved in research on human subjects. The subcontractor's IRB reviews policies and procedures for labeling, data collection and storage, access, and security. The IRB will review protection of privacy issues prior to acceptance of any new work and in the event of change impacting privacy issues in existing work. It is the intent and purpose of the subcontractor to accept only de-identified samples and sample information. To the limit of our ability, every effort will be made to ensure that protected information is not sent electronically or by hard copy or on vial labels.  
Sample data is stored in the BioSpecimen Inventory System II (BSI). This inventory tracking system is used to manage the storage and retrieval of specimens as well as to maintain specimen data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user environment for tracking millions of specimens. The system controls how and in what order database updates and searches are performed. This control prevents deadlocks and race conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user permissions (levels of access) that can be set to control access to the system functions. BSI
provides audit tracking for processes that are done to specimens including shipping, returning to inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the repository. If a specimen goes out of the inventory, the system maintains data associated with the withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable and bar-coded format. No participant-specific information is encoded in this ID.  
Investigators are granted view, input, and withdrawal authority only for their specimens. They may not view specimen data or access specimens for which they have not been authorized. Access to specimen storage is confined to repository staff. Visitors to the repositories are escorted by repository staff at all times.  
  
Labmatrix creates a unique barcode ID for every sample and sample box, which cannot be traced back to participants without Labmatrix access. The data recorded for each sample includes the participant ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well as box and freezer location. Participant demographics associated with the clinical center participant number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.).  
Sample bar-codes are linked to participant demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the Labmatrix. It is critical that the sample remains linked to participant information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.  
5.4.2.3 Sample Storage Barcoded samples are stored in barcoded boxes in a locked freezer at either -20 or -80°C
according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times.  
Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in Labmatrix. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the NIH Intramural IRB approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with NIH
Intramural IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following NIH Intramural IRB approval of an additional protocol, granting the rights to use the material.  
If, at any time, a participant withdraws from the study and does not wish for their existing samples to be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the participant, if so requested)
The PI will record any loss or unanticipated destruction of samples as a deviation. Reports will be made per the requirements of section 7.2.  
Translational Tumor Immunology Program (TTIP) Laboratory, 5.4.3 All samples are physically stored in in secure, limited-access facilities with sufficient security, backup, and emergency support capability and monitoring to ensure long-term integrity of the specimens for research. Samples are logged, barcoded and tracked using Freezerworks Summit. This data storage software allows secure tracking of specimens that are completely de-identified, coded linked and tracked with barcodes only. Freezerworks has the capacity to fully audit all individual specimen processes such as location, aliquoting, thawing and shipping. Acquired samples are immediately transported to the NIDCD tissue core where they are processed and barcoded. The participant sticker that was used for transport is immediately destroyed. Unique barcodes generated for each individual sample are linked to participant identification numbers given to laboratory staff by NIDCD research nurses. These unique participant numbers correspond to participant information that is stored in CTDM. Protected participant information in CTDM will be recorded by NIDCD Research Nurses. Aside from the participant label that is immediately destroyed after specimen transport, laboratory staff will not have access to protected participant information.  
Investigators are granted view, input, and withdrawal authority only for their specimens. They may not view specimen data or access specimens for which they have not been authorized.  
Access to specimen storage is confined to repository staff. Visitors to the repositories are escorted by repository staff at all times Tissue biopsies will be ordered in CRIS and any linked protected participant data will be stored in the Clinical Trial Data Management (CTDM) system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All tissue biopsies collected will be coded and stored in the NIDCD Biospecimen Tissue Bank.  
Contact information:
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procedures for storage of tissue

Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP)
where they are examined grossly, and relevant portions are fixed, embedded in paraffin and sectioned and stained for diagnostic interpretation. Unutilized excess tissue that is not embedded in paraffin is stored in formalin for up to three months, in accordance with College of American Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO)
guidelines, and then discarded. Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely in the LP's clinical archives. All specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed when the appropriate IRB approval has been obtained. In some cases, this approval has been obtained via the original protocol on which the participant was enrolled.  
 Samples will be processed immediately upon receipt by the
. Biospecimens will be collected and processed using validated SOPs that will ensure both specimen quality and 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.
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6 data collection and evaluation

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: - Results in discontinuation from the study - 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**
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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.