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3.6 questionnaires

The rationale for questionnaires is discussed in Section **1.2.16** and timing is specified in Study Calendar **3.7.** The average time to complete these instruments is 20 minutes. For English speaking subjects only.  
| Long  Term  FU,20 28 Days  FU20 EOT  visit20                                                                         | X                              | X               | X                                     | X                       | X                        |    |    |    |    |    |
|-------------------------------------------------------------------------|--------------------------------|-----------------|---------------------------------------|-------------------------|--------------------------|----|----|----|----|----|
| X                                                                       | X                              | X               | X                                     |                         |                          |    |    |    |    |    |
| 8-N                                                                     | X                              | X               | X                                     | X                       | X                        | X  |    |    |    |    |
| X                                                                       | X                              | X               | X                                     | X                       | X                        |    |    |    |    |    |
| 7                                                                       | X                              | X               | X                                     | X                       | X                        | X  |    |    |    |    |
| 6 5                                                                     | X                              | X               | X                                     | X                       | X                        | X  |    |    |    |    |
| Cycles 1 (14 days each cycle)                                           | Screening Baseline 4           | X               | X                                     | X                       | X                        | X  | X  |    |    |    |
| 3                                                                       | X                              | X               | X                                     | X                       | X                        | X  |    |    |    |    |
| X                                                                       | X                              | X               | X                                     | X                       | X                        |    |    |    |    |    |
| 2                                                                       | X/X6                           |                 |                                       |                         |                          |    |    |    |    |    |
| X                                                                       | X                              | X               | X                                     | X                       |                          |    |    |    |    |    |
| 1                                                                       |                                |                 |                                       |                         |                          |    |    |    |    |    |
| Abbreviated Title: M7824/Gemcitabine for AAPC  Version date: 03/20/2019 | X                              | X               | Confirmation of Pathology X           | Height X                | X                        | X  | X  | X  | X  | X  |
| M7824 2                                                                 | NIH Advance Directives  Form 4 | 3K\VLFDO H[DP ZHLJKW ECOG 5                 | TB testing (if clinically  indicated) | CBC with differential 7 | Biochemical profile 7, 8 |    |    |    |    |    |
| 3.7 Study Calendar                                                      | Procedure                      | Medical History |                                       |                         |                          |    |    |    |    |    |
| Gemcitabine 3                                                           | Vital signs 23                 | EKG             |                                       |                         |                          |    |    |    |    |    |  
| Long  Term  FU,20                                                                         | X                         | X                                   |                         |                       |                    |                        |             |    |    |
|-------------------------------------------------------------------------|---------------------------|-------------------------------------|-------------------------|-----------------------|--------------------|------------------------|-------------|----|----|
| 28 Days  FU20 EOT  visit20                                              | X                         | X                                   | X                       | X                     | X                  | X                      | X           | X  |    |
| X9 X                                                                    | X9 X                      | X                                   | X                       | X                     | X                  |                        |             |    |    |
| 8-N                                                                     | X10                       | X9                                  | X                       | X                     | X                  |                        |             |    |    |
| X                                                                       | X                         | X                                   | X                       | X                     | X                  |                        |             |    |    |
| 7                                                                       | X                         | X                                   | X                       | X                     | X                  |                        |             |    |    |
| 6 5                                                                     | X                         | X                                   | X                       |                       |                    |                        |             |    |    |
| Cycles 1 (14 days each cycle)                                           | Screening Baseline 4      | X                                   | X                       | X                     | X                  | X                      | X           | X  | X  |
| X/X                                                                     |                           |                                     |                         |                       |                    |                        |             |    |    |
| 3                                                                       | X                         | X                                   | X                       | X                     |                    |                        |             |    |    |
| X                                                                       | X                         | X                                   | X                       | X                     | X                  | X/X X                  | X           |    |    |
| 2                                                                       | X                         | X                                   | X                       | X                     | X                  | X                      | X           | X  |    |
| 1                                                                       |                           |                                     |                         |                       |                    |                        |             |    |    |
| Abbreviated Title: M7824/Gemcitabine for AAPC  Version date: 03/20/2019 | X                         |                                     |                         |                       |                    |                        |             |    |    |
| X                                                                       | X                         | X                                   |                         |                       |                    |                        |             |    |    |
| Research blood for PK                                                   | sampling - gemcitabine 14 |                                     |                         |                       |                    |                        |             |    |    |
| Pregnancy testing (urine or  serum)                                     | PT, INR, aPTT, fibrinogen | Tumor evaluation (CT  Scan / MRI)11 | Concomitant Medications | Research blood for PK | sampling - M782413 | Research blood for ADA | sampling 15 |    |    |
| Amylase / lipase                                                        | Brain CT/MRI 12           | Adverse events                      |                         |                       |                    |                        |             |    |    |
| T4 and TSH                                                              |                           |                                     |                         |                       |                    |                        |             |    |    |
| Procedure                                                               | Urinalysis                |                                     |                         |                       |                    |                        |             |    |    |  
70  
| Long  Term  FU,20                                                                         | X                    |                                                          |                         |                              |                          |           |                          |                     |                                                                   |
|-------------------------------------------------------------------------|----------------------|----------------------------------------------------------|-------------------------|------------------------------|--------------------------|-----------|--------------------------|---------------------|-------------------------------------------------------------------|
| 28 Days  FU20 EOT  visit20                                              | X16                  | X                                                        | X                       |                              |                          |           |                          |                     |                                                                   |
| X16 X                                                                   | X                    | X                                                        |                         |                              |                          |           |                          |                     |                                                                   |
| 8-N                                                                     | X                    | X                                                        |                         |                              |                          |           |                          |                     |                                                                   |
| X                                                                       | X                    | X                                                        |                         |                              |                          |           |                          |                     |                                                                   |
| 7 6 5                                                                   | X                    | X                                                        | X                       |                              |                          |           |                          |                     |                                                                   |
| Cycles 1 (14 days each cycle)                                           | Screening Baseline 4 | X                                                        | X                       | X                            |                          |           |                          |                     |                                                                   |
| 3                                                                       | X                    | X                                                        | X                       | X                            |                          |           |                          |                     |                                                                   |
| X                                                                       | X                    | X                                                        | X                       |                              |                          |           |                          |                     |                                                                   |
| 2                                                                       | X                    | X                                                        | X                       | X                            |                          |           |                          |                     |                                                                   |
| 1                                                                       |                      |                                                          |                         |                              |                          |           |                          |                     |                                                                   |
| Abbreviated Title: M7824/Gemcitabine for AAPC  Version date: 03/20/2019 | X                    | X                                                        | X                       | X                            |                          |           |                          |                     |                                                                   |
| evaluation - DCE-MRI 21                                                 |                      |                                                          |                         |                              |                          |           |                          |                     |                                                                   |
| Research blood for  Cytokines 15                                        | 5HVHDUFK EORRG IRU 7*)ȕ 1, 2 and 3 15                      | Research blood for  Circulating free tumor  DNA (cftDNA) | Research blood for DMET | pharmacogenomic  screening22 | Research Tumor biopsy 17 | Perfusion | Phone call or e-mail for | survival/new cancer | treatments every 3 months  for 1 year, every 6 months  after that |
| CEA, CA19-9, CA-125                                                     | FACT-Hep 18          |                                                          |                         |                              |                          |           |                          |                     |                                                                   |
| Procedure                                                               | Research             |                                                          |                         |                              |                          |           |                          |                     |                                                                   |  
71 1 Cycle indicated procedures will be performed on Day 1 of each cycle. Cycle length is 2 weeks (+/- 3 days). If any Screening/Baseline procedures are conducted within 3 days prior to Day 1 of Cycle 1, the assessments scheduled on Day 1 of Cycle 1 do not need to be repeated. 2 M7824 will be administered as a 1 hour (-10 minutes / +20 minutes) IV infusion on Day 1 of each cycle before gemcitabine when both drugs are given on the same day. 3 Gemcitabine will be given starting on Day 1 of Cycle 2 at assigned dose over 30 (+/- 10) minutes once weekly for the 4 weeks (cycles 2-3)). Starting on Cycle 4 once weekly for 3 weeks with one week without gemcitabine. Gemcitabine will be discontinued after Cycle 13 (after a total of 6 months of gemcitabine therapy). 4 As indicated in section **10.3**, all subjects will be offered the opportunity to complete an NIH advanced directives form. This should be done preferably at baseline but can be done at any time during the study as long as the capacity to do so is retained. The completion of the form is strongly recommended, but is not required 5 Assessed prior to trial treatment. (\HVLJQVDQGV\PSWRPVDQGDVVHVVPHQWRIVNLQVKRXOGEHLQFOXGHGLQWRSK\VLFDOH[DPRQEDVHOLQHand following visits. If clinically indicated, ophthalmology and dermatology consults should be ordered. 6 X/X means before and after infusion of M7824. Within 2 hours prior to M7824 infusion and within 2 hours after completion of M7824. 7 Must be drawn and reviewed within 72 hours prior to drug administration. During screening within 28 days of enrollment. 8 Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total bilirubin, calcium, phosphorus, albumin, magnesium, uric acid. 9 Every 6 weeks 10 Every 4 weeks 11 CT or PET of chest, abdomen and pelvis (or MRI abdomen) with tumor measurements. For the purposes of this study, patients should be re-evaluated for response every 6 weeks. If a scan identifies objective response or PD, a confirmatory scan should be obtained 4 weeks following initial documentation of objective response or PD. Allowed time window is 5 days prior to dosing (-5 days). Forsubjects continuing treatment beyond 12-month tumor evaluations should take place every 12 weeks. Subjects without PD at the 28-Day Safety Follow-up visit will be followed till disease progression (CT / MRI scans every 12 weeks with the first assessment 12 weeks after the previous tumor assessment until PD)  
12 Brain CT/MRI scan (either, with contrast preferred) only if clinically indicated at Screening (in case of neurological symptoms, previous history of brain metastases, or at the discretion of the Investigator). 13 X/X means before and after infusion at Cycles 1 and 3. Pre-M7824 PK levels to be taken within 45 minutes prior M7824 infusion.Post-M7824 PK levels to be taken within 45 minutes after completion of M7824 infusion / as close as possible to completion of following gemcitabine infusion. Within 45 minutes prior to infusion at Cycles 2, 6 and EOT. 14 Blood samples for the determination of gemcitabine (GEM) plasma levels will be obtained just prior to drug administration, end of infusion (EOI), and 0.5hr, 1hr, 2hr, and 4hr post EOI. These samples will be collected for the doses received on Day 1 of Cycles 2, 3, 4 and 5. Blood draws will be permitted to have a window of +/- 5 minutes to accommodate logistical challenges. 15 To be taken within 30 minutes prior to start of M7824 infusion. 16 On Cycles 8-13 every 6 weeks and then every 12 weeks. 17 Optional Research biopsies might be performed at baseline and within 7 days after the Day 1 Cycle 4 M7824 administration. 18 Subject-reported outcomes / symptom severity assessmHQWVWKYHUVLRQRIWKHµ)XQFWLRQDO$VVHVVPHQWRI&DQFHU7KHUDS\ZLWKWKHhepatobiliary and pancreatic specific module (FACT-Hep) will be completed at Baseline, after cycle 3, 7 and every 12 weeks after start of treatment. By English speaking subjects only. 19 All SAEs ongoing at the 28-Day Safety Follow-up visit must be monitored and followed up by the Investigator until stabilization or until the outcome is known, unless the subject is documented as "lost to follow-up." In addition, all trial drug-related SAEs occurring after 28 Day Safety Follow up visit and ongoing at the Safety Follow-up visit should be followed up in the same manner. 20 If subjects are unable or not willing to come to NIH after treatment discontinuation for FU visits, they will be followed quarterly (± 14 days) by phone call or e-mail for survival, adverse events and further tumor therapy 21 At baseline, cycles 2, 4, 10 and EOT visit. Patients who have heart pacemakers, metal implants, or metal chips or clips in or around the eyeballs cannot be scanned with an MRI because of the risk that the magnet may move the metal in these areas. DCE-MRI in cycle 2 should be obtained before first gemcitabine infusion, DCE-MRI at baseline and in cycles 2, 4 and 10 are mandatory, at EOT visit it is per PI discretion. If DCE-MRI is not obtained in cycle 2, it may be obtained in cycle 3, with the following DCE-MRI studies moving to cycle 5 and 11. 22 Prior to study treatment, patients (under NCI 16-C-0076) will provide one peripheral blood sample to analyze genomic DNA via the '0(73OXVNLWIRUWKHDVVHVVPHQWRIWKHSDWLHQW¶VF\WLGLQHGHDPLQDVH&'$JHQRW\SH%DVHGRQWKH&'$JHQRW\SHSDWLHQWVZLOO be stratified into a specified dosing strategy (as per Section 3.1). 23 During treatment vital signs must be measured within 1 hour before and 40 minutes following M7824 infusions. In addition, at least one time during the infusion of M7824.
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3.8 criteria for removal from

