Abbreviated T itle: STAT Trial Version Date : 08/17/2022 1 Abbreviated Title: STAT Trial NIH Protocol # 20C0155 Version Date: 08/17/2022 NCT # NCT04574583 IBC # RD- 20-IV-09 Title: Phase I/II Trial Investigating the Safety, Tolerability, Pharmacokinetics, Immune and Clinica l Activity of S X-682 in Combina tion with Bi nTrafusp Alfa (M7824 or TGF -β “Trap”/PD -L1) with CV301 TRICOM in Advanced Solid Tumors (STAT ). NIH Principal Investigator : James Gulley, MD, PhD Genitourinary Malignancies Branch (GMB) Center for Cancer Research (CCR) National Ca ncer Institute (NCI) Drug Nam e: SX-682 Bintrafusp alfa (M7824) MVA- BN- CV301 FPV-CV301 IND Numbe r: 21166 Sponsor: CCR , NCI Manufacturer: Syntrix EMD Serono Bavarian Nordic Bavarian Nordic Supplier: Syntrix EMD Serono Bavarian Nordic Bavarian Nordic Commercial Agents: None Abbreviated T itle: STAT Trial Version Date : 08/17/2022 2 PRÉCIS Background: • Combination immunotherapy approaches ar e being act ively explored to further improve response s, enhance clinical bene fit, and overcome resistance to PD(L)- 1 agents in cancer participant s. • 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 i n many human cancers i ncluding 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- recruitm ent to tumor and other pro- tumoral mec hanisms. • Bintrafusp a lfa (M7824 or MSB0011359C) is a bifunctional protein composed of the extracellular domain of the TGF -βRII receptor (TGF -β “trap”) fused to a human IgG1. Preclinical data shows bintrafusp al fa trea tment increases T-cell trafficking, an tigen - specific CD8+ T -cell lysis and NK cell activation. • CV301 is a poxviral -based vaccine comprised of recombinant Modified vaccinia Ankara (MVA- BN-CV301 , prime) and recombinant fowlpox (FPV -CV301, boost). CV301 contai ns transgenes encoding two (2) tumor -associated antigens (T AA), mucin 1 (MUC1) and ca rcinoembryonic antigen (CEA), as well as three costimulatory molecules (B7.1, ICAM -1 and LFA -3, designated TR ICOM). A recent phase 1 clinical trial demonstrated that anti gen-specific T cells to MUC1 and CEA, as well as to a cascad e antigen, brachyury, w ere generated in most participant s. • Preclinical studies performed in LTIB with SX -682, M7824 and a CEA- based vaccine showed a significant reduction in tumor growth a s well as a significan t 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 determi ne the MTD of SX -682 followed by M7824 and CV301 vaccines in participant s with advanced or meta static solid tumors. If the MT D is not reached the st udy will be focused to describe the safety and tolerability of SX -682 followed by M7824 and CV301 vaccines. • Arm 2 (Combination Dose Escalation):  To de termine the recomm ended phase 2 dose (RP2D) of SX -682 with M7824 and CV301 vaccines in participant s with adva nced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of the drug com bination. • Arm 3 (Expansio n): Abbreviated T itle: STAT Trial Version Date : 08/17/2022 3  To eval uate preliminary effica cy based on Objective Response Rat e (ORR), in each disease c ohort separately. Eligibility: • Age > 18 years old • Arms 1 and 2 (Dose -Escalation Cohort): Subjects with cytologically or histologically confirmed locally advanced or metastat ic solid tumors. • Arm 3 (Expansion Cohorts): o TNBC: Subjec ts with cytologically o r 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 cytologicall y or histologically con firmed 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 invo lving a platinum drug or cetuxi mab in advanced or in the m etastatic 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 par ticipant declines standard treatm ent after approp riate counseling has been provided. • ECOG perform ance 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 dis ease (e.g. present on b one scan, rising tumor markers, non -measur able by RECIST but visi ble on CT scan). Participant s with third space fluid (for example pleural effusions) as only site of disease wi ll not be eligible. Subjects in Arm 3 must have measurabl e disease according to RECIST 1.1 Design: • Arm 1 is a phase I, open- label, 3+3 sequential dos e escalation trial with short term , 2- week SX-682 monotherapy lead- in followed by treatment with M7824 and CV301 vaccine series in advanced solid tumors ( Q2W dosing schedule) for the dura tion of treatment. • Arm 2 is a phase I, open -label, 3+3 combination dose escalation trial with short term SX - 682 monotherapy lead in followed by SX -682 combination with M7824 and CV301 vaccine series in advanced solid tumor s (Q2W dosing schedule). Each enrolled participant will re ceive SX -682 as monotherap y for 2 weeks then will receive SX -682, M7824 and CV301 for the duration of treatment • Arm 3 has two expansion cohorts. F ollowing 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) a dvanced/metastatic triple negative breast cancer and 2) advanced/metastatic, platinum -refractory HPV negative head and neck squamous cell carcinoma. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 4 TABLE OF CONTENTS PRÉCIS ........................................................................................................................................... 2 TABLE OF CONTENTS ................................................................................................................ 4 STATEMENT OF COMPLIANCE ................................................................................................ 7 1. INTRODUCTION .................................................................................................................. 8 1.1 Study Objectives .............................................................................................................. 8 1.2 Background and Rationale ............................................................................................... 9 2 ELIGBILITY ASSESSMENT AND ENROLLMENT ........................................................ 39 2.1 Eligibility Criteria .......................................................................................................... 39 2.2 Screening Evaluation ...................................................................................................... 42 2.3 Participant Registration And Status Update Procedures ................................................ 44 2.4 Baseline Evaluation ........................................................................................................ 45 3 STUDY IMPLEMENTATION ............................................................................................ 45 3.1 Study Design .................................................................................................................. 45 3.2 Study Stopping rules ...................................................................................................... 52 3.3 Drug Administration ...................................................................................................... 53 3.4 Dose Modifications ........................................................................................................ 54 3.5 Study Calendar ............................................................................................................... 68 3.6 Cost and Compensation .................................................................................................. 77 3.7 Criteria for Removal from Protocol Therapy and Off Study Criteria ............................ 77 4 Conc omitant Therapy ............................................................................................................ 78 4.1 The Following Treatments Should not be Administered During the Trial: ................... 78 5 CORRELATIVE STUDIES FOR RESEARCH ................................................................... 79 5.1 Samples .......................................................................................................................... 79 5.2 Correlative Studies for Research/Pharmacokinetic Studies ........................................... 80 5.3 Samples for Genetic/Genomic Analysis ........................................................................ 83 5.4 Sample Storage, Tracking and Disposition .................................................................... 84 6 DATA COLLECTION AND EVALUATION ..................................................................... 88 6.1 Data Collection ............................................................................................................... 88 6.2 Data Sharing Plans ......................................................................................................... 89 6.3 Response C riteria ........................................................................................................... 89 7 NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN .. 96 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 5 7.1 Definitions ...................................................................................................................... 96 7.2 OHSRP Office of Compliance and Training / IRB Reporting ....................................... 96 7.3 NCI Clinical Director Reporting .................................................................................... 96 7.4 Institutional Biosafety Committee (IBC) Reporting Criteria ......................................... 96 7.5 NIH Required Data and Safety Monitoring Plan ........................................................... 98 8 SPONSOR PROTOCOL /SAFETY REPORTING ............................................................... 98 8.1 Definitions ...................................................................................................................... 98 8.2 Assessment of Safety Events ........................................................................................ 100 8.3 Reporting of Serious Adverse Events .......................................................................... 100 8.4 Waiver of expedited reporting to CCR ........................................................................ 101 8.5 Safety Rep orting Criteria to the Pharmaceutical Collaborators ................................... 101 8.6 Reporting Pregnancy .................................................................................................... 101 8.7 Regulatory Reporting for St udies Conducted U nder 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 Determ ination ...................................................................................... 104 10.3 Populations for Analyses .......................................................................................... 105 10.4 Statistical Analyses ................................................................................................... 106 11 Collaborative Agreements .................................................................................................. 107 11.1 Cooperative Research and Development Agreement (CRADA) ............................. 107 12 HUMAN SUBJECTS PROTECTIONS ............................................................................. 108 12.1 Rationale for Subject Selection ................................................................................ 108 12.2 Participation of Children .......................................................................................... 108 12.3 Participation of Su bjects Unable to Give Consent ................................................... 108 12.4 Risk/Ben efit Assessment for All Participants .......................................................... 108 12.5 Consent Process and Documentation ....................................................................... 111 13 REGULATORY AND OPERATIONAL CONSIDERATIONS ....................................... 112 13.1 Study Discontinuation and Closure .......................................................................... 112 13.2 Quality Assurance and Quality Control.................................................................... 112 13.3 Conflict of Interest Policy ......................................................................................... 112 13.4 Confidentiality and Pr ivacy ...................................................................................... 113 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 6 14 PHARMACEUTICAL INFORMATION ........................................................................... 113 14.1 SX-682 (IND#21166) ............................................................................................... 113 14.2 M7824 (IND#21166) ................................................................................................ 114 14.3 CV301 (IND#21166) ................................................................................................ 115 15 REFERENCES ................................................................................................................... 117 16 Appendices .......................................................................................................................... 124 16.1 Appendix A- Performance Status Criteria ................................................................. 124 16.2 Appendix B: Drugs Known to Significantly Prolong the Qtc* ................................ 125 16.3 Appendix C Participant’s Medication Diary ________________________ ........... 127 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 7 STAT EMENT OF COMPLIANCE The trial will be carr ied out in accordance with Intern ational Conf erence on Harmonisation Good Clinical Practice (ICH GCP) and the following: • United St ates (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Par t 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Pa rt 312, and/or 21 CFR Par t 812) National Institutes of Health ( NIH) -funded investigators and clinica l trial site staff who are responsible for the conduct, management, or oversight of NIH -funded clinical t rials have completed Human Subjects Prote ction and IC H GCP T raining. The protocol, infor med consent form(s), r ecruitment materials, and all participant materials will be submitted to the Institutional Review Board (IRB) for review and approval. Approval o f both the protocol and the consent form m ust be obta ined bef ore 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; a n IRB determi nation wi ll be made regardi ng whet her a new consent needs to be obtained f rom participants who provided consent, using a previously approved consent form. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 8 1. INTRODUCTION 1.1 STUDY OBJECTIVES 1.1.1 Primary Objectives: • Arm 1 (S equen tial Dose Escalation):  To evaluate the safet y and tole rability of sin gle agent SX-682.  To determine the MTD of S X-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 tolerabi lity of SX -682 follow ed by M7824 and CV301 vaccines. • Arm 2 (Combination D ose Escalation):  To determine t he RP2D of SX -682 with M7824 and CV301 vaccines in participant s with advanced or metast atic solid tumors. If the MTD is not reached the study will be focused to des cribe the sa fety and tolerability of t he drug combination. • Arm 3 (Expansion):  To evaluate prelim inary efficacy based o n objective response r ate (ORR), in each disease cohort sepa rately. 1.1.2 Secondary Objectives: • Arms 1 and 2 (Dose Escalat ions) :  To c haracteriz e the PK/PD profile of SX -682 as a si ngle agent and in combinati on. • All Arms:  To evaluate preli minary efficacy: d isease control rate (DCR ; CR+PR+SD) and progression- free surviva l (PFS) using RECIST1.1. 1.1.3 Exploratory Objectives (may be performed on select ed participants if there are adequate samples.): • All Arms:  To eva luate the effect on immune cell subset s and soluble factors in peripheral blood.  To evaluate the effect on cy tokine levels (IL -8, IL -6 and others) in peripheral blood.  To evaluate t he effect on T cell clonality in peripheral blood and t umor samples .  To evaluate the effect on antigen -specific T cells responses to CE A, MUC1 and the cascade antigen brachyury in peripheral blood.  To evaluate the effect on antigen -specific T cell response s to CEA, MUC 1 and the cascad e antigen brachyury in tum or biopsies. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 12 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 17 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 22 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 23 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 24 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 34 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 36 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 39 2 ELIGBILITY ASSESSMENT AND ENROLLMENT 2.1 ELIGIBILITY CRITERIA 2.1.1 Inclusion Criteria • Participant s m ust have histologically or cytologically confirmed:  Metastatic o r locally adva nced, S olid tumor (Co hort 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 bre ast cancer is def ined 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 mus t have been performed in a laboratory accred ited by the College of American Pathology (CAP) or another accrediting entity (Cohort 2). OR  Metasta tic or locally recurrent, non -resectable p16 negative Head and Neck Squamous Cell Cancer (HNSCC). Orop haryngeal 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 h ave 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. p resent on bone scan, ris ing tumor mark ers, non- measurable by RECIST but visible on CT scan). Participant s with third space fluid (for example pleural effusions) as only site of disease will not be eligible. Subjects in Arm 3 must hav e measurable disease ac cording to RECIST 1.1 See Sectio n 6.3.1 for the evaluation of measurable disease. • Participant s must  have received at least one prior systemic therapy for metastatic or locally advan ced disease, unless there is n o standard treatment avail able, 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 atezol izumab + nab- paclitaxel. Participant s 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. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 40 • ECOG perfo rmanc e status 0 or 1 ( Appendix A ). • Participant s 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 Gilbe rt’s Syndrome, a total bilirubin < 3.0 x ULN  AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal OR in subjects w ith known liver metastasis, AST/ALT < 3.0 X ULN  An e stimated creatinine clear ance (CrCl) > 60 mL/min/1.73 m2 using the Cockroft -Gault calculation ( https://www.kidney.org/profession als/K DOQI/gfr_calculatorCoc ). • The effects of immuno therapies on the dev eloping human fetus are unknown. For this reason and becaus e 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 (hormona l or barrier method of birth control; abstinence) at the ti me 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 woma n become pregnant or suspect she is pregnant while she or her partn er is participating in this study, she should inform her tr eatin g physician immediately. • Participant s with well -controlled HIV infection are eligible for trial as long as:  On a n eff ective anti -retroviral therapy (ART) > 4 weeks an d with evidence of viral suppr ession defined as HIV viral load < 400 copies/mL at enrollment  CD4+ count > 200 cells/ µL at enrollment • No reported opportunistic infections within 6 months prior to enrollment except for the following which will be allowed: o Esophag eal candidiasis tr eated 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 Myco bacterium avium infection in last 6 months or tha t has b een 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 t o enrollment for long term use (> 14 days). • Participant s mu st have a received their last treatment > 4 weeks or 5 half -lives of the las t treatment drug, whichever is shorter before starting on trial. • Participant s w ith known history of hepatitis B (HBV) infection are eligible for trial as long as the HBV viral load is undetectable. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 41 • Participant s with known history of hepatiti s C (HCV) infection m ust have bee n treated and cured (viral load is undetectable). For participant s 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 mu st be able to understand and be willing to sign a written informed consent document. 2.1.2 Exclusion Criteria • Participant s w ho are receiving any other investigational agents. • Participant s with active brain metastases or central nervous system met astasis (less th an 28 days out from definitive radiotherapy or surgery of brain metastasis) are excluded from this clinical trial. However, participant s with treated brain metastasis are eligible if there is no magnetic resonance imaging (MRI) evidence of progression for 6 we eks after treatment is complete and the MRI within 28 days prior to enrollment. Participants requiring immunosuppressive doses of systemic corticosteroids (> 10 mg/day prednisone e quivalent) for palliation are excluded. Participants with evidence of intratumoral or peritu moral 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 attr ibuted 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, alope cia, psoriasis, hypo- or hyperthyroid disease or other mild autoimmune disorder not requiring immunosuppressive treatment;  Participant s req uiring hormone replacement with corticosteroid are eligible if the steroids are administered only for the purpose of adr enal 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 acceptabl e;  Participant s on physiologic doses of systemi c 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. • Participant s 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 ade quately treated. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 42 • Receipt of any organ transplantation requiring ongoing immunosuppression including allogenic stem- cell transplant. • Participant s with bone metastases who have initiated denosumab or a bisphosphonate therapy within 28 days prior to e nrollment. Continuation of prior therapy is allowed. • Participant s who have a QTc f interval > 475 msec or > 480 msec with a BBB on screening electro cardiogram. • Participant s with a personal or family history of long -QT syndrome or are on a concomitant drug t hat is known to cause significant QTc prolongation within 2 weeks or 5 half -lives (which ever is sho rter) 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 ac ute 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 Princ ipal Investigator in dicated the subject is a poor candi date for the clin ical trial or wo uld jeopardize the subject or the integrity of the data obtained. • Pregnant women are excluded from this study because study drugs potential for teratogenic or abortifac ient effects are unknown. Because there is an unknown but potential ris k for adverse eve nts in nursing infants secondary to tr eatment 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 pla in l anguage announcement posted on NIH websites, including www.clinicaltrials.gov and the CCR website, and on NIH social media forums. Outside providers and colleagues may directly refer participants for screening into this study. 2.2 SCRE ENING 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 includ e the fo llowing: • Email, written, in person or telephone communications with pro spective 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 existi ng pathology specimens/reports from a s pecimen 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 t he st udy consent OR the consent for study #01-C-0129 (provi ded the proc edure is permitte d on the study) on which screening activities will be performed. Assessments performed at outside facilities or on another Abbreviated T itle: STAT Trial Version Date : 08/17/2022 43 NIH protoc ol within the timeframes below may also be used to dete rmine eligibility once a participant has si gned the consent. All scr eening tests and procedures must b e 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 perf ormance s tatus). • CT of ch est, abdomen and pelvis with contr ast (preferred) • A brain CT • Clinical laboratory tests (within 16 days prior to enrollment) − Biochemical Profile : sodium, potassium, ch loride m agnesium , phosph orus, bicarbonate, calcium, glucose, BUN, creat inine, A LT, AST, alkaline phosphatase, total protein, albumin, and total and direct bilirubin ,. − Hematology: complete blood count (CBC) with di fferential and platelets − CD4 (if clinically indicated) − TSH, fr ee T4, lipase, amylase − Lymphocyte panel (T BNK) − Coag ulation p anel: PT, INR, PTT − Urinalysis − Serum pregnancy test (β -HCG) f or 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 Cen ter at Bethesda. However, if no pathologic specimen is avail able or if participant s arrived with a diagnosis from Walter Reed National Military Medical Center at Bethesda, patients may enroll with a pathologist’s report showing a histologic diagnos is of me tastatic cancer, TNBC or HPV n egative HNSCC in a College of American Pathologists (CAP) accredited laboratory and a clinical course consistent with the disease. If there is no available tumor samp le or pathology report from a CAP accredited lab , a biopsy w ill be performed to confirm th e 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 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 44 negative or unamplified brea st cancer is defined by IHC and FISH HER2 t esting. FISH must have been pe rformed 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) • Docu mentation of IHC confir mation of HPV negative, oropharyngeal tum or is defined by negative p16 overexpression in the tumor ( Arm 3, Cohort 3 only) (at any time point prior to initiation of study the rapy). Other head and neck malignancies do not require p16 t esting . 2.3 PARTICIPANT REGISTRATI ON AND STATUS UPDATE PROCEDURES Registration and status updates (e.g., when a participant is taken off protocol therapy and when a participant is taken off -study) will take place per CCR SOP ADCR- 2, CCR Participant Registratio n & Status Updates found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825. 2.3.1 Screen Failures Screen failures are defined as part icipa nts who consent to participate in the clinical trial but are not subse quently assigned to the study i ntervent ion or entered in the study. A minimal set of screen failure information is required to ensu re transparent reporting of screen failure partici pants, to meet the Conso lidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen fai lure details, eligibility criteria, and any serious adverse event (SAE). Individuals who do not meet the criteria for participation in thi s trial (screen failure) because of a lab abnormal ity or temporary condition may be rescreened. . 2.3.2 Treatment Assignment Proc edures (for registration purpose only): Cohorts Number Name Description 1 Phase 1: Solid Tumor Participant s with any solid tumor enrolled to SX-682 escalation dose leve ls 2 Phase 2: TNBC Expansion Participant s with Triple Negative Breast Cancer enrolled at the RP2D of SX -682 in combinatio n with M7824 and CV301 3 Phase 2: HPV -HNSCC Expansion Participant s with HPV negative He ad and Nec k Cancer e nrolled at the RP2D of SX-682 in combination with M7824 and CV301 Arms Number Name Description 1 Sequentia l Dose Escalation Escalating dose s of SX-682 for 2 weeks THEN M7824 + CV301 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 45 Number Name Description 2 Combination Dose Escalation Escalating doses of SX-682 for 2 weeks THEN Escalating doses of SX -682 + M7824 + CV301 3 Disease -Specific Expansion RP2D of SX -682 + M7824 + CV3 01 Participant s in Cohor t 1 will be sequentially assigned to Arms 1 and 2. Participant s in Cohorts 2 and 3 will be assigned to Arm 3. 2.4 BASELINE EVAL UATION Tests done at screening do not need to be repeated on baseline if performed in designated time fram e prior to start of study treatment Within 7 days prior to first dose of any study drug: • Physical exam including height, weight, E COG perf ormance stat us and vital signs. • Concomita nt Medicat ions and Baseline Signs and Symptoms evaluation. • EKG • Serum pregnan cy test (β -HCG) for females of childbearing -potential and women < 12 months si nce the onset of natural menopause ( i.e., amenorrhe a not induced by chem otherapy or other medication). • Biochemic al Profile : sodium, potassium, chloride, magnesium, phosphorus, bicar bonate, calcium , glucose, BUN, creatinine, ALT, AST, alkaline phosphatase, total protein, albumin, and total a nd direct bilirubin. • TSH , free T4, l ipase, amylase • Hem atology: CBC with differential and platelets. Lymphocyte panel (TBNK) • Coag ulation panel : PT, INR, and PTT • Urinalysis • Flexible clinic -based pharyngolaryngoscopy to ev aluate the airw ay for safety and for mucosal in volvement (if clinically indicated in parti cipant s with hea d and neck cancers) • Collection of archival tumor samples for re search if available (any time prior to treatment). • Optional tumor biopsy for research purposes. 3 STUDY IMPLEMENTATION 3.1 STUDY DESIGN This is an open label Phase I/II trial, consis ting of a safety run-in phase I (Arms 1 and 2) and an expansion phase II , disea se-specif ic cohorts ( Arm 3). In Arm 1 the safety and MTD dose of short term (2 weeks) S X-682 monothera py lead-in following by t reatment wi th M7824 and CV301 will b e determined i n participants with solid Abbreviated T itle: STAT Trial Version Date : 08/17/2022 46 tumo rs (Schema 1 ). An eval uation of DLTs (eDLTs) will o ccur at the completion of each dose level an d will be done prior t o enrolling on the next dose level. In Arm 2 the safety , MTD /RP2D o f continuing treatme nt of SX -682 in combination with M7824 and CV301 will be determined in participant s with so lid tumors ( Schema 2). An eva luation of DLTs (eDLTs) will occur a t the com pletion of each dose level and will be done prior to e nrolling on the next dose level. During Arm 3 expansion cohort s, when RP2D of SX- 682 in combination with M7824 and CV301 is estimated, we will proceed with e nrollment to Cohorts 2 ( participant s with triple negative breast cancer) and Cohort 3 ( participant s with HP V negative head and neck canc er) to evaluate efficacy of the SX-682 in combination with M7824 and CV301 (Schema 3 ). SX-682 will be self -adminis tered by the participant orally twice d aily according to designated Dose Level ( Table 4). Admini stration of M7824 will b e at a flat dose of 1 ,200 mg every 2 weeks by IV . Participants will receive M7824 treatment ev ery 14 ( -1/+3) days. CV301 will be administered at a flat dose for both the prime and booster vaccines. The priming MVA- BN-CV30 1 is delivered as four subcutaneous injections of 4x108 infectiou s 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 wee ks start ing on Cycle 2 Day 1 x 4 cycle s then on Day 1 of every 3 cycles (every 12 weeks) for up to 1 ye ar on trial. Participant s will receive CV3 01 as scheduled ( -1/+3) days . Subjects on all arms will recei ve combined tr eatment with study drugs for up to 2 years (BN- CV301 will be administered for up to 1 year on trial; M7824 and SX -682 will be administered for up to 2 years on trial). Furthermore, after 2 years on treat ment with M7824 and/or SX -682, the PI can discuss an additional treatment period with CRADA p artners as long as in the opinion of the PI the participant continues to gain cli nic benefit and is tolerating the drug regimen . Disease progression should be conf irmed wit h a subsequent scan 4 to 8 weeks later prior to removing a particip ant from study therapy , unless the participant is clinically progressing or is no longer gaining be nefit in the opinion of the investigator. Subjects with evidence of disease progre ssion ca n remain on treatment beyond r adiographic progression if in the opinion of the investi gator the subject is benefiting from treatment . For complete list of off treatme nt criteria, see S ection 3.7.2. Patients may undergo u p to thr ee optional biopsies for research purposes only: at base line, at first restaging (+/- 1 week) an d at time of progression. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 47 Schema 1. Cohort 1, Arm 1 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 48 Schema 2. Cohort 1, Arm 2. Combination Dose Escalat ion Cohort. 3.1.1 Dose Limiting Toxicity Dose -limiting toxicity ( DLT ) will be defined as an y one of t he following adverse e vents (AEs), as defined by CTCA E v5.0, possibly attribu table to study drugs by the Investigator, that occur within 28 days after t he start of study therapy: • Any Grade 4 AEs, except for: o laboratory values that are determined to not be clinically significan t or single laboratory valued t hat re solve to Gr ade ≤ 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 th e participant (e.g. placemen t of a pleura l catheter for recurrent inflammatory pleural effusions) • Average QTcf ≥ 501 msec or > 60 msec change from baseline (Grade 3) • Any Grade 3 AEs except for a ny of the following: o Grade 3 flu -like symptoms or fever, as well as associated sympto ms of fatig ue, 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. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 49 o Any Grade ≥ 3 drug- related amylase or lipas e abnormality that is no t 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 tre atment discontinuatio n. 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]. The refore a grade 3 bleeding e vent will not be considered a DLT. o Any grade 3 adverse drug reaction which in the opinion of the investigator is not clinical ly relevant or can b e medic ally manage d with minimal risk to the participant (e.g. placement of a pleural catheter fo r recurrent in flammatory pleural effusions) • Any grade 3 or higher adverse event or unexpected toxicities due to the combina tion of therapie s that would not be expe cted wi th individual agents alone, will be considered a DLT . 