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6.3 response criteria

For the purposes of this study, participants should be re-evaluated for response according to schedule in the Study Calendar, section 3.5. In the event of a PR or CR tumor imaging assessments may be performed every 3 months (+/- 2 weeks) at the discretion of the investigator. In addition to a baseline scan, confirmatory scans can also be obtained 4 to 8 weeks following initial documentation of objective response per the discretion of the primary investigator. The preferred method of disease assessment is CT with contrast. If CT with contrast is contraindicated, CT of the chest without contrast and MRI scan of the abdomen/pelvis is preferred. Additional assessment of tumor response may include the following evaluations; nuclear bone scan for subjects with known/suspected bone lesions; and CT or MRI scan of the brain (only as clinically warranted based on symptoms/findings). Brain CT / MRI scan should be performed, if clinically indicated by development of new specific symptoms or on the discretion of the Primary Investigator. For each subject, the Investigator will designate 1 or more of the following measures of tumor status to follow for determining response: CT or MRI images of primary and / or metastatic tumor masses, physical examination findings, and the results of other assessments. All available images collected during the trial period will be considered. The most appropriate measures to evaluate the tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to the measures used to document the progressive tumor status that qualifies the subject for enrollment. Progressive disease should be confirmed by imaging 4 to 8 weeks (preferably at 4 weeks, but not more than 8 weeks) after progression has been diagnosed according to RECIST 1.1. before the participant is removed from treatment [93]. If progression is based on the occurrence of a new lesion in an area not scanned at Baseline, a further on-study scan 4 to 8 weeks later should be considered before performing the 28-Day Safety Follow-up visit.  
Tumor responses to treatment will be assigned based on the evaluation of the response of target, non-target, and new lesions according to RECIST 1.1 (all measurements should be recorded in metric notation). To assess objective response, the tumor burden at baseline will be estimated and used for comparison with subsequent measurements. At baseline, tumor lesions will be categorized in target and non-target lesions according to RECIST 1.1. Results for these evaluations will be recorded with as much specificity as possible so that pre and post-treatment results will provide the best opportunity for evaluating tumor response. The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if the Investigator suspects PD. iRECIST will also be used for exploratory endpoints (See section **6.3.3)** For the primary endpoint antitumor activity will be evaluated with target and/or non-target lesions according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. [93]. Palliative radiotherapy delivered in a normal organ-spearing technique may be administered during this trial. The assessment of PD will not be based on the necessity for palliative radiotherapy. If a target lesion is radiated during the course of treatment, this target lesion will no longer be considered a measurable lesion and will be removed from the target lesion sum moving forward as is recommended in RECISTv1.1.
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6.3.1 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
By chest x-ray: >20 mm;  
By CT scan:
o Scan slice thickness 5 mm or under: as >10 mm o Scan slice thickness >5 mm: double the slice thickness With calipers on clinical exam: >10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Tumor lesions that are situated in a previously irradiated area may be considered measurable if there is demonstrated progression in the radiated lesion prior to starting on the trial. Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by CT or MRI), are considered as non-measurable. Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts. 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same participant, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease.  
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are not acceptable as measurable lesions. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a participant to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published. [94-96] In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer.[97] Cytology, Histology: These techniques can be used to differentiate between partial responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDGPET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication. However, it must be acknowledged that both approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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evaluation of target lesions

Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.
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evaluation of non-target lesions

Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a participant to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Progressive Disease (PD): Appearance of one or more new lesions and/or *unequivocal* progression of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).
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evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria. Table 12. Response Criteria for Participants with Measurable Disease (i.e., Target Disease)  
| Target    | Non-Target   | New                   | Overall                     | Best Overall Response when                        |
|-----------|--------------|-----------------------|-----------------------------|---------------------------------------------------|
| Lesions   | Lesions      | Lesions               | Response                    | Confirmation is Required*                         |
| CR        | CR           | No                    | CR                          | > 4 to 8 wks. Confirmation**                      |
| CR        | NonCR/Non-PD              | No                    | PR                          |                                                   |
| CR        | Not          | No                    | PR                          |                                                   |
| evaluated | No           | PR                    | >4 to 8 wks. Confirmation** |                                                   |
| PR        | NonCR/NonPD/not  evaluated              |                       |                             |                                                   |
| SD        | NonCR/NonPD/not  evaluated              | No                    | SD                          | Documented at least once >4  wks. from baseline** |
| PD        | Any          | Yes                   | or                          | PD                                                |
| No        | PD           | no prior SD, PR or CR |                             |                                                   |
| Any       | PD***        | Yes                   | or                          |                                                   |
| No        |              |                       |                             |                                                   |  
Any Any Yes PD * See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. ** Only for non-randomized trials with response as primary endpoint. *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease progression. Note: Participants with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be reported as "*symptomatic deterioration."* Every effort should be made to document the objective progression even after discontinuation of treatment.
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6.3.3 irecist