3.8.1 Criteria for Removal from Protocol Therapy  
x Progressive disease. Subjects should continue treatment beyond the initial determination RI3'WKURXJKWKHLUQH[WWXPRUDVVHVVPent, which in this case should be in 4 weeks if:
¾ 7KHUHDUHQRQHZ*UDGHRUJUHDWHUV\PSWRPVRUVLJQLILFDQWZRUVHQLQJRIH[LVWLQJ
symptoms.  
¾ There is no increase in ECOG. ¾ In the opinion of the Investigator, the subject does not require new anticancer therapy.  
x Occurrence of DLT (see section **3.1.1**)
x ([FHVVLYHWR[LFLW\ (see section 3.4)
x Necessity to administer a non-permitted concomitant drug x PI discretion x Positive pregnancy test 3.8.2 Off -Study Criteria x Death x Patient request to be withdrawn from study x PI discretion x PI decision to end the study
3.8.3 Off Protocol Therapy and Off-Study Procedure Authorized staff must notify Central Registration Office (CRO) when a subject is taken off protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from the web site (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be completed and sent via encrypted email to: NCI Central Registration Office ncicentralregistrationl@mail.nih.gov.
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4 concomitant medications / measures

Any medications RWKHU WKDQ WKRVH H[FOXGHG E\ WKH FOLQLFDO WULDO SURWRFRO that are considered necessary to protect subject welfare and will not interfere with the trial medication may be given at thH,QYHVWLJDWRU¶VGLVFUHWLRQ Palliative radiotherapy delivered in a normal organ-sparing technique may be administered during the trial. The assessment of PD will not be based on the necessity for palliative radiotherapy.
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4.2 prohibited medicines the following

x Immunotherapy including interferons, immunosuppressive drugs (IRUH[DPSOH, chemotherapy RU V\VWHPLF FRUWLFRVWHURLGV H[FHSW IRU VKRUW WHUP WUHDWPHQW RI DOOHUJLF UHDFWLRQV, endocrine replacement therapy at low dose prednisone >PJGDLO\@or glucocorticoid equivalent doses, or for the treatment of irAEs or other appropriate short term steroid useRURWKHUH[SHULPHQWDO pharmaceutical products. Short term administration of systemic steroid or other LPPXQRVXSSUHVVDQWVXFKDVLQIOL[LPDERUP\FRSKHQRODWH (that is, for allergic reactions or the management of irAEs) is allowed. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.  
x Prophylactic use of corticosteroids for infusion related reactions is prohibited. x +HUEDOUHPHGLHVZLWKLPPXQRVWLPXODWLQJSURSHUWLHVIRUH[DPSOHPLVWOHWRHH[WUDFWRUNQRZQ
WRSRWHQWLDOO\LQWHUIHUHZLWKPDMRURUJDQIXQFWLRQIRUH[DPSOHK\SHULFLQ
x Any live attenuated vaccine therapies for the prevention of infectious disease. Administration of inactivated vaccines is allowed (IRUH[DPSOH inactivated influenza vaccines).
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the subject will be withdrawn from trial treatment.
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5 biospecimen collection 5.1. correlative

Correlative studies rationale is discussed in detail in Section **1.2.17** Justification of Research 6WXGLHVRIWKLVSURWRFRO ,QJHQHUDOVWXGLHVZLOODGGUHVVWKHHIIHFWRQ7*)ȕFRQFHQWUDWLRQVDQG other soluble factors in plasma upon response to the study drugs, DCE-MRI as a measure if impact on perfusion upon stromal modulation by M7824 and the impact of the somatic genotype on response to M7824. We also will evaluate intratumoral alterations of the immune milieu / stroma of pre- versus on-treatment biopsies as well as follow copies of circulating free tumor DNA levels during treatment.  
| Test/assay           | Volume                            | Type of tube                 | Collection point   | Location of       |
|----------------------|-----------------------------------|------------------------------|--------------------|-------------------|
| (approx.)            | specimen  analysis                |                              |                    |                   |
| 50-cancer gene panel | Tumor                             |                              | Before treatment   | Laboratory of Dr. |
| sample               | M. Raffeld,  Molecular  Pathology |                              |                    |                   |
| 0XOWLSOH[HG immunohistochemical  evaluation of immune  cell populations                      | Tumor                             | Before and after 7           | Dr. Raffeld,       |                   |
| sample               | weeks of treatment                | Laboratory of  Pathology NCI |                    |                   |  
| Version date: 03/20/2019  Test/assay Volume                    | Type of tube                                           | Collection point   | Location of              |             |
|----------------------------------------------------------------|--------------------------------------------------------|--------------------|--------------------------|-------------|
| (approx.)                                                      | specimen  analysis                                     |                    |                          |             |
| Serum  Separator  Tubes  (SST®)  (gold  capped)                |                                                        |                    |                          |             |
| M7824                                                          | Blood, 3.5                                             |                    |                          |             |
| Pharmacokinetics                                               | mL                                                     | See Study calendar | EMD Serono *             |             |
| 3.7                                                            | (Processed in Figg  Lab)                               |                    |                          |             |
| Sodium  Heparin  (green top)  tube (pretreated with  THU)                                                                |                                                        |                    |                          |             |
| Gemcitabine                                                    | Blood, 4                                               |                    |                          |             |
| Pharmacokinetics                                               | mL                                                     | See Study calendar | Dr. Figg Lab             |             |
| 3.7                                                            |                                                        |                    |                          |             |
| Cytokines                                                      | Blood, [                                                        | Gold top           | See Study calendar       | EMD Serono* |
| mL                                                             | SST                                                    | 3.7                |                          |             |
| by ELISA                                                       | (Processed in Figg  Lab)                               |                    |                          |             |
| 7*)ȕOLJDQG concentrations                                                                | Blood, 4.5                                             | Blue top           | See Study calendar       | EMD Serono* |
| mL                                                             | CTAD                                                   | 3.7                | (Processed in Figg  Lab) |             |
| by ELISA  Circulating free  tumor DNA  (cftDNA)                | Blood, 3.5                                             | EDTA               |                          |             |
| mL                                                             | (purple top)  tubes                                    | See Study calendar | Dr. Raffeld,             |             |
| 3.7                                                            | Laboratory of  Pathology NCI  (Processed in Figg  Lab) |                    |                          |             |
| ADA by ELISA                                                   | Blood, 2.5                                             | Gold top           | See Study calendar       | EMD Serono* |
| mL                                                             | SST                                                    | 3.7                | (Processed in Figg  Lab) |             |
| EDTA  (purple                                                  | top)                                                   |                    |                          |             |
| tubes                                                          |                                                        |                    |                          |             |
| Plasma,  3.5 mL                                                | Baseline                                               | Dr. Figg Lab       |                          |             |
| DMET  pharmacogenomic  screening                               |                                                        |                    |                          |             |
| * Coded linked samples without key will be sent to EMD Serono: |                                                        |                    |                          |             |  
Laureen Ojalvo, MD, PhD Associate Medical Director Immuno-Oncology (0'6HURQR5HVHDUFK'HYHORSPHQW,QF 0LGGOHVH[7XUQSLNH%LOOHULFD0$86$ +1 978 821 6144 +1 978 294 1400 laureen.ojalvo@emdserono.com Samples will be sent for barcoding and initial storage to Blood Processing Core (BPC). Patients will undergo blood and tissue sampling for research purposes on the time points outlined in the Study Calendar 3.7. 5.1.1 Tumor and Tissue Collection Tumor samples might be collected at baseline and within 7 days after the Cycle 4 Day 1 M7824 administration for flow cytometry and RNA evaluation. Of any tumor biopsy, one sample will always be sent to Laboratory of Pathology for disease evaluation first (confirmation of metastatic pancreatic cancer). Leftover samples will be used for research.  
It is preferable to QRWELRSV\DWDUJHWOHVLRQKRZHYHULIRQO\RQHOHVLRQLVDPHQDEOHIRUELRSV\, biopsy will be performed on this lesion. Tissue processing: Fresh tumor tissue obtained from subjects for research purposes and not used for surgical pathology evaluation should undergo a tumor digest and used for flow cytometry to study immune cell populations. Other parts of obtained cancer tissues should either be snap frozen DQGXVHGIRUODWHU51$H[WUDFWLRQDQGIL[HGLQQHXWUDOEXIIHUHGIRUPDOLQ1%) followed by paraffin-embedding or used for the generation of a tumor digest. Formalin substitutes are not suited DVIL[DWLYH Tissue storage: Fresh tumor tissue digest obtained from subjects for the evaluation of efficacy should be stored in defined cryopreservation mHGLXP FRQWDLQLQJ  GLPHWK\O VXOIR[LGH [CryoStor® CS10]. Prioritization of limited sample of fresh tumor biopsy for research purposes: First priority: fresh VDPSOHIRUWXPRUGLJHVWDQGIORZF\WRPHWU\DQG51$6HTDQDO\VLVVHFRQGSULRULW\WRIRUPDOLQ IL[DQGJHQHUDWHDSDUDIILQHPEHGGHG))3(WLVVXHEORFNLIWKHDUFKLYDOWXPRUFRQWDLQLQJ))3( tissue block cannot be provided, sections from the tumor biopsy used for FFPE should be provided which are freshly cut, 4 μm thick and mounted on positively-charged microscope slides. SuperFrost Plus glass slides are recommended for samples designated for IHC to reduce IHC assay failure. If the archival tumor block is available preferably 15 VOLGHV VKRXOG EH SURYLGHGLI QRW possible a minimum of 5 slides is required. 5.1.2 0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ in tumor samples 0XOWLSOH[HGLPPXQRKLVWRFKHPLFDOHYDOXDWLRQRILPPXQHFHOOSRSXODWLRQ WRH[DPLQHWKHLPPXQH ODQGVFDSH IRU 7*)ȕ VLJQDOLQJ-dependent immune cell populations like T cells including T regulatory cells, MDSCs, or tumor-associated macrophages and will be done in the Laboratory of Pathology. 5.1.3 Pharmacokinetics of M7824 and gemcitabine Pharmacokinetic parameters are limited to &PD[ (in μg/mL plasma) WLPH WR UHDFK PD[LPXP concentraWLRQWPD[and minimum serum concentration (CminLQJP/SODVPD). Blood will be collected for PK assessments according to Study Calendar 3.7. Plasma M7824 PK measurements will be done at EMD Serono, plasma gemcitabine measurements in the Clinical Pharmacology Core (Dr. W. Figg). 5.1.3.1 M7824 Pharmacokinetics (EMD Serono) Plasma M7824 PK measurements will be done at EMD Serono 5.1.3.2 Gemcitabine Pharmacokinetics (Figg Lab) Blood samples for the determination of gemcitabine (GEM) plasma levels will be obtained from participating patients via 4 mL sodium heparin (green top) tube (BD, Franklin Lakes, NJ) collected according to Study Calendar 3.7. Bioanalytical measurements will be conducted on an ultra HPLCMS/MS system by the Clinical Pharmacology Program (CPP).  
Because GEM is rapidly deactivated by cytidine deaminase (CD), green top tubes will be fortified with 100 uM tetrahydrouridine (THU). These tubes will be prepared in advance by the CPP and provided to the clinic. In advance of PK samples being drawn, please notify the CPP at least 24 hrs. prior to prepare fresh green top tubes with 100 uM THU. This data will be used to monitor GEM plasma concentrations to assess any drug interactions with M7834 and/or correlations with pharmacogenomics, adverse events, and clinical response. 7KHVDPSOHVZLOOEHSODFHGLPPHGLDWHO\RQZHWLFHDQGUHIULJHUDWHG7KHGDWHDQGH[DFWWLPHRI each blood draw should be recorded on the sample tube and the PK sheet. Please page 102-11964 for immediate pick-up. CoQWDFW 'U )LJJ¶V&OLQLFDO 3KDUPDFRORJ\ 3URJUDP %ORRG 3URFHVVLQJ Core) in Bldg. 10/5A09 at 301-402-3622 or 301-594-6131 with any questions.  
Upon arrival in the Clinical Pharmacology Program, samples will be centrifuged and the plasma transferred into cryovials for storage at -80 C until the time of analysis. In addition, samples will be barcoded as described in Section **5.2.1**. 5.1.4 Soluble Factors Investigation Blood will be collected to analyze soluble factors including cytokines and T*)ȕligand concentrations according to Study Calendar 3.7. The investigation will be done by EMD Serono using ELISA.
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5.1.5 ada analysis.