3.1.2 Dose Escala tion Common Rules Starting dose of SX -682 wi ll be 25 mg by mouth twice daily (50 mg total daily dose). The first 3 partic ipant s enrolled on a given dose level of Arms 1 and 2 will be observed for DLT. If no DLT i n those 3 participants, the next dos e level will open. If DLT(s) occur, see Table 5. There will be a n interval of at least 28 days bet ween enrolling the last parti cipant on a given dose level and enrolling a particip ant on the next dose level in Arms 1 and 2, in order to assess for DLTs . Subje cts who do not complete the DLT observation period for re asons other than a DLT w ill be replaced and not included in t he evaluat ion. Participant s will be eligible for the DLT ev aluation if at least ≥85 per cent of SX -682 scheduled doses were taken and 100% of scheduled doses of M7824 or CV301 were administered within the DLT peri od. In case of DLT, DLT will be documented and participant , per PI disc retion, may continue study treatment if toxicity could be managed by interruption of the dose of study treatment or dose reductions (See sect ion 3.4). Participant , once having DLT, will not be used for DLT evalua tion on another dose level if treated on a lo wer dose level. Any of the trial drugs may be discontinued for toxicity per th e discretion of the p rimary investigator if is it felt that the toxicity can be directly linked to a spe cific drug or drugs . Per PI Abbreviated T itle: STAT Trial Version Date : 08/17/2022 50 discretion participant can continue treatment with 2 other drugs. However, if 2 drugs or more must be discon tinued, the participant will be taken off tre atme nt. 3.1.3 Sequential Dose Escalation (Arm 1) In Arm 1 participants wil l recei ve SX -682 as monotherapy for 2 weeks during the lead-in (Day s - 14L to -1L) and then continue treatment with M7824 and CV301 starting Cycle 1, Day 1. The dose escal ation will sta rt from dose level 1 and continue until dose level 3 ( Table 4 ) in sequential order us ing a standa rd 3+3 design ( Table 5 ). Aside from looking at DLTs within a given dose level , the t otal number of DLTs will also be evaluated among the initial 3DL s in Arm 1 to guide further safety assessments. If there are 0 DLT s reported in the initial 3 DLs (minimum of 12 participants) in Arm 1, then Arm 2 can open as depicted in Sc hema 2 with starting at DL2 . If there is 1 or more DLTs identified among a ll the participant s 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 determi ne the maximally to lerated dose (MTD) before proceeding to Arm 2 , DL 1 . Dose escalation will proceed in groups of 3–6 particip ants. The MTD is the dose level at w hich no more than 1 of up to 6 participant s experience DLT during 28 days of tr eatment, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. Table 4: Dose levels of SX -682 Dose Escalation Schedule Dose Level Dose of SX -682 Total SX -682 daily dose Level 1 25 mg by mouth twice daily 50 mg Leve l 2 50 mg b y 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. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 51 Tabl e 5. Escalation Decision Rules Number of Participant s with DLT at a Given Dose Level Escalation Decision Rule * 0 out of 3 Enter up to 3 participant s at the next dose le vel > 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 participan ts were treated previously at that dose. 1 out of 3 Enter up to 3 more participant s at this dose le vel. • 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 participa nts 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 participant s must be entered at the recommended phase 2 dose. 3.1.4 Combination Dose Escalation (Arm 2) In Arm 2 participan ts wi ll 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 Cy cle 1 Day 1 . If 6 participant s 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 particip ants. The MTD is the dose level at which no more than 1 of up to 6 participant s experience DLT during 28 days of treatment, and the dose below that at which at least 2 (of ≤6) participant s hav e DLT as a result of the drug. The RP2D may not ne cessarily be the same as the MTD. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 52 3.1.5 Expans ion Cohorts (Arm 3 , Cohorts 2 and 3) The safety, tolerability and efficacy evaluation of combination will conti nue 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 cohort s 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 Bre ast Cancer and HPV ne gative HNSCC 3.2 STUDY STOPPING RULES For safety reasons, enrol lment 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 inves tigational 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. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 53 3.3 DRUG ADMINISTRATION 3.3.1 General Dosing Rules: Excep t where stated otherwise in the study calendar a window of - 1/+ 3 da ys for every two weeks M7824 dosing and/or study calendar a window of - 1/+ 3 days for the scheduled CV3 01 dosing is allowed in the event of scheduling issues (i.e. holiday, bad weather or other scheduling issues). Any dose that cannot be accommodated within this window will be skipped and the dose not made up. Similar drug administrations should not be given less than 11 days from one another. The preferred order of drug administration in the day hospital is CV301 , then M7824 administration; when possible, administer the vaccine within 60 minutes prior to the M7824 administration; however, the exact timing of vaccine administration is flexible. 3.3.2 SX-682 SX-682 will be given orally at designated dose twi ce 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 approxima tely the same times each day. Participants should take SX - 682 with water once in the morning ( suggested between 6 -9 am) and once in the e vening (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 do se (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 P I/AI to hold additional doses of SX-682 during a planned cycle. Participant s will complete and return Participant ’s Diary (Appendix C ), which will be reviewed by research staff at the end of each cycl e. 3.3.3 CV301 Vaccines Participant s will be p rimed 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 we eks) x 4 cycles (Cycle 2 through Cycle 5) then on Day 1 of e very 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 i njection containing 1x109 Inf.U/0.5ml. For participant comfort, it is generally preferred if FPV -CV301 is administered in the upper arm; however, the vacc ine can b e 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. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 54 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 mic ron in -line filter is required for administra tion of M7824. The preference is for M7824 to be given via peripheral line. However, if the resear ch team documents that the main material of the port is titanium, M7824 can be administered via mediport. It is t he responsibility of the research team to con firm and document this in CRIS . Once documented, the ordering physician can change the route of ad ministration to mediport. Please refer to the pharmacy manual for a list of acceptable materials known t o be compatible with M7824. In order to mitigate potential infusion -related reaction s, premedic ation 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 dos ing of M7824 is optional and at the discretio n of the Investigator. Steroid s as premed ication are not permitted . 3.4 DOSE MODIFICATIONS 3.4.1 General Rules When, at the beginning of a treatment week , treat ment delay related to one of study drugs is indicat ed, treat ment 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 disc retion of the primary investigator if is it felt that the toxicity can be d irectly lin ked 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 investiga tor doing so will minimize the risks to the participant and maximize clinic ben efit (e.g., in the event of observed tumor reduction but also intole rable ADRs at the full dose). If one drug is discontinued during first year of treatment, a partici pant may per PI discretion continue trea tment with 2 other drugs. However, if 2 d rugs 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 d iscretion contin ue treatm ent with the othe r drug . For non- medical logistical reason s, unrelated acute illnesse s, 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 origina l treatme nt 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 c ontinue s 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 possibil ity of continuing the participant on treatment with the assigned trial drugs for an additiona l specified period of time. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 55 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 t o a lowe r tolerab le grade the study treatment might be resume d in the subsequent week. If the AE remains the s ame despite the medical treatment until the next treatment (second cycle a fter the AE occurred) a consideration of a possible extension of the dose interr uption for u p to 1 additional cycle or a permanent wi thdrawal 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 considere d. Grade 3 and 4 lab oratory abnormalities that do not have cl inical significance and are not related to study drugs do not require dose interruption. 3.4.2 SX-682 If any SX -682 related AE observed is grade > 2 (except for electrolyte abnormalities that can be easil y rep lenished or other lab abnormalities that have no clin ical consequence or can be easily medically managed with minimal risk to the participant ), treatment should be delayed by 1 wee k (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 st ill not resolved (to grade ≤ 1), then any furt her treatment with SX -682 should be delayed until AEs are resolved (to grade ≤ 1), and then reduced by one dose level at the time of reinitiating . 3.4.3 CV301 Dose delays or dose omissi ons of CV301 vaccines are allowed per P I 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 d iscretion . 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 Adver se Events (CTCAE) version 5.0. Any Grade 4 ADRs r equire permanent treatment discontinuation except for any of the following: • Single laboratory values out of norm al 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) , treatm ent should be delayed, and tre atmen t 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 discretio n. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 56 • Asym ptoma tic 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 e xplanati on is identified, trea tment must be permanently discontinued . Any Grade 3 ADRs require treatment tempo rary discontinuation except for any of the following: • Transient (≤ 48 hours) Grade 3 flu -like s ymptoms or fever, which is controlled with medical manageme nt. • Transient (≤ 48 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that is controlled with medical management. • Tumor flare phenomenon de fined as local pain, irritation, or rash localized at sites of known or suspected tumor. • Any s ingle Grade ≥ 3 drug -related transaminase, alkaline phosphatase, or bilirubin abnormality with no other associated laboratory (or other) abnormality that is not a ssociated with symptoms or clinical manifestations of hepatitis. If the liver function abnorma lity 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 manifestati ons of pancreatitis. If the amylase or lipase abnormality not assoc iated with symptoms or clinical manifestations of pa ncreatitis has not resolved to Grade ≤ 1 within the subsequent 2 cycles ( 56 days), the subject should permanently discontinue treatment w ith M7824. • Grade 3 Hgb decrease (< 8.0 g/dL) that is clinically manageable with blood transfusions or erythroid grow th 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 a dministration 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 derma tological 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 G rade 3 bleeding event, study treatment should be held until recovery to at lea st 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 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 57 suggestions based on current knowledge; however, given this is an evolving field, investigators are encouraged to consult professional guidelines. o In addition to NCCN gui delines, th e following recom mendations 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, a cquired thrombotic thrombocytopenic purpura inflammatory arthritis, myositis and polymyalgia -like syndrome. • For Grade 4 immune -related lymphopenia, permanent treatment discontinuation will be required, if lymphopen ia is considered immu ne- related in natur e, no cl ear 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 norm al range without any clinical correlat es. 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 c linically 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 rituxim ab, treatment should be discontinued. • For Grade 3 or 4 endocrinopathies: withhold until cli nically stable or permanently discontinue depending on severity. • For hepatitis with no tumor involvement of the liver: withhold if tot al bilirubin increa ses to m ore 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- relate d Reactio ns 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 a re identified based on a list of MedDRA PTs and divided into reactions versus sig ns and sym ptoms. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 58 • 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 , hype rsensitivity and/or Type 1 hypersensitivity. • Signs and symptoms of infusion related reactions and hype rsensitivity/allergic reactions should be considered when onset is on the day of infusion (during or after the infusion) and resolved compl etely with the end date wit hin 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, feel ing of passi ng 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; howeve r, given this is an evolving field, investigators are encouraged to consult the most updated professional guidelines. Table 6: Trea tmen t Modifications for Symptoms of Infusion -related Reactions NCI-CTCAE Grade Treatment Modificatio n for M7824 Grade 1 – mild Mild transient reaction; infusion interruption not indicated; intervention not indicated. Consider decreasing th e infusio n rate of the particular agent by 50% and monitoring closely for any worsening. Grade 2 – moderate Therap y or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDs, narcotics, i.e. fluids); prophylac tic me dications in dicated for ≤ 24 hours. Consider temporarily discontinuing infusion of the particular age nt. Consider resuming infusion of the particular agent at 50% of previous rate once infusion related reaction has resolved or decreased to at least Grade 1 in severity and monitor closely for any worsening. Grade 3 or Grade 4 – severe or life - threatening Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief interruption of infusion); hospitalization indicated for clinical sequelae. Grade 4: Life -threatening consequences; urgent intervention indicated. Stop the infusion imm ediately and disconnect infusion tubing from the subject. For grade 3 events: Consider withdrawing immediately from treatment with that particular agent and not offeri ng any further treatment with that agent based upon if the clinical condition can be safe ly 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 be en decreased by 50% or interrupted due to an infusion reaction, keep it decreased for the next sc heduled infusion. If no infusion reaction is observed in the next scheduled infusion, the infusion rate may be returned to baseline at the s ubsequent infusions based on investigator’s medical judgment. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 66 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: Cons ider tapering steroids over at least 1 month Requirement for 10 mg per day or greater prednisone or equivalent for more than 12 weeks for reasons other than hormonal replacement for adrenal insufficiency Persistent Grade 2 or 3 irAE lasting 12 weeks or l onger Consider permanently disc ontinuing M7824 Consider specialty consult as appropriate 3.4.4.4.1 Rash with Hyperkeratosis / Keratoacanthoma / Squamous Cell Carcinoma of the Skin Dermatological consults will be requested on a case -by-case basis as needed with potential biopsy of suspicious skin lesions. 3.4.4.4.2 Suggested Evaluation of Suspected Bleeding or Hemorrhage Events and Treatment Modification For anemia or hemorrhage events assessed as treatment -related, items queried may include but are not limited to detail ed 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 dosi ng information and recent tumor evaluation scans. In this protocol, anemia may be due to M7824 (documented in 29% of patient s based on pooled safety analysis set from a total of 765 participants, refer to IB v7) and/or SX -682. For M7824 anemia i s an AESI and important identified risk (see Investigators’ Brochure ). Notably, there are many reasons for hemo rrhage and/or anemia in patient s with advanced cancer, and Hb level of at least 9 g/d L is required for this study. A thorough investigation of ne w anemia cases of unspecifie d etiology is re commended: • Participants must enter the study with Hgb values at lea st 9 g/ dL a nd baseline anemia evaluation is conducted per recommendations below. • Consider hematology consult for severe and or refractory anemi as. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 67 • All relevant h ematologic testing for treatment related anemias should be done prior to blood transfusion, i f clini cally feasible. • Transfusion should be performed at the discretion of the investigator, based on clinical assessment and considered when p articipant experien ces significant anemia. • Guidance for evaluation of baseline anemia or suspected treatment -related anemi as is provided below. Investigators may consider the following laboratory evaluations in participant s with anemia. o Hb and CBC with d ifferential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes counts) o Peripheral blood smear for cell morpho logical assessment o Com plete metabolic panel including liver panel -LFTs, bilirubin, LDH, renal function, and serum folate, B12 values and other chemistri es o Coagulation fac tors (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 mucosa l bleeding events r anging from low grade gingival bleeding and epistaxis to more serious hemoptysis, GI bleeding and he maturia have been observed. Some of these events can be attributed to bleeding events related to cancer directly and others bleeding even ts can be attributed to an inflammatory process (e.g. colitis) which is a known toxicity of anti -PD-L1 ag ents 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 m ucosal bleeding ri sk may be due to the known mucoprotective effects of TGF β. Accordingly, partici pants 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). Abbreviated T itle: STAT Trial Version Date : 08/17/2022 71 5 MVA- BN-CV301 will be giv en on days 1 and 15 of Cycle 1. F PV-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 holi days, inclement weather, conflicts, or similar reasons except where explicitly noted elsewhere. CV301 adm inistrations should not be given less than 11 days a part. See Table 8 6 EOT – End of treatment visit: Where feasible, on the day of or within 30 da ys of the decision to discontinue treatment prematurely before co mpletion of one year of treatment. Doe s not need to be completed if drug is withheld after one year of treatment. Research labs will be collected if fea sible. Participants continuing to exper ience toxicity at the off- treatment visit will be contacted for additional assessments until the t oxicity has resolved or is deemed irreversible. Participants must remain on the study to have additional assessments co mpleted 7 30 days (+/- 7 days) a fter 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 perfor med within this time frame. 