| For Participants with Non-Measurable Disease (i.e., Non-Target Disease) Non-Target Lesions New Lesions Overall Response CR No CR Non-CR/non-PD No Non-CR/non-PD* Not all evaluated No not evaluated Unequivocal PD Yes or No PD Any Yes PD * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since  SD is increasingly used as an endpoint for assessment of efficacy in some trials   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
As an exploratory endpoint antitumor activity will also be evaluated according to iRECIST.[98] Using iRECIST criteria the following will be incorporated into the assessment:  
An increase in the sum of target lesions of more than 20%, unequivocal increase in the non-target lesions or new lesions result in iUPD (unconfirmed progression disease); iUPD can be assigned multiple ties as long as iCPD (confirmed progressive disease) is not confirmed at the next assessment.  
Progression is confirmed in the target lesion category if the next imaging assessment after iUPD (4-8 weeks later) confirms a further increase in sum of measures of target disease from iUPD, with an increase of at least 5mm. Progression is confirmed in the non-target lesion category if subsequent imaging, done every 4-8 weeks after iUPD shows a further unequivocal increase in non-target lesions. Progression is confirmed in the new lesions category if at next assessment additional new lesions appear or an increase in the size of previously seen new lesions is seen (>5 mm for sum of new target lesion).
However, the criteria for iCPD (after iUPD) are not considered to have been met if complete response, partial response or stable disease criteria (compared with baseline and as defined by RECIST 1.1) are met at the next assessment after iUPD. The status is reset (unlike RECIST 1.1, in which any progression precludes later complete response, partial response, or stable disease). iCR, iPR, or iSD should then be assigned; and if no change is detected, then the timepoint response is iUPD. 6.3.4 Duration of Response Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. Duration of stable disease: Stable disease is measured from the start of the treatment until the criteria for progression are met. 6.3.5 Progression-Free Survival (PFS) PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first
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7 nih reporting requirements /

Please refer to definitions provided in Policy 801: Reporting Research Events found here.
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7.2 ohsrp office of compliance

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director.  
In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to
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7.4 institutional biosafety committee (ibc)

The Principal Investigator (or delegate) will notify IBC of any unexpected fatal or lifethreatening experience associated with the use of CV301 vaccines as soon as possible but in no event later than 7 calendar days of initial receipt of the information. Serious adverse events that are unexpected and associated with the use of the CV301 vaccines, but are not fatal or lifethreatening, must be reported to the NIH IBC as soon as possible, but not later than 15 calendar days after the investigator's initial receipt of the information. Adverse events may be reported by using the FDA Form 3500a.
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7.4.2 annual reports to ibc

Within 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC protocol number on the report.
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7.4.3 clinical trial information

A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information:
the title and purpose of the trial  
clinical site the Principal Investigator clinical protocol identifiers; participant population (such as disease indication and general age group, e.g., adult or pediatric);
the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed, if the trial has been completed, a brief description of any study results.  
7.4.4 Progress Report and Data Analysis
Information obtained during the previous year's clinical and non-clinical investigations, including:  
a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system a summary of all serious adverse events submitted during the past year a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death
a brief description of any information obtained that is pertinent to an understanding of the gene transfer product's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability.
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7.5 nih required data and

The clinical research team will meet on a weekly basis when participants are being actively treated on the trial to discuss each participant. Decisions about dose level enrollment and dose escalation will be made based on the toxicity data from prior participants. Evaluation of DLTs (eDLTs; Schema 1 and 2) will occur after all participants are enrolled on a given dose level. All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section **7.2.1** will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each participant to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff. 7.5.2 Data Safety Monitoring Board (DSMB) The DSMB is an independent group of at least 3 experts that monitors participant safety and advises The Sponsor. DSMB members will be separate and independent of study staff participating in this trial and should not have scientific, financial, or other conflicts of interest related to this trial. The DSMB will consist of members with appropriate expertise to contribute to the interpretation of data from this trial. A quorum will consist of a simple majority. The DSMB will review cumulative safety data from this trial at least annually. The DSMB will meet when trial halting criteria (see Section **3.2)** are met, or as requested by the sponsor or PI. The DSMB will have a final review meeting at the end of the study. Procedures for DSMB reviews/meetings will be defined in the DSMB charter. The DSMB will review applicable data, including, but not limited to, enrollment, demographics, dosing data, clinical laboratory data, and safety data, at scheduled timepoints during this trial as defined in the DSMB charter. The DSMB will review blinded aggregate data in the open session of the DSMB meetings. Additional data may be requested by the DSMB, and interim statistical reports may be generated as deemed necessary and appropriate by the Sponsor. As an outcome of each review/meeting, the DSMB will make a recommendation as to the advisability of proceeding with study product administration, and to continue, modify, or terminate this trial.
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8 sponsor protocol/safety reporting 8.1

Any untoward medical occurrence in a participant or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product (ICH E6 (R2))
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8.1.2 serious adverse event (sae)

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
Death, A life-threatening adverse event (see section **8.1.3**)  
Inpatient hospitalization or prolongation of existing hospitalization:
o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for participant convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect.  
8.1.3 Life-threatening
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
8.1.4 Severity The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0. 8.1.5 Relationship to Study Product All AEs will have their relationship to study product assessed using the terms: related or not related.  
Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
Not Related - There is not a reasonable possibility that the administration of the study product caused the event.  
Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.6

Adverse Events of Special Interest (AESI)
An adverse event of special interest (AESI) is one of scientific and medical interest specific to understanding of the Investigational Product(s) and may require close monitoring and rapid communication by the investigator to the sponsor. An AESI may be serious or non-serious. The rapid reporting of AESIs assessed as severe allows ongoing surveillance of these events to characterize and understand them in association with the use of these investigational products. Only AESIs that match the definition of SAE will be reported within 7 days from the knowledge of event. Other non-SAE AESIs do not need to be reported to OSRO but only collected in the clinical database.  
The adverse events related to mucosal bleeding, regardless of site, will be collected as an AESI
to enable evaluation of potential risk factors, such as site/past radiation/associated infection at site/recent instrumentation and other variables such as time to onset, exposure history, grade of bleeding, anatomical sites, etc. can be collected.
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assessment of safety events 8.2

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.  
SEs will be:
.  
Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.
.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the Sponsor with the exception of any listed in section 8.4.
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8.3 reporting of serious adverse

Any AE that meets a protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section 8.4 All SAE reporting must include the elements described in 8.2.  
  
Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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w waiver of expedited reporting

As death due to disease progression is part of the study objectives (PFS), and captured as an endpoint in this study, death due to disease progression will not be reported in expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section 8.3.  
Hospitalization that is deemed to be due to disease progression, and not attributable to the intervention will not be reported as an SAE. The event, and the assessment that it was caused by disease progression will be documented in the medical records. The causality assessment of hospitalization will be re-evaluated any time when new information is received. If the causality assessment changes from disease progression to related to the study intervention, SAE report will be sent to the Sponsor in an expedited manner according to section 8.3. If there is any ucertainty whether the intervention is a contributing factor to the event, the event should be reported as AE or SAE as appropriate.  
8.5 SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS
Reporting will be per the collaborative agreement.  
8.6 REPORTING PREGNANCY
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8.6.1 maternal exposure

If a participant becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy become known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section 8.1.2) should be reported as SAEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.  
8.6.2 Paternal exposure Male participants should refrain from fathering a child or donating sperm during the study treatment and for 6 months after the last dose of study drug (s).  
Pregnancy of the participant's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 6 months after the last dose should, if possible, be followed up and documented.
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8.7 regulatory reporting for studies

Following notification from the investigator, CCR, the IND sponsor, will report any suspected adverse reaction that is both serious and unexpected. CCR will report an AE as a suspected adverse reaction only if there is evidence to suggest a causal relationship between the study product and the adverse event. CCR will notify FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of potential serious risks from clinical trials or any other source, as soon as possible, in accordance to 21 CFR Part 312.32. All serious events will be reported to the FDA at least annually in a summary format.
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8.8 sponsor protocol deviation reporting

A Protocol Deviation is defined as any non-compliance with the clinical trial Protocol, Manual of Operational Procedures (MOP) and other Sponsor approved study related documents, GCP, or protocol-specific procedural requirements on the part of the participant, the Investigator, or the study site staff inclusive of site personnel performing procedures or providing services in support of the clinical trial. It is the responsibility of the study Staff to document any protocol deviation identified by the Staff or the site Monitor in the CCR Protocol Deviation Tracking System (PDTS) online application. The entries into the PDTS online application should be timely, complete, and maintained per CCR PDTS user requirements. In addition, any deviation to the protocol should be documented in the participant's source records and reported to the reviewing IRB per their guidelines. OSRO required protocol deviation reporting is consistent with E6(R2) GCP: Integrated Addendum to ICH E6(R1): 4.5 Compliance with Protocol; 5.18.3 (a), and 5.20 Noncompliance; and ICH E3 16.2.2 Protocol deviations.
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9 clinical monitoring

Clinical site monitoring is conducted to ensure:
that the rights of the participants are protected;  
that the study is implemented per the approved protocol, Good Clinical Practice and standard operating procedures; and the quality and integrity of study data and data collection methods are maintained.
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable regulatory requirements. Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human subject protections and integrity of the study data. OSRO will determine the intensity and frequency of monitoring based on several factors, including study type, phase, risk, complexity, expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger CMP updates. OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit (SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) (IMVs), and a study Close-Out Visit (COV). Some monitoring activities may be performed remotely, while others will occur at the study site(s). Monitoring visit reports will describe visit activities, observations, and associated action items or follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating center (if applicable), and the Sponsor regulatory file.  
The site Monitor will inform the study team of any deviations observed during monitoring visits. If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per institutional and IRB guidance.
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10 statistical considerations 10.1 statistical

Arm 1 (Sequential Dose Escalation):
To evaluate the safety and tolerability of single agent SX-682.  
.  
To determine the MTD of SX-682 followed by M7824 and CV301 in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of SX-682 followed by M7824 and CV301.  
Arm 2 (Combination Dose Escalation):
To determine the RP2D of SX-682 with M7824 and CV301 in participants with advanced or metastatic solid tumors. If the MTD is not reached the study will be focused to describe the safety and tolerability of the drug combination.  
Arm 3 (Expansion):
To evaluate preliminary efficacy based on Objective Response Rate (ORR), in each disease cohort separately.
Secondary Objectives:
Arms 1 and 2 (Dose Escalations):
To characterize the PK/PD profile of SX-682 as a single agent and in combination.
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all arms

To evaluate preliminary efficacy: Disease control rate (DCR) and Progressionfree survival (PFS) using RECIST1.1
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10.2 sample size determination