Blood will be collected to analyze ADA according to Study Calendar 3.7. Samples positive for ADAs will be re-analyzed to determine the titer. The investigation will be done by EMD Serono using ELISA.
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5.2 sample storage tracking and

Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. Should a CRIS screen not be available, the CRIS downtime procedures will be followed. All samples will be sent to Blood Processing Core (BPC) for processing and storage until they are distributed to Dr. Rudloff¶VODEVDPSOHDQDO\VLVDVGHVFULEHGLQWKHSURWRFRO Samples will not be sent outside NIH without ,5%QRWLILFDWLRQDQGDQH[HFXWHG07$. 5.2.1 6DPSOHV0DQDJHGE\'U)LJJ¶V%ORRGProcessing Core (BPC)
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5.2.1.1 bpc contact information

Please e-mail NCIBloodcore@mail.nih.gov at least 24 hours before transporting samples (the Friday before is preferred). For sample pickup, page 102-11964. For immediate help, call 240-760-6180 (main blood processing core number) or, if no answer, 240-760-6190 (main clinical pharmacology lab number). For questions regarding sample processing, contact NCIBloodcore@mail.nih.gov.
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5.2.2 sample data collection

All samples sent to the Blood Processing Core (BPC) will be barcoded, with data entered and stored in the LABrador (aka LabSamples) utilized by the BPC. This is a secure program, with access to LABrador limited to defined Figg lab personnel, who are issued individual user accounts. Installation of LABrador is limited to computers specified by Dr. Figg. These computers all have a password restricted login screen. All Figg lab personnel with access to patient information annually complete the NIH online Protection of Human Subjects course. LABrador FUHDWHVDXQLTXHEDUFRGH,'IRUHYHU\VDPSOHDQGVDPSOHER[ZKLFKFDQQRWEHWUDFHG back to patients without LABrador access. The data recorded for each sample includes the patient ID, name, trial name/protocol number, time drawn, cycle time point, dose, material type, as well DV ER[ DQG IUHH]HU ORFDWLRQ 3DWLHQW GHPRJUDSKLFV DVVRFLDWHG ZLWK WKH FOLQLFDO FHQWHU SDWLHQW number are provided in the system. For each sample, there are notes associated with the processing method (delay in sample processing, storage conditions on the ward, etc.). Sample bar-codes are linked to patient demographics and limited clinical information. This information will only be provided to investigators listed on this protocol, via registered use of the LABrador. It is critical that the sample remains linked to patient information such as race, age, dates of diagnosis and death, and histological information about the tumor, in order to correlate genotype with these variables.
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5.2.3 sample storage

Barcoded saPSOHVDUHVWRUHGLQEDUFRGHGER[HVLQDORFNHGIUHH]HUDWHLWKHU-20 or -80qC according to stability requirements. These freezers are located onsite in the BPC and offsite at NCI Frederick Central Repository Services in Frederick, MD. Visitors to the laboratory are required to be accompanied by laboratory staff at all times. Access to stored clinical samples is restricted. Samples will be stored until requested by a researcher named on the protocol. All requests are monitored and tracked in LABrador. All researchers are required to sign a form stating that the samples are only to be used for research purposes associated with this trial (as per the IRB approved protocol) and that any unused samples must be returned to the BPC. It is the responsibility of the NCI Principal Investigator to ensure that the samples requested are being used in a manner consistent with IRB approval. Following completion of this study, samples will remain in storage as detailed above. Access to these samples will only be granted following IRB approval of an additional protocol, granting the rights to use the material. ,IDWDQ\WLPHDSDWLHQWZLWKGUDZVIURPWKHVWXG\DQGGRHVQRWZLVKIRUWKHLUH[LVWLQJVDPSOHVWR be utilized, the individual must provide a written request. Following receipt of this request, the samples will be destroyed (or returned to the patient, if so requested), and reported as such to the IRB. Any samples lost (in transit or by a researcher) or destroyed due to unknown sample integrity (i.e. broken free]HUDOORZVIRUH[WHQVLYHVDPSOHWKDZLQJetc.) will be reported as such to the IRB.
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5.2.4 procedures for storage of

Tissues designated for clinical diagnostics are transported to the Laboratory of Pathology (LP) ZKHUH WKH\ DUH H[DPLQHG JURVVO\ DQG UHOHYDQW SRUWLRQV DUH IL[HG HPEHGGHG LQ SDUDIILQ DQG sectioned and stained for diagnostic interpretation. 8QXWLOL]HGH[FHVVWLVVXHVDUHVWRUHGIRUXSWR three months, in accordance with College of American Pathologists/Joint Commission on Accreditation of Healthcare Organizations (CAP/JCAHO) guidelines, and then discarded. Following completion of the diagnostic workup, the slides and tissue blocks are stored indefinitely LQ WKH /3¶V FOLQLFDO DUFKLYHV All specimens are catalogued and retrieved utilizing the clinical laboratory information systems, in accordance with CAP/JCAHO regulations. The use of any stored specimens for research purposes is only allowed when the appropriate IRB approval has been obtained. In some cases, this approval has been obtained via the original protocol on which the patient was enrolled.
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5.2.5 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are remaining at the completion of the protocol will be stored in the conditions described in Section 5.2.1. The study will remain open so long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or if a subject withdraws consent for their continued use, at which time they will be destroyed. The PI will report any loss or destruction of samples to the NIH Intramural IRB as soon as he is made aware of such loss. If tKH SDWLHQW ZLWKGUDZV FRQVHQW WKH SDUWLFLSDQW¶V GDWD ZLOO EH H[FOXGHG IURP IXWXUH distributions, but data that have already been distributed for approved research use will not be able to be retrieved. The PI will report destroyed samples to the IRB if samples become unsalvageable because of HQYLURQPHQWDOIDFWRUVH[EURNHQIUHH]HURUODFNRIGU\LFHLQDVKLSSLQJFRQWDLQHURULIDSDWLHQW withdraws consent. Samples will also be reported as lost if they are lost in transit between facilities or misplaced by a researcher. Freezer problems, lost samples or other problems associated with samples will also be reported to the NIH Intramural IRB and to the NCI Clinical Director.
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5.3 samples for genetic/genomic analysis

5.3.1 Description of the scope of genetic/genomic analysis  
x We will use baseline archival or fresh biopsy specimens for somatic tumor variant sequencing which will be performed by the CLIA-approved 50-cancer gene panel of the Molecular Pathology section (Dr. M. Raffeld lab).  
x We plan to characterize cfDNA from blood at baseline and during treatment. All samples will be subjected to targeted sequencing. This will allow us to characterize somatic point mutations, and copy-number changes DQGZLOOEHSHUIRUPHGLQ'U05DIIHOG¶VODERUDWRU\
x DMET genotyping (DMET samples will be drawn under 16-C-0076 and sent to the Clinical Pharmacology Program for processing and analysis to determine polymorphisms in genes involved in gemcitabine metabolism). Prior to study enrollment, patients will enroll on NCI 16-C-0076 (Prospective Screening for Patient Specific Genotypes and Phenotypes that Influence Drug Dosing and Trial Selection in Cancer Patients, PI: William D. Figg). As per NCI 16-C-0076, one peripheral blood sample per patient will be collected in a EDTA
(purple top) tube for pharmacogenetics studies to analyze the genomic DNA and assess genotype of the most relevant drug metabolizing enzymes and transporters (DMET). DNA ZLOOEHDQDO\]HGRQD'0(73OXV$II\PDWUL[JHQRW\SLQJSODWIRUPWKDWWHVWVIRU genetic variations in 225 drug disposition genes, including 47 CYP (phase I metabolism) genes, 13 non-CYP (phase I metabolism) genes, 78 phase II metabolizing genes (including UGTs), 63 transporters, 4 genes involved in facilitation of drug transporters, 9 genes involved in global regulation of drug metabolizing/transporting proteins, 4 drug binding proteins, and 4 drug targets. The samples will be sent to the NCI Frederick National Laboratory for Cancer Research (CLIA certificate 21D0947274) for analysis via the '0(73OXVNLWIRUWKHSXUSRVHRIGHWHUPLQLQJWKHSDWLHQW¶V&'A genotype.
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5.3.2 privacy and confidentiality of

Fresh tumor samples will be stored in a minus 80-degree freezer. Initially the samples of each patient will be barcoded. $WQRWLPHZLOOSDWLHQW¶VQDPHVEHXVHGRQWKHEORRGDnd tissue samples.  
Sometimes, because a group collaboration or jouUQDOSROLF\UHTXLUHVLWDVXEMHFW¶VJHQHWLFGDWD
may be deposited in a database such as dbGaP. Although there is controlled access to such a database, such a submission carries theoretical risks of revealing the identity of the subject. This is discussed in the consent.
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5.3.3 management of results

Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically actionable findings for the purpose of this study are defined as disorders appearing in the American College of Medical Genetics and Genomics recommendations for the return of incidental findings that is current at the time of primary analysis. (A list of current guidelines is maintained on the CCR intranet: https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists). Subjects who still remain on the study will be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified laboratory.
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5.3.4 genetic counseling

If the research findings are verified in the CLIA certified lab, the subject will be offered the RSSRUWXQLW\WRFRPHWR1,+DWRXUH[SHQVHWRKDYHJHQHWLFHGXFDWLRQDQGFRXQVHOLQJZLWK the 1&,*HQHWLFV%UDQFKWRH[SODLQWKLVUHVXOW If the subject does not want to come to NIH, a referral WRDORFDO JHQHWLFKHDOWKFDUHSURYLGHUZLOOEHSURYLGHG DWWKHLUH[SHQVH This is the only time during the course of the study that incidental findings will be returned. No interrogations regarding clinically actionable findings will be made after the primary analysis.
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6 data collection and evaluation

The PI will be responsible for overseeing entry of data into an in-house password protected electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or data manager will assist with the data management efforts. All data obtained during the conduct of the protocol will be kept in secure network drives or in approved alternative sites that comply with NIH security standards. Primary and final analyzed data will have identifiers so that research data can be attributed to an individual human subject participant. All adverse events, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, will be followed until return to baseline or stabilization of event. Patients will be followed for adverse events for 28 days after removal from study treatment or until offstudy, whichever comes first.  
An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:  
x Results in discontinuation from the study x Is associated with clinical signs or symptoms x Requires treatment or any other therapeutic intervention x Is associated with death or another serious adverse event, including hospitalization. x Is judged by the Investigator to be of significant clinical impact x If any abnormal laboratory result is considered clinically significant, the investigator will SURYLGHGHWDLOVDERXWWKHDFWLRQWDNHQZLWKUHVSHFWWRWKHWHVWGUXJDQGDERXWWKHSDWLHQW¶V outcome.
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grade 1 adverse events will

6.1.1 Tumor data The tumor disease information that will be documented and verified at the Screening visit for each subject includes:  
x Detailed history of the tumor, including histopathological diagnosis, grading and staging in accordance with the Union Internationale Contre le Cancer Tumor Node Metastasis Classification **at diagnosis** (UICC TNM).  
o The M category (M0 or M1) of the tumor at the time of study entry, based on screening assessments x All therapy used for prior treatment of the tumor (including surgery, radiotherapy and chemotherapy, immunotherapy).  
x Any other conditions that were treated with chemotherapy, radiation therapy, or immunotherapy.
6.1.2 Concomitant Medications and Therapies All concomitant medications taken by the subject during the trial, from the date of signature of informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, duration and indication of each drug. Nondrug interventions (other than vitamins) and any changes to a concomitant medication or other intervention should also be recorded in the eCRF. End of study procedures: Data will be stored according to HHS, FDA regulations and NIH Intramural Records Retention Schedule as applicable. Loss or destruction of data: Should we become aware that a major breach in our plan to protect subject confidentiality and trial data has occurred, the IRB will be notified.
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what data will be shared?