8 Participant s who are taken off treatment for reasons other than disease progression, will be invited for optional imaging studies every 3 mo nths (+/- 2 we eks) until they exp erience PD in order to assess PFS. If participant s unable to come, participant s will be followed by phone or e mail and outside images will be requested. Participants who opt out of these scans will have their data censo red in data analysis at the time t hey become unfollowable for PFS. After progression and 30 days Safety Follow up visit, participant s will be followe d 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 scre ening, before SX- 682 administratio n at bas eline and then every two weeks until cycle 6, at EOT and at the safety FU visit. 10 Biochemical profi le: sodium, potassium, m agnesium , phosphorus, chloride, bic arbonate, calcium, glucose, BUN, creatinine, ALT, AST , alkaline phosphatase, total protein, albumin , and total and direc t bilirubin . 11 Performed every 8 weeks: Lymphocyte panel (TBNK), TSH, Free T4, li pase, amylase, ur inalysis, PT/PTT/IN R, unless there i s a clinical concern that warrants evaluation on a more frequent basis 12 For women of childbea ring potential at screen ing and baseline serum pregnancy test must be performed, but on day 1 of each c ycle and EOT, urine pre gnancy test can also be used . 13 In Arms 1 a nd 2, the first restaging will occur 6 weeks after starting treatment (+/ - 1 w eek) and the n 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 discret ion of the investigator. Tumor asse ssment should be continued beyond end of treatment in participant s who have not experienced PD until they experience PD in order to assess PFS. In addi tion to a baselin e 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 pe lvis (if partic ipant has contradiction to CT). 14 Brain CT/M RI 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 restagin g (+/ - 1 week if possib le). Optional biopsy also at t ime of progression. In addition, tissue collected during unscheduled proc edures may also be collected for research purp oses. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 74 Cycle (Day) Time SX-682 M7824 Immune and Other Analyses PK PK ADA Soluble Factors Immune phenotyp ing/ RNA analysis, Antigen -specific response, T-cell clona lity CTCs 30 minutes X Cycl e 1 (1) predose X X X X X X End of Infusio n (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 (Sequentia l Dose Escal ation ). **The last M7824 PK/ADA timepoint should be Cycle 3, Day 1 predose or EOT, whichever comes firs t. Table 10: Arm 2 Research Blood Draws Cycle (Day) Time SX-682 M7824 Immune and Other Analyses PK PK ADA Soluble Factor s Imm une phen otyping/ RNA analysis, Antigen- specific respo nse, T -cell clonalit y CTCs Abbreviated T itle: STAT Trial Version Date : 08/17/2022 76 Cycle (Day) Time Immune and Other An alyses Soluble Factors Immune phenotyping/ RNA analysis, Antigen-specific response, T-cell clonality CfDNA CTCs Cycle 1 (1) predose X X X X Cycle 1 (15) predose X X X Cycle 2 (1) predose X X X X Cycle 3 (1) predose X X X EOT X X X Abbreviated T itle: STAT Trial Version Date : 08/17/2022 77 3.6 COST AND COMPENSATION 3.6.1 Costs NIH does not bill health insurance companies o r part icipants for any res earch or related clinical care that participants receive at the NIH Clinical Center. If some tests and proc edures performed outside the N IH Clinical Cen ter, particip ants may have to pay for the se costs if they are not covered by i nsurance company. Medicine s that are not part of the study treatment will not be provided or paid for by the NI H Clinical Center. 3.6.2 Com pensation There will no compensation provided in this stud y. 3.6.3 Reimbursement The NCI will cover th e cos t s of some expenses a ssociated with protocol par ticipation. Some of these costs may be paid directly by the NIH and some may be r eimbursed to the partic ipant/guard ian as appropriate. T he amount and for m of thes e payments are determined by the NCI Tr avel and Lodging Reimburse ment Policy . 3.7 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY A ND OFF STUDY CRITERIA Prior to removal from study, e fforts must be made to h ave all subjects complete a safe ty visit approxima tely 30 days (+/ - 7 days) following the last do se of study therapy. 3.7.1 Crite ria for Removal from Protoc ol Therapy • Participant re quest to be withdrawn from active therapy • Confirme d clinical or radiograp hic progression of dis ease except when t he investigator feels the subj ect is still benefiting from treatment. NOTE: treatme nt may be continued despite progres sion a ccording 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 t o administer a salvage therapy. • Unacceptable Toxicity as described in sections 3.3 • Investigator disc retion • Positive pregnancy test • Need to use restricted medication, section 4.1 • Completion of 2 years of therapy unless th e PI feels that the participant continues to gain benefit from two or more of the trial drugs and discus ses continuing on tria l with the CRADA partners for an additional specified period of t ime. 3.7.2 Off -Study Criteria • Completion of 2 years follow -up period af ter confirmed disease progression • PI decis ion to end the study • Partici pant lost to follow up Abbreviated T itle: STAT Trial Version Date : 08/17/2022 78 • Investigator discretion • Death • Participant request to be withdrawn fr om the study • Screen Failu re 3.7.3 Lost to Follow-up A participant will be consid ered los t to follow -up if he or she fails to return for 3 consecuti ve scheduled visits and is u nable to be contacted by the study site sta ff. The following actions must be taken if a part icipant fails to re turn to the clinic fo r a required study visit: • The site will attempt to contact the participant and re schedule the m issed visit and counsel the participant on the i mportance of maintaini ng the assigned visit schedule and ascertain if the participant wishes to and/or should continue in the study. • Before a part icipant is deemed lost to follow -up, the inves tigator or designee will make every effort t o regain contact wi th the participant (whe re possible, 3 telephone calls and, if necess ary, a n IRB approved ce rtified letter to the participant’s l ast known mail ing address or loc al equivalent methods). These contact attempts should be docume nted in the participant’s me dical record or stu dy file. • Should the pa rticipant continue to be unreachable, he or she wil l be considered to ha ve withdrawn from the study with a primary reason o f lost to follow -up. 4 CONCOMITANT THERAPY For th is protocol, a pr escription medication is de fined as a medicati on that can be prescribed only by a properly authorized/licens ed clinician . Medications to be reported in the Case R eport Form (CRF) are concomitant prescription medications, over -the-counter m edications and s upplements. Any medications (other than those e xcluded by the clinical trial protocol) that are considered necessar y to p rotect subject welf are or alleviate symp toms and will not i nterfere with the trial medications may be given at the Investigator’s discretion. Palliative radiothera py delivered in a normal organ -spearing te chnique may be administered during the t rial. The asse ssment of PD wil l not be based on the necessity for palliative radiotherapy. 4.1 THE FOLLOWING TREATMENTS SHOULD NOT BE ADMINISTERED DURING THE TRIAL : • Other immunotherapies or immuno suppressive drugs for e xample, chemotherapy or systemic corticostero ids ex cept for prophylaxi s or treatment of aller gic reaction s, endocrine repla cement therapy at low dose prednisone [≤ 10 mg daily] or equiva lent, for the treatment of i rAEs, or for short courses (≤ 14 days) as appropriate medical therapy for unrelated medical conditions (e.g. asthma). Steroids with n o or minimal systemic effect (topical, inhalation) are allowed. • Prophylactic us e of corticosteroids for infusion related reactions. Corticosteroid administration prior to CT scans in participants with intravenous contrast allergy is allowed. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 79 • QTc prolonging drugs: The drug- drug int eraction s of SX -682 in humans have not yet been determ ined. 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, s hould 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 cau tion aft er review ing the risks/ benefits and potential al ternative options. QTc prolonging agents are not prohibited in partici pants no longer receiving SX -682. • In vitro studies indicate SX -682 inhibits CYP2C8. Medications that are substrate s of this enzyme may have altered metabo lism when administered concurren tly 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 shoul d be consulted (e.g. https://drug- interactions.medicine.iu.edu/MainTable.aspx). • Any live vaccine t herapies for the prevention of infectious disease. Administration of inactivated vaccines is allowed (for example, inactiv ated influenza vaccines ). Locally approved COVID vaccines are permitted. • System ic anticancer treatment other than the investigational agents in this trial except for disease specif ic appropriate hormonal therapies (e.g., ADT for prostate cancer, anti - estrogen for breas t cancer, somatostatin an alogue for neuroendocri ne cancer). • All an ticoagulation drugs will be r eviewed by the investigator to determine the potent ial for interactions or potential safety concerns with the investigational agents. Any anticoagulation agent de emed to have a potential ly clinic ally sign ificant interaction with the investigational agent(s ) by the investigator should not be administered while on the clinical tr ial. • All herbal supplements will be reviewed by the investigator to determine the poten tial for herbal interactions or pot ential s afety concerns with the investigational agents. Any herbal supplement deemed to have a potential ly clinically significant in teraction with the investigational agent(s) by the investigator should not be administere d while on the clinical tr ial. 5 CORRELATIVE S TUDIES FOR RESEARCH Biospecimens will be evaluated to help identify the effect of the study dugs on t he immune response before and after treatment, to gain insight into potential biomarkers, and help improve the a dministered therapy. 5.1 SAMPLES 5.1.1 Tumor Samples Wher e available, archival tumor samples will be req uested. O ptional bio psies may be performed as per S tudy Calendar 3.5. Attempts will be made to obtain up to six cores (18G or 20G preferred) or direct b iopsies with biopsy forceps if safe and f easible. These tumo r core biopsies will be obtained percutaneously by interventional radiology as long as considered minimal procedural risk. Direct biopsies with biopsy forceps wil l be obtain ed by Otolaryngology as long as cons idered minimal procedural ri sk. Two 3 -millimeter punch biopsies Abbreviated T itle: STAT Trial Version Date : 08/17/2022 83 5.2.4 ADA Serum samples may be analyzed by a validated electrochemiluminescence immunoassay (ECL A) to detect the presence of anti -M7824. Samples that screen positive will be subsequently tested in a confirmatory assay. Those confirmed pos itive will be titered for a q uasi-quantitative result. Samples may be fur ther 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 com panies. 5.2.5 Analyses of Tumor Ti ssue for Immune Markers Biopsy samples may be used t o study immune infiltration as well as PD -L1 status within the tumor microenvironment pre vs. post treatment by IHC and/or mu ltiplex immunofluorescence. Biopsies may be subj ected to dissociation and ana lysis by flow cytometry to determine immune infiltration. Tumor infiltrating lymphocytes may be cultured from biopsies fo r assessment of T cell clonality and antigen specificity. Tumor samples will be sent to the Laboratory of Pa thology 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 ant igen brachyury in tumor biopsies. Tumor infiltrating lymp hocytes (TIL) may be cultured from tumor fragme nts 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 ne gative magnetic selection. B cells will be sorted from PBM C using negative magnetic isolation and w ill be ex panded using flt3 -expressin g 3T3 cells and IL -7. Expanded B cells will serve as autologous antigen presenting cells for coincubation assays. B cells w ill be electroporated with full length capped and tailed mRNA encoding for MUC1, CEA or the cascade anti gen brachyury. Autologous B c ells loaded with mRNA will be co-incubated w ith TIL cultured from tumor fragments (2:1 APC: T cell ratio) and IFNg produc tion will be measured by ELISA. 5.3 SAMPLES FOR GENETIC /GENOMI C ANALYSIS 5.3.1 RNA and T -cell Receptor Clonal ity Ana lysis of Blood and Tumor Tissue RNA expression and T -cell recept or clonal ity 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 wi th treatment as well as to de termine 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. D igital Spatial Profiling (D SP) including RNA in situ hybridization may also be performed on tissue for spatially resolved high plex profiling of RNA and protein targets. De - identified, coded samples may be analyzed for RNA expression levels and DS P using the Nanostring platform and T-c ell receptor clonality using the ImmunoSe q platform (LTIB and NCI Frederick Genomic Core Facility) . NCI Fredrick Genomic Core Facility: Leidos Biomedical Research, Inc: Abbreviated T itle: STAT Trial Version Date : 08/17/2022 88 participant conf identiality. Using a computerized inventory system and a backup hardcopy process, all specimen collection and processing ste ps will be documented, and the specific location of eac h 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 in ventory system. Specimen labels will indic ate protocol nu mber, order in which the participant enrolled on the trial, type of s ample, as appropriate. The inventory proc ess contains other security provisions sufficient to safeguard participant privacy and conf identiality. Access to the inventory syst em and associated documents is r estricted to app ropriate individuals. Request s to use specimens stored in the repository must be approved by the trial Principal Investi gator. SOPs ensure that any changes in informed consent made by a partici pant and relayed to the tr ial Principal Investigator will be reflec ted in the invent ory system to ensure t hat specimens are dest royed as appropriat e. All laboratory personnel are trai ned 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 appropriat e) according to stabil ity requirements. These freezers are located in the 5.4.6 Protocol Completion/Sa mple Destruction All specimens obtained in the protocol are used as defined i n the protocol. Any s pecimens that are rema ining at the comple tion of the protocol will be stored in the conditions described in sections above. Th e study will remain open so long as sample or data analysis continues. Samples from consent ing 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 dest royed. The PI will record any los s or unantici pated destruction of sampl es as a deviation. R eports will be per the requirements of section 7.2 . If the participant w ithdraws consent the participant’s data will be excluded from future distributions, but data that have a lready been dist ribute d for approved res earch use will not be able to b e retrie ved. 6 DATA COLLECTION AND EVALUATION 6.1 DATA COLLECTION The PI will be respo nsible for overseeing entry of data into a 21 CFR Part 11-compliant data capture system provided by the NCI CCR and ens uring data accuracy, consistency and timeliness. The principal investiga tor, assoc iate inve stigators/research nurses and/ or a contracted data manager wil l assist with the data management efforts. Prim ary and fina l analyzed data will have identifiers so that research data can be attributed to an individual human subje ct participant. All adverse e vents, including clinically significant a bnormal findings on l aboratory evaluati ons, regardless of severity, wi ll be followed until return to baseline or stabilizatio n of event. Document AEs from the administration of the first study intervention through 30 after the study agent (s) was/were last admin istered . Beyond 30 days after the last inter vention, only adve rse events w hich are serious and related to the study int ervention need to be recorded. An abnormal laboratory value will be recorded in the databa se as an AE only if the laboratory abnorm ality is characterized by any of the following: • Results in discont inuation fro m the study Abbreviated T itle: STAT Trial Version Date : 08/17/2022 89 • Is associated with clinical sig ns or symptoms • Requires treatment or any other therapeutic intervention • Is associated with death or another serious adverse event, i ncluding hospitalization. • Is judged by the Investigator to be of signif icant clinical impact If any abnormal laboratory result is considered clinically significant, the investig ator will provide details abo ut the action taken with respect to the t est dr ug and about the participant ’s outcom e. Adverse Events of grade 1 will not be collected. End of study procedures: Data will be stored according to HHS, FDA regulations and N IH Intramural Records Reten tion Schedule as applicable. Loss or destruction of data: Should we be come aware that a majo r breech in our plan to pro tect subject c onfidentiality and trial data has occu rred, his will be reported expeditiously per requirements in section 7.2.1 6.2 DATA SHARING PLANS 6.2.1 Human Data Sharin g Plan The PI will sha re cod ed linked human dat a generated in t his research for future research − in a NI H-funded or approved public repository clinicaltrials.gov and dbGaP − in BTRIS − in publication and/or public presentations − with approved outside collabora tors under appropriate agreements − at the time of publication or shortly thereafter. 