The trial will begin with two phase I evaluations (Cohort 1, Arms 1 and 2; Dose Escalation) as follows: initially participants will be enrolled in Arm 1 involving monotherapy with SX-682 followed by M7824 + CV301. This will initially include up to 3 dose levels, with 3 participants per dose level if no DLTs are experienced. However, if in any of the dose levels, a DLT is identified in the 3 participants, 3 more participants will be enrolled in that dose level, with subsequent escalation only if there are <=1 DLTs in 6 participants. Thus, up to 18 participants may be enrolled in these first 3 dose levels. If there is one or more DLTs identified in in the first 3 dose levels, escalation will continue to DL4 and 5 using the above 3+3 design. If there are no DLTs in the first 3 dose levels, then participants will be enrolled to Arm 2. As a result, depending on toxicities identified, between 9 and 30 participants may be treated within this sequential dose escalation arm. In Arm 2, a combination arm with SX-682 followed by the triplet combination (SX-682, M7824, CV301), up to 5 dose levels may be explored. Using a standard 3+3 design, up to 5x6=30 participants may be included in this arm. Thus, up to 30+30=60 total participants may be treated in the phase I portion (Cohort 1, Arms 1 and 2) of the trial. The phase II evaluation (Arm 3) will take place separately in two cohorts:
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tnbc

Based on prior studies [70-72], the clinical response rate for similar participants with advanced disease receiving a single agent checkpoint inhibitor is expected to be 8-10%. Thus, an observed response rate of approximately 15% or higher would be desirable. In Arm 3, Cohort 2 (TNBC), the trial will be conducted using a Simon minimax two-stage phase II trial design [99] to rule out an unacceptably low response rate (CR+PR) of 5% (p0=0.05) in favor of an improved response rate of 20% (p1=0.20). With alfa=0.10 (probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of rejecting a good treatment=0.20), the first stage will enroll 12 evaluable participants, and if 0 of the 12 has a response, then no further participants will be accrued in that cohort. If 1 or more of the first 12 participants has a response, then accrual would continue until a total of 21 evaluable participants have been treated in that cohort. As it may take up to several months to determine if a participant has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 1-2 participants with a response out of 21 participants in this cohort, this would be an uninterestingly low response rate. If there were 3 or more of 21 (14.3%) who experienced a response, this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (5% response rate), the probability of early termination is 54.0%.
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hpv negative hnscc

Based on prior studies [82, 87, 88], the clinical response rate for similar participants with this disease is expected to be 13-18%. Thus, an observed response rate of greater than 25% would be desirable. In Arm 3, Cohort 3 (HPV negative HNSCC), the trial will be conducted using a Simon minimax two-stage phase II trial design[99] to rule out an unacceptably low response rate (CR+PR) of 15% (p0=0.15) in favor of an improved response rate of 40% (p1=0.40). With alfa=0.10(probability of accepting a poor treatment=0.10) and beta = 0.20 (probability of rejecting a good treatment=0.20), the first stage will enroll 9 evaluable participants, and if 0 to 1 of the 9 have a response, then no further participants will be accrued in that cohort. If 2 or more of the first 9 participants have a response, then accrual would continue until a total of 16 evaluable participants have been treated in that cohort. As it may take up to several months to determine if a participant has experienced a response, a temporary pause in the accrual may be necessary to ensure that enrollment to the second stage is warranted. If there are 2-4 participants with a response out of 16 participants in this cohort, this would be an uninterestingly low response rate. If there were 5 or more of 16 (31.3%) who experienced a response, this would be sufficiently interesting to warrant further study in later trials. Under the null hypothesis (15%
response rate), the probability of early termination is 60.0%.  
It is expected that up to 1.5 years may be required to enroll up to 60 participants in Arms 1 and 2. It is then expected that 2-3 years may be required to complete accrual to Arm 3. Thus, accrual is expected to be completed in 4-5 years. The total number of evaluable participants is no more than 60+21+16=97. To allow for a small number of inevaluable participants, the accrual ceiling for treated participants in the dose escalation and expansion cohorts combined will be set at 105 participants
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10.3 populations for analyses

Intention to treat: any subjects who enroll onto the trial and provide consent and who receive at least 1 dose of SX-682, will be included in safety analyses in Arms 1 and 2. In Arm 3, any participants who receive at least one cycle (defined as 28 days) of SX-682, M7824, and CV301 will be included in safety evaluations as well as efficacy evaluations for the appropriate cohort. 10.3.1 Evaluable for toxicity All participants will be evaluable for toxicity from the time of their first treatment with SX-682. Participant will be eligible for the DLT evaluation if at least ≥85 percent of SX-682 scheduled doses were taken and 100% of scheduled doses of M7824 or CV301 were administered within the DLT period. 10.3.2 Evaluable for objective response Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These participants will have their response classified according to the definitions in section 6.3). (Note: Participants who receive at least treatment cycle and exhibit objective disease progression prior to the first restaging will also be considered evaluable.) 10.3.3 Evaluable Non-Target Disease Response Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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10.4 statistical analyses 10.4.1 general

