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for arm b

| Adverse Event                                                                                                                                                                                                             | First Occurrence                                                                                                                                                                                                                                                                                                                                   | Second Occurrence                                                                                                                                                                                   | Third Occurrence                                                                                                                                                    | Fourth Occurrence   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------|
| ANC <1000/mL                                                                                                                                                                                                              | Hold all therapy and check CBC weekly until                                                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| OR                                                                                                                                                                                                                        | covery to: ANC ≥1000/mLand Platelets                                                                                                                                                                                                                                                                                                               |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| Platelets <75000/mL                                                                                                                                                                                                       | ≥75000/mL                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| OR                                                                                                                                                                                                                        | 3. For thrombocy topenia: Decrease Oxaliplatin                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| Any Febrile Neutropenia                                                                                                                                                                                                   | to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| Hematologic Toxicity                                                                                                                                                                                                      | Hold all therapy and check CBC weekly until ecovery to: ANC ≥1000/mLand Platelets ≥75000/mL  For thrombocy topenia: Decrease Oxaliplatin to 0mg/m2 on Day 1 at the next cycle Hold all therapy and check CBC weekly until recovery to: ANC ≥1000/mLand Platelets ≥75000/mL  For thrombocy topenia: Decrease 5-FU continuous  infusion to 1800mg/m2 | Hold all therapy and check CBC weekly until recovery to: ANC ≥1000/mLand Platelets ≥75000/mL  Decrease 5-FU continuous infusion to 1200mg/m2 and discontinue Oxaliplatin on Day 1 at the next cycle |                                                                                                                                                                     |                     |
| For neutropenia: Decrease 5-FU continuous  infusion to 1800mg/m2 and decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                                                                                           |                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| For neutropenia: Add growth factor support                                                                                                                                                                                | For neutropenia: Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                                                                        |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| ANC ≥1000/ml but <1500/mL                                                                                                                                                                                                 | OR                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                     |                                                                                                                                                                     |                     |
| Platelets ≥75000/ml but  <100000/mL                                                                                                                                                                                       | For thrombocy topenia: Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                                                                  | For thrombocy topenia: Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle For thrombocy topenia: Decrease 5-FU continuous infusion to 1800mg/m2                                             | For thrombocy topenia: Decrease 5-FU continuous infusion to 1200mg/m2                                                                                               |                     |
| For neutropenia: Add growth factor support                                                                                                                                                                                | For neutropenia: Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                                                                        | For neutropenia: Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                                                                                                                         | For neutropenia: Decrease 5-FU continuous infusion to 1800mg/m2                                                                                                     |                     |
| Any other CTC ≥ Grade 3 hematologic toxicity , (e.g.  HgB <8.0g/dL)  Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                                                                                                                                                                                               | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1800 mg/m2  on Day 1 at the next cycle                               | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1200mg/m2 on Day 1 at the next cycle |                     |  
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| Version Date:10.30.2019 Nausea/Vomiting CTC ≥ Hold all therapy until recovery to Grade 1 (or Grade 3  Grade 2 level, if present at baseline) AND Add a aprepitant if not already receiving. If  already receiving, consider addin g  olanzapine and/or administerin g  dexamethasone 4mg PO day s at 24 and 48  hrs after oxaliplatin.  Non-Hema tolo gic Toxicity   | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Reduce oxaliplatin to 65mg/m2 on Day 1 at the next cycle                   | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1800mg/m2 and decrease Oxaliplatin to 50mg/m2  on Day 1 at the next cycle   | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1200mg/m2 and discontinue Oxaliplatin on Day 1 at the next cycle   |     |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----|
| Diarrhea CTC ≥ Grade 3, despite optimal antidiarrheal therapy                                                                                                                                                                                                                                                                                                        | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                 |                                                                                                                                                                                                            |                                                                                                                                                                                                   |     |
| Fatigue CTC ≥ Grade 3 OR Mucositis CTC ≥ Grade 3  OR Other Toxicity Not  Defined Herein CTC ≥ Grade 3 despite optimal supportive care Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1800mg/m2 on Day 1 at the next cycle                                                            | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1200mg/m2 on Day 1 at the next cycle  | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 65mg/m2 on Day 1  at the next cycle                                                      |                                                                                                                                                                                                   |     |
| Hold all therapy until recovery to Grade 1 (or rade 2 level, if present at baseline) AND Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                  | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1800mg/m2 on Day 1 at the next cycle  | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 50mg/m2 on Day 1  at the next cycle                                                      | Hold all therapy until recovery to Grade 1 (or Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1200mg/m2 on Day 1 at the next cycle                               |     |
| Peripheral Neuropathy CTC Hold all therapy until recovery to Grade ≤ 2 ≥ Grade 2  AND Decrease Oxaliplatin to 65mg/m2 on Day 1 at the next cycle                                                                                                                                                                                                                     |                                                                                                                                                                      |                                                                                                                                                                                                            |                                                                                                                                                                                                   |     |
| FOLFOX-Specific Toxicities                                                                                                                                                                                                                                                                                                                                           | Hold all therapy until recovery to Grade ≤ 2 AND Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                                                          | Hold all therapy until recovery to Grade ≤ 2 AND Discontinue Oxaliplatin on Day 1 at the next  cycle                                                                                                       |                                                                                                                                                                                                   | N/A |
| Hand-Foot sy ndrome CTC Hold all therapy until recovery to Grade 1 (or  ≥ Grade 3  Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1800mg/m2 on Day 1 at the next cycle                                                                                                                                                              | Hold all therapy until recovery to Grade 1 (or  Grade 2 level, if present at baseline) AND Decrease 5-FU continuous infusion to 1200mg/m2 on Day 1 at the next cycle | Hold all therapy until recovery to Grade 1 (or  Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 65mg/m2 on Day 1  at the next cycle                                                     | Hold all therapy until recovery to Grade 1 (or  Grade 2 level, if present at baseline) AND Decrease Oxaliplatin to 50mg/m2 on Day 1 at the next cycle                                             |     |  
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3.6 study calendar