6.2.2 Genomic Data Shar ing Plan Unlinked genomic data will be deposited in publi c genom ic databases such as dbGaP in compliance with the NIH Genomic Data Sh aring Policy. 6.3 RESPONSE CRITERIA For the purposes of this study, part icipant s should be r e-evaluated for response according to schedule in the Study Calendar, section 3.5. In the e vent of a PR or CR tumor imaging assessm ents may be performed every 3 months (+ /- 2 weeks) at the di scretion of the inve stigator. In add ition to a baseline scan, confirmatory scans can also be obtained 4 to 8 weeks following initial documentation of objec tive response per the discretion of the primary investigator. The pre ferred meth od of disease assessm ent is CT with contrast. If CT with contrast is contraindicated, CT of the chest without contrast and MR I scan of the abdomen/pelvis is preferred. Additiona l assessment of tumor re sponse may inclu de the follow ing evaluations ; nuclear bone scan for subjects w ith known/suspecte d bone lesions; and CT or M RI scan of the brain (only as clinically warranted based on symptoms/findings). Brain CT / MRI scan should b e performed, if clinically indicated by development of new specific symptoms or on the discretion of th e Primary Investig ator. For each subject, the Investiga tor will Abbreviated T itle: STAT Trial Version Date : 08/17/2022 90 designate 1 or more of the following m easures of tumor status to follow for determining r esponse: CT or MRI images of primary and / or metastat ic tumor masses, physical examination findings, and the results of other assessments. All available imag es collected during the trial period will be considered. The most appropriate mea sures to evaluate the tumor status of a su bject should be used. The mea sure(s) to be chosen for s equential evaluation during the trial hav e to correspond to the measures used to document the progressive tumor status that qualifies the subject for enrollment. Progressive di sease should be confirmed by imaging 4 to 8 weeks (preferably at 4 we eks, but not more than 8 weeks) af ter progression ha s been diag nosed according to RECIST 1.1. before the participant is removed f rom treatment [ 93]. If progression is based on the occurrence of a new lesion in an area not scanned a t Baseline, a fur ther on- study scan 4 to 8 weeks later sh ould be considered before performing the 28- Day Safety Follow -up visit. Tumor responses to treatment will be assigned ba sed on t he evaluation of the response of target, non-target, a nd new lesions according to RECIST 1.1 (all measurement s should be recorde d in metric notation). To assess objectiv e response, the tumor burden at ba seline will be estimated an d used for compar ison with subsequent m easurements. At baseline, tumor lesions w ill be categorized in target and non- target lesions according to RECIST 1.1. Results for these evaluations will be recorded with as muc h specificity as possible so that pre and post-treatment re sults will provide th e best opportunity f or evaluating tumor r esponse. The Inve stigator may perform scans in addition to a scheduled tri al scan for medical reasons or if the Investigator suspects P D. iRECIST wil l also be used for exploratory endpoi nts (See section 6.3.3) For the primary endpoint antitumor activity will be evaluated with target an d/or non- target lesions according to Resp onse Evaluation Crite ria in Solid T umors (RECIST) Version 1.1 . [93]. Palliativ e radiotherapy delivered in a nor mal org an-spearing technique may be administered during this trial. The assessmen t of PD will not be based on the neces sity f or palliative radiothe rapy. If a target l esion is radiated during the course of t reatment, this ta rget lesion will no longer be considered a measurable lesion and will be removed from the target les ion sum moving forward as is recommended in RECISTv1 .1. 6.3.1 Disease Parameters Measurable disease : Mea surable l esions are defined as those tha t can be accurately measured in at least one dimen sion (l ongest diameter to be recorded) as: • By chest x -ray: >2 0 mm; • By CT scan: o Scan slice thickness 5 mm or under: a s >10 mm o Scan slice thickness >5 mm: double the slice thickness • With calipers on clini ca l exam: > 10 mm. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 91 All tumor measurements must be recorded in millimete rs (or decimal fractions of centimeters). Tumor lesions that a re situated in a previousl y irradiate d area may be considered measurable if there is demonstrated progress ion in the radiate d lesion prior to starting on the trial. Malignan t lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness re commended to be no gre ater than 5 mm). A t baseline and in follow -up, only the short axis w ill be measured and followed. Non-measurable disease . All oth er les ions (or sites of disease), including sma ll lesions (longe st diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), ar e considered non-measurable disease. Bone lesions, leptom eningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non- measurable. Note: Cystic lesions that meet the criteria for radiog r aphically defined simple cysts should not be considered as malignant lesions (neither measurable nor non- measurable) since they are, by definition, simple cys ts. ‘Cystic lesions’ thought to represen t cystic metastases can be considered as measurabl e lesio ns, if they meet the definition of measurability described above. However, if non- cystic lesions are present in the same participant , these are preferred for s election as target lesions. Targe t lesions. All me asurable lesions up to a maximum of 2 le sions per organ and 5 lesions in total, representative of all involved organs, should be identified as target le sions and recorded and measured at base line. Target le sions should be selected on the basis of th eir size (lesions with the longest diameter), b e representative of all involved organs, but in addition should be those that lend themselves to reproducible re peated measurements. It may be the case that, on occasio n, the largest lesion does not lend itself to reproducible measurement in which circumst ance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non -nodal lesions, s hort axis for nodal lesions) for all target lesions will be calculate d and reported as the baseline sum diameters. I f lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum di ameters will be used as reference to fu rther character ize any objective tumor regression in the m easurable dimension of the disease. Non-target lesions . All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified a s non-targe t lesions and s hould also be recorded at baselin e. Measure ments of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2 Methods for Evaluation of Measu rable Disease All measuremen ts shoul d be taken and recorded in metric notation using a ruler or calipers. All baseli ne evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatme nt. The same meth od of assessment and the same t echnique s hould be used to characterize each identified and reported lesion at baseline and during follow -up. Imaging- based evaluation is preferred to evaluation by clinical examination unless the lesion(s) b eing followed c annot be imaged but are assessabl e by clini cal exam. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 92 Clinical lesions: Clinica l lesions wi ll only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed usi ng calipers (e.g., skin nodules). In the case of skin lesio ns, documentation by color photography, including a ruler to estimate the size of the lesio n, is recommended. Chest x -ray: Lesio ns on chest x -ray are not acceptable as measurable lesions. Conventional CT and MRI: This guide line has defined measurabi lity of lesions on CT scan based on the assumption that CT sli ce thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measura ble lesion should be twice t he slice th ickness. MRI is also acceptable in certain situa tions (e.g. for body scans). Use of MRI remains a complex issue. MR I has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatl y impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is vari able globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore , as with CT, the modality used at follow -up should be the sam e as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guide lines to prescribe specifi c MRI pulse sequence paramet ers for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with br eath-hold scanning techniques, if possible. PET- CT: At present, the low dose or attenuation correction CT portion of a combined PET -CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that t he CT performed as part of a PET- CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET -CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions ove r tim e. Note, however, that the PET portion of the CT introduc es additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of l esion size and sh ould not be used as a meth od of measurement. Ultrasound examinations cannot be reproduce d in their entirety for independent review at a later date and, because they are operator dependent, it cannot b e guaranteed that the same t echnique and measurements wi ll be taken from one asses sment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instanc es. Endoscopy, Laparoscopy: The utiliza tion of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to det ermine relapse in trials w here recurrence following co mplete response (CR) or surgical resection is an endpoint. Tum or markers: Tumo r markers alone cannot be used to assess response. If markers are initially above the upper norm al limit, they must normaliz e for a participant to be co nsidered in complete clinical response. Specific guidelines for both CA -125 respo nse (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published. [ 94-96] In addition, the Abbreviated T itle: STAT Trial Version Date : 08/17/2022 93 Gynecologic Cancer Intergroup has de veloped CA -125 progression criteria which are to be integrated with objective tumor assessment for use in first- line trials in ovarian cance r.[97] Cytology, Histology: These techniques can be used to differentiat e between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of th e neoplast ic origin of any effusion t hat ap pears or worsens during tr eatment when the measurable tumor has met criteria for re sponse or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment ) and progressive disease. FDG- PET: While F DG-PET response assessments need additional study, it is sometimes reason able to incorporate the use of FDG -PET scanning to complement CT scanning in assessment of progression (particularly possibl e 'new' disease) . New lesions on the ba sis of FDG - PET imaging can be identi fied according to the following algorithm: a. Negative FDG -PET at baseline, with a positive FDG -PET at follow -up is a sign of PD based on a new lesion. b. No FDG- PET at baseline and a po sitive FDG -PET a t follow -up: If the pos itive FDG- PET at follow -up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG -PET at follow -up is not confirmed as a new site of disease on CT, additional follow -up CT scans are needed to determine if there is truly progressi on occur ring at that site (if so , the date of PD will be the date of the initial abnormal FDG- PET scan). If the positive FDG -PET at follow -up corresponds to a pre -existing site of disease on CT that is not progressing on the basi s of the anatomic image s, this is not PD. c. FDG- PET may be us ed to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG -PET in this circumsta nce should be prospect ively desc ribed in the protocol and supported by disease -specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG -PET and biopsy resolution/sensitivity. Note: A ‘pos itive’ FDG -PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image. Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non- target) must have reduction in short axis to <10 mm. Partial Response (PR): At l east a 30% decrease in the sum of the diameters of target lesions, taking as referenc e the baseline sum of diameters. Progre ssive Disease (PD) : At lea st a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition t o the relative increase of 20%, t he sum must also demonstrate an absolute i ncrease of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Abbreviated T itle: STAT Trial Version Date : 08/17/2022 94 Stable Disease (SD) : Neith er sufficient shrinkage to qualify for PR nor sufficient incre ase to qualify for PD, taking as reference the smallest sum of diameters while on study. Evaluation of Non- Targe t Lesions Complete Response (CR): Disappearance of all non -targe t lesions and normalization of tumor marker level. All lymph nod es must be non-pa thological in size (<1 0 mm short a xis). Note: If tumor markers are initially above the upper normal limit, they mus t normaliz e for a participant to be considered in complete clinical response. Non-CR/Non -PD: Per sistence of one or more non -target lesion(s) and/or maintenance of tumo r mark er level above the normal limits. Progressive Disease (PD) : Appear ance of one or more new lesions and/or unequivocal progression of existing non- target lesions. Unequivocal progression should not normally trump targe t lesion status. It must be repres entative of overall disea se status change, not a single lesion increase. Although a clear progression of “non- tar get” lesions only is exceptional, the opinion of the treating physician should prevail in such circumsta nces, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator). Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progr ession/recurrence (taking as reference f or progressive dise ase the smallest measurements recorded since the treatmen t started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Table 12. Response Crit eria for Participant s with Measurable Disease (i.e., Target Disease) Target Lesions Non-Target Lesions New Lesions Overall Response Best Overall Response when Confirmation is Required* CR CR No CR > 4 to 8 wks. Confir mation** CR Non- CR/Non -PD No PR >4 to 8 wks. Confirmation** CR Not evaluated No PR PR Non- CR/No n- PD/not evaluated No PR SD Non- CR/Non - PD/not evaluated No SD Documented at least once > 4 wks. from baseline** PD Any Yes or No PD no prior SD, PR or CR Any PD*** Yes or No PD Abbreviated T itle: STAT Trial Version Date : 08/17/2022 95 Any Any Yes PD * See RECIST 1.1 manuscript for further details on what i s evidence of a new lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivoc al progression in non- target lesions may be accepted as dis ease progression. Note : Participant s with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported a s “symptomatic deterioration.” Every effort s hould be made to document the objective progression even after discontinuation of treatment. For Participant s with Non -Measurable Disease (i.e., Non -Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non -PD No Non-CR/non-PD* Not all e valuated No not evaluated Unequivocal PD Yes or No PD Any Yes PD * ‘Non -CR/non -PD’ is preferred over ‘stable disease’ for non -target disease since SD is increasingly used as a n endpoint for assessment of efficacy i n some trials so to assign th is categor y when no lesions can be measured is n ot advised 6.3.3 iRECIST As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST.[ 98] Using iRECIST criteria the following will be incorporat ed into the assessment: • An increase in the sum of target les ions of more than 20%, unequivocal increase in the non-target lesions or new lesions result in iUPD (unconfirmed progression disease); iUPD can be assigned multiple ties as long as iCPD (confirmed progress ive disease) is not confirmed at the next assessment. • Progression is confirmed in the target lesion category if the next imaging assessment afte r iUPD (4 -8 weeks later) confirms a furthe r increase in sum of measures of target disease from iUPD, with an i ncrease of at least 5mm. Progression is confirme d in the non-target lesion category if subsequent imaging, done every 4 -8 weeks after iUPD shows a further unequivocal increase in non- targe t lesions. Progression is confirmed in the new lesions category if a t next assessment additional new lesions appear or an increase in the size of previously seen new lesions is seen ( >5 mm for sum of new target lesion). However , the criteria for iCPD (aft er iUP D) are not considered to have been met if complete response, par tial response or stable disease criteria (comp ared with baseline and as defined by RECIST 1.1) are met at the next assessment after iUPD. The status is reset (unlike RECIST 1.1, in which a ny progression precludes later complete response, partial response, or stable disease). iCR, iPR, or iSD should then be assigned; and if no change is detected, then the timepoint response is iUPD. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 96 6.3.4 Duration of Response Duration of overall response : The dura t ion of overall response is measured f rom the time measur ement cri teria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Duration of stabl e disease: Stable disease is m easured from the start of the treatmen t until the criteri a for pro gression ar e met. 6.3.5 Progression- Free Survival (PF S) PFS is defined as the duration of time from start of treatment to time of progression or death, whichev er occurs first 7 NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING PLAN 7.1 DEFINITIONS Please refer to definitions provided in Policy 801: Reporting Research Events found at: https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance- 800Series-ComplianceandResearchEventReportingRequirements . 7.2 OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 7.2.1 Expedited Repor ting Please refer t o the re porting requ irements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found at: https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance- 800Series -ComplianceandResearchEventReportingRequirements . Note: Only IND Safety Reports t hat meet the definit ion of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requireme nts for PI Reporting at Continuing Review Please refer t o the re porting requirements in Policy 801: Reporting Research Events found at: https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance- 800Series-Complia nceandResearchEventReportingRequirements. 7.3 NCI CLINICAL DIRECTOR REPORTING Problems exped itiously reported to the OHSRP in the NIH eIRB system will also be reported to the NCI Clinical Director/designee ; therefore, a separate submission for these reports is not necessary . In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death t 7.4 INSTITUTIONAL BIOSAFE TY COMM ITTEE (IBC) REPORTING CRITERIA 7.4.1 Serious Adverse Event Reports to IBC The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or life - threatening experience associated with the use of CV301 vaccines as soon as possible but in no Abbreviated T itle: STAT Trial Version Date : 08/17/2022 97 even t later than 7 calend ar days of initial receip t of the information. Serious adverse events that are unexpected and associated with the use of the CV301 vaccines, but are not fatal or life - threatening, must be re ported to the NIH IBC as soon as possible, but not later than 15 c alendar days after the in vestigator’s initial re ceipt of the information. Adverse events may be reported by using the FDA Form 3500a. 7.4.2 Annual Reports to IBC Within 60 days after the one -year anni versary of the date on which the I BC appr oved the ini tial protoc ol, and a fter each subs equent anniversary unti l the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to the IBC in lieu of a separate re port. Please include the IBC pro tocol number on the report. 7.4.3 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary i s required to include the following information: • the title a nd purpos e of the trial • clinica l site • the Princ ipal Investigator • clinical protocol identifiers; • participant population (such as disease indication and general age group, e.g., adult or pediatric); • the total number of particip ants pl anned for inclusion i n the tri al; the number e ntered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons • the status of the trial, e.g., open to a ccrual of subjects, closed but data col lection ongoing, or fully completed, • if the trial has been completed, a brief description of any study results. 7.4.4 Progres s Report and Data Analysis Information obtained during th e pre vious year's clinical and non- clinical i nvestigations, includ ing: • a narrative or tabu lar sum mary showing the most frequent and most serious adverse experiences by body system • a summary of all serious adverse events submitted during the past year • a summary of serious adverse events that w ere exp ected or considered t o have caus es not associa ted with the use of the gene transfer product such as disease progression or concurrent medications • if any deaths have occurred, the number of participants who died during participation in the investigation and causes of d eath Abbreviated T itle: STAT Trial Version Date : 08/17/2022 98 a brief descr iption of any in formati on obtained that is pertinent to an understanding of the gene transfer product’s actions, including, for example, information about dose -response, informati on from controlled trials, and information about bioavailability . 7.5 NIH REQUIRED DATA AND SAFETY MONIT ORING PLAN 7.5.1 Princ ipal Investigator/Research Team The clinical research team will meet on a weekly basis when participant s are bein g actively treated on the trial to discuss each participant . Decisions about dose level enroll ment and dose escal ation will be m ade based on the toxicity data from prior participants. Evaluation of DLTs (eDLTs; Schema 1 and 2) will occur after all particip ants are enrolled on a given dose level. All data will b e collected in a timely manner and re viewed by the princi pal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as descri bed in section 7.2.1 will be submitted with in the appropria te timelines. The pr incipal investigator will review adverse event and response data on each participant to ensure safety and data accuracy. The princip al investigator will personally conduct or supervise the investigation and provi de appropriate delegation of respons ibilitie s to othe r members of the research staf f. 7.5.2 Data Safety Monitoring Board (DSMB) The DSMB is a n independent group of at least 3 experts that monitors participant safety and advises The Sponsor . DSMB members will be separate and independent of study staff participating in this trial and should not have scientific, financial, or other conflicts of interest related to this trial. The DSMB will consist of members with appropriate expertise to contribute to the interpretation of data from this trial. A quorum will co nsist o f a simple majority. The DSMB will review cumulative safety data from this tr ial at least annually. The DSMB will meet when trial halting criteria (see Section 3.2) are met, or as requested by the sponsor or PI. The DSMB will ha ve a final review meeting at the end of the study. Procedures for DSMB reviews/meetings will be defined in the DSMB charter . The DSMB will review applicable data, including, but not limited to, enrollment, demographics, dosing data, clinical laborat ory dat a, and safety data, at scheduled timepoints during this trial as defined in the DSMB charter. The DSMB will review blinded aggre gate data in the open session of the DSMB meetings. Additional data may be requested by the DSMB, and interim statistical report s may be generat ed as deemed necessary and appropriate by the Sponsor . As an outcome of each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with study product administration, and to continue, modify, or term inate t his trial . 8 SPO NSOR PROTOCOL/SAFETY REPORTING 8.1 DEFINITIONS 8.1.1 Adverse Event Any untoward medical occurrence in a participant or clinica l investigation subject admi nistered a pharmaceutical product and which does not necessarily have a causal relationship wit h this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign Abbreviated T itle: STAT Trial Version Date : 08/17/2022 99 (including an abnormal labora tory findi ng), symptom, or disease temp orally a ssociated with the use of a medicinal (investigational) p roduct, whether or not related to the medicina l (investigational) product (ICH E6 (R2)) 8.1.2 Serious Adverse E vent (SAE) An adverse event or suspected adverse reaction is co nsidered se rious if in the view of the investigator or the sponsor, it results in any of the following: • Death, • A life -threatening adve rse event (see section 8.1.3 ) • Inpatient hospitalization or prolonga tion of existing hospit alization : o A hospitalization/admission that is pre -planned (i.e., elective or scheduled surgery arranged pr ior to the start of the study), a planned hospitalization for pre -existing condition, or a procedure required by the protocol, without a serious dete rioration in health, is not considered a serious adverse event. o A hospitaliza tion/admission that is solely driven by non- medical reasons (e.g., hospitalization for participant convenience) is not considered a serious adverse event . o Emergency room visits or stays in obser vation units that do not result in admission to the hospital would not be considered a serious adverse even t. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria • Persistent or significant in capacity or subs tantial disruption of the ability to conduct normal life func tions • A congenital anom aly/birth defect . • Impor tant medical events that may not result in death, be life-threatening, or require hospitalization may be conside red a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or s ubject and may r equire medical or surgical intervention to prevent one of the outcomes listed in this definition. 8.1.3 Life-threatening An adverse event or suspected adverse reaction is considered "life -threa tening" if, in the view of either the investigator o r spons or, its o ccurren ce places the patient or subject at immediate risk o f death. It does not include an adverse event or suspec ted a dverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32) 8.1.4 Severity The severity of eac h Adverse E vent will be assessed utilizing the CTCAE version 5.0. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the ter ms: related or not related. • Related – Th ere is a reasonable possibility that the st udy product caused the adverse event. Reasonable possibility means t hat there is evidence to suggest a causal relationship between the study product and the adverse event. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 100 • Not Related – The re is not a reasonable possibility th at the administration of the s tudy produc t cau sed the event. 8.1.6 Adverse Events of Special Interest (A ESI) An adverse event of special interest (AESI) is one of scient ific and medical interest specif ic to understanding of the Investigational Product(s) and may require close monitoring and rapid communicat ion by the investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs as sessed as severe a llows ongoing surveil lance of these events to characterize and understand them in association with the use of th ese inves tigatio nal products. Only AESIs that match the definition of SAE will be reported within 7 days from the knowledge of ev ent. Other non- SAE AESIs do not need to be reported to OSRO but only collected in the clinical d atabase. The adverse ev ents re lated to mu cosal bleeding, regardless of site , will be collected as an AESI to enable evaluation of pote ntial risk factors, such as si te/past radiation/associated in fection at site/recent instrumentation and other variables su ch as time to onset, ex posure history, gr ade o f bleeding, anatomical sites, etc. can be collected. 8.2 ASSESSMENT OF SAFETY EVENTS AE inf ormation collected wil l includ e event descrip tion, date of onset, assessment of severity and relationship to study product and alternate etiology (if no t related to study product), date of resolution of the event, seriou sness and outcome. The assessment of severity and relat ionsh ip to the study product will be done only by those with the training a nd authority to make a diagnosis and listed on the Form FD A 1572 as the si te principal investigator or sub -investigator. AEs occurring during the collection and reporting period wil l be docume nted appropriat ely regardless of relationship. AEs will be follo wed through resolution. SAEs will be: • Assessed for severit y and rel ationship to study product and alternate etiology (if not related to study product) by a licens ed study physician lis ted on the Form FDA 1572 as the site pr incipal investigator or sub -inves tigator. • Recorded on the appropriate SAE report form, the medical record and captured in the clinical database. • Followed through resolution by a licensed study physician listed on t he Form FDA 1572 as the si te principal inv estigator or sub -investigator. For timeframe of recording adv erse events, please ref er to s ection 6.1. All serious adverse events recorded from the time of first investig ational pro duct administra tion must be reported to the Sponsor with the exception of any listed in sect ion 8.4. 8.3 REPORTING OF SERIOUS ADVERSE EVENTS Any AE th at meets a protocol -defined serious criteria or meets the de finition of Adverse E vent of Special Interest that require expedited r eporting must be submitted i mmediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requ irements are found in se ction 8.4 All SAE reportin g must include the elements described i n 8.2. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 102 Pregnancy of the participant ’s partner is not considered to be an AE. However, the outcome of all pregnancies occurrin g from the date of the first dose until 6 mont hs after the last d ose should, if possibl e, be followed up and documented. Pregnant pa rtners may be offered t he opportunity to participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry study) to provide data about the outcome of the pregnancy for safety reporting purposes. 8.7 REGULATORY REPORTIN G FOR STUDIES CONDUCTED UNDER CCR-S PONSORED IND Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious a nd unexpected. CCR wil l report an AE as a suspected advers e reaction only i f there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e ., all investigator s to whom the sponsor is providing drug under its INDs or under any investi gator’s IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious even ts will be reported to the FDA at least annually in a summ ary format. 8.8 SPONSOR PROTOCOL DEVIATION REPORTING A Protocol Deviation is defined as any non- compliance with the clinical trial Protocol, Manual of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or protocol- specific pr ocedural requirem ents on the part of the participant, the Investigator, or the study site staff inclusive of site personnel performing procedures or providing services in support of the clinical trial. It is the responsibility of the study Sta ff to documen t any protocol deviation identified by the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online applic ation. The entries into the PDTS online application should be timely, complete, and maintained per CCR PDTS user requirements. In additi on, any deviati on to the protocol should be documented in the participant’s source records and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: Integ rated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5. 18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations. 9 CLINICAL MONITORING Clinical site monitoring is conducted to ensure : • that the rights of the participants are protected ; • that the study is implemented per the approved protocol, Good Clinical Pra ctice and standard operating procedures; and • the quality and integrity of study data and data collection methods are maintained. Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regul atory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contrac tor. Clinical site monitoring activities will be based on OSRO standa rds, FDA Guidance E6(R2) Good Clinical Practice: Integrated Adden dum to ICH E6(R1) Marc h 2018, and a pplicable regulatory r equirement s. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 103 Details of clinical site monitoring will be documen ted in a Clinical Monitoring Plan (CMP) developed by OSR O. CMPs will b e protocol -specific, risk -based and tailored to address human subject protections a nd integrity of the study data. OSRO will determine the int ensity and frequency of monitoring based on several factors, including study type, phase, risk, complexity, expe cted enrollmen t rate, and any unique attributes of the study and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change to the protocol, significant or pervasive non- compliance with GCP, or the protocol may trigger CMP updates. OSRO SROS Monitoring visits and related activities will be cond ucted throughout the life cycle of each protocol . The first activity is before the study start s to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close- Out Vi sit (COV). Some monitoring activities may be performed remotely, while others will occur at the study site(s). Monitoring visit reports will describe visit activities, observations, and associated action items or follow -up required for resolution of any is sues, discrepancies, or deviatio ns. Monitoring reports will be d istributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating center (if applicable), and the Sponsor regulatory file. The site Monitor will inform the stu dy team of any deviations observed during monitoring visits. If unresolved, the M onitor will request that the site Staff enter the deviations in the CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per institutional and IRB guidance. . 10 STATISTICAL CONSIDERATIONS 10.1 S TATISTICAL HYPOT HESIS Primary Objectiv es: • Arm 1 (Sequ e ntial Dose Escalatio n):  To evaluate the safety and tolerability of single agent SX-682.  