Following a determination of safety, tolerability, and the MTD in Arms 1 and 2, the fraction of participants who experience a response in each disease-specific cohort of Arm 3 will be reported along with confidence intervals. 10.4.2 Analysis of the Primary Endpoints The toxicity grades per participant will be tabulated and reported by dose level during dose escalation (Arms 1 and 2). This will also include separate evaluations for the initial monotherapy evaluations preceding the evaluation of the combination at each dose level. In Arm 3, the fraction of participants who experience a response in each disease-specific cohort will be reported along with 95% two-sided confidence intervals. 10.4.3 Analysis of the Secondary Endpoint(s)  
10.4.4 PK evaluations will be performed on participants in both dose escalation Arms (both for single agent SX-682 and the combination of agents); results will be reported using standard descriptive statistics. In Arm 3, separately by cohort, the disease control rate (DCR; CR+PR+SD) will be reported as the fraction of participants who experience this outcome, along with a 95% two-sided confidence interval for each fraction. Progression free survival (PFS) will be calculated using the Kaplan-Meier method, including progressions or death without progression as events. Participants who come off study for reasons other than progression and choose not to participate in optional imaging will be censored in data analysis at the time when they become unfollowable for PFS.
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10.4.5 safety analyses

The fraction of participants who experience a toxicity, by grade and type of toxicity, will be tabulated per dose level (both single agent and combination of agents) during the Arms 1 and 2 portion of the trial. Participants who take one dose or more of SX-682 will be evaluable for safety. 10.4.6 Baseline Descriptive Statistics Baseline demographic characteristics will be reported. 10.4.7 Planned Interim Analyses As indicated in the two-stage designs, the number of responses after 9 or 12 evaluable participants have been treated in the appropriate cohort will be noted and will be used to determine if enrollment to the second stage of accrual may proceed for that cohort. 10.4.8 Sub-Group Analyses In Arm 3, analyses will be performed separately by histology. 10.4.9 Tabulation of individual Participant Data None 10.4.10 Exploratory Analyses All Arms:  
To evaluate response via iRECIST To evaluate the effect on immune cell subsets and soluble factors in peripheral blood. To evaluate the effect on serum cytokine levels (IL-8, IL-6 and others) in peripheral blood.  
To evaluate the effect on T cell clonality in peripheral blood and tumor samples. To evaluate the effect on antigen-specific T cells responses to CEA, MUC1 and the cascade antigen brachyury in peripheral blood.  
To evaluate the effect on antigen-specific T cell responses to CEA, MUC1 and the cascade antigen brachyury in the tumor biopsies.  
To evaluate the presence of lymphocytic infiltrates and other tumor markers as well as to evaluate RNA in situ hybridization for IL-8, TGF- and other soluble factors in tumor biopsies.  
To evaluate M7824 PK profile in this drug combination To evaluate ADA in this drug combination To evaluate long term (2 years after completion of treatment) clinical outcomes To evaluate CTCs
In Arms 1 and 2 (Dose-Escalations), the following are the parameters will be evaluated, separately per dose level:
To evaluate ORR per RECISTv1.1 In Arm 3 (Expansions) the following are the parameters will be evaluated, separately per cohort.  
To evaluate changes in circulating free DNA.  
Any exploratory evaluations which generate quantitative measures will be done using descriptive statistics including confidence intervals when appropriate. Any statistical tests performed for evaluation of exploratory objectives will be done without formal adjustment for multiple comparisons, but in the context of the number of tests performed.
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11 collaborative agreements 11.1 cooperative

A CRADA (03153) is in place with Syntrix for the supply of SX-682. A CRADA (02666) is in place with EMD Serono for the supply of M7824. A CRADA (02561) is in place with Bavarian Nordic for the supply of CV301.
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12 human subjects protections 12.1

No individual who meets the criteria for eligibility will be excluded from participation based on their race, ethnicity, gender, or socioeconomic status. Particular attention will be made to acquire a broad and diversified population.
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12.2 participation of children

Children (younger than 18 years) will not be included in this protocol due to the limited data on study drugs in children and the different biology of childhood malignancy.
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12.3 participation of subjects unable

Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (Section **12.4.2**), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR as needed. . Please see section **12.5.1** for consent procedure.
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12.4.1.1 study drug risks

Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or sections **1.2.2.2, 1.2.3.1, 1.2.4.1** of this protocol document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of the study agents. 12.4.1.2 Risk of Biopsy All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection and visceral injury) that will be explained fully during informed consent. 12.4.1.3 Risks of local anesthesia and/or light sedation. Biopsies will be done under local anesthesia and/or light sedation. Potential side effects of sedation include headache, nausea and drowsiness. These side effects usually go away quickly. 12.4.1.4 Risks of contrast dye used in CT scans There is a chance of developing an allergic reaction from the contrast material, which may cause symptoms ranging from mild itching or a rash to severe difficulty breathing, shock or rarely, death. The contrast material may also cause kidney problems. For IV contrast: Potential side effects include discomfort when the contrast material is injected, feeling warm, flushed, a metallic taste, or rarely vomiting or nausea. For oral contrast: Potential side effects include vomiting, nausea, cramping, bloating, constipation or diarrhea after drinking the contrast.
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12.4.1.5 risks of exposure to

This research study involves up to nine (9) CT scans (C/A/P) and up to three (3) CT guided biopsies (optional) collected for research purposes only. Subjects undergoing these scans and optional biopsies collection will be exposed up to 12.3 rem. The CT scans that participant will get in this study will expose them to the roughly the same amount of radiation as 41 years of background radiation. The risk of getting cancer from the radiation exposure in this study is 1.2 out of 100 (1.2 %) and of getting a fatal cancer is 0.6 out of 100 (0.6 %)
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12.4.1.6 risks of mri

People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. It may be unsafe to have an MRI scan for participants with pacemakers or other implanted electrical devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments. Welders and metal workers may have small metal fragments in the eye. People with fear of confined spaces may become anxious during an MRI. Those with back problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. There are no known long-term risks of MRI scans.
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12.4.1.7 risks of gadolinium