- Weight may be assessed within 2 days prior to avelumab dosing for all cycles
- Cycle 1 day 1 assessments may be performed within 16 days prior to what is indicated
- Other day 1 assessments in cycles 2 and beyond may be performed within 1 week prior to indicated time
- **D1 and D2 of each cycle may be moved +/- 2 days for logistical reasons** - When a cycle must be delayed for logistical or medical reasons that cycle can be given the following week (as opposed to waiting 2 weeks) and future dosing should reset to every other week following that administration.  
| Maintenance                  | Post Therapy   |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
|------------------------------|----------------|-----------|----|----|----------------|----|----|----|----|-----|-----|-----|----|----------------|----|----|
| Induction Therapy            | Therapy        | Follow-up |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| 30  day  safety  visit4      | Long  term     |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| follow up                    |                |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| Bevacizumab12                | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  |                |    |    |
| FOLFOX13                     | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   |    |                |    |    |
| Capecitabine/5-FU            | X              |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| Avelumab 14                  | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  |                |    |    |
| Ad-CEA vaccine 14            | X              | X         | X  | X  | X              | X  | X  |    |    |     |     |     |    |                |    |    |
| History and PE               | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | Every 4 cycles | X  |    |
| Height                       | X              |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| Weight                       | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  |    |
| Vital signs                  | X              | X         | X  |    |                |    |    |    |    |     |     |     |    |                |    |    |
| Performance Score            | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  |    |
| CBC with  differential       | X              | X         | X2 | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  | X  |
| Hepatic +Acute  Care Panels5 | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  | X  |
| Mineral Panel4               | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  |    |
| ACTH, ANA, RF,  TSH, T46     | X              | X         | X  | X  | Every 4 cycles | X  |    |    |    |     |     |     |    |                |    |    |
| PT/INR, PTT                  | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  |    |
| Urinalysis7                  | X              | X         | X  | X  | X              | X  | X  | X  | X  | X   | X   | X   | X  | X              | X  |    |
| Screening1                              | Baseline2                |           |    |    |                |    |    |    |    |     |     |     |    |                |    |    |
| Procedure                    | C1             | C2        | C3 | C4 | C5             | C6 | C7 | C8 | C9 | C10 | C11 | C12 | CX |                |    |    |
| D13  D1                      | D1             | D1        | D1 | D1 | D1             | D1 | D1 | D1 | D1 | D1  | D1  |     |    |                |    |    |  
62  
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| Version Date:10.30.2019                                  | Maintenance   | Post Therapy   |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
|----------------------------------------------------------|---------------|----------------|----|----------------|----------------------------------|----|----------------|----|----|-----|-----|-----|----|----|----|
| Induction Therapy                                        | Therapy       | Follow-up      |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| 30  day  safety  visit4                                  | Long  term    |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| follow up                                                |               |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| 12 lead EKG                                              | X             | X              | X  | X              | X                                |    | Every 4 cycles |    |    |     |     |     |    |    |    |
| HBV, HCV and  HIV testing                                | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Serum or urine  HCG in women of  childbearing  potential | Screening1               | Baseline2                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Procedure                                                | C1            | C2             | C3 | C4             | C5                               | C6 | C7             | C8 | C9 | C10 | C11 | C12 | CX |    |    |
| D13  D1                                                  | D1            | D1             | D1 | D1             | D1                               | D1 | D1             | D1 | D1 | D1  | D1  |     |    |    |    |
| X                                                        | X             | X              | X  | X              | X                                | X  | X              | X  | X  | X   | X   | X   | X  | X  | X  |
| Pathology  confirmation of dx                            | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| HLA profiling,  HLA A, B, C                              | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| subtype Archival tumor  tissue                           | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Optional Biopsy8                                         | X             | X              |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Correlative  research blood9                             | X             | X              | X  | X              | Every 4 cycles  (with restaging) |    |                |    |    |     |     |     |    |    |    |