To determine the MTD of SX -682 followed by M7824 a nd CV301 in partic ipant s with advanced or metastat ic solid tumors. If the MTD is not reached t he study will b e focused to describe the sa fety and tolerability of SX -682 followed by M7824 and CV301 . • Arm 2 (Combi nat ion Dose Escalation):  To determine th e RP2D of SX -682 with M 7824 and CV301 in participan ts with advanced or metastatic so lid tumo rs. If the MTD is not reached the st udy will be focused to describe the safety and tolerability of the drug combination. • Arm 3 (Expansion):  To evaluate pre liminary effica cy based on Objec tive Response Rate (ORR), in each disease cohort separately. Secondar y Objectives: Abbreviated T itle: STAT Trial Version Date : 08/17/2022 104 • Arms 1 and 2 (Dose Esc alati ons):  To characterize the PK/PD profile of SX -682 as a single agent and in combinatio n. • All Arms:  To evaluate pr eliminary effic acy: Disease cont rol rate (DCR) and Progression - free survival (PFS) using RECIST1.1 10.2 SAMPLE SIZE DETER MINATION The trial wi ll begin with two phase I evaluations (Cohort 1, Arms 1 and 2; Dose Escalation) as follows: initially participan ts will be enrolled in Arm 1 involving monother apy with SX -682 followed by M7824 + CV301. This will i nitially includ e up to 3 dose levels, with 3 participant s per dose level if no DLTs are experienced. However, if in any of the dose levels, a DLT is identified in the 3 particip ants, 3 more part icipant s will be enr olled in tha t dose le vel, with subsequent escalation only if there are <=1 DLTs in 6 participant s. Thus, up to 18 participant s may be enrolled in these first 3 do se levels. If there is one or more DLTs identified in in the first 3 dose levels, escalation will con tinue to DL4 an d 5 using the above 3+3 design. If there are no DLTs in the fir st 3 dose leve ls, then participant s will be enrolled to Arm 2 . As a resu lt, depending on toxicities identified, between 9 and 30 participant s may be tr eated within this sequential dose escalation arm . In Arm 2, a combination arm with SX -682 followed by the triplet comb ination (SX -682, M7824, CV301 ), up to 5 dose leve ls may be explored. Using a standard 3+3 design, up to 5x6=30 participa nts may be included in this arm. Thus, up to 30+30=60 tot al participants may be treated in the phase I portion (Cohort 1, Arms 1 and 2) of the trial. The phase II evaluati on (Arm 3) will take place separately in two cohorts: TNBC: Based on prior studies [70-72] , the clinical response r ate fo r simila r participant s with advanced disease receivi ng a single agent checkpoint inhibitor is expected to be 8 -10%. Thus, an obs erved response ra te of a pproximately 15% or higher would be desir able. In Arm 3, Cohort 2 (TNBC), the trial will be conduc te d using a Si mon minimax two -stage phase II trial design [ 99] t o rule out a n unac ceptably low response ra te (CR+PR) of 5% (p0=0.05) i n favor of an improved response rate of 20% ( p1=0.20). With al fa=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probabil ity of rejecting a good treatment=0.20), t he first stage will enroll 12 eva luable participant s, an d if 0 of the 12 has a response, then no further participant s will be accrued in that cohort. If 1 or more of the first 12 participants h as a response, then accrual would continue until a total of 21 evaluable pa rticipants have been treated in that cohort. As it may tak e up to several months to determine if a participant has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the secon d stage is warranted. If there are 1 -2 participant s with a response out of 21 participa nts in this cohort, this would be an uninterestingly low response rate. If there were 3 or more of 21 (14.3%) who experi enced a response, this would be sufficiently inte resting to warrant further study in later trials. Under the null hypothes is (5 % respons e rate), the probability of early termination is 54.0%. HPV negative HNSCC: Abbreviated T itle: STAT Trial Version Date : 08/17/2022 105 Based on prior stud ies [82, 87, 88], the clinical response rate for si milar participant s with this disease is expected t o be 13- 18%. Thus, an observed r esponse rate of greater than 25% would be desirable. In Arm 3, Cohort 3 ( HP V negative H NSCC) , the trial will be conducted using a Simon minimax two-stage phase II trial design [99] to rule out an unacceptably low response rate (CR+PR) of 15% (p0=0.15) in favor of an improved response ra te of 40% (p1=0.40). With alfa=0.10(proba bility of accepting a poor treatment=0.10) and beta = 0.20 (probability of rejecting a good treatmen t=0.20), the first sta ge will enroll 9 evaluable participant s, and if 0 to 1 of the 9 have a response, then no furthe r participants will be accrued in that cohort. If 2 or m ore of the first 9 participants have a response, then accrual would c ontinu e until a total of 1 6 evaluable participant s have been treated in that cohort. As it may take up to seve ral months to determine if a pa rticipant has experienced a response, a tempor ary pause in the accrual may be necessary to ensure that enrollment t o the second stage is warranted. I f there are 2 -4 participants with a response ou t of 16 participants in this cohort, this would be an uninterestingly low response rate. If there were 5 o r more of 16 (31.3%) who experie nced a response , this would be sufficiently interesting to warrant furthe r stud y in lat er trials. Under the nul l hypothesis (15% response rate), the probability of early termination is 60.0%. It is expected that up to 1.5 ye ars may be required to enroll up to 60 participant s in Arms 1 and 2. It is then e xpected that 2- 3 years may be required to complete accr ual to Arm 3 . Thus, accrual is expected to be completed in 4- 5 years. The total number of evaluable participant s is no m ore than 60+21+16=97. To al low for a small number of inevalua ble participant s, the accrual ceiling for treated participants in the dose escalation and expansion cohorts combined will be set at 105 participant s 10.3 POPULATIONS FOR ANALYSES Intention to treat: a ny subj ects who enroll onto the trial and provide consent and who receive at least 1 dose of SX-682, will be included in sa fety analyses in Arms 1 and 2. In Arm 3, any participant s who receive at least one cycle (defined as 28 days) of SX -682, M7824, and CV301 will be included in safety evaluations as well as effic acy evaluations for the appropriate cohort. 10.3.1 Evaluable f or toxicity All participants will be evaluable for toxicity from the time of their first treatment with SX-682. Part icipan t will be eligibl e for the DLT evaluation if at least ≥85 percent of SX -682 sc heduled doses were taken and 100% of schedul ed doses of M7 824 or CV301 were admini stered within the DLT period. 10.3.2 Evaluable for objective response Only those parti cipant s who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re -evaluated will be co nsidered evaluable for response. These participant s will have their response classified according to the defi nitions in section 6.3). (Note: Participants who receive at least treatment cycle and exhibit objective disease progression prior to the first restaging will also be considered evaluable.) Abbreviated T itle: STAT Trial Version Date : 08/17/2022 106 10.3.3 Evaluable Non- Target Disease Respo nse Participant s who have lesions present at base line that are evalu able but do not meet the definitions of measurable dis ease, have received at least one cycle of therapy, and have had their disease re -evaluated will be considered evaluable for non- target disease. The response assessment is based on the presence, absence, or unequi vocal progression of the lesions. 10.4 STATISTICAL ANALYSES 10.4.1 General Approach Following a determination of saf ety, tolerability, and the MTD in Arms 1 and 2, the f raction of participant s who experienc e a response in each disease-spe cific cohort of Arm 3 w ill be reported along with confidence intervals. 10.4.2 Analysis of the Primary Endpoints The toxicity grades per participant will be tabulated and repo rted by dose level during dose escalation (Arms 1 and 2) . This will also include separate evaluations for the initi al monotherapy evaluations preceding the evalu ation of the combination at each dose level. In Arm 3, the fraction of participant s who expe rience a resp onse in each disease -specific cohort will be reported along with 95% two-side d confidence intervals. 10.4.3 Analy sis of the Secondary Endpoint(s) 10.4.4 PK evaluati ons will be performed on participant s in both dose escalation Arms (bo th for single ag ent SX -682 and the combination of agents); results will be report ed using standard descriptive statistics. In Arm 3, separatel y by cohort, the disease control rate (DCR; CR+PR+SD) will be reported as the fraction of participant s who experience this outcome, along with a 95% two -sided confidence interval for eac h fractio n. Progression free survival (PFS) will be calculated using the Kaplan -Meier method, including progressions or death without progression as events. Participants who come off study for reasons other than progression and choose not to participate in optional imaging will be censored in dat a analysis at the time when t hey become unfollowable for P FS. 10.4.5 Safety Analyses The fra ction of part icipan ts who experience a toxicity, by grade and type of toxicity, will be tabulated per dose level (both single agent and c ombination of agents) during the Arms 1 and 2 portion of the trial. Participants who take one dose or mor e of SX -682 w ill be evalua ble for safety. 10.4.6 Baseline Descriptive S tatistics Baseline demographic characteristics will be reported. 10.4.7 Planned Inte rim Analy ses As indicated in the two-stage d esigns, the number of responses after 9 or 12 evaluable participant s have be en treat ed in the appropriate cohort will be noted and will be used to determine if enrollment to the second stage of accrual may proceed for tha t cohort. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 107 10.4.8 Sub-Group Analyses In Arm 3, analyses will be perfo rmed separately by histology. 10.4.9 Tabulation of indivi dual Par ticipant Data None 10.4.10 Exploratory Analyses All Arms:  To evaluate response via iRECIST  To evaluate the effect on immune cell subsets and soluble factors in peripheral blood.  To evaluate the effect on serum cytokine levels (IL -8, IL -6 and others) i n per ipheral blood.  To evaluate t he effect on T cell clon ality in perip heral blood and tumor samples .  To evaluate the effect on antigen- speci fic T cells responses to CEA, MUC1 and th e cascade antigen brachyury in peripheral blood.  To evaluate the effect o n antigen- specific T cell responses to CEA, MUC1 and the cascade antigen brachyury in the tumor biopsies .  To evaluate the presence of lymphoc ytic infiltrates and oth er tumor markers as well as to evaluate RNA in situ hybridization for IL -8, TGF -β and othe r soluble fact ors in tumor biopsie s.  To evaluate M7824 PK profile in thi s drug combination  To evaluate ADA in this drug combination  To evalua te long t erm (2 years after completion of treatment) clinical outcomes  To evaluate CTCs In Arms 1 and 2 (Dose -Es calations), the following are the parameters will be evalua ted, separately per dose level:  To evaluate ORR per RECISTv1.1 In Arm 3 ( Expansions) the f ollowing are the p arameters will be evaluated, separately per co hort.  To evaluate changes in circulating fr ee DNA. Any e xplora tory evaluatio ns which generate quanti tative measures will be done using descriptive statistics including confidence inter vals when appropriate. A ny statistical tests performed for evaluation of exploratory objectives will be done without formal adju stmen t for multiple comparisons, but in the context of the number of tests performed. 11 COLLABORATIVE AGREEMENTS 11.1 COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT (CRADA) A CRADA (03153) is in place with Syntrix for the supply of SX -682. A CRADA (02666) is in place with EMD Sero no for the supply of M7824. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 108 A CRADA ( 02561) is in place with Bavarian Nordic for the supply of CV301 . 12 HUMAN SUBJECTS PROTECTIONS 12.1 RATIONALE FOR SUBJECT SELECTION No individual who meets the criteria for eligibility will be exclu ded from parti cipation based on their race, ethnicit y, gender, or socioeconomic status. Particular attention will be made to acquire a broad and diversified population. 12.2 PARTICIP ATION OF CHILDREN Children (y ounger than 18 years) will not be included i n this protoco l due to the limited data on study drugs in children and the different biology of childhood malignancy. 12.3 PARTICIPATION OF SUBJECT S UNABLE TO GIVE CONSENT Adults unable to give consent are excluded fr om enrolling in the protocol. However, re-consent may be necessa ry and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and beca use there is a prospect of direct benefit from research participation (Section 12.4.2), a ll subjects w ill be offered the opport unity to fill in the ir wishes for research and care, and assign a substitute decisio n maker on the “NIH Adva nce Directive for Health Care and Medical Research Participation” form so that another pers on ca n make d ecisions about thei r medical care in the event that they b ecome incapacitated or cognitively impaired during the course of the study. Not e: The PI or AI will contact the NIH Ability to Consent Asses sment Team (ACAT) for evaluation to assess o ngoing capacit y of the subjects and to identify an LAR as needed . . Please see section 12.5.1 for consent procedure. 12.4 RISK/BENE FIT ASSESSMENT FOR ALL PARTICIPANTS 12.4.1 Known Potential Risks 12.4.1.1 Study Drug Risks Ris ks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or sections 1.2.2.2, 1.2.3.1, 1.2.4.1 of this protocol d ocument. Frequent monitoring for adverse effects will help to minimize the risks associat ed with admin istration of the study agents . 12.4.1.2 Risk of Bi opsy All car e wil l be taken t o minimize risks that may be incurred by tumor samplin g. However, there are procedur e-related risks (such as bleeding, infection and visceral injury) that will be e xplained fully during informed consent. 12.4.1.3 Risks of local anesthes ia and/or light sedation. Biopsies will be done under local anesthesi a an d/or light sedation. Potential side effe cts of sedation include headache, nausea and drowsiness. T hese side effects usually go aw ay quickly. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 109 12.4.1.4 Risks of c ontrast dye used in CT scans There is a chance o f developing a n allergic reaction from the contrast mate rial, whic h ma y cause symptoms ranging f rom mild itching or a rash to severe difficulty breathing, shock or rarely, death. The contrast mater ial may a lso cause kidney problems. For I V contrast: Poten tial side ef fects in clude discomfort when the contra st material is injected , feeling warm, flush ed, a metallic t aste, or rarely vomiting or nausea. For o ral contrast: Potential side effects includ e vomitin g, nausea, cramping, bloating, constipation or di arrhea after drinking the contrast. 12.4.1.5 Risks of exposure t o Ionizing Rad iation This research stud y involves up to nine (9) CT scans (C/A/P) and up to three (3) CT gu ided biopsies (optional) collected for rese arch purposes only. Subjects undergoing thes e scans and optional biopsies collec tion will be exposed up to 12.3 re m. The CT scans that particip ant will get in this study will expose them to the roughly the same amount of radiation as 41 years of background radiation. The risk of gettin g cancer fr om the radiation e xpos ure in th is stud y is 1.2 out of 100 (1.2 %) and of getting a fatal cancer is 0. 6 out of 100 (0.6 %) 12.4.1.6 Risks of MRI People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. It may be unsafe to h ave an MRI scan for participants with pacemakers or other implanted electri cal devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metal prostheses (including metal pins and rods, heart val ves, and cochlear implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. Welders and metal workers may have small metal fragments in the eye. People with fear of conf ined spaces may become anxious during an MRI. Those w ith back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. There are no known long- term risks of MRI scans. 12.4.1.7 Risks of Gadolinium The risks of an IV catheter include bleeding, infe ction, or infl amma tion of the skin and vein with pain and swelling. Mild symptoms from gadolinium infusion occ ur in fewer than 1% of those who r eceive it and usually go away quickly. M ild symptoms may include cold ness in the arm during the injection, a meta llic taste , headache, and nausea. In an extremely small number, fewer than one in 300,000 people, more seve re symptoms have been reported inc luding shortness of breath, wheezing, hives, and lowe ring of blood pressure. People with kidney disease are a t risk for a serious reaction to gadolinium contrast called “nephrogenic systemic fibrosis (NSF)”. This condition always involves the skin and can also involve the mus cles, joints and in ternal organs. N SF has resul ted in a very small number of deaths. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 110 Most of the ga dolinium contrast leaves the b ody in the urine. However, the FDA has issued a safety alert that indicates small amounts of gadolini um may remain in the body for months to years. The long-t erm effects of the retained gadolinium are not known. Some types of gadolinium contrast drugs are less likely to remain in the body than others. The gadolinium contrast drugs that are less likely to remain in the body will be used on this study. 