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6.2 data sharing plans 6.2.1

The PI will share coded linked human data generated in this research for future research:
in an NIH-funded or approved public repository clinicaltrials.gov and dbGaP  
in BTRIS
in publication and/or public presentations  
with approved outside collaborators under appropriate agreements at the time of publication or shortly thereafter.
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6.2.2 genomic data sharing plan

Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.3 response criteria

For the purposes of this study, patients should be re-evaluated for response at Cycle 3 day 15 (+/- 5 days) and every 2 Cycles (+/-5 days) thereafter. In addition, if PD, a confirmatory scan should be obtained 4 weeks (+ 1 week) following initial documentation of PD. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) [[70, 71]] and Modified Immune-related response criteria (6.4). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.
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6.3.1 disease parameters

For the purpose of this study, the primary pancreatic tumor should be the target lesions with no other disease present. However, for the purpose of defining criteria for progression of disease, all RECIST criteria are reviewed here: 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). 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 patient, 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.
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6.3.2 methods for evaluation of

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. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable.  
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.
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6.3.3 response criteria

All the scans performed at Baseline and other imaging performed as clinically required (other supportive imaging) need to be repeated at subsequent visits. In general, lesions detected at Baseline need to be followed using the same imaging methodology and preferably the same imaging equipment at subsequent tumor evaluation visits. Brain CT / MRI scan should only be performed, if clinically indicated by development of new specific symptoms or on the discretion of the Principal Investigator. For each subject, the Investigator will designate the measure of primary tumor status to follow for determining response: CT or MRI images of primary tumor mass. 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. The tumor response assessment will be assessed and listed according to the Study Calendar 3.8. The foreseen treatment duration is until disease progression verified by a scan subsequent to the initial documentation of PD, unacceptable toxicity, or any criterion for withdrawal from the trial occurs (see Section 3.11.1). Before stopping the treatment, progressive disease should be confirmed by imaging 4 weeks after progression has been diagnosed according to RECIST 1.1. If progression is based on the occurrence of a new lesion in an area not scanned at Baseline, a further on-study scan 4 weeks later should be considered before performing the 28-Day Safety Follow-up visit. Treatment may be continued despite progression according to RECIST 1.1 at any time if:
There are no new symptoms or worsening of existing symptoms.  
There is no new lesion outside the pancreas There is no decrease in ECOG PS.
The Investigator does not consider it necessary to administer a salvage therapy.  
The treatment should be stopped immediately, if the subject does not tolerate M7824 and M9241 in combination with CRT anymore or if therapeutic failure occurs, which requires urgent treatment with an additional drug or results in clinically significant progression / deterioration. 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. Any CR or PR should be confirmed according to RECIST 1.1 (**Error! Reference source not** found.). **In the case of a PR or CR, a confirmatory CT or MRI scan should be done no sooner** than 4 weeks. The Investigator may perform scans in addition to a scheduled trial scan for medical reasons or if the Investigator suspects PD.  
| Target    | Non-Target                                                                                                                                                                                                                                                                                                                   | New     | Overall   | Best Overall Response when                        |
|-----------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|-----------|---------------------------------------------------|
| Lesions   | Lesions                                                                                                                                                                                                                                                                                                                      | Lesions | Response  | Confirmation is Required*                         |
| CR        | CR                                                                                                                                                                                                                                                                                                                           | No      | CR        | >4 wks. Confirmation**                            |
| CR        | NonCR/Non-PD                                                                                                                                                                                                                                                                                                                              | No      | PR        |                                                   |
| CR        | Not                                                                                                                                                                                                                                                                                                                          | No      | PR        |                                                   |
| evaluated | >4 wks. Confirmation**                                                                                                                                                                                                                                                                                                       |         |           |                                                   |
| PR        | NonCR/NonPD/not  evaluated                                                                                                                                                                                                                                                                                                                              | No      | PR        |                                                   |
| SD        | NonCR/NonPD/not  evaluated                                                                                                                                                                                                                                                                                                                              | No      | SD        | Documented at least once >4  wks. from baseline** |
| PD        | Any                                                                                                                                                                                                                                                                                                                          | Yes     | or        | PD                                                |
| No        |                                                                                                                                                                                                                                                                                                                              |         |           |                                                   |
| Any       | PD***                                                                                                                                                                                                                                                                                                                        | Yes     | or        | PD                                                |
| No        | no prior SD, PR or CR                                                                                                                                                                                                                                                                                                        |         |           |                                                   |
| 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:     | Patients 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. |         |           |                                                   |  
Table 16. Response Criteria for Patients with Measurable Disease (i.e., Target Disease) Subjects who have experienced SD, PR, or CR should continue treatment through the end of 24 months, although additional treatment is possible. If the Investigator believes that a subject may benefit from treatment beyond 24 months, it may be permissible.
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6.3.4 responses 6.3.4.1 best overall

The duration of best overall response is measured from the time measurement criteria are met for CR, PR or SD (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
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6.3.4.2 duration of stable disease

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements. Stable Disease (SD) when sum of all target lesions does not qualify for CR/PR/PD for Target Lesion Response and Persistence of non-target lesions on Non-Target Lesion Response.
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6.4 immune-related response criteria (irrecist)

Modified immune-related response criteria (irRECIST) will also be employed in this study. This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. For this trial, the concepts of the irRECIST are combined with RECIST 1.1. Please refer to **Appendix E** for further details.
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6.5 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_50). We are also using additional grading criteria for radiation related adverse events (section **3.4.3.1**)
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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.
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7.2.2 irb requirements for pi

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 Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death.
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7.4 nih required data and