| CT CAP or CT  chest + MRI                                | X             | X              | X  | Every 4 cycles |                                  |    |                |    |    |     |     |     |    |    |    |
| abdomen/pelvis Brain MRI if  clinically indicated        | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Adverse Events                                           | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Concomitant  Medications                                 | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| Consent                                                  | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |
| NIH Advanced  Directives Form10                          | X             |                |    |                |                                  |    |                |    |    |     |     |     |    |    |    |  
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| Maintenance                                                                                                                                         | Post Therapy   |           |    |    |    |    |    |    |    |     |     |     |    |
|-----------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-----------|----|----|----|----|----|----|----|-----|-----|-----|----|
| Induction Therapy                                                                                                                                   | Therapy        | Follow-up |    |    |    |    |    |    |    |     |     |     |    |
| 30  day  safety  visit4                                                                                                                             | Long  term     |           |    |    |    |    |    |    |    |     |     |     |    |
| follow up                                                                                                                                           |                |           |    |    |    |    |    |    |    |     |     |     |    |
| Annual phone call  for survival 11                                                                                                                  | X              |           |    |    |    |    |    |    |    |     |     |     |    |
| Screening1                                                                                                                                                     | Baseline2                |           |    |    |    |    |    |    |    |     |     |     |    |
| Procedure                                                                                                                                           | C1             | C2        | C3 | C4 | C5 | C6 | C7 | C8 | C9 | C10 | C11 | C12 | CX |
| D13  D1                                                                                                                                             | D1             | D1        | D1 | D1 | D1 | D1 | D1 | D1 | D1 | D1  | D1  |     |    |
| 1 Screening assessments are performed within 16 days prior to enrollment except for: scans - done within 28 days prior to enrollment; viral screens |                |           |    |    |    |    |    |    |    |     |     |     |    |  
1 Screening assessments are performed within 16 days prior to enrollment **except** for: scans - done within 28 days prior to enrollment; viral screens
(HIV, HBV, HCV) - done within 3 months prior to enrollment; confirmation of dx which requires specimens collected within 6 month prior to study enrollment 2 May be performed within 16 days prior to initiation of study therapy.  
3 Cycle 1 day 1 assessments may be performed within 16 days prior to what is indicated.  
4 30 day safety visit occurs approximately 4 - 5 weeks after the last administration of study drug regardless of reason for discontinuation.  
Information may be obtained by telephone if patient refuses visit.  
5 **Acute Care Panel:** Sodium (NA), Potassium (K), Chloride (CL) Total CO2 (Bicarbonate), Creatinine, Glucose, Urea nitrogen, eGFR; Hepatic Panel: Alkaline Phosphatase, ALT/GPT, AST/GOT, Total Bilirubin, Direct Bilirubin; **Mineral Panel:** Albumin, Calcium, Magnesium (Mg),
Phosphorus 6 **ACTH**: adrenocorticotropic hormone; **ANA:** anti-nuclear antibody; RF: rheumatoid factor; **TSH:** Thyroid-stimulating hormone; T4: Free thyroxine.  
7 Only urine dipstick required initially. If positive for protein content, a 24 hour urine collection for protein will be performed.  
8 Two optional biopsies can be performed: one at Baseline and second at any time after completion of C4 per PI discretion.  
9 Correlative blood samples: baseline sample: 2.5 mL in PAX gene tube; On therapy: blood collected pre-dose: 5 (10mL) green top sodium heparin tubes for PBMC; 1 (8mL) SST tube for serum samples. Samples will be collected in selected patients at the investigator's discretion.  
10 As indicated in section **12.3**, 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.  
11 Patients who have come off treatment for disease progression will be followed by phone annually for survival. Patients who have not progressed on treatment will continue to be followed and scanned per investigator discretion until progression.  
12 On Day 1 in Arm A and Day 2 in Arm B (Day 1 for Arm B maintenance) 13 On Days 1 and 2 in Arm A and Days 2 and 3 in Arm B
64 Version Date:10*.30.2019* 14 Only Arm B; While avelumab will be given at every cycle, Ad-CEA will only be given on C 1, 2, 3, 5, 7, 9 and every 6 cycles (approximately 12 weeks) thereafter.
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3.7 criteria for removal from