The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with pain and swelling. Mild symptoms from gadolinium infusion occur in fewer than 1% of those who receive it and usually go away quickly. Mild symptoms may include coldness in the arm during the injection, a metallic taste, headache, and nausea. In an extremely small number, fewer than one in 300,000 people, more severe symptoms have been reported including shortness of breath, wheezing, hives, and lowering of blood pressure. People with kidney disease are at risk for a serious reaction to gadolinium contrast called "nephrogenic systemic fibrosis (NSF)". This condition always involves the skin and can also involve the muscles, joints and internal organs. NSF has resulted in a very small number of deaths. Most of the gadolinium contrast leaves the body in the urine. However, the FDA has issued a safety alert that indicates small amounts of gadolinium may remain in the body for months to years. The long-term effects of the retained gadolinium are not known. Some types of gadolinium contrast drugs are less likely to remain in the body than others. The gadolinium contrast drugs that are less likely to remain in the body will be used on this study.
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12.4.1.8 research blood collection risks

Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting and infection. When large amounts of blood are collected, low red blood cell count (anemia) can develop.
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12.4.1.9 risk of rapid progression

Three large studies of bintrafusp alfa were recently stopped when the drug manufacturer reviewed data that suggested that the studies would not be likely to prove the study treatment better than standard treatments. This data also suggested that there may be a portion of patients that have either no benefit from bintrafusp alfa, or that bintrafusp alfa will make the tumor grow faster. This has been described with other immunotherapy approaches also with studies suggesting this happens in about 15% of cases.
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12.4.1.10 other risks

Risks include the possible occurrence of any of a range of side effects which are listed in the Consent Document or this protocol document. Frequent monitoring for adverse effects will help to minimize the risks associated with administration of the study agents.
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12.4.2 known potential benefits

The study drugs may help to control the disease. The results may help the investigators learn more about the disease and develop new treatments for participants with this disease. 12.4.3 Assessment of Potential Risks and Benefits Solid tumors treatment needs improved therapy options. Current studies suggest that study therapy may have tremendous anti-tumor efficacy. A number of clinically appropriate strategies to minimize risks to participants have been built into the protocol through the means of inclusion/exclusion criteria, monitoring strategies, and management guidelines. Overall, the potential benefit of the study therapy in subjects with solid tumors outweigh the risks associated with this drug. The potential benefit to a participant that participates in this study is better control of their tumor growth and disease recurrence which may or may not have a favorable impact on symptoms and/or survival. Potential adverse reactions attributable to the administration of the study drug utilized in this trial are discussed in Sections **1.2.2.2, 1.2.3.1, 1.2.4.1**. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity
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12.5 consent process and documentation

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

This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written notification, documenting the reason for study suspension or termination, will be provided by the suspending or terminating party to study participants, investigators, and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants and the Institutional Review Board (IRB) and will provide the reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit schedule. Circumstances that may warrant termination or suspension include, but are not limited to:
Determination of unexpected, significant, or unacceptable risk to participants  
Demonstration of efficacy that would warrant stopping Insufficient compliance to protocol requirements Data that are not sufficiently complete and/or evaluable Determination that the primary endpoint has been met Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and satisfy the sponsor, IRB and Food and Drug Administration (FDA).
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13.2 quality assurance and quality

Clinical site will perform internal quality management of study conduct, data and biological specimen collection, documentation and completion. An individualized quality management plan will be developed to describe a site's quality management. Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that will be run on the database will be generated. Any missing data or data anomalies will be communicated to the site(s) for clarification/resolution. Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial is conducted and data are generated and biological specimens are collected, documented (recorded), and reported in compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). The investigational site will provide direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory authorities.
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13.3 conflict of interest policy

The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of this trial. The study leadership in conjunction with the NCI has established policies and procedures for all study group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported dualities of interest.
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13.4 confidentiality and privacy

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

Investigational SX-682 is manufactured and supplied for the trial by Syntrix. Drug will be delivered directly to the NIH Pharmacy. Individual bottles with tablets will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. Participants will pick up bottles at NIH Pharmacy and will return bottles and not-used tablets after completion of every cycle together with Medication Diary to Study Coordinator. After review of leftover tablets and Medication Diary, unused tablets will be returned to pharmacy and disposed by pharmacy personnel 14.1.2 Formulation, Appearance, Packaging, and Labeling SX-682 is dispensed as either 25 mg or 100 mg tablets for oral administration.  
SX-682 exhibits 99.4% protein binding. The anticipated half-life of the drug varies by dose administered with a 25mg flat dose resulting in a half-life of 2.6 hours and a 200 mg flat dose resulting in a half-life is 14 hours. 14.1.3 Product Storage and Stability Store SX-682 between 15 to 30C. On the basis of available stability data for the API and a drug product demonstration batch, SX-682 is projected stable for at least 2 years when stored as above.
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14.1.4 preparation

SX-682 is dispensed as 25 mg or 100 mg tablets for oral administration. If necessary, the 100 mg tablets can be cut in half using a pill splitter; the tablets are pre-scored for this purpose. The tablets should not be crushed, chewed, or dissolved before being swallowed. 14.1.5 Administration Please see Section **3.3.2**
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14.2 m7824 (ind#21166)