The clinical research team will meet on a weekly basis when patients are being actively treated on the trial to discuss each patient. Decisions about dose level enrollment and dose de-escalation will be made based on the toxicity data from prior patients. 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 patient 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.
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8 sponsor protocol/safety reporting 8.1

Any untoward medical occurrence in a patient 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 patient or subject convenience) is not considered a serious adverse event.  
o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions A congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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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)
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
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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.
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8.1.6 adverse events of special

Adverse events of special interest (AESIs) are serious or nonserious AEs that are of clinical interest and should be closely followed.  
AESIs include following:
- Infusion-related reactions including immediate hypersensitivity.  
- Immune-related adverse events. - M7824 mediated skin reactions. - Anemia. - Bleeding AEs
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution. SAEs will be:  
Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events recorded from the time of first investigational product administration must be reported to the Sponsor with the exception of any listed in section 8.4.
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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 section 8.2. SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions 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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8.4 waiver of expedited reporting

As death due to disease progression is part of the study objectives (PFS and OS), and captured as an endpoints 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 uncertainty whether the intervention is a contributing factor to the event, the event should be reported as AE or SAE as appropriate.
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8.6 reporting pregnancy

All required pregnancy reports/follow-up to OSRO will be submitted to: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. Forms and instructions can be found here: https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions.
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8.6.1 maternal exposure

If a patient 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 after the Investigator becomes aware of it. 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.
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8.6.2 paternal exposure

Male patients should refrain from fathering a child or donating sperm during the study and for 120 days after the last dose of study drug. Pregnancy of the patient'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 120 days 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 with 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 non-adherence reporting

Protocol non-adherence is defined as any noncompliance with the clinical trial protocol, 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 non-adherence identified by the Staff or the site Monitor on the OSRO Site Protocol Non-Adherence Log. The protocol-specific, cumulative non-adherence log should be maintained in the site essential documents file and submitted to OSRO via OSROMonitoring@mail.NIH.gov on the first business day of each month over the duration of the study. In addition, any non-adherence to the protocol should be documented in the participant's source records and reported to the local IRB per their guidelines. OSRO required protocol non-adherence 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 that 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) Monitoring 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. The intensity and frequency of monitoring will be based on several factors, including study type, phase, risk, complexity, expected enrollment rate, and any unique attributes of the study and the site. OSRO Monitoring visits and related activities will be conducted throughout the life cycle of each protocol, with the first activity being before study start 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 take place at the study site(s). Monitoring visit reports will describe visit activities, observations, findings of protocol non-adherence and associated action items or follow-up required for resolution of findings. Monitoring reports will be distributed to the study PI, NCI CCR QA, coordinating center (if applicable) and the OSRO regulatory file. If protocol non-adherence is identified by the Monitor (i.e., any noncompliance with the clinical trial protocol, GCP, or protocol-specific procedural requirements on the part of the participant, the Investigator, or the site Staff) the Monitor will note the observation, review with site Staff and if unresolved, request that the Staff document the non-adherence on the protocol-specific OSRO Site Protocol Non-Adherence Log (see Section 8.8).
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10 statistical considerations 10.1 statistical

To determine the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in subjects with pancreas cancer:  
number, severity, and duration of treatment-related AEs for the combination treatment of M7824 and M9241 administered in combination with a 5-day course of SBRT according to CTCAE v5.0 rate of completion of neoadjuvant SBRT courses when given with M7824 and M9241.  
To determine a preliminary estimate of efficacy as best overall response (BOR) according to RECIST 1.1 of M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in subjects with locally advanced pancreas cancer will be measured by Best Overall Response (BOR) according to RECIST 1.1
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10.1.2 secondary endpoints

Overall survival in patients after completion of SBRT in combination with M9241 and M7824.  
Progression-free survival of all patients and PFS of patients who did not undergo surgical resection (expressed as median PFS).  
Fraction of patients with LAPC who can undergo surgical resection after M7824 and M9241 in combination with SBRT treatment.  
Time-to-recurrence in patients who underwent surgical resection will be measured as time from surgical resection to disease recurrence (expressed in months).  
Rate of complete pathologic response will be measured as fraction of patients who had a complete pathologic response of all patients who underwent surgery.
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10.2 sample size determination phase

The investigational agents M7824 and M9241 will be first tested in combination for safety and tolerability prior to assessing both in combination with SBRT. The safety phase IA run-in of M7824 and M9241 will accrue either pancreatic cancer patients with locally advanced surgically unresectable disease or patients with stage IV disease. Dose Level 0 of 1,200 mg for M7824 every 2 weeks will be tested in combination with 16.8µg/kg of M9241 every four weeks will be first given to 6 patients as a safety run-in. If there are 0-1 DLTs, the study will proceed to the phase IB of M7824 and M9241 in combination with SBRT starting with DL0. If there are ≥2 DLTs at DL0, 6 patients will be enrolled at DL -1 (1,200 mg M7824 q2 weeks and 12µg/kg every 4 weeks ). If 6 patients at the DL-1 have 0-1 DLTs, DL-1 will be combined with SBRT and the study will move to phase IB. If 2 or more DLTs are seen at the DL-1, there will be no further attempts of combining M7824 with M9241 and neither the M7824 and M9241 in combination with SBRT phase IB or the phase II part will be carried out. The first safety run-in of M7824 in combination with M9241 might have a minimum of 6 and a maximum of 12 patients. The safe dose of M7824 and M9241 will then be given in combination with a 5-day course of SBRT. Estimated during phase IA DL of M7824 and M9241 will be given to 6 patients. If there are 0-1 DLTs in the first 6 subjects, the dose of M7824 and M9241 will be used as the recommended phase 2 dose and the study will proceed to the phase II part. If there are ≥2 DLTs in the initial combination with SBRT, there will be a dose reduction of M9241 (if recommended dose was 16.8 µg/kg, M9241 will be reduced to 12 µg/kg, if the safe dose of M9241 when combined with M7824 in the phase IA part was 12.0 µg/kg, the dose will be reduced to 8.0µg/kg). If there are 0-1 DLTs in the first 6 subjects, this dose of M7824 and M9241 will be used as the recommended phase 2 dose and the study will proceed to the phase II part. If there are ≥2 DLTs in 6 patients treated with the reduced M7824 levels in combination with SBRT, no further attempts will be made to combine M7824 and M9241 with SBRT and the study will not proceed to the phase II part. The second safety run-in of M7824 and M9241 in combination with SBRT might have a minimum of 6 and a maximum of 12 patients. Following determination of safe doses of M7824 and M9241 when combined with SBRT the study may proceed to the phase II part. Thus, a minimum of 12 and a maximum of 24 evaluable patients will be enrolled in the phase I cohorts.
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phase ii