Prior to removal from study, effort must be made to have all subjects complete a safety visit approximately 30 days following the last dose of study therapy.
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3.7.1 criteria for removal from

- Completion of protocol therapy. - Progressive disease requiring a change in systemic therapy (exception: patients Arm A
that have opted to cross over to Avelumab + Ad-CEA vaccine + standard of care).  
- Participant requests to be withdrawn from active therapy. - Unacceptable Toxicity as defined as any serious adverse event that is unexpected relative to the known safety profile of the investigational agents in the opinion of the investigator, many of which are described in sections 3.5 and **3.2.**
- Start of another systemic anticancer treatment or participation in another investigational therapeutic trial. Focal palliative radiotherapy, ablation, or surgery to a site of disease will not necessitate removal from protocol therapy. Although where appropriate progressive disease per RECIST v1.1 should be clearly documented and the decision to continue treatment beyond PD should be noted in the medical records (e.g. overall response to treatment except for isolated progressive lesion which has been treated by local intervention).  
- Positive pregnancy test. - Investigator discretion.
Regardless of reason for removal from study therapy, patients will be asked to have a 30 day follow up safety visit. Patients who refuse to return for this visit will be asked to review any safety concerns by phone within this time period.
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3.7.2 off-study criteria

- Screen Failure - Investigator discretion
- Participant requests to be withdrawn from study  
- Death
- PI decision to end the study
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3.7.3 clinical center site off

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 Update 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 .  
66 Version Date:10*.30.2019* 3.7.4 Participating Site **Off Therapy and Off-Study Procedure** 4 THE PARTICIPANT STATUS UPDATE FORM WILL BE SUPPLIED BY THE CCR
STUDY COORDINATOR. SEND THE COMPLETED FORM TO THE CCR STUDY COORDINATOR.CONCOMITANT MEDICATIONS/MEASURES
4.1 **SUPPORTIVE CARE** 4.1.1 **Recommended Management for Severe Hypersensitivity Reaction and Flu-like**
Symptoms Management 1. Epinephrine injection and dexamethasone infusion (or equivalent) 2. Patient should be placed on monitor immediately 3. Alert intensive care unit (ICU) for possible transfer if required For prophylaxis of flu-like symptoms, 25 mg indomethacin or comparable NSAID dose (e.g., ibuprofen 600 mg, naproxen sodium 500 mg) may be administered 2 hours before and 8 hours after the start of each dose of avelumab i.v. infusion. Alternative treatments for fever (e.g., acetaminophen) may be given to subjects at the discretion of the investigator.
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4.1.2 recommendations for the management