14.2.1 Acquisition and Accountability M7824 is manufactured and supplied for the trial by EMD Serono Research and Development Institute. Drug will be delivered directly to the NIH Pharmacy. Individual IV bags will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel. IV bags will be delivered from NIH Pharmacy to participant unit where drug will be infused to the participant. 14.2.2 Formulation, Appearance, Packaging, and Labeling M7824 is provided as a sterile liquid formulation and packaged at a 10 mg/mL concentration in USP/ Ph Eur type I 50R vials that are filled with drug product solution to allow an extractable volume of 60 mL (600 mg/60 mL). The vials are closed with rubber stoppers in serum format complying with USP and Ph Eur with an aluminum crimp seal closure. Each single-use vial contains 600mg of M7824, formulated as 10mg/mL of active, 6% (w/v) Trehalose, 40 mM NaCl, 5 mM Methionine, 0.05% (w/v) Tween 20, 10 mM LHistidine at pH 5.5. The liquid formulation is diluted directly with 0.9% sodium chloride solution for injection. The estimated volumes of delivery are anticipated to be no more than 250mL. The verified concentration range in the infusion solution is 0.16 mg/mL to 9.6 mg/mL. 14.2.3 Product Storage and Stability M7824 drug product must be stored at 2°C to 8°C until use. The storage condition is based on data from ongoing longterm stability studies with M7824. M7824 drug product stored at room (23°C to 27°C) or higher temperatures for extended periods of time might be subject to degradation. The chemical and physical in-use stability for the infusion solution of M7824 in 0.9% saline solution has been demonstrated for a total of 72 hours at room temperature. However, from a microbiological point of view, the diluted solution should be used immediately and is not intended to be stored unless dilution has taken place in controlled and validated aseptic conditions. If not used immediately, in-use storage times and conditions prior to administration are the responsibility of the user. Do not freeze or shake the diluted solution. No other drugs should be added to the infusion containers containing M7824. 14.2.4 Preparation Preparation is described in pharmacy manual. 14.2.5 Administration Please see Section 3.3.4
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14.3 cv301 (ind#21166)

14.3.1 Acquisition and Accountability Investigational CV301 vaccines (MVA-BN-CV301 and FPV-CV301) will be supplied by the manufacturer, Bavarian Nordic. Drug will be delivered directly to the NIH Pharmacy. Individual syringes with the drugs will be prepared for each study participant by NIH Pharmacy personnel. Syringes will be delivered from NIH Pharmacy to participant unit where drug will be injected to the participant. 14.3.2 Formulation, Appearance, Packaging, and Labeling The manufacturing department of Bavarian Nordic will supply MVA-BN-CV301 and FPV-CV301, with each vaccine provided in 2 mL type I borosilicate glass vials closed with sterile bromobutyl rubber stoppers, crimped with aluminum caps and covered with polypropylene closures. 14.3.3 Product Storage and Stability Supplies of both the MVA-BN-CV301 and the FPV-CV301 vaccines will be shipped temperature controlled and monitored to the clinical trial site. Once at the site, the package should be handed over to personnel in charge of vaccine preparation (e.g., the pharmacist or representative). Site personnel are responsible for proper storage of vaccine upon receipt. Both the MVA-BN-CV301 and the FPV-CV301 vaccines must be shipped to site and stored at a minimum temperature of -4°F +/- 9°F (-20°C +/- 5°C) or -80ºC ± 10ºC, avoiding direct light. A
vial must not be re-frozen once it has been thawed. A provisional shelf life of 2 years at -80°C ± 10°C has been given. Expiry date may be extended due to real time stability data. Storage at - 20°C ± 5°C is limited to 12 months after moving from -80°C ± 10°C to -20°C ± 5°C.
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14.3.4 preparation

MVA-BN-CV301 and FPV-CV301 encode the human MUC-1 and the human CEA gene in combination with human TRICOM. No marker gene is present in both recombinant viruses. MVA-BN-CV301 is a liquid-frozen, highly attenuated, live recombinant virus based on the viral vector MVA-BN. It is administered as s.c. injection. Packaging and vials will be labeled according to the respective product specifications.  
One MVA-BN-CV301 vaccine vial has a nominal titer of 4 x 108 infectious units (Inf.U) in 0.5 mL of the drug product.  
FPV-CV301 is a liquid-frozen, highly attenuated, live recombinant virus. It is administered as s.c. injection. The packages and vials will be labeled according to the respective product specifications.  
One FPV-CV301 vaccine vial has a nominal virus titer of 1 x 109 Inf.U in 0.5 mL of the drug product. 14.3.5 Administration Please see Section 3.3.3.
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15 references