I will share human data generated in this research for future research as follows:  
x Coded linked data in an NIH-funded or approved public repository.  
x Coded linked data in BTRIS (automatic for activities in the Clinical Center) x Coded linked or identified data with approved outside collaborators under appropriate agreements.
Data will be shared through:
x An NIH-funded or approved public repository: clinicaltrials.gov.  
x BTRIS (automatic for activities in the Clinical Center)
x Approved outside collaborators under appropriate individual agreements.  
x Publication and/or public presentations.  
Data will be shared:
x Before publication.  
x At the time of publication or shortly thereafter.  
6.2.2 Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in compliance with the NIH Genomic Data Sharing Policy.
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6.3 response criteria

For the purposes of this study, patients should be re-evaluated for response every 6 weeks for. In addition, if a scan identifies objective response, a confirmatory scan should be obtained 4 weeks following initial documentation of objective response. For subjects continuing treatment beyond 12 months tumor evaluations should take place every 12 weeks 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) [[36, 37]] and Modified Immune-related response criteria (Section 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

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as: - %\FKHVW[-UD\!PP  
- By CT scan:
o Scan slice thickness 5 mm or under as >10 mm with CT scan o Scan slice thickness >5 mm: double the slice thickness
- :LWKFDOLSHUVRQFOLQLFDOH[DP!PP
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 >PPLQVKRUWD[LVZKHQDVVHVVHGE\&7VFDQ&7VFDQVOLFHWKLFNQHVVUHFRPPHQGHG
to be no greater than 5 mm). At baseline and in follow-XSRQO\WKHVKRUWD[LVZLOOEHPHDVXUHG
and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or SDWKRORJLFDOO\PSKQRGHVZLWKWRPPVKRUWD[LVDUHconsidered 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.  
µ&\VWLFOHVLRQV¶WKRXJKWWRUHSUHVHQWcystic 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. AlOPHDVXUDEOHOHVLRQVXSWRDPD[LPXPRIOHVLRQVSHURUJDQDQGOHVLRQVLQ 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 WR UHSURGXFLEOHPHDVXUHPHQWLQZKLFKFLUFXPVWDQFHWKHQH[W largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-QRGDOOHVLRQVVKRUWD[LVIRUQRGDOOHVLRQVIRUDOOWDUJHWOHVLRQVZLOOEHFDOFXODWHG and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then RQO\WKHVKRUWD[LVLVDGGHGLQWRWKHVXP The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up. 6.3.2 Methods for Evaluation of Measurable Disease All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is SUHIHUUHG WR HYDOXDWLRQ E\ FOLQLFDO H[DPLQDWLRQ XQOHVV WKH OHVLRQV EHLQJ IROORZHG FDQQRW EH imaged but are assessable by clinicaOH[DP Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and t10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. &KHVW[-ray: /HVLRQVRQFKHVW[-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). 8VHRI05,UHPDLQVDFRPSOH[LVVXH 05,KDVH[FHOOHQWFRQWUDVWVSDWLDODQGWHPSRUDOUHVROXWLRQ 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 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 1 or more of the following measures of tumor status to follow for determining response: CT or MRI images of primary and / RUPHWDVWDWLFWXPRUPDVVHVSK\VLFDOH[DPLQDWLRQILQGLQJV and the results of other assessments. All available images collected during the trial period will be considered. The most appropriate measures to evaluate the tumor status of a subject should be used. The measure(s) to be chosen for sequential evaluation during the trial have to correspond to the measures used to document the progressive tumor status that qualifies the subject for enrollment. The tumor response assessment will be assessed and listed according to the Study Calendar 3.7. The foreseen treatment duration is until disease progression verified by a scan subsequent to the initial documentation of PDXQDFFHSWDEOHWR[LFLW\RUDQ\FULWHULRQIRUwithdrawal from the trial occurs (see Section 3.8). **Before stopping the treatment, progressive disease should be** confirmed by imaging 4 to 6 weeks (preferably 6 weeks, but not later) 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 6 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:
x 7KHUHDUHQRQHZV\PSWRPVRUZRUVHQLQJRIH[LVWLQJV\PSWRPV  
x There is no decrease in ECOG PS.
x 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 in combination with gemcitabine 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).  
x 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 (Table ). In the case of a PR or CR, a confirmatory CT or MRI scan should be done no sooner than 4 weeks (preferably at the scheduled 6-week interval). 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**       |  
Table . Response Criteria for Patients with Measurable Disease (i.e., Target Disease)  
| Version date: 03/20/2019  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 | no prior SD, PR or CR                             |
| PD        |                                                                                                                                                                                                                                                                                                                              |      |    |                                                   |
| No        |                                                                                                                                                                                                                                                                                                                              |      |    |                                                   |
| Any       | Any                                                                                                                                                                                                                                                                                                                          | Yes  | PD |                                                   |
| *         | See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.                                                                                                                                                                                                                                           |      |    |                                                   |
| **        | Only for non-randomized trials with response as primary endpoint.                                                                                                                                                                                                                                                            |      |    |                                                   |
| ***       | ,QH[FHSWLRQDOFLUFXPVWDQFHVXQHTXLYRFDOSURJUHVVLRQLQQRQ-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. |      |    |                                                   |
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for patients with non-measurable disease

| Non-Target Lesions   | New Lesions   | Overall Response   |
|----------------------|---------------|--------------------|
| CR                   | No            | CR                 |
| Non-CR/non-PD        | No            | Non-CR/non-PD*     |
| Not all evaluated    | No            | not evaluated      |  
| Unequivocal PD   | Yes or No   | PD   |
|------------------|-------------|------|
| Any              | Yes         | PD   |  
* µ1RQ-CR/non-3'¶LVSUHIHUUHGRYHUµVWDEOHGLVHDVH¶IRUQRQ-target disease since SD is increasingly used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised SXEMHFWV ZKR KDYH H[SHULHQFHGSD, 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. 6.3.4 Responses
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6.3.4.1 best overall response (bor)

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. 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 C** for further details.
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6.4.1 immune-related bor (irbor)

The duration of Immune-related best overall response is measured from the time measurement criteria are met for irCR or irPR (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). irSD, not meeting criteria for irCR or irPR, in absence of irPD. The duration of overall irCR is measured from the time measurement criteria are first met for irCR until the first date that progressive disease is objectively documented. Confirmation of assessment might be delayed up to 12 weeks to confirm PD to account for flare.
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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). The safety assessments will be performed according to the Study Calendar, Section 3.7.
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7 safety reporting requirements /

$Q\XQWRZDUGPHGLFDORFFXUUHQFHLQDKXPDQVXEMHFWLQFOXGLQJDQ\DEQRUPDOVLJQIRUH[DPSOH abnorPDOSK\VLFDOH[DPRUODERUDWRU\ILQGLQJV\PSWRPRUGLVHDVHWHPSRUDOO\DVVRFLDWHGZLWK WKH VXEMHFW¶V SDUWLFLSDWLRQ LQ UHVHDUFK ZKHWKHU RU QRW FRQVLGHUHG UHODWHG WR WKH VXEMHFW¶V participation in the research.
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7.1.2 suspected adverse reaction

Suspected adverse reaction means any adverse event for which there is a reasonable possibility WKDWWKH GUXJ FDXVHGWKH DGYHUVH HYHQW )RUWKH SXUSRVHV RI ,1' VDIHW\ UHSRUWLQJ µUHDVRQDEOH SRVVLELOLW\¶PHDQVWKHUHLV HYLGHQFHWR VXJJHVW D FDXVDO UHODWLRQVKip between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, which means any adverse event caused by a drug. 7.1.3 8QH[SHFWHGDGYHUVHUHDFWLRQ An adverse event or suspected adYHUVHUHDFWLRQLVFRQVLGHUHG³XQH[SHFWHG´LILWLVQRWOLVWHGLQWKH LQYHVWLJDWRUEURFKXUHRULVQRWOLVWHGDWWKHVSHFLILFLW\RUVHYHULW\WKDWKDVEHHQREVHUYHGRULIDQ investigator brochure is not required or available, is not consistent with the risk information GHVFULEHGLQWKHJHQHUDOLQYHVWLJDWLRQDOSODQRUHOVHZKHUHLQWKHFXUUHQWDSSOLFDWLRQ8QH[SHFWHG´ also refers to adverse events or suspected adverse reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as anticipated from the pharmacological properties of the drug but are not specifically mentioned as occurring with the particular drug under investigation.
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7.1.4 serious

An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious Adverse Event or if it compromises the safety, welfare or rights of subjects or others.
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7.1.5 serious adverse event

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:
x Death, x A life-WKUHDWHQLQJDGYHUVHGUXJH[SHULHQFH  
x ,QSDWLHQWKRVSLWDOL]DWLRQRUSURORQJDWLRQRIH[LVWLQJKRVSLWDOL]DWLRQ x Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions x A congenital anomaly/birth defect. x Important medical events that may not result in death, be life-threatening, or require KRVSLWDOL]DWLRQPD\ EHFRQVLGHUHGD VHULRXVDGYHUVH GUXJH[SHULHQFHZKHQ EDVHG XSRQ 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.  
7.1.6 Disability
$VXEVWDQWLDOGLVUXSWLRQRIDSHUVRQ¶VDELOLW\WRFRQGXFWQRUPDOOLIHIXQFWLRQV 7.1.7 Life-threatening DGYHUVHGUXJH[SHUience Any adverse event or suspected adverse reaction that places the patient or subject, in the view of the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does not include a reaction that had it occurred in a more severe form, might have caused death. 7.1.8 Protocol Deviation (NIH Definition) Any change, divergence, or departure from the IRB-approved research protocol. 7.1.9 Non-Compliance (NIH Definition) The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of human research subjects. 7.1.10 Unanticipated Problem $Q\LQFLGHQWH[SHULHQFHRURXWFRPHWKDW
x ,VXQH[SHFWHGLQWHUPVRIQDWXUHVHYHULW\RUIUHTXHQF\LQUelation to
(a) the research risks that are described in the IRB-approved research protocol and LQIRUPHGFRQVHQWGRFXPHQW,QYHVWLJDWRU¶V%URFKXUHRURWKHUVWXG\GRFXPHQWVDQG EWKHFKDUDFWHULVWLFVRIWKHVXEMHFWSRSXODWLRQEHLQJVWXGLHGAND  
x ,VUHODWHGRUSRVVLEO\UHODWHGWRSDUWLFLSDWLRQLQWKHUHVHDUFKAND x Suggests that the research places subjects or others at a *greater risk of harm* (including physical, psychological, economic, or social harm) than was previously known or recognized
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7.2 nih intramural irb and