The study will be conducted using a Simon two-stage phase 2 minimax design. The objective of the trial will be to determine whether this novel combination of M7824 and M9241 in combination with SBRT can be associated with a response rate (PR + CR; RECIST) that can rule out 10% (p0=0.10) in favor of an improved response rate of 30% (p1=0.30). Using alpha=0.10 (probability of accepting a poor agent) and beta=0.10 (probability of rejecting a good agent), initially 16 evaluable patients will be enrolled into the phase II study, including up to 6 patients from the completed safety cohort Phase IB of M7824 and M9241 in combination with SBRT if they are completely eligible for the phase II portion of the trial. If 0 to 1 of 16 patients respond, then no further patients will be enrolled. If 2 or more of the first 16 evaluable patients enrolled have a response (PR or CR), then accrual will continue until a total of 25 evaluable patients have been enrolled. If 2 to 4 of the 25 has a clinical response, then this will be considered inadequate for further investigation of this regimen. If 5 or more of 25 (20%) respond, then this will warrant further investigation in a subsequent trial. Under the null hypothesis (10% response rate), the probability of early termination is 51.5%. Thus, with up to 24 participants in the phase I cohort and up to 25 evaluable participants in phase II, the trial may require up to 49 participants to be treated. This number may be reduced by up to 6 patients if there are <2 DLTs in the second safety run-in of M7824 and M9241 in combination with SBRT and those patients are included in phase II. To allow for a small number of inevaluable patients, the accrual ceiling will be set at 52 participants. With an anticipated accrual rate of 10 patients per year, it is expected that the trial may complete accrual within 5 years.
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10.3 populations for analysis

Evaluable for overall response: all patients who receive at least one dose of M7824 and M9241 in combination with SBRT at the dose level determined to be safe in the safety run-in Phase IB of M7824 and M9241 in combination with SBRT will be included in the statistical analyses performed. Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with M7824 and M9241 in combination with SBRT. Evaluable for MTD: Subjects enrolled to the safety run-in portion of the study are evaluable. However, subjects who do not complete the DLT observation period for reasons other than a DLT will be replaced and not included in the evaluation.
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10.4 statistical analyses 10.4.1 general

Patients who are in the safety evaluation will have the number of patients with a DLT determined. Patients who are in the efficacy evaluation and patients from the safety run-in administered the M7824 and M9241 in combination with SBRT dose used in the phase II part of the study will have the fraction of clinical responses determined.
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10.4.2 analysis of the primary

For the patients in the dose de-escalation portion, the safety and tolerability and the recommended phase 2 dose (RP2D) of M7824 and M9241 in combination with SBRT as neoadjuvant / perioperative treatment in subjects with pancreas cancer will be evaluated by reporting the number, severity, and duration of treatment-related AEs for the combination treatment of M7824 and M9241 administered in combination with a 5-day course of SBRT according to CTCAE v5.0 . The rate of completion of neoadjuvant SBRT courses when given with M7824 and M9241 will be reported as well using descriptive statistics. Patients who are in the efficacy evaluation will have the fraction objective responses measured by RECIST1.1 determined by dividing the number of patients with an objective response by the number of evaluable patients who are treated at the MTD and reported along with two sided 80% and 95% confidence intervals.
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10.4.3 analysis of the secondary

The secondary endpoints will be analyzed as follows:  
Overall survival in patients after completion of SBRT in combination with M9241 and M7824 and Progression-Free Survival (PFS) of all patients and PFS of patients who did not undergo surgical resection (expressed as median PFS). Overall survival and PFS will be determined in all patients treated at the MTD of M7824 and M9241 in combination with SBRT, as well as patients who did not undergo surgery, using Kaplan-Meier curves.  
Fraction of patients with LAPC who are able to undergo surgical resection after M7824 and M9241 in combination with SBRT treatment. This will be reported along with a 95% confidence interval on the fraction.  
Time-to-recurrence in patients who underwent surgical resection will be measured as time from surgical resection to disease recurrence (expressed in months). Time-to-recurrence in patients will be calculated via Kaplan-Meier curves. Any comparisons with published results will be interpreted as being exploratory.  
Rate of complete pathologic response will be measured as fraction of patients who had a complete pathologic response of all patients who underwent surgery. This will be reported along with a 95% confidence interval.
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10.4.4 safety analyses

Patients in the phase I portion of the trial will be assessed for toxicity by reporting the grades of toxicity and the type of toxicity observed for all patients. Patients will be enrolled and evaluated in the phase I cohorts of the trial as described in the phase I sample size determination section. Patients will continue to be enrolled onto the phase II cohort if the cumulative fraction of patients with greater or equal grade 3 DLT is less than 1/3.
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10.4.5 baseline descriptive statistics