12.4.1.8 Research Blood Collection Risks Risks of blood draws include pain and brui sing in the area where the needle is placed, lightheadedness, and rarely, fainti ng and inf ection . When large amounts of blood are collected, low red blood cell count (anemia ) can develop. 12.4.1.9 Risk of Rapid Progression Three large studies of bintrafu sp alfa were r ecently stopped when the drug manuf acturer reviewed data that suggested that the studies would not be likely to prove the study treatment better than standard treatments . This data also suggested th at there may be a portion of patients that h ave either no benefit from bintrafusp alfa, or that bintrafusp alfa will make the tumor grow faster. This has been described with other immuno therapy approaches also with studies sugg esting this happens in about 15% of cases. 12.4.1.10 Other R isks Risks include the possible occu rrence of any of a range of side effects which are listed in the Cons ent Document or this protocol document. Frequent mo nitoring for adve rse effects will help to minimiz e the risks associated with administrati on of the study agents. 12.4.2 Known Pot ential Benefit s The study drugs may help to control the disease. The result s may help the investigators learn more about the dis ease a nd devel op new tr eatments for parti cipant s with this disease. 12.4.3 Assessment of Po tential R isks and Benef its Solid tumors trea tment needs im proved therapy options. Current studies suggest that study therapy may have tremendous anti-tumor efficacy. A number of clinica lly appropriate strategies to minimize risks to participant s have been built into the protocol through the means of inclusio n/exclusion cr iteria, monitoring strategies, and management guidelines. Overall, the potential benefit of the st udy therapy i n subje cts with solid tumors outweigh the risks associated with this drug. The potential bene fit to a participant that pa rticipates in thi s study is better control of their tumor growth and disease recurrence which may or may not have a favorable impa ct on sym ptoms and/or survival. Potential adverse reactions attributable to the ad ministra tion of the study drug utilized in this trial are dis cussed in Sections 1.2.2.2, 1.2.3.1, 1.2.4.1. All car e wil l be taken to minim ize side effects, but they can be unpredictable in nature and severity Abbreviated T itle: STAT Trial Version Date : 08/17/2022 111 12.5 CONSENT PROCESS AND DOCUMENTATION The informed consent document will be pr ovided as a physical or e lectronic document to the participan t or consent designee (s) for review prior to consenting. A des ignat ed study invest igator will carefully explain the pro cedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minim ize potential co ercion, a s much time as is needed to review t he document will be given, inclu ding an oppo rtunity to dis cuss it with friends, family members and /or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to ent ry onto the study. The initial consent process as well as r e-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms used in compliance with policy including HRPP policy 303) pe r discretion of the designate d study inve stigator and wit h the ag reemen t of the participant/conse nt designee(s). W hether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and part icipa nt/consent designee, when in person) will be located in a private ar ea (e.g., clinic consult room). When c onsent i s conducte d remotely, the pa rticipant/consen t designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. Consent will be documented with required signatures on the p hysical document (which includes the pr intout of an electronic document sent to participant) or as described below, with a manual (non- electronic) s ignature on the electronic document. When required , witness signature will be obtained similarly as descr ibed for the investigator and participant. Manual (n on-electro nic) signature on electronic document: When a manual signature on an electroni c documen t is used for the documentation of consent at the NIH Clinical Center, this study will use the following to obtain the required signatures: • Adobe platform (which is not 21 CFR Part 11 compliant); or, • iMedConsent platform (which is 21 CFR Part 11 compliant) During the consent process, participants and investigators w ill view individual copies of the approved consent docum ent on screens at their respective locations (if r emote consent); the same scr een may be used when in the same location but is not required. Both the investigator and the participant will sign the document using a finger, stylus or mouse. Note: Refer to the CCR SOP PM -2, Obtaining and Documenting the I nformed Consent Process for additional information (e.g., verification of part icipant identity when obtaining consent remotely) found at: https://ccrod.cancer.gov /confluence/pages/viewpage.actio n?pageId=73203825. 12.5.1 Consent Process for Adults Who Lack Capaci ty to Consent to Re search Participation For participants addr essed in sectio n 12.3, an LA R will be identified consistent with Policy 403 and inf ormed consent obtained from the LAR, as described in Section 12.5 Abbreviated T itle: STAT Trial Version Date : 08/17/2022 112 13 REGULATORY AND OPERATIONAL CONSI DERATIONS 13.1 STUDY DISCONTI NUATIO N AND CLOSURE This study may be temporarily suspended or prematurely terminated if the re is sufficient reasonable cause. Written notification, docume nting the reason f or study suspension or termination, will be provided by the suspen ding or terminating party to study par ticipants, investigators, and regul atory a uthorities. If the study is p rematurely terminate d or suspended, the Principal Investigator (PI) will promptly inform study participants and the Inst itutional R eview Board (IRB ) and wi ll provid e the reason(s) for t he termina tion or suspension. Study participants will be contacted, as applicable, and be i nformed of changes to study visit schedule. Circumstances th at may warrant termination or suspensio n inc lude, but are n ot limited to: • Determina tion of unexpected, significant, o r unacceptable risk to parti cipants • Demon stration of effic acy that would warra nt stopping • Insufficient compliance to protocol requirements • Data that are not sufficiently complet e and /or ev aluable • Determin ation that the pr imary endpoint has be en met • Determination of futility Study ma y resume once concerns about s afety, protocol compliance, and data quality are addressed, and sati sfy the sponsor, IRB and Food and Drug Adm inistration (FD A). 13.2 QUAL ITY ASSURANCE AND QUALITY CONTROL Clinical site wi ll perform internal quality managemen t of study conduc t, data an d biologi cal specimen collectio n, documentation and comple tion. An individualized quality management plan will be developed to de scrib e a site’ s quality management. Quality control (QC) proced ures will be imp lemented beginning w ith the data entry system an d data QC checks that will be r un on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) fo r clarification/resolution. Following w ritten Stan dard Operating P rocedures (SOPs), the monitors will ve rify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and re porte d in complian ce with the protocol, International Con ference on Harmonis ation Go od Clinical Pract ice (ICH GCP), and appl icable r egulatory requirements (e.g., Good Laboratory Practices (G LP), Good Manufacturing Practices (GMP)). The investigational sit e wil l pro vide dir ect access to all trial related sites, source data/do cuments, and reports for the p urpose of monitoring an d auditi ng by the sponsor, and inspecti on by local and regulatory authorities. 13.3 CONFLICT O F INTEREST POLICY The independence of this study from any act ual or perceived influence, such as by the pharmaceut ical industry, is critical. Therefore, any actual con flict of in terest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disc losed and managed. Furthermore, persons who have a perceived conflic t of int erest wi ll be required to have such conflicts ma naged in a way th at is appropriate to their participation in the d esign and Abbreviated T itle: STAT Trial Version Date : 08/17/2022 113 conduct of this trial. The study leadership in conjunction wi th th e NCI ha s established policies and procedures f or all stud y group me mbers to disclose all confl icts of interest an d will e stablish a mechanism for the ma nagement of all reported dualities of interest. 13.4 CONFIDENTIALITY AND PRIVACY Participant confidenti ality and pri vacy is strictly held in trust by the p articipatin g investigators, their staff, and the sponsor(s). This confident iality is extended to cover tes ting of biological samples and genetic tests in ad dition to the clinical information relating to partic ipants. Therefore, the study protocol, document ation, data , and all other information gener ated w ill be held in st rict con fidence. No information concern ing the study or the data w ill be released to any unauthorized third party without prior writ ten approval of th e sponsor. All research activities wil l be conduc ted in as privat e a setting as possi ble. The study monitor, othe r authori zed representatives of the sponsor, representativ es of the Institutional Revie w Board (IRB), and/or regulatory agencies may i nspect al l documents and records required to be maintained by the investig ator, including but not limited to, me dical records (office, clinic, or hospita l) and pharmacy records for the participants in this stu dy. The clinical study site will permit ac cess to such r ecords. The study participant’s contac t information will be secur ely stored at each c linical site for internal us e during the study. At the end of the study, all records w ill continue to be kept in a secure location for as long a period as di ctate d by the reviewing IRB, Institutional policies, or sponsor re quireme nts. Study participant research data, which is for pur poses of statistical analysis a nd scientific reporting, wi ll be stor ed at NCI CCR. This will not include the p articipant’s contact or identifying information. Rather, indivi dual participants and the ir research data will be iden tified by a unique study identificatio n number. The study da ta entry and study management s ystems used by clinical sites and by NCI CCR research staff w ill be secu red and password protected. At the end of the study, all study databases wi ll be archived at th e NIH. To further p rotect the privac y of study participant s, a Certificate of Confide ntiality has been issued by the National Instit utes of Health (NIH ). This c ertificate protects identifiable resear ch information from force d disclosure. It allows the investigator and others who ha ve access to research records to refuse to disclose identi fying information on research participation in any civil, crimina l, administ rative, legislative, or othe r proceedin g, whether at th e federal , state, or local level. By prote cting researchers and ins titutions from being compelled to disclose information tha t would identify research participants, Certifi cates of Confident iality help achieve the research object ives and pr omote participat ion in st udies by helping assure confi dentiality and privac y to par ticipants . 14 PHARMACEUTICA L INFORMATION 14.1 SX-682 (IND# 21166) 14.1.1 Acqui sition and Accountability Investigational S X-682 is ma nufactu red and s upplied for the trial by Syntrix. Drug wi ll be delivered directly to the N IH Pharmacy. Individual bottles with tablets will be prepar ed for each study participant according to assigned dose by NIH Pharmacy personnel. Parti cipan ts will pick Abbreviated T itle: STAT Trial Version Date : 08/17/2022 114 up bottles at NIH Ph armacy and will ret urn bottles and not -used tablets after compl etion of every cycle together with Medication Diary to St udy Coordinator. After review of leftover tablets and Medi cation Diary, unused tablets will be returned to pharmacy a nd disposed by phar macy personnel 14.1.2 Form ulation, Appearance, Packaging, and La belin g SX-682 is dispensed as either 25 mg or 100 mg tablets fo r oral ad ministration. SX-682 exhibits 99.4% protein binding. The anticipated half -life of the drug varies by dose administered with a 25mg flat dose resulting in a half- life of 2.6 hours and a 200 mg flat dose resulting in a hal f-life is 14 hour s. 14.1.3 Prod uct Stora ge and Stabi lity Store SX -682 between 15 to 30°C. On the basis of avai lable stability data for the AP I and a drug product demonstration batch, SX -682 is projected stabl e for at least 2 y ears when stored as above . 14.1.4 Prepara tion SX-682 is dispensed as 25 mg or 100 mg tablets f or or al administration. If necessary, the 100 mg tablets can be cut in half using a pill splitter; the table ts are pre- scored for this p urpose. The tablets should not be crushed, chewed, or dissolved bef ore being swallowed. 14.1.5 Adm inistration Please see Section 3.3.2 14.2 M7824 (IND#21166) 14.2.1 Acquisition and Accountability M7824 is manufactured and suppl ied for the trial by EMD Serono Research an d Development Institute . Drug will be deliver ed dir ectly to th e NIH Pharmacy. Individual IV bags will be prepar ed for each study participant a ccording to assigned dose by NIH Pharmacy per sonnel. IV bags w ill be delivered fro m NIH Pharmacy to partici pant unit w here dru g will be infu sed to the particip ant. 14.2.2 Formula tion, Appearance, Pack aging, and Labeling M7824 is provided a s a steril e liquid formulation and packaged at a 10 m g/mL concentrati on in USP/ Ph Eur type I 50R vials that a re filled with drug product solution to allo w an extra ctable volume of 60 mL (600 mg/60 mL ). The vials are closed with rubber stoppers in s erum fo rmat compl ying with USP and Ph Eur with an aluminum c rimp seal closur e. Each single -use vial contains 600mg of M782 4, formul ated as 1 0mg/mL of active, 6% (w/ v) Treh alose, 40 m M NaCl, 5 mM Met hionine, 0.05% (w/v) Tween 20, 10 mM LHistidine at pH 5.5. The l iquid formulation is diluted directly with 0.9% sodium chl oride solut ion for injection. The estimated volumes of de livery are anticip ated to be no more th an 250mL. The ver ified concen tration ran ge in the infusion solu tion is 0.16 mg/mL to 9.6 mg/mL . 14.2.3 Product Storage and Stability M7824 drug product must be s tored a t 2°C to 8°C until use. The storage condition is based on data f rom ongoing longterm s tability studies w ith M7824. M7824 drug product stored at room Abbreviated T itle: STAT Trial Version Date : 08/17/2022 115 (23°C to 27°C) or higher temperatures for exten ded periods of time might be subject to degradation. The c hemical and physical in -use stability for the infusion s olution of M7824 in 0.9% saline solution has been dem onstrated for a total of 72 hours at room temperat ure. However, from a microbiolog ical po int of vie w, the diluted solution should be used imme diate ly and is not intended to be stored unless dilution has taken plac e in controlled and va lidated aseptic conditions. If not us ed immed iately, in-use storage tim es and conditions prior to administration are the responsibility of the user. Do not freeze or sh ake the dil uted solution. No other drugs should be added to the in fusion containers containing M 7824. 14.2.4 Preparation Preparation is desc ribed i n pharmacy manual. 14.2.5 Administration Please see Sectio n 3.3.4 14.3 CV 301 (IND# 21166) 14.3.1 Acquis ition and Accountability Investigational CV30 1 vaccin es (MVA -BN-CV301 and FPV -CV301) will be su pplied by the manuf acturer, Bavarian Nordic . Drug will be delivered directly to the N IH Phar macy. Indi vidual syringes with the drugs will be prep ared for each st udy participant by NIH Pharmacy personnel . Syringes will be deli vered from NIH Pharma cy to participant unit where drug wil l be injected to the participant. 14.3.2 Formulation, Appeara nce, Packag ing, and Labeling The manufacturing departme nt of Bavarian Nordic wil l supply MVA -BN-CV301 and F PV-CV301, with each vaccin e provided in 2 mL type I borosilicate gla ss vials close d with sterile b romobutyl rubber stoppers, crimped with aluminum caps and covered with polypropylene closures . 14.3.3 Product St orage and Stab ility Suppl ies of both the MVA -BN-CV3 01 and the FPV -CV301 vaccine s will be shipped temperature controlled and monitored to the clinic al trial site. Once at the site, the package should be handed ove r to personnel in charge of vaccine pre parat ion (e.g., the pharmacist or representative). Site p ersonnel are r esponsible f or proper s torage of vaccine upon receipt. Both the MVA -BN-C V301 and the FPV-CV3 01 vaccines must be shipped to site and st ored at a minimum temperature of - 4°F +/ - 9°F ( -20°C +/ - 5°C) or - 80ºC ± 10ºC, avoiding direct light . A vial must n ot be re -frozen once it has been thawed . A provisional shelf life of 2 years at -80°C ± 10°C has been given. Expiry date may be extended due to r eal time stability data. Storage at - 20°C ± 5°C is limited to 12 months afte r moving from -80°C ± 10°C to -20°C ± 5°C. 14.3.4 Preparation MVA- BN-CV301 and FPV -CV301 enc ode the huma n MUC- 1 and the hum an CEA gene in combination with human TRICOM. No marker gene is present in both r ecom binant viruses. Abbreviated T itle: STAT Trial Version Date : 08/17/2022 116 MVA- BN-CV301 is a liquid -frozen, highl y attenuated, live recombinant virus base d on the viral vector M VA-B N. It is administere d as s.