7.2.1 NIH Intramural IRB DQG1&,&'([SHGLWHG5HSRUWLQJRI8QDQWLFLSDWHG3UREOHPVDQG
Deaths The Protocol PI will report in the NIH Problem Form to the NIH Intramural IRB and NCI Clinical Director:
x $OOGHDWKVH[FHSWGHDWKVGXHWRSURJUHVVLYHGLVHDVH  
x All Protocol Deviations
x All Unanticipated Problems x All non-compliance Reports must be received within 7 days of PI awareness via iRIS. 7.2.2 NIH Intramural IRB Requirements for PI Reporting at Continuing Review The protocol PI will report to the NIH Intramural IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation occurred, a brief description of the deviation and any corrective action.  
2. A summary of any instances of non-compliance 3. A tabular summary of the following adverse events:
x All Grade 2 **unexpected** events that are possibly, probably or definitely related to the UHVHDUFK
x All Grade 3 and 4 events that are possibly, probably or definitely related to tKHUHVHDUFK x All Grade 5 events regardless of attribution.
x All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NIH Intramural IRB Reporting of IND Safety Reports Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported to the NIH Intramural IRB.
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7.3 ind sponsor reporting criteria

From the time of the first study treatment through the first 28 days after the subject receives the last investigational agent/intervention, the investigator must **immediately** report to the sponsor, using the mandatory MedWatch form 3500a or equivalent, any serious adverse event, whether or not considered drug related, including those listed in the protocol or investigator brochure and must include an assessment of whether there is a reasonable possibility that the drug caused the event. For events that occur more than 28 days after the last administration of investigational agent/intervention, only report serious adverse events that have an attribution of at least possibly related to the agent/intervention. Required timing for reporting per the above guideline:  
x Deaths H[FHSW GHDWK GXHWR SURJUHVVLYH GLVHDVHPXVW EH UHported via email within 24 hours. A complete report must be submitted within one business day.  
x Other serious adverse events including deaths due to progressive disease must be reported within one business day
Events will be submitted to Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov and to the CCR PI and study coordinator. 7.3.1 Reporting Pregnancy  
7.3.1.1 Maternal H[SRVXUH
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. The potential risk of H[SRVXUH RI WKH IHWXV WR WKH LQYHVWLJDWLRQDO DJHQWV RU FKHPRWKHUDS\ DJHnts (s) should be GRFXPHQWHGLQER[%RIWKH0HG:DWFKIRUP³'HVFULEH(YHQWRU3UREOHP´ Pregnancy itself is not regarded as an SAE. However, as patients who become pregnant on study ULVNLQWUDXWHULQHH[SRVXUHRIWKHIHWXVWRDJHQWVZKLFKPD\EHWHUDWRJHQLc, the CCR is requesting WKDWSUHJQDQF\VKRXOGEHUHSRUWHGLQDQH[SHGLWHGPDQQHUDVGrade 3 "Pregnancy, puerperium and perinatal conditions - *Other (pregnancy*)" under the *Pregnancy, puerperium and perinatal* conditions SOC. Congenital abnormalities or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.  
If any pregnancy occurs in the course of the study, then the investigator should inform the Sponsor within 1 day, i.e., immediately, but **no later than 24 hours** of when he or she becomes aware of it. The designated Sponsor representative will work with the investigator to ensure that all relevant information is provided to the Sponsor within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available.
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7.3.1.2 paternal h[srvxuh

Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last treatment with M7824 or gemcitabine whichever occurs later. Pregnancy of WKH SDWLHQW¶V SDUWQHU LV QRW FRQVLGHUHG WR EH DQ $( +RZHYHU WKH RXWFRPH RI DOO SUHJQDQFLHV (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 4 months after the last treatment with M7824 or gemcitabine whichever occurs later should, if possible, be followed up and documented.
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7.4 reporting criteria to the

All events listed below must be reported in the defined timelines to CCRsafety@mail.nih.gov. The CCR Office of Regulatory Affairs will send all reports to the manufacturer as described below, H[FHSWDVQRWHG.
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7.4.1 emd-serono

The following reportable events must be submitted to EMD Serono within 2 business days or 3 calendar days (whichever comes first) using the Medwatch form or equivalent. The Sponsor will assume responsibility for submitting the reportable event(s) to EMD Serono as well as ensuring that any local reporting requirements are completed in parallel.  
x Serious Adverse Events x ([SRVXUHGXULQJ3UHJQDQF\RU%UHDVWIHHGLQJHYHQLIQRWDVVRFLDWHGZLWKDQDGYHUVH
event)
x 2FFXSDWLRQDOH[SRVXUHHYHQLIQRWDVVRFLDWHGZLWKDQDGYHUVHHYHQW  
x Potential drug-LQGXFHGOLYHULQMXU\+\¶V/DZFDVHV7KHVHHYHQWVDUHFRQVLGHUHG
important medical events and should be reported as SAEs.  
x In addition, all AEs will be collected in tabulated form and reported to EMD Serono as outlined in the Collaborative Agreement. **Note:** The PI and Research Team will be responsible for reporting the AEs that are not specifically listed above.  
7.4.1.1 Reporting of Overdose of M7824
$QRYHUGRVHLVGHILQHGDVDQ\GRVHJUHDWHUWKDQWKHKLJKHVWGRVHLQFOXGHGLQWKHFOLQLFDOWULDO protocol. Any overdose must be recorded in the trial medication section of the eCRF. For monitoring purposes, any case of overdose, whether or not associated with an AE (serious or non-serious), must be reported to the sponsor.  
There are no known symptoms of M7824 overdose to date. The Investigator should monitor closely for AEs should an overdose occur and use his or her clinical judgment in providing symptomatic / supportive care as medically indicated. There is no known antidote for M7824.
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contact information for submission of

E-mail: ICSR_CT_GPS@merckgroup.com Specifying: PROTOCOL Number and/or Title EMD Serono assigned Study Number (MS200647_0015) SUBJECT Number PI Name SAE/ONSET DATE.
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7.5 data and safety monitoring

7.5.1 Principal Investigator/Research Team The clinical research team will meet on a regular basis (every two weeks by teleconference with the pharmaceutical collaborator) when patients are being actively treated on the trial to discuss each patient, enrollment and data management issues. Decisions about dose level enrollment and GRVHHVFDODWLRQZLOOEHPDGHEDVHGRQWKHWR[LFLW\GDWDIURPSULRUSDWLHQWV All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Adverse events will be reported as required above. Any safety concerns, new information that might affect either the ethical and or scientific conduct of the trial, or protocol deviations will be immediately reported to the IRB using iRIS. 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. 7.5.2 Sponsor Monitoring Plan As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring SURJUDP7KH&&5¶VSURJUDPDOORZVIRUFRQILUPDWLRQRIVWXG\GDWDVSHFLILFDOO\GDWDWKDWFRXOG affect the interpretation of prLPDU\VWXG\HQGSRLQWVDGKHUHQFHWRWKHSURWRFRO UHJXODWLRQVDQG 623VDQGKXPDQVXEMHFWVSURWHFWLRQ7KLVLVGRQHWKURXJKLQGHSHQGHQWYHULILFDWLRQRIVWXG\GDWD with source documentation focusing on:  
x Informed consent process x Eligibility confirmation x Drug administration and accountability x Adverse events monitoring x Response assessment.
7KHPRQLWRULQJ SURJUDPDOVRH[WHQGVWRPXOWL-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified E\WUDLQLQJDQG H[SHULHQFHWRPRQLWRUWKH SURJUHVV RIFOLQLFDOWULDOV3HUVRQQHOPRQLWRULQJWKLV study will not be affiliated in any way with the trial conduct.
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8 statistical considerations 8.1 statistical

The primary objectives of this trial are to determine the safety and tolerability, measured by number, severity and duration of treatment-related AEs for the combination treatment M7824 and gemcitabine according to CTCAE v5.0, and the occurrence, severity, and duration of TreatmentEmergent Adverse Events (TEAEs) for the combination treatment M7824 and gemcitabine according to the NCI-CTCAE v5.0. and the efficacy, as measured by Best Objective Response (BOR) rate according to RECIST 1.1 8.1.2 Secondary efficacy endpoints The secondary endpoints are the following:  
x Progression-free Survival (PFS)
x Overall survival (OS) x Immune-related BOR (irBOR) using the immune-related RECIST (irRECIST)
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8.2 6dpsohvl]hghwhuplqdwlrq

Prior to amendment B, the protocol enrolled 6 evaluable patients into safety run-in and according to DLT definition, DLTs were recorded. We want to change DLT definition and the results from these initial 6 patients will be reported as a separate group, and accrual will begin again using the same phase IB design as initially proposed, but with new DLT definition described in amendment B. Total amount of patient on trial will be the same as with this amendment we are removing 200 mg M7824 dose level.
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phase ib

This combination will be first given to 6 patients as a safety run-in: the doses are 1,200 mg for M7824 and an assigned gemcitabine dose: 600 or 1,000 mg/m2 weekly according to baseline pharmacogenomic profiling. If there are 0-1 grade 3 and 4 DLTs, the study will proceed to the phase 2 cohorts ,IWKHUHDUHJUDGHDQG'/7VWKHUHZLOOEHDGRVH UHGXFWLRQWR mg M7824 and the safety run-in in 6 patients will be repeated. With these 6 patients who have 0-1 DLTs in 6 patients at the reduced level of M7824, the trial will then be carried out in the phase 2 cohorts,IRUPRUHJUDGHRUJUHDWHUWR[LFLWLHVDUHVHHQLQWKLVVHFRQGUXQ-in of 6 patients, the study will be halted. Thus, no more than 12 evaluable patients will be enrolled in the phase IB cohort with Amendment B.
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phase ii

The study will be conducted using a Simon two-VWDJHSKDVHPLQLPD[GHVLJQ The objective of the trial will be to determine whether this novel combination can be associated with a response UDWH35&55(&,67WKDWFDQUXOHRXWS LQIDYRURIDQLPSURYHGUHVSRQVHUDWHRI S  8VLQJ DOSKD  SUREDELOLW\ RI DFFHSWLQJ D SRRU DJHQW DQG EHWD (probability of rejecting a good agent), initially 13 evaluable patients will be enrolled into the phase II study, including up to 6 patients from the completed safety cohort if they are completely eligible for the phase II portion of the trial. If 0 of 13 patients respond, then no further patients will be enrolled. If 1 or more of the first 13 evaluable patients enrolled have a response (PR or CR), then accrual will continue until a total of 20 evaluable patients have been enrolled. Since it may take several weeks for a response to be identified, a pause in the accrual of 6 weeks will be made before accruing to the second stage. If 1 to 2 of the 20 has a clinical response, then this will be considered LQDGHTXDWHIRUIXUWKHULQYHVWLJDWLRQRIWKLVUHJLPHQ,IRUPRUHRIUHVSRQGWKHQWKLV will warrant further investigation in a subsequent trial. Under the null h\SRWKHVLVUHVSRQVH UDWHWKHSUREDELOLW\RIHDUO\WHUPLQDWLRQLV Although participants who are in the phase II cohort will receive different levels of gemcitabine based on their genetic results, the participants will have their outcomes combined and will be evaluated using a single two-stage design with up to 20 participants. This will then assess the ability of the treatment strategy of gemcitabine (regardless of dose 600 or 1000 mg/m2) and M7824 at a consistent dose to act together and produce responses. Thus, with 6 patients enrolled prior to Amendment B, up to 12 participants in the phase IB cohort starting with Amendment B and up to 20 evaluable participants in phase II, the trial may require up to 38 participants to be treated. This number may be reduced by up to 6 participants treated at the RP2D in the phase IB portion of the study. To allow for a small number of inevaluable patients, the accrual ceiling will be set at 41 participants. With an anticipated accrual rate of 10-12 patients SHU\HDULWLVH[SHFWHGWKDWWKHWULDOPD\FRPSOHWHDFFUXDOZLWKLQWR\HDUV 8.2.1 Populations for analysis Evaluable for objective response: all patients who receive at least one dose of M7824 in combination with gemcitabine at the dose level determined to be safe in the initial safety run-in in 6 patients will be included in the statistical analyses performed.) Evaluable Non-Target Disease Response: all patients who receive at least one dose of M7824 in combination with gemcitabine at the dose level determined to be safe in the initial safety run-in in 6 patients will be included in the statistical analyses performed. The response assessment is based on the presence, absence, or unequivocal progression of the lesions. (YDOXDEOH IRU WR[LFLW\: $OO SDWLHQWV ZLOO EH HYDOXDEOH IRU WR[LFLW\ IURP WKH WLPH RI WKHLU ILUVW treatment with M7824. Evaluable for RP2D: Subject 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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8.3 description of statistical analyses