Limited demographic and clinical characteristics of all patients will be reported, for both the phase I and the phase II cohorts.
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10.4.6 planned interim analyses

Toxicity will be assessed within each group of 6 patients accrued in the phase I cohorts M7824 in combination with M9241, and M7824 and M9241 in combination with SBRT. The fraction of patients who respond in the phase IB part who received M7824 and M9241 in combination with SBRT will be included into the efficacy assessment of the phase II cohort, as indicated in the phase II sample size determination section.
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10.4.7 exploratory analyses

The following are the exploratory objectives, along with the method of analysis of each:
To determine M7824 PKs. This will be done using descriptive measures only.  
To determine ADA profile of M7824 in combination with M9241. This will be done using descriptive measures only.  
To evaluate serum cytokines and tumor necrosis factor (TNF) levels pre-treatment and ontreatment. These measures will be evaluated using descriptive statistics. Comparisons between pre-treatment and on-treatment levels may be done using a paired test such as a Wilcoxon signed rank test.  
To correlate the tumoral immune infiltrate via IHC with clinical outcome, the levels will be compared between responders and non-responders using an exact Wilcoxon rank sum test.  
To evaluate impact of genomic profile of advanced pancreatic cancers on clinical response to M7824 and M9241 in combination with SBRT. The prevalence of common somatic mutations identified within the 50-cancer gene panel (Molecular Pathology; Dr. M. Raffeld; for example, KRAS, TP53, SMAD/TGBR2, CDKN2A) obtained from each patient will be compared between responders and non-responders. This will be done using
either a Fisher's exact test, Cochran-Armitage trend test, or exact Wilcoxon rank sum test depending on the distributions of values.  
To correlate circulating free tumor DNA (ctDNA) levels with clinical course of pancreatic cancer patients treated with M7824 and M9241 in combination with SBRT. The levels will be compared between responders and non-responders using an exact Wilcoxon rank sum test.  
To measure subjective Health-related Quality of Life (HRQoL) affecting disease-specific symptoms and treatment-related concerns pre-treatment and on-study and compare HRQoL scores with historical controls of other QoL interventions in advanced pancreas cancer patients. Health-related Quality of Life (HRQoL) scores measuring patient-reported disease-specific symptoms and treatment-related concerns will be compared between responders and non-responders using an exact Wilcoxon rank sum test. The results will also be compared informally with historical controls of other QoL interventions in advanced pancreas cancer patients, using descriptive methods.  
To evaluate the impact of M7824 in combination with M9241 on tumoral perfusion measured by perfusion-weight Dynamic Contrast-enhanced (DCE) Magnetic Resonance Imaging (DCE-MRI). This will be done using descriptive statistics.
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11 collaborative agreement 11.1 cooperative

A CRADA (02666) is in place with EMD Serono for the supply of M7824 and M9241.
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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

Individuals under the age of 18 will not be eligible to participate in this study because they are unlikely to have pancreatic cancer, and because of unknown toxicities in pediatric patients.
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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 direct their wishes for research and care to a surrogate, 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 a LAR, as needed. Please see section **12.5.1** for consent procedure.
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12.4 risk/benefit assessment for all

The primary risk to patients participating in this research study is from the toxicity of M7824 and M9241, or from both drugs in combination with SBRT. M7824 and M9241 are investigational agents designed to enhance antitumor efficacy of standard treatment, standard CRT in this protocol. The protocol provides for detailed and careful monitoring of all patients to assess for toxicity.
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12.4.1.1 risk of rapid progression

Three large studies of bintrafusp alfa were recently stopped when the drug manufacturer reviewed data that suggested that the studies would not be likely to prove the study treatment better than standard treatments. This data also suggested that there may be a portion of patients that have either no benefit from bintrafusp alfa, or that bintrafusp alfa will make the tumor grow faster. This has been described with other immunotherapy approaches also with studies suggesting this happens in about 15% of cases.  
12.4.1.2 Risks of Blood Collection 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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12.4.1.3 risks of ekg

Risks include some minor skin irritation from the electrodes 12.4.1.4 Risks of exposure to ionizing radiation Subjects in Cohort 1 in this study may be exposed to radiation from up to 7 CT scans per year for disease assessment (approximately 7.7 rem per year). This amount is more than would be expected from everyday background radiation. Being exposed to excess radiation can increase the risk of cancer. The risk of getting cancer from the radiation exposure in this study is 0.8 out of 100 (0.8%) and of getting a fatal cancer is 0.4 out of 100 (0.4%). During a year in this research study subjects in Cohort 2 and 3 will be exposed to 25 Gy (5 Gy X 5 days) of radiation from stereotactic body radiation therapy or SBRT. These subjects will also receive a much smaller amount of radiation from up to 7 CT scans for disease assessment. The amount of radiation from these scans adds minimal additional risk to the higher radiation doses received in the course of treatment. This radiation is currently under review by the NIH Radiation Safety Committee.
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12.4.1.5 risks of ct scans