Since avelumab can induce ADCC, there is a potential risk of tumor lysis syndrome. Should this occur, subjects should be treated as per local guidelines and the management algorithm (Figure 23) published by Howard et al.74 Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC
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4.1.3 general supportive care

Additional supportive care guidelines for avelumab are found in the management tables in section 3.5.1.2 Because there is a potential for interaction of capecitabine with other concomitantly administered drugs through the CYP2C9 system, the case report form (CRF) must capture the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. The Principal Investigator should be alerted if the patient is taking any agent known to affect or with the potential to interact with capecitabine. Patients will be transitioned to an acceptable alternative if available. Common examples include aluminum and magnesium hydroxide containing antacids, coumadin, and phenytoin. Diarrhea will be managed with the following regimen: loperamide (4 mg PO) at onset of symptoms, followed by 2 mg loperamide every 2 hours while awake (or 4 mg PO every 4 hours while sleeping) up to a maximum of 16 mg loperamide per day. Additional agents may be used concurrently if loperamide is not adequate to control diarrhea as a single agent. Nausea and vomiting will be managed through the use of appropriate simple supportive measures. Recommended premedication for oxalaplatin includes aprepitant 125mg PO, dexamethasone 12mg PO, ondansetron 24mg PO and aprepitant 80mg 24 and 48 hours after receiving oxaliplatin. Alternative options may be considered, including 10-20mg IV dexamethasone and 16mg ondansetron intravenously 30-60 minutes prior to infusion, for example. Patients will receive full supportive care per NIH CC guidelines as needed while on this study including blood product support, intravenous hydration, antibiotic treatment and treatment of other newly diagnosed or concurrent medical conditions. Patients should be advised to drink plenty of water or take rehydration fluids to avoid dehydration if diarrhea occurs.
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5 biospecimen collection 5.1 correlative

Samples from patients enrolled at Georgetown and the Clinical Center will be available for immunologic correlative studies as described below. Samples will be collected in selected patients at the investigator's discretion.
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5.1.1.1 peripheral blood

Five (10mL) green top sodium heparin tubes for PBMC; 1 (8mL) SST tubes for serum samples will be drawn on day 1 of Cycle 1, 3, 5, 9 and every 4 cycles thereafter as described in the **Study** Calendar. The following assessments are planned in the Laboratory of Tumor Immunology and Biology (LTIB), CCR, NCI for the samples collected. Please see section **5.1.1.3.1** for sample processing information. 5.1.1.1.1 Leukocyte subpopulations and immune activation status: Leukocyte subpopulations and immune activation status will be assessed by flow cytometry (FACS) on PBMC. Multiparameter FACS analysis using combination of markers will be performed to characterize leukocyte subpopulations and their functional state such as:
- T-cells subsets and activation state  
- T-cells functionality
- PD-1 signaling pathway - Regulatory T-cells - Other leukocytes subsets including B-cells, monocytes - NK cells and related cytotoxicity - Differentiation stage of T-cells subsets
- Myeloid derived suppressor cells and APCs 5.1.1.1.2 Comparison presence of TAA-specific T lymphocytes using TAA-specific peptides will be performed on pre- and post-treatment samples if enough PBMCs are available 5.1.1.1.3 Further exploratory markers related to the mechanism of action of the drug such as soluble PD-L1 sera level, cytokine profile, and auto-antigen proteomic arrays may be explored.  
5.1.1.1.4 T Cell Clonal Expansion Assay
cDNA from PBMC will be amplified using locus specific primers for TCR-β. Previously described methods will be used to map the V region and identify the J region (Klinger) and identify clonal sequences of interest. Analytics tools will be used to sort and identify clonal populations of interest in the post- versus pre-treatment samples. Correlation of expansion of a clonal TCR population post treatment will be correlated with clinical outcomes.  
5.1.1.1.5 Serum soluble factors and ADCC-related side effects (such as in vitro ADCC activity assays, sCD40L and/or sCD27) may be explored.  
5.1.1.2 Tissue analysis (Optional)
Patents will be asked to provide archival tumor sample if available. Tumor specimens may be collected at baseline and any time after completion of C4 per DI discretion by the CT guided biopsies. . Biopsies may be