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 0GRVHXVHGLQWKHSKDVH,,H[SDQVLRQZLOOKDYHWKHIUDFWLRQRIFOLQLFDOUHVSRQVHVGHWHUPLQHG 8.3.2 Analysis of the primary efficacy endpoints Patients who are in the efficacy evaluation will have the fraction of clinical responses determined DQGUHSRUWHGDORQJZLWKWZRVLGHGDQGFRQILGHQFHLQWHUYDOV. 8.3.3 Analysis of the secondary efficacy endpoints Overall survival and PFS will be determined in all patients treated at the RP2D of the combination of M7824 and gemcitabine using Kaplan-Meier curves. Any comparisons with published results ZLOOEHLQWHUSUHWHGDVEHLQJH[SORUDWRU\7KHLPPXQH-related BOR (irBOR) rate will be determined by dividing the number of patients with an immune-related response by the number of evaluable patients who are treated at the RP2D. The fraction with irBOR will be reported along with two-VLGHGDQGFRQILGHQFHLQWHUYDOV
At the end of the trial, as a secondary analysis, a retrospective evaluation will be performed to GHWHUPLQHWKHLQGLYLGXDOUHVSRQVHUDWHVEDVHGRQWKHSDUWLFLSDQWV
JHQHWLFWUHDWPHQWUHVXOWV7KLV HYDOXDWLRQZLOOLQFOXGH DQG WZR-sided confidence intervals for each of the treatment arms within the phase II cohort.
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8.3.4 safety analyses

3DWLHQWVLQWKHSKDVH,SRUWLRQRIWKHWULDOZLOOEHDVVHVVHGIRUWR[LFLW\E\UHSRUWLQJWKHJUDGHVRI WR[LFLW\DQGWKHW\SHRIWR[LFLW\REVHUYHGIRUDOOSDWLHQWV3DWLHQWVZLOOEHHQUROOHGDQGHYDOXDWHG in the phase IB cohort of the trial as described in the phase IB 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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8.3.5 baseline descriptive statistics

Limited demographic and clinical characteristics of all patients will be reported, separately for the phase IB and the phase II cohorts. 8.3.6 Planned interim analyses:
7R[LFLW\ ZLOO EH DVVHVVHG ZLWKLQ HDFK group of 6 patients accrued in the phase IB cohort. An evaluation of the fraction of patients who respond in the phase IB part will be included in the phase II cohort, as indicated in the phase II sample size determination section.  
8.3.7 ([SORUDWRU\ analyses
([SORUDWRU\objectives of the study are to compare each of following parameters between patients in the phase II cohorts of the trial who are clinical responders vs. non-responders, using the approach described below for each: Tumor perfusion measured by Dynamic Contrast Enhanced MRI (DCE-05,WKLVZLOOSULPDULO\ compare the Houndsfield units obtained between responders and non-UHVSRQGHUV XVLQJ DQ H[DFW :LOFR[RQUDQNVXPWHVW Impact of baseline somatic genomic profile of advanced pancreatic cancers on clinical response to M7824 in combination with gemcitabine. The number of somatic mutations obtained for each patient will be compared between responders and non-responders. This will be done using either a )LVKHU¶VH[DFWWHVW&RFKUDQ-Armitage trend test, oUH[DFW:LOFR[RQUDQNVXPWHVWGHSHQGLQJRQWKH distributions of values. Determination of circulating free tumor DNA (cftDNA) levels to correlate with clinical course of SDQFUHDWLFFDQFHUSDWLHQWVWUHDWHGZLWK0LQFRPELQDWLRQZLWKJHPFLWDELQHthe levels will be compared between responders and non-UHVSRQGHUVXVLQJDQH[DFW:LOFR[RQUDQNVXPWHVW Measures of intra-tumoral immune cell fractions to evaluate the intra-tumoral immunogenicity of 0 LQ FRPELQDWLRQ ZLWK JHPFLWDELQH WKHVHfractions per patient will be compared between responders and non-responders using an appropriate non-parametric test.  
Health-related Quality of Life (HRQoL) scores measuring patient-reported disease-specific symptoms and treatment-UHODWHG FRQFHUQVWKHVH ZLOO EHFRPSDUed between responders and non-UHVSRQGHUVXVLQJDQH[DFW:LOFR[RQUDQNVXPWHVW
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collaborative agreements cooperative research and

A CRADA (02666) is in place with EMD Serono for the supply of M7824.
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10 human subjects protections 10.1

Subjects from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria. (IIRUWVZLOOEHPDGHWRH[WHQGWKHDFFUXDOWRDUHSUHVHQWDWLYHSRSXODWLRQ.
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10.2 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 cancerDQGEHFDXVHRIXQNQRZQWR[LFLWLHVLQSHGLDWULFSDWLHQWV
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10.3 participation of subjects unable

Adults XQDEOHWRJLYHFRQVHQWDUHH[FOXGHGIURPHQUROOLQJLQWKHSURWRFRO 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 **10.4.2**), 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 as needed for the following: an independent assessment of whether an individual has the capacity to provide FRQVHQWDVVLVWDQFHLQLGHQWLI\LQJDQGDVVHVVLQJDQDSSURSULDWH VXUURJDWHZKHQLQGLFDWHGDQGRUDQDVVHVVPHQWRIWKHFDSDFLW\WRDSSRLQWDVXUURJDWH. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in MEC Policy 87-4 and NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisional impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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10.4 evaluation of benefits and

The primary ULVNWRSDWLHQWVSDUWLFLSDWLQJLQWKLVUHVHDUFKVWXG\LVIURPWKHWR[LFLty of M7824 and gemcitabine, or both drugs. M7824 is an investigational agent designed to enhance antitumor efficacy of standard treatment. Gemcitabine is an approved agent for treatment of pancreatic cancer. 7KH SURWRFRO SURYLGHV IRU GHWDLOHG DQG FDUHIXO PRQLWRULQJ RI DOO SDWLHQWV WR DVVHVV IRU WR[LFLW\ 7R[LFLW\GDWDIURPWKHphases I and II dose levels will be collected and reviewed to ensure that there ZHUHQRVHYHUHWR[LFLWLHVWKDWZRXOGSUHFOXGHIXUWKHUSDWLHQWHQUROOPHQW3DWLHQWVZLOOEHWUHDWHGZLWK
therapeutic intent and response to the therapy will be closely monitored.
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10.4.1 risks 10.4.1.1 risk of

All care will be taken to minimize risks that may be incurred by tumor sampling. Biopsies will be taken by Interventional Radiology sampling the lesion which is most accessible and can be sampled with the least morbidity. Up to 6 passages are allowed if deemed safe by the Interventional Radiologist. All procedure-related risks (such as bleeding, infection and visceral injury) that will be H[SODLQHGIXOO\GXULQJLQIRUPHGFRQVHQW.  
10.4.1.2 5LVNVRIH[SRVXUHWRLRQL]LQJUDGLDWLRQ
This research study involves two optional CT guided biopsies collected for research purposes. Subjects undergoing two biopsies FROOHFWLRQVZLOOEHH[SRVHGWR6 rem. This amount of radiation is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee.  
10.4.1.3 Risks of Dynamic Contrast Enhanced MRIs (DCE-MRI)
This research study involves up to 5 Dynamic Contrast Enhanced MRIs (DCE-MRI) 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.  
10.4.1.4 Research Blood Collection Risks Risks of blood draws include pain and bruising in the area where the needle is placed, lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) can develop.
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10.4.1.5 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.  
10.4.1.6 Non-Physical Risks of Genetic Research Risk of receiving unwanted information
$Q[LHW\DQG VWUHVVPD\DULVHDVD UHVXOW RIWKHDQWLFLSDWLRQWKDW XQZDQWHGLQIRUPDWLRQ UHJDUGLQJ 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.  
10.4.2 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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10.5 risks/benefits analysis for all

For patients with advanced pancreas cancer, median survival is in the range of 6 months. It is possible that treatment on this protocol may reduce tumor burden or lessen symptoms caused by the cancer. While treatment on this protocol may not individually benefit subjects, the knowledge gained from this study may help others in the future who have pancreatic cancer. Potential risks include the possible occurrence of any of a range of side effects listed. If patients suffer any physical LQMXU\DVD UHVXOWRIWKH ELRSVLHVLPPHGLDWHPHGLFDOWUHDWPHQWLVDYDLODEOHDWWKH1,+¶V&OLQLFDO Center in Bethesda, Maryland. Although no compensation is available, any injury will be fully evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations.
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10.6 consent process and documentation

The investigational nature and research objectives of this trial, the procedures and treatments involved and their attendant risks and discomforts and benefits, and potential alternative therapies ZLOOEHFDUHIXOO\H[SODLQHGWRWKHSDWLHQWDQGDVLJQHGLQIRUPHGFRQVHQWGRFXPent will be obtained by a study investigator prior to entry onto the study. The PI or associate investigator will meet with the patient to discuss the protocol treatment and alternative options in detail. It will be stated clearly that participation in the research study is voluntary and that participants can withdraw from the study without losing benefits they would otherwise be entitled to. The patient will be encouraged to ask questions, and additional meetings to discuss the treatment options will be arranged as necessary.  
10.6.1 Re-Consent via Telephone The informed consent document will be sent to the subject. $QH[SODQDWLRQ RIWKH VWXG\ZLOO EH provided over the telephone after the subject has had the opportunity to read the consent form. The subject will sign and date the informed consent. The original informed consent document will be sent back to the consenting investigator who will sign and date the consent form with the date the consent was obtained via telephone. $IXOO\H[HFXWHGFRS\ZLOOEHUHWXUQHGYLDPDLOIRUWKHVXEMHFW¶VUHFRUGV.
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11 pharmaceutical information 11.1 m7824

Other names: Anti PDL-1 TGF Beta-Trap, "TRAP", MSB0011359C The finished injectable dosage form is manufactured by EMD 6HURQR5HVHDUFK'HYHORSPHQW Institute, Inc. 11.1.1 Status: For Investigational Use Only. 11.1.2 Brief Mechanism of Action/Drug Classification: M7824 is a fully human antibody of the IgG1 isotype designed as a single molecule that blocks the following two major immune escape mechanisms (negative immunoregulatory pathways) simultaneously: PD-L1/PD1 signaling and TGF-EHWDVLJQDOLQJ3'/LVKLJKO\H[SUHVVHGLQWXPRU cells, which strongly correlates with poor prognosis in a variety of human cancers. TGF-beta is associated with malignant progression, evasion of immune surveillance, invasion and metastasis. Elevated levels of TGF-beta correlate with poor outcome in many different human cancers. 11.1.3 How Supplied:
M7824 is supplied in two different formulations: a sterile lyophilized powder and a sterile liquid.  
Lyophilized (freeze-dried) formulation: Supplied as a Type 1 glass vial containing a white lyophilized powder. Each vial contains 45 mg RI0DQGZYWUHKDORVHGLK\GUDWHP0VRGLXPFKORULGHP0/-methionine and ZYSRO\VRUEDWH7ZHHQDQGP0/-histidine at pH 5.5.
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liquid formulation

6XSSOLHGDVD7\SH  JODVV YLDOFRQWDLQLQJDQ H[WUDFWDEOH YROXPH RI P/ RID VWHULOHFOHDU cRORUOHVVVROXWLRQ(DFKP/FRQWDLQVPJRI0DQGZ/v) trehalose dihydrate, 40 mM sodium chloride, 5 mM L-PHWKLRQLQHDQGZYSRO\VRUEDWH7ZHHQDQGP0/- histidine at pH 5.5.
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11.1.4 storage