In addition to the radiation risks discussed above, CT scans may include the risks of an allergic reaction to the contrast. Participants might experience hives, itching, headache, difficulty breathing, increased heartrate and swelling 12.4.1.6 Questionnaires risk Questionnaires may contain questions that are sensitive in nature. The patients are asked to only answer questions they are comfortable with.  
12.4.1.7 Risks of urine collection There are no risks of urine collection.  
12.4.1.8 Risks of MRIs (DCE-MRI)
This study involves MRIs performed for research purposes. The main risk is allergic reaction to IV
administered contrast agent. This risk is in the range of 1 to 1.5 %. There is also risk of claustrophobia during MRI and feeling uncomfortable because of loudness of the scanner.  
12.4.1.9 Risk of losing data This includes the risk that data obtained during this study can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document
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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.  
12.4.1.11 Non-Physical Risks of Genetic Research Risk of receiving unwanted information Anxiety and stress may arise as a result of the anticipation that unwanted information regarding disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will be clearly informed that the data related to DNA sequencing and genetic analysis is coded, investigational and will not be shared with patients, family members or health care providers. Risk related to possibility that information may be released This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency or trait can be released to members of the public, insurers, employers, or law enforcement agencies. Although there are no plans to release results to the patients, family members or health care providers, this risk will be included in the informed consent document.
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12.4.2 known potential benefits

The potential benefit to a patient that goes onto study is a reduction in the bulk of their tumor which may or may not have favorable impact on symptoms and/or survival.
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12.4.3 assessment of potential risks

For patients with locally advanced pancreas cancer, median overall survival is in the range of 9 months. It is possible that treatment on this protocol may reduce tumor burden, improve resection rates, increase survival, or lessen symptoms caused by the cancer. Potential adverse reactions attributable to the administration of the study drugs utilized in this trial are discussed in sections **1.2.5.1, 1.2.6.1, 1.2.7**. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity A number of clinically appropriate strategies to minimize risks to patients 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 pancreas cancer outweigh the risks associated with study treatment.
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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) (e.g., legally authorized representative [LAR] for reconsent purposes if participant is an adult unable to consent) as applicable 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 subject 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.
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12.5.1 consent process for adults

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, associate investigators, the Investigational New Drug (IND) sponsor and regulatory authorities. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor 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 as applicable, Food and Drug Administration (FDA).
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13.2 quality assurance and quality

The 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. 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 the 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 site 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 and investigational device

Investigational 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 patient unit where drug will be infused to the patient.
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14.1.3 formulation and preparation

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
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14.1.4 storage and stability

Store intact vials, both lyophilized and liquid formulations, in the refrigerator (2°C - 8°C). Do NOT freeze the vials. The vials must be stored in the original packaging and protected from light until use. Store reconstituted lyophilized vials and diluted infusion solutions at room temperature. Reconstituted lyophilized vials, if not used immediately, are stable at room temperature for up to 24 hours. When diluted with 0.9% Sodium Chloride Injection, USP to a concentration of 0.16 mg/mL to 9.6 mg/mL, chemical and physical in-use stability has been demonstrated for 72 hours when stored at room temperature.
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14.2 m9241 (146972) 14.2.1 acquisition

Investigational M9241 is manufactured and supplied for the trial by EMD Serono Research and Development Institute. Drug will be delivered directly to the NIH Pharmacy. Individual syringes will be prepared for each study participant according to assigned dose by NIH Pharmacy personnel.  
Syringes will be delivered from NIH Pharmacy to patient unit where drug will be infused to the patient.
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14.2.2 formulation and preparation

M9241 is supplied as 1.5 mg/mL in 2 mL clear type 1 glass vials. Each vial contains 1 mL of the sterile M9241 solution.
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14.2.3 storage and stability

Store the intact vials in the refrigerator (2ºC - 8ºC), in the original packaging. Stored the syringes prepared for SC injection at controlled room temperature (15ºC - 25ºC).  
M9241 may be administered undiluted or doses may be diluted with 0.9% Sodium Chloride Injection, USP to a concentration =/> 0.05 mg/mL (50 mcg/mL). Although chemical stability has been demonstrated for 24 hours at 25°C for syringes prepared as above, the manufacturer recommends immediate use and pharmacy will assign a 4-hour expiration to prepared syringes.
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14.3 stereotactic body radiation therapy