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64. Brenton, J.D., et al., Molecular classification and molecular forecasting of breast cancer:
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70. Dirix, L.Y., et al., *Avelumab, an anti-PD-L1 antibody, in patients with locally advanced* or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat, 2017.  
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73. Fakhry, C., et al., *Improved survival of patients with human papillomavirus-positive head* and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst, 2008. 100(4): p. 261-9.  
74. Zhang, L., et al., Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, openlabel, phase 3 trial. Lancet, 2016. 388(10054): p. 1883-1892.  
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77. Baselga, J., et al., Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol, 2005. 23(24): p. 5568-77.  
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16 appendices 16.1 appendix a-performance

| ECOG Performance Status Scale   |                                                                                                                                                                                       |
|---------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade                           | Descriptions                                                                                                                                                                          |
| 0                               | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous activity,              |
| 1                               | but ambulatory and able to carry out work of a light or sedentary nature  (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                               | unable to carry out any work activities. Up and about more than 50% of  waking hours.                                                                                                 |
| 3                               | In bed >50% of the time. Capable of only limited self-care, confined to  bed or chair more than 50% of waking hours.                                                                  |
| 4                               | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                |
| 5                               | Dead.                                                                                                                                                                                 |
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16.2 appendix b drugs known

| Generic Name*                       | Brand Name*                 |
|-------------------------------------|-----------------------------|
| Aclarubicin                         | Aclacin and others          |
| Amiodarone                          | Cordarone and others        |
| Anagrelide                          | Agrylin and others          |
| Arsenic trioxide                    | Trisenox                    |
| Astemizole                          | Hismanal                    |
| Azithromycin                        | Zithromax and others        |
| Bepridil                            | Vascor                      |
| Chloroquine                         | Aralen                      |
| Chlorpromazine                      | Thorazine and others        |
| Cilostazol                          | Pletal                      |
| Ciprofloxacin                       | Cipro and others            |
| Cisapride                           | Propulsid                   |
| Citalopram                          | Celexa and others           |
| Clarithromycin                      | Biaxin and others           |
| Cocaine                             | Cocaine                     |
| Disopyramide                        | Norpace                     |
| Dofetilide                          | Tikosyn                     |
| Domperidone                         | Motilium and others         |
| Donepezil                           | Aricept                     |
| Dronedarone                         | Multaq                      |
| Droperidol                          | Inapsine and others         |
| Erythromycin                        | E.E.S. and others           |
| Escitalopram                        | Cipralex and others         |
| Flecainide                          | Tambocor and others         |
| Fluconazole                         | Diflucan and others         |
| Gatifloxacin                        | Tequin                      |
| Grepafloxacin                       | Raxar                       |
| Halofantrine                        | Halfan                      |
| Generic Name*                       | Brand Name*                 |
| Haloperidol                         | Haldol (US & UK) and others |
| Ibogaine                            | None                        |
| Ibutilide                           | Corvert                     |
| Levofloxacin                        | Levaquin and others         |
| Levomepromazine (methotrimeprazine) | Nosinan and others          |
| Levomethadyl acetate                | Orlaam                      |
| Levosulpiride                       | Lesuride and others         |
| Mesoridazine                        | Serentil                    |
| Methadone                           | Dolophine and others        |
| Moxifloxacin                        | Avelox and others           |
| Ondansetron                         | Zofran and others           |
| Oxaliplatin                         | Eloxatin                    |
| Papaverine HCl (Intracoronary)      | None                        |
| Pentamidine (systemic)              | Pentam                      |  
| Pimozide           | Orap                  |          |
|--------------------|-----------------------|----------|
| Probucol           | Lorelco               |          |
| Procainamide       | Pronestyl and others  |          |
| Propofol           | Diprivan and others   |          |
| Quinidine          | Quinaglute and others |          |
| Roxithromycin      | Rulide and others     |          |
| Sevoflurane        | Ultane and others     |          |
| Sotalol            | Betapace and others   |          |
| Sparfloxacin       | Zagam                 |          |
| Sulpiride          | Dogmatil and others   |          |
| Sultopride         | Barnetil and others   |          |
| Terfenadine        | Seldane               |          |
| Terlipressin       | Teripress and others  |          |
| Terodiline         | Micturin and others   |          |
| Thioridazine       | Mellaril and others   |          |
| Vandetanib         |                       | Caprelsa |
| * CredibleMeds.org |                       |          |
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16.3 appendix c participant's medication

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

Participant's ID _________________________ Treatment Cycle:_____________________ Participant SX-682 Dose:__________________ Treatment Dates:______________________ INSTRUCTIONS TO THE PARTICIPANT:
1. Complete one form for each cycle on the trial. 2. You will take SX-682 twice a day for every day of the cycle. This drug should be taken in a fasting state, meaning no food 2 hours prior to taking the drug and no food 1 hour after taking the drug.  
3. Record the date, the number of tablets that you took, and when you took them. 4. If you have any comments or notice any side effects, please record them in the comment's column.  
5. Please bring this form and your bottles (even it is empty) when you come for your clinic visit.  
Oral SX-682 (every 12 hours)  
| visit.                                                         | Oral SX-682 (every 12 hours)   |                                                        |           |
|----------------------------------------------------------------|--------------------------------|--------------------------------------------------------|-----------|
| Day                                                            | Date                           | Comments (Side effects, reason for missing  dose, etc) |           |
| Morning Dose                                                   | Evening Dose                   |                                                        |           |
| Time                                                           | # Tablets                      | Time                                                   | # Tablets |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 |                                |                                                        |           |  
| Day                                                                                      | Date         | Oral SX-682 (every 12 hours)   | Comments (Side effects, reason for missing  dose, etc)   |
|------------------------------------------------------------------------------------------|--------------|--------------------------------|----------------------------------------------------------|
| Morning Dose                                                                             | Evening Dose |                                |                                                          |
| Time                                                                                     | # Tablets    | Time                           | # Tablets                                                |
| 25 26 27 28 Participant's signature: ___________________________________________________ |              |                                |                                                          |