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. 11.1.5 Reconstitution: For lyophilized formulation only: Allow each vial to equilibrate to room temperature preferably for 10 to 20 minutes. Reconstitute each 45 mg vial with 4.5 mL of Sterile Water for Injection, USP (SWI) using a sterile syringe and needle. An 18 gauge needle is suggested. Avoid forceful impact of the SWI on the powder and avoid foaming. Slowly and gently add the SWI to the vial, aiming the flow of water towards the vial wall and NOT directly onto the lyophilized powder cake. Start the clock at this SRLQW*HQWO\LQYHUWHDFKYLDOVHYHUDOWLPHVWRPL['RQRWshake or agitate vigorously. Stop the clock after the product is completely dissolved. The reconstitution time MUST be no more than 120 seconds. When reconstituted as recommended, each mL will contain 10 mg of M7824 as a clear, colorless solution. NOTE: If the reconstitution time is greater than 120 seconds, put the vial aside to return to IDMRS and get a new vial to prepare the dose. 11.1.6 Stability: Reconstituted lyophilized vials, if not used immediately, are stable at room temperature for up to 24 hours. When GLOXWHGZLWK6RGLXP&KORULGH,QMHFWLRQ863WRDFRQFHQWUDWLRQRIPJP/WR mg/mL, chemical and physical in-use stability has been demonstrated for 72 hours when stored at room temperature. 11.1.7 Administration: M7824 is administered as an intravenous (IV) infusion via a peripheral OR central vascular access device (VAD). Confirm patient has a titanium port before accessing the Central VAD. A 0.2 micron polyethersulfone (PES) in-line filter is mandatory for administration. 11.1.8 Compatibility:
M7824 is coPSDWLEOHZLWK6RGLXP&KORULGH,QMHFWLRQ863 M7824 is compatible with DEHP-free infusion bags composed of polyethylene and/or SRO\SURS\OHQH $FFHSWDEOH EDJV LQFOXGH % %UDXQ (;&(/ FRQWDLQHUV SUHILOOHG ZLWK 6RGLXP&KORULGH,QMHFWLRQ863%D[WHU INTRAVIA™ empty containers and AVIVA pre-filled bags may also be used. M7824 is compatible with DEHP-free polyvinylchloride (PVC) and polyurethane (PUR) infusion lines. A polyethersulfone (PES) 0.2 micron in-line filter is required during administration. 11.1.9 Preparation of Infusion: 1. If using the liquid formulation, allow each vial to equilibrate to room temperature preferably for 10 to 20 minutes. If using the lyophilized formulation, first follow reconstitution instructions above.  
2. Gently invert the vial(s) several times before use. Do NOT shake or agitate vigorously. &DOFXODWH WKH YROXPH RI 0  PJP/ UHTXLUHG WR SUHSDUH D SDWLHQW¶V GRVH 1RWH Pharmacy will add 25 mL overfill (fluid plus drug). 4. Prepare DEDJFRQWDLQLQJWKHDPRXQWRI Sodium Chloride Injection, USP required to dilute the dose to a total volume of 250 mL. Note: Pharmacy will add 25 mL overfill (fluid plus drug). 5. With a syringe and sterile 18 gauge needle, withdraw from the vials containing the M7824 the volume calculDWHGLQ6WHSDQGLQMHFWWKHGUXJLQWRWKHEDJFRQWDLQLQJWKH6RGLXP&KORULGH Injection, USP. 6. GeQWO\PL[WKHVROXWLRQE\VORZO\LQYHUWLQJWKHFRQWDLQHUWLPHVWRHQVXUHDKRPRJHQHRXV clear solution free of visible particles. Do NOT shake the adPL[WXUHWRPL[ 7. Purge all air from the container. 8. Attach to the container an administration set for ambulatory pump with an integral 0.2 micron filter. Prime the tubing close to its distal end and cap the administration set with a Luer-locking cap. 9. The prescription label will identify the total volume to infuse: "Volume to Infuse is 250 mL" and will state the product contains overfill (25 mL fluid + drug). 11.1.10Hazards and Precautions: M7824 should be handled and labeled as a hazardous drug 11.1.11Labeled: M7824 AAPC.
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11.2 gemcitabine

Gemcitabine HCl is a white to off-white solid. It is soluble in water, slightly soluble in methanol, and practically insoluble in ethanol and polar organic solvents. Gemcitabine will be provided and prepared by the Clinical Center Pharmacy Department. The clinical formulation is supplied in a sterile form for intravenous use only. Vials of gemcitabine contain either 200 mg or 1 g of JHPFLWDELQH+&OH[SUHVVHGDVIUHHEDVHIRUPXODWHGZLWK mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, respectively) as a sterile lyophilized powder. +\GURFKORULFDFLGDQGRUVRGLXPK\GUR[LGHPD\KDYHEHHQDGGHG for pH adjustment
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11.2.17r[lflw

Data in **Table 10** are based on 979 patients receiving gemcitabine as a single-agent administered weekly as a 30-minute infusion for treatment of a wide variety of malignancies. The gemcitabine starting doses ranged from 800 to 1250 mg/m2. The frequency of all grades and severe (WHO
Grade 3 or 4) adverse events were generally similar in the single-agent safety database of 979 patients and the subset of patients with pancreatic cancer. Adverse reactions reported in the singleagent safety database resulted in discontinuation of gemcitabine WKHUDS\LQDERXWRISDWLHQWV
In the comparative trial in pancreatic cancer, the discontinuation rate for adverse reactions was IRUWKHJHPFLWDELQHDUPDQGIRUWKe 5-FU arm. All WHO-graded laboratory events are listed in **Table 10**, regardless of causality. Non-laboratory adverse events were reported, regardless oIFDXVDOLW\ IRUDWOHDVW  RIDOO SDWLHQWVH[FHSWWKH FDWHJRULHV RI([WUDYDVDWLRQ
Allergic, and Cardiovascular and certain specific events under the Renal, Pulmonary, and Infection categories (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf).  
Abbreviated Title: M7824/Gemcitabine for AAPC Version date: 03/20/2019  
| All Patients'                                                                      | Pancreatic Cancer        | Discontinuations   |        |       |          |     |     |
|------------------------------------------------------------------------------------|--------------------------|--------------------|--------|-------|----------|-----|-----|
| Patients                                                                           | (%)                      |                    |        |       |          |     |     |
| All                                                                                | Grade                    | Grade              | All    | Grade | Grade    | All |     |
| Grades                                                                             | 3                        | 4                  | Grades | 4     | Patients |     |     |
| Laboratory                                                                         |                          |                    |        |       |          |     |     |
| Hematologic                                                                        |                          |                    |        |       |          |     |     |
| Anemia                                                                             | 68                       | 7                  | 1      | 73    | 8        | 2   | <l  |
| Leukopenia                                                                         | 62                       | 9                  | <l     | 64    | 8        | l   | <l  |
| Neutropenia                                                                        | 63                       | 19                 | 6      | 61    | 17       | 7   |     |
| Thrombocytopenia                                                                   | 24                       | 4                  | l      | 36    | 7        | =   | < 1 |
| Hepatic                                                                            | <l                       |                    |        |       |          |     |     |
| ALT                                                                                | 68                       | 8                  | 2      | 72    | 10       | l   |     |
| AST                                                                                | 67                       | 6                  | 2      | 78    | 12       | s   |     |
| Alkaline Phosphatase                                                               | 55                       | 7                  | 2      | 77    | 16       | 4   |     |
| Bilirubin                                                                          | 13                       | 2                  | v      | 26    | 6        | 2   |     |
| Renal                                                                              | <                        |                    |        |       |          |     |     |
| Proteinuria                                                                        | 45                       | <                  | 0      | 32    | <        | 0   |     |
| Hematuria                                                                          | 35                       | v                  | 0      | 23    | 0        | 0   |     |
| BUN                                                                                | 16                       | 0                  | 0      | 15    | 0        | 0   |     |
| Creatinine                                                                         | 8                        | <l                 | 0      | 6     | 0        | 0   |     |
| Non-laboratory                                                                     |                          |                    |        |       |          |     |     |
| Nausea and Vomiting                                                                | 69                       | 13                 | l      | 71    | 10       | 2   | <l  |
| Pain                                                                               | 48                       | 9                  | <l     | 42    | 6        | <l  | <l  |
| Fever                                                                              | 41                       | 2                  | 0      | 38    | 2        | 0   | <l  |
| Rash                                                                               | 30                       | <l                 | 0      | 28    | <l       | 0   | <l  |
| Dyspnea                                                                            | 23                       | 3                  | <l     | 10    | 0        | < 1 | <l  |
| Constipation                                                                       | 23                       | 1                  | <l     | 31    | 3        | < 1 | 0   |
| Diarrhea                                                                           | 19                       | l                  | 0      | 30    | 3        | 0   | 0   |
| 2                                                                                  |                          |                    |        |       |          |     |     |
| Hemorrhage                                                                         | 17                       | <l                 | v      | 4     | vl       | <l  |     |
| Infection                                                                          | 16                       | l                  | <l     | 10    | 2        | <l  | <l  |
| Alopecia                                                                           | 15                       | v                  | 0      | 16    | 0        | 0   | 0   |
| Stomatitis                                                                         | 11                       | <l                 | 0      | 10    | < 1      | 0   | < 1 |
| Somnolence                                                                         | 11                       | v                  | v      | 11    | 2        | v   | <l  |
| Paresthesias                                                                       | 10                       | <                  | 0      | 10    | <l       | 0   | 0   |
| Grade based on criteria from the World Health Organization (WHO).                  |                          |                    |        |       |          |     |     |
| N=699-974; all patients with laboratory or non-laboratory data.                    |                          |                    |        |       |          |     |     |
| b N=161-241; all pancreatic cancer patients with laboratory or non-laboratory data |                          |                    |        |       |          |     |     |
| ° N=979.                                                                           |                          |                    |        |       |          |     |     |
| Cod                                                                                | Regardless of causality. |                    |        |       |          |     |     |  
Table 10. Selected WHO-graded AEs in patients receiving single-agent gemcitabine (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033 lbl.pdf)
Table includes non-laboratory data with incidence for all patients > 10%. For approximately 60% of the patients, non-laboratory events were graded only if assessed to be possibly drug-related Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle. Gemcitabine clearance is affected by age. There is no evidence, however, that unusual dose adjustments are necessary in patients over 65 years of age, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65 years. Grade 3/4 thrombocytopenia was more common in the elderly. Gemcitabine clearance is affected by gender: in the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments are necessary in women. In general, in single-agent studies of gemcitabine, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a VXEVHTXHQWF\FOHDQGWRH[SHULHQFH*UDGHQHXWURSHQLDDQGWKURPERF\WRSHQLD*HPFLWDELQH VKRXOGEHXVHGZLWKFDXWLRQLQSDWLHQWVZLWKSUHH[LVWLQJUHQDOLPSDLUPHQWRUhepatic insufficiency. Gemcitabine has not been studied in patients with significant renal or hepatic impairment.
untitled h1
11.2.2formulation

Gemcitabine 200 mg white, lyophilized powder in a 10-mL size sterile single use vial (No. 7501) NDC 0002-7501-01 1 gram white, lyophilized powder in a 50-mL size sterile single use vial (No. 7502) NDC 0002-7502-01 Store at controlled room temperature (20° to 25°C) (68° to 77°F). (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf).
untitled h1
11.2.3preparation

7KHUHFRPPHQGHGGLOXHQWIRUUHFRQVWLWXWLRQRI*HP]DULV6RGLXP&KORULGH,QMHFWLRQZLWKRXW SUHVHUYDWLYHV 'XH WR VROXELOLW\ FRQVLGHUDWLRQV WKH PD[LPXP FRQFHQtration for Gemzar upon reconstitution is 40 mg/mL. Reconstitution at concentrations greater than 40 mg/mL may result in LQFRPSOHWH GLVVROXWLRQ DQG VKRXOG EH DYRLGHG 7R UHFRQVWLWXWH DGG  P/ RI  6RGLXP Chloride Injection to the 200-mg vial or 25 mL RI6RGLXP&KORULGH,QMHFWLRQWRWKH-g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200mg vial or 1.3 mL for the 1-g vial). The total volume upon reconstitution will be 5.26 mL or 26.3 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg or 1 g of gemcitabine, respectively. The appropriate amount of drug may be administered as prepared or IXUWKHU GLOXWHG ZLWK  6RGLXP &KORULGH ,QMHFWLRQ WR FRQFHQWUDWLRQV DV ORZ DV  PJP/ Reconstituted Gemzar is a clear, colorless to light straw-colored solution. After reconstitution with 6RGLXP&KORULGH,QMHFWLRQWKHS+RIWKHUHVXOWLQJVolution lies in the range of 2.7 to 3.3. The solution should be inspected visually for particulate matter and discoloration, prior to administration, whenever solution or container permit. If particulate matter or discoloration is found, do not administer. (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf). &DXWLRQVKRXOGEHH[HUFLVHGLQKDQGOLQJDQGSUHSDULQJJHPFLWDELQHVROXWLRQV7he use of gloves is recommended. If Gemcitabine solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animDO VWXGLHV  RI  UDEELWV H[KLELWHG GUXJ-UHODWHGV\VWHPLFWR[LFLWLHVGHDWKK\SRDFWLYLW\QDVDOGLVFKDUJHVKDOORZEUHDWKLQJGXHWRGHUPDO
absorption. (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf).
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11.2.4 stability and storage