The radiation device is an FDA cleared commercial device located in the NIH Clinical Center. The device will be used/investigated in accordance with labeling and therefore will be IDE exempt under 812.2 (c) - category 1.
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48. Strauss, J., et al., *First-in-Human Phase I Trial of a Tumor-Targeted Cytokine (NHSIL12) in Subjects with Metastatic Solid Tumors.* Clin Cancer Res, 2019. 25(1): p. 99-109.  
49. Loehrer, P.J., Sr., et al., Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol, 2011. 29(31): p. 4105-12.  
50. Guckenberger, M., et al., Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer. Strahlenther Onkol, 2014. 190(1): p. 26-33.  
51. Myrehaug, S., et al., *Stereotactic body radiotherapy for pancreatic cancer: recent* progress and future directions. Expert Rev Anticancer Ther, 2016. 16(5): p. 523-30.  
52. Pollom, E.L., et al., Single- versus multifraction stereotactic body radiation therapy for pancreatic adenocarcinoma: outcomes and toxicity. Int J Radiat Oncol Biol Phys, 2014. 90(4): p. 918-25.  
53. Brunner, T.B., et al., *SBRT in pancreatic cancer: what is the therapeutic window?*
Radiother Oncol, 2015. 114(1): p. 109-16.  
54. Gillen, S., et al., *Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic* review and meta-analysis of response and resection percentages. PLoS Med, 2010. 7(4): p. e1000267.  
55. Chang, D.T., et al., Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas. Cancer, 2009. 115(3): p. 665-72.  
56. Moningi, S., et al., *The Role of Stereotactic Body Radiation Therapy for Pancreatic* Cancer: A Single-Institution Experience. Ann Surg Oncol, 2015. 22(7): p. 2352-8.  
57. Polistina, F., et al., Unresectable locally advanced pancreatic cancer: a multimodal treatment using neoadjuvant chemoradiotherapy (gemcitabine plus stereotactic radiosurgery) and subsequent surgical exploration. Ann Surg Oncol, 2010. 17(8): p. 2092-101.  
58. Schellenberg, D., et al., *Single-fraction stereotactic body radiation therapy and* sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys, 2011. 81(1): p. 181-8.  
59. Mahadevan, A., et al., Induction gemcitabine and stereotactic body radiotherapy for locally advanced nonmetastatic pancreas cancer. Int J Radiat Oncol Biol Phys, 2011. 81(4): p. e615-22.  
60. Goyal, K., et al., Stereotactic body radiation therapy for nonresectable tumors of the pancreas. J Surg Res, 2012. 174(2): p. 319-25.  
61. Gurka, M.K., et al., Stereotactic body radiation therapy with concurrent full-dose gemcitabine for locally advanced pancreatic cancer: a pilot trial demonstrating safety. Radiat Oncol, 2013. 8: p. 44.  
62. Herman, J.M., et al., *Phase 2 multi-institutional trial evaluating gemcitabine and* stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer, 2015. 121(7): p. 1128-37.  
63. Rajagopalan, M.S., et al., Pathologic response with neoadjuvant chemotherapy and stereotactic body radiotherapy for borderline resectable and locally-advanced pancreatic cancer. Radiat Oncol, 2013. 8: p. 254.  
64. Mellon, E.A., et al., Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Acta Oncol, 2015. 54(7): p. 979-85.  
65. Rwigema, J.C., et al., Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. J Gastrointest Cancer, 2012. 43(1): p. 70-6.  
66. Huguet, F., et al., Modeling pancreatic tumor motion using 4-dimensional computed tomography and surrogate markers. Int J Radiat Oncol Biol Phys, 2015. 91(3): p. 579-87.  
67. Chuong, M.D., et al., *Stereotactic body radiation therapy for locally advanced and* borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys, 2013. 86(3): p. 516-22.  
68. Murphy, J.D., et al., A dosimetric model of duodenal toxicity after stereotactic body radiotherapy for pancreatic cancer. Int J Radiat Oncol Biol Phys, 2010. 78(5): p. 1420-6.  
69. Webster, K., D. Cella, and K. Yost, *The Functional Assessment of Chronic Illness* Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes, 2003. 1: p. 79.  
70. Eisenhauer, E.A., et al., New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer, 2009. 45(2): p. 228-47.  
71. Wolchok, J.D., et al., *Guidelines for the evaluation of immune therapy activity in solid* tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20.
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16 apendices

16.1 APPENDIX A: D**IAGNOSTIC CRITERIA OF BORDERLINE RESECTABLE PANCREAS CANCER**  
| Criteria                                    | Year                                                  | SMV/PV                                                                                                                                                             |
|---------------------------------------------|-------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| MDACC                                       | 2006                                                  | - Short-segment occlusiona                                                                                                                                         |
| AHPBA/SSO/SSAT                              | 2009                                                  | - Tumor abutment - Encasement, but without encasement of the nearby arteries - Short segment venous occlusion resulting from either tumor thrombus  or encasementa |
| Intergroup                                  | 2013                                                  | -                                                                                                                                                                  |
| (Alliance)                                  | Interface between tumor and vessel ≥180° - Occlusiona |                                                                                                                                                                    |
| ISGPS                                       | 2014                                                  | - Distortion or narrowing - Occlusiona                                                                                                                             |
| NCCN 2017                                   | 2017                                                  | - Contact >180° - Contact ≤180° with contour irregularity of the vein or thrombosis of  the veina                                                                  |
| SMV - superior mesenteric, PV- portal vein. |                                                       |                                                                                                                                                                    |  
SMV - superior mesenteric, PV- portal vein. a With suitable vessel proximal and distal.
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artery criteria.

| Criteria            | Year                                                                              | GDA                                                                                                                                                                                                                                                                                                                                                                                                      | HA                                             | CA   | SMA   |
|---------------------|-----------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------|------|-------|
| MDACC               | 2006                                                                              | - Short-segment  encasement/abutment of CHA                                                                                                                                                                                                                                                                                                                                                              | - Abutment ≤180°                               |      |       |
| AHPBA/SSO/SSAT 2009 | - Encasement  up to the  HA - Short segment encasement or  direct abutment        | -                                                                                                                                                                                                                                                                                                                                                                                                        | -                                              |      |       |
| No extension        | Abutment ≤180°                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                          |                                                |      |       |
| Intergroup          | 2013                                                                              | -                                                                                                                                                                                                                                                                                                                                                                                                        |                                                |      |       |
| (Alliance)          | Reconstructable, short-segment  interface between tumor and  vessel of any degree | - Interface between tumor  and vessel < 180°                                                                                                                                                                                                                                                                                                                                                             | - Interface  between tumor  and  vessel < 180° |      |       |
| ISGPS               | 2014                                                                              | - Encasement  up to the  HA - Short segment encasement or  direct abutment                                                                                                                                                                                                                                                                                                                               | -                                              | -    |       |
| No extension        | Abutment ≤180°                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                          |                                                |      |       |
| NCCN                | 2017                                                                              | Head/uncinate process; - Contact with CHA without  extension to HA bifurcation - Contact with variant arterial  anatomy (ex: accessory/replaced  RHA, replaced CHA, the origin of  replaced or accessory artery) Head/uncinate process; - No extension Body/tail: - Contact with the CA of  ≤180° - Contact with the CA of  >180° without  involvement of the aorta  and with intact and  uninvolved GDA | - Contact ≤180°                                |      |       |  
GDA, gastroduodenal artery; HA, hepatic artery; CA, celiac axis; SMA, superior mesenteric artery; CHA, common hepatic artery; RHA, right hepatic artery 16.2 APPENDIX B: M9241 MULTIPLE DOSE PK PROFILE IN HUMANS AND M9241-INDUCED ALTERATIONS IN PLASMA C**YTOKINE**
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profiles and peripheral blood immune

M9241 and plasma cytokine levels are shown from human subjects who received ≥2 doses of 16.8µg/kg M9241 by subcutaneous injection. Values for immune cell subsets are the frequency of the subset out of all PBMC shown as median (IQR). Graphs depicting three of these subsets. Changes of the immune chekcpoints TIM3 and PD-1 on NK between two administrations are shown.  
  
  
25 37-DL8 C1 8 15 22 C2 8 15 22 C3 C1 8 15 22 C2 8 15 22 C3 C1 8 15 22 C2 8 15 22 C3  
| Immune          |      |     |
|-----------------|------|-----|
| cell            |      |     |
| subset          |      |     |
| Day             |      |     |
| 1               |      |     |
| Day             |      |     |
| 8               |      |     |
| Direction       |      |     |
| of              |      |     |
| (Pre            |      |     |
| treatment)      |      |     |
| (Post           |      |     |
| 1               |      |     |
| cycle)          |      |     |
| the             |      |     |
| change          |      |     |
| CD4-EMRA-PD-L1+ |      |     |
| 0.06            |      |     |
| (0.04-0.09)     |      |     |
| 0.03            |      |     |
| (0.01-0.05)     |      |     |
| Down            |      |     |
| 0.002           |      |     |
| 0.038           |      |     |
| NK-Tim3+        |      |     |
| 0.07            |      |     |
| (0.02-0.24)     |      |     |
| 0.49            |      |     |
| (0.08-1.42)     |      |     |
| Up              |      |     |
| 0.0059          |      |     |
| 0.047           |      |     |
| NK-Mature       |      |     |
| Tim3+           |      |     |
| 0.07            |      |     |
| (0.03-0.21)     |      |     |
| 0.93            |      |     |
| (0.25-1.53)     |      |     |
| Up              |      |     |
| 0.002           |      |     |
| 0.018           |      |     |
| NKT-PD1+        |      |     |
| 0.08            |      |     |
| (0.03-0.13)     |      |     |
| 0.22            |      |     |
| (0.08-0.35)     |      |     |
| Up              |      |     |
| 0.002           |      |     |
| 0.008           |      |     |
| pDC             |      | 0.2 |
| (0.1-0.4)       |      |     |
| 0.1             |      |     |
| (0.1-0.2)       | Down |     |
| 0.0039          |      |     |
| 0.02            |      |     |
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16.3 appendix c fact-hep version

FACT-Hep (Version 4)
Below is a list of statements that other people with your illness have said are important. Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
  
| Not    | A little   | Some-   | Quite   | Very   |
|--------|------------|---------|---------|--------|
| at all | bit        | what    | a bit   | much   |
| 0      | 1          | 2       | 3       | 4      |
| a      | i          | 2       | 3       | 4      |
| o      | I          | 2       | n       | 4      |
| o      | l          | 2       | a       | 4      |
| 0      | I          | 2       | 3       | 4      |
| 0      | l          | 2       |         | 4      |
| l      | 2          | 3       |         |        |
| 0      | 4          |         |         |        |
| Not    | A little   | Some-   | Quite   | Very   |
| at all | bit        | What    | a bit   | much   |
| o      | 1          | 2       | 3       | 4      |
| i      | 2          | 3       | 4       |        |
| o      |            |         |         |        |
| a      | 1          | 2       | 3       | 4      |
| 2      |            |         |         |        |
| o      | i          | 3       | 4       |        |  
2 3  
| 4   |
|-----|  
2 3  
| 4   |
|-----|  
2 3 4 Torol of the Content.
One of the state of the content 16 Hormon 2007
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fact-hep (version 4)

Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
o 062 o a o as cen s er e cs ces s  
| EMOTIONAL WELL-BEING                                         | Not   | A little Some- Quite   | Very   |      |    |
|--------------------------------------------------------------|-------|------------------------|--------|------|----|
| at all                                                       | bit   | what,                  | a bit  | much |    |
| I feel sad .                                                 | o     | 1                      | 2      | 3    | 4  |
| I am satisfied with how I am coping with my illness......... | 0     | 1, 1                   | 2      | n    | 4  |
| I am losing hope in the fight against my illness             | 0     | i                      | 2      | 3    | 4  |
| I feel nervous .                                             | 0     | 1                      | 2      | 3    | 4  |
| I worry about dying                                          | 0     | i                      | 2      | 3    | 4  |
| I worry that my condition will get worse .                   | 0     | i                      | 2      | 3    | 4  |
| FUNCTIONAL WELL-BEING                                        | Not   | A little Some-         | Quite  | Very |    |
| at all                                                       | bit   | what                   | a bit  | much |    |
| I am able to work (include work at home) .                   | 0     | 1                      | 2      | a    | 4  |
| My work (include work at home) is fulfilling                 | 0     | 1                      | 2      | 3    | 4  |
| I am able to enjoy life.                                     | 0     | 1                      | 2      | m    | 4  |
| I have accepted my illness                                   | 2     |                        |        |      |    |
| 0                                                            | I     | 3                      | 4      |      |    |
| I am sleeping well .                                         | 2     |                        |        |      |    |
| 0                                                            | 1     | 3                      | 4      |      |    |
| I am enjoying the things I usually do for fun                | ()    | 1                      | 2      | 3    | 4  |
| I am content with the quality of my life right now           | 0     | i                      | 2      | 3    | 4  |  
FACT-Hep (Version 4)
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
| days.                               | ADDITIONAL CONCERNS                                                | Not at A little Some- Quite   | Very   |    |    |    |
|-------------------------------------|--------------------------------------------------------------------|-------------------------------|--------|----|----|----|
| a bit                               |                                                                    |                               |        |    |    |    |
| al                                  | bit                                                                | what                          | much   |    |    |    |
| o                                   | I have swelling or cramps in my stomach area ..................... | o                             | l      | 2  | m  | 4, |
| a                                   | I am losing weight .                                               | 0                             | 1      | 2  | 3  | 4  |
| a                                   | I have control of my bowels.                                       | 0                             | 1      | 2  | 3  | 4  |
| I can digest my food well           |                                                                    |                               |        |    |    |    |
| c                                   | o                                                                  | 1                             | 2      | 3  | 4  |    |
| s                                   | I have diarrhea (diarrhoea).                                       | o                             | i      | 2  | 3  | 4. |
| I have a good appetite .            |                                                                    |                               |        |    |    |    |
| a                                   | 0                                                                  | 1                             | 2      | 3  | 4  |    |
| r                                   | I am unhappy about a change in my appearance                       | 0                             | i      | 2  | m  | 4  |
| es                                  | I have pain in my back .                                           | 0                             | I      | 2  | 3, | 4  |
| s                                   | I am bothered by constipation                                      | o                             | l      | 2  | s  | 4  |
| 1117                                | I feel fatigued                                                    | 2                             | 3      |    |    |    |
| 0                                   | l                                                                  | 4                             |        |    |    |    |
| I am able to do my usual activities |                                                                    |                               |        |    |    |    |
| A7                                  | 0                                                                  | i                             | 2      | 3  | 4  |    |
| "                                   | I am bothered by jaundice or yellow color to my skin........       | 0                             | l      | 2  | 3  | 4  |
| F                                   | I have had fevers (episodes of high body temperature) ......       | 0                             | 1      | 2  | 3  | 4  |
| -                                   | I have had itching .                                               | 3                             |        |    |    |    |
| o                                   | i                                                                  | 2                             | 4      |    |    |    |
| i                                   | I have had a change in the way food tastes .                       | o                             | 1      | 2  | 3  | 4  |
| i                                   | I have had chills                                                  | 0                             | i      | 2  | 3  | 4  |
| s                                   | My mouth is dry                                                    | ()                            | 1      | 2  | 3  | 4  |
| e                                   | I have discomfort or pain in my stomach area .                     | 0                             | I      | 2  | 3  | 4  |  
16.4 APPENDIX D:PERFORMANCE STATUS C**RITERIA**  
| 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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16.5 appendix emodified immune-related response

This new classification is based on the recent learning from clinical studies with cancer immunotherapies that even if some new lesions appear at the beginning of a treatment or if the total tumor burden does not increase substantially, tumor regressions or stabilizations might still occur later. The irRC were created using bi-dimensional measurements (as previously widely used in the World Health Organization criteria). For this trial, the concepts of the irRC are combined with RECIST 1.1 to come up with the modified irRC. For modified irRC, only target and measurable lesions are taken into account. In contrast to the RECIST 1.1 criteria, the modified irRC criteria (a) require confirmation of both progression and response by imaging at 6 weeks after initial imaging and (b) do not necessarily score the appearance of new lesions as progressive disease if the sum of lesion diameters of target lesions (minimum of 10 mm per lesion, maximum of 5 target lesions, maximum of 2 per organ) and measurable new lesions does not increase by ≥ 20%. The same method of assessment and the same technique should be used to characterize each identified and reported target lesion(s) at baseline, during the trial, and at the end of trial visit. All measurements should be recorded in metric notation. The modified irRC based on RECIST 1.1 are displayed below.  
Overall Responses Derived from Changes in Index, Non-Index, and New Lesions  
| Measurable Response                                                                                      | Non-Measurable Response   | Overall Response   |        |
|----------------------------------------------------------------------------------------------------------|---------------------------|--------------------|--------|
| Using Modified irRC                                                                                      |                           |                    |        |
| Index and New, Measurable                                                                                | Non-Index Lesions         | New, Non-          |        |
| Lesions (Tumor Burden)¹                                                                                  | Measurable Lesions        |                    |        |
| Decrease 100%                                                                                            | Absent                    | Absent             | irCR²  |
| Decrease 100%                                                                                            | Stable                    | Any                | irPR²  |
| Decrease 100%                                                                                            | irPR²                     |                    |        |
| Unequivocal progression                                                                                  | Any                       |                    |        |
| Decrease ≥ 30%                                                                                           | Absent / Stable           | Any                | irPR 2 |
| Decrease ≥ 30%                                                                                           | Unequivocal progression   | Any                | irPR²  |
| Decrease < 30% to increase <                                                                             | Absent / Stable           | irSD               |        |
| Any                                                                                                      |                           |                    |        |
| 20%                                                                                                      |                           |                    |        |
| Decrease < 30% to increase <                                                                             | Unequivocal progression   | Any                | irSD   |
| 20%                                                                                                      |                           |                    |        |
| Increase ≥ 20%                                                                                           | Any                       | Any                | irPD   |
| Decreases assessed relative to baseline                                                                  |                           |                    |        |
| Assuming that the response (irCR and irPR) and progression (irPD) are confirmed by a second, consecutive |                           |                    |        |  
assessment at least 4 weeks apart (normally it should be done 6 weeks apart).