When prepared as directed, gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F). Discard unused portion. Solutions of reconstituted gemcitabine should not be refrigerated, as crystallization may occur. The compatibility of gemcitabine with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets. Unopened vials of gemcitabine DUH VWDEOH XQWLO WKH H[SLUDWLRQ GDWH LQGLFDWHG RQ WKH SDFNDJH ZKHQ VWRUHG DW FRQWUolled room temperature 20° to 25°C (68° to 77°F). (from https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/020509s033lbl.pdf).  
11.2.5Administration Procedures See Section **3.3.2**. 11.2.6 Incompatibilities and Overdose The compatibility of gemcitabine with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets. There is no known antidote for overdoses of gemcitabine. Myelosuppression, paresthesias, and severe rash ZHUHWKHSULQFLSDOWR[LFLWLHVVHHQZKHQDVLQJOHGRVHDVKLJKDV,700 mg/m2 was administered by I.V. infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.
untitled h1
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13 appendices 13.1 appendix a

| 13.1                                                                                                                                                            | Appendix A Performance Status Criteria  ECOG Performance Status Scale   | Karnofsky Performance Scale                                        |                 |           |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|--------------------------------------------------------------------|-----------------|-----------|-------------|
| Grade                                                                                                                                                           | Descriptions                                                            | Percent                                                            | Description     |           |             |
| 100                                                                                                                                                             | Normal,                                                                 | no                                                                 | complaints,     | no        |             |
| evidence of disease.                                                                                                                                            |                                                                         |                                                                    |                 |           |             |
| Normal activity. Fully active, able                                                                                                                             |                                                                         |                                                                    |                 |           |             |
| 0                                                                                                                                                               | to                                                                      | carry                                                              | on              | all       | pre-disease |
| performance without restriction.                                                                                                                                | Able to carry on QRUPDODFWLYLW\                                                                         |                                                                    |                 |           |             |
| 90                                                                                                                                                              | minor                                                                   | signs                                                              | or              | symptoms  | of          |
| disease.                                                                                                                                                        |                                                                         |                                                                    |                 |           |             |
| Symptoms,                                                                                                                                                       | but                                                                     | ambulatory.                                                        |                 |           |             |
| Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (e.g., light  housework, office work). | 80                                                                      | Normal activity ZLWKHIIRUWVRPH signs or symptoms of disease.                                                                    |                 |           |             |
| 1                                                                                                                                                               | Cares for self, unable to carry on                                      |                                                                    |                 |           |             |
| 70                                                                                                                                                              | normal activity or to do active  work.  Requires occasional assistance, |                                                                    |                 |           |             |
| 60                                                                                                                                                              | but is able to care for most of  his/her needs.                         |                                                                    |                 |           |             |
| ,Q                                                                                                                                                                 | EHG                                                                         |                                                                     | RI                 | WKH           | WLPH             |
| Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and about  PRUHWKDQRIZDNLQJKRXUV                                                                                                                                                                 |                                                                         |                                                                    |                 |           |             |
| 2                                                                                                                                                               | 50                                                                      | Requires considerable assistance  and frequent medical care.       |                 |           |             |
| 40                                                                                                                                                              | Disabled, requires special care  and assistance.                        |                                                                    |                 |           |             |
| ,QEHG!RIWKHWLPH Capable  of only limited self-care, confined  to EHGRUFKDLUPRUHWKDQRI waking hours.                                                                                                                                                                 |                                                                         |                                                                    |                 |           |             |
| 3                                                                                                                                                               | 30                                                                      | Severely disabled, hospitalization  indicated. Death not imminent. |                 |           |             |
| 20                                                                                                                                                              | Very                                                                    | sick,                                                              | hospitalization |           |             |
| indicated. Death not imminent.                                                                                                                                  |                                                                         |                                                                    |                 |           |             |
|                                                                                                                                                                  | EHGULGGHQ                                                                         | Completely                                                         |                 |           |             |
| disabled. Cannot carry on any selfcare. Totally confined to bed or  chair.                                                                                                                                                                 |                                                                         |                                                                    |                 |           |             |
| 4                                                                                                                                                               | 10                                                                      | Moribund,                                                          | fatal           | processes |             |
| progressing rapidly.                                                                                                                                            |                                                                         |                                                                    |                 |           |             |
| 5                                                                                                                                                               | Dead.                                                                   | 0                                                                  | Dead.           |           |             |
untitled h1
13.2 appendix b fact-hep

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  
  
tage for the state.
Copyright  Inst. Inv  
| Not    | A little   | Sorne-   | Quite   |
|--------|------------|----------|---------|
| at all | bit        | what     | a bit   |
| 0      | I          | 2        | 3       |
| o      | 1          | 2        | 3       |
| 2      | 3          |          |         |
| 0      | 1          |          |         |
| o      | 1          | 2        | 3       |
| o      | 1          | 2        | 3       |
| o      | 1          | 2        | 3       |
| o      | 1          | 2        | 3       |
| Not    | A little   | Some     | Quite
a bit         |
| at all | bit        | what     |         |
| o      | 1          | 2        | 3       |
| 2      |            |          |         |
| o      | 1          | 3        |         |
| 0      | 1          | 2        | 3       |
| o      | 1          | 2        | 3       |  
  
| Very   |
|--------|
| much   |  
| 4   |
|-----|
| 4   |
| 4   |
| 4.  |
| 4   |
| 4   |
| 4.  |  
| Very   |
|--------|  
much  
| 4   |
|-----|
| 4.  |
| 4   |  
4 4 3 2 2 3 4 2 3 4 10 services 2007.  
| o   |
|-----|
| ol  |
| a   |
| 024 |
| o   |
| ors |
| o   |  
| os   |
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| 02   |
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untitled h1
fact-hep (version 4)

Please circle or mark one number per line to indicate your response as it applies to the past 7 days.  
16 Version 2007.  
1999 biological institutions of the state of the sta  
| EMOTIONAL WELL-BEING                                             | Not   | A little Some- Quite Very   |             |      |    |
|------------------------------------------------------------------|-------|-----------------------------|-------------|------|----|
| at all                                                           | bit   | what,                       | a bit       | much |    |
| I feel sad .                                                     | 0     | -                           | 2           | e    | 4  |
| I am satisfied with how I am coping with my illness.             | 0     | 1                           | 2           | 1.3  | 4  |
| I am losing hope in the fight against my illness .               | 0     | l                           | 2           | 1.3  | 4  |
| I feel nervous .                                                 | o     | 1                           | 2           | 3    | 4  |
| I worry about dying                                              | 0     | 1                           | 2           | 3    | 4  |
| I worry that my condition will get worse .                       | 0     | 1                           | 2           | 3    | 4  |
| FUNCTIONAL WELL-BEING                                            | Not   | A little                    | Some- Quite | Very |    |
| at all                                                           | bit   | whath                       | a bit       | much |    |
| I am able to work (include work at home) .                       | 0     | 1                           | 2           | 1.3  | 4  |
| My work (include work at home) is fulfilling                     | 0     | 1                           | 2           | 3    | 4  |
| I am able to enjoy life.                                         | 0     | i                           | 2           | 3    | 4  |
| I have accepted my illness                                       | 0     | 1                           | 2           | 3    | 4  |
| I am sleeping well .                                             | 0     | 1                           | 2           | 3    | 4  |
| I am enjoying the things I usually do for fun                    | l     | 2                           | 3           |      |    |
| 0                                                                | 4     |                             |             |      |    |
| I am content with the quality of my life right now.............. | 1     | 2                           | 3           |      |    |
| 0                                                                | 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.  
| Not at A little Some- Quite                                  | Very                                           |     |      |       |     |    |
|--------------------------------------------------------------|------------------------------------------------|-----|------|-------|-----|----|
| ADDITIONAL CONCERNS                                          | al                                             | bit | what | a bit | muh |    |
| ca                                                           | I have swelling or cramps in my stomach area . | 0   | I    | 2     | 3   | 4  |
| I am losing weight .                                         |                                                |     |      |       |     |    |
| a                                                            | 0                                              | 1   | 2    | 3     | 4   |    |
| c                                                            | I have control of my bowels.                   | 0   | 1    | 2     | 3   | 4  |
| I can digest my food well                                    |                                                |     |      |       |     |    |
| c                                                            | 0                                              | 1   | 2    | 3     | 4   |    |
| c                                                            | I have diarrhea (diarrhoea)                    | o   | 1    | 2     | 3   | 4  |
| o                                                            | I have a good appetite .                       | 0   | 1    | 2     | 3   | 4  |
| I am unhappy about a change in my appearance                 |                                                |     |      |       |     |    |
| r                                                            | 0                                              | 1   | 2    | 3     | 4   |    |
| --                                                           | I have pain in my back .                       | 0   | i    | 2     | 3   | 4  |
| I am bothered by constipation                                |                                                |     |      |       |     |    |
| Cas                                                          | o                                              | '   | 2    | 3     | 4   |    |
| H                                                            | I feel fatigued                                | 0   | 1    | 2     | 3   | 4  |
| a                                                            | I am able to do my usual activities.           | o   | 1    | 2     | 3   | 4  |
| I am bothered by jaundice or yellow color to my skin         |                                                |     |      |       |     |    |
|                                                              | 0                                              | 1   | 2    | 3     | 4   |    |
| I have had fevers (episodes of high body temperature) ...... |                                                |     |      |       |     |    |
| is                                                           | o                                              | l   | 2    | 3     | 4   |    |
| is                                                           | I have had itching .                           | o   | 1    | 2     | n   | 4  |
| n                                                            | I have had a change in the way food tastes .   | i   | 2    | 3     |     |    |
| 0                                                            | 4                                              |     |      |       |     |    |
| e                                                            | I have had chills                              | o   | 1    | 2     | 3   | 4  |
| s                                                            | M My mouth is dry                              | o   | 1    | 2     | 3   | 4  |
| I have discomfort or pain in my stomach area .               |                                                |     |      |       |     |    |
| Ito                                                          | o                                              | i   | 2    | 3     | 4   |    |  
Indian Congress)
Copyright 1987, 1991 16 Version 2007.  
1999 biological institutions
untitled h1
13.3 appendix c modified immune-related

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 PP SHUOHVLRQ PD[LPXP RI WDUJHWOHVLRQV PD[LPXP RI  SHU RUJDQ DQG PHDVXUDEOHQHZOHVLRQVGRHVQRWLQFUHDVHE\ 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.  
Abbreviated Title: M7824/Gemcitabine for AAPC
Version date: 03/20/2019 Overall Responses Derived from Changes in Index, Non-Index, and New Lesions  
| Measurable Response                                                                                      | Non-Measurable Response   | Overall Response   |        |
|----------------------------------------------------------------------------------------------------------|---------------------------|--------------------|--------|
| Using Modified irRC                                                                                      |                           |                    |        |
| Non-Index Lesions                                                                                        |                           |                    |        |
| Index and New, Measurable                                                                                | New, Non-                 |                    |        |
| Lesions (Tumor Burden)¹                                                                                  | Measurable Lesions        |                    |        |
| Decrease 100%                                                                                            | Absent                    | Absent             | irCR²  |
| irPR²                                                                                                    |                           |                    |        |
| Decrease 100%                                                                                            | Stable                    | Any                |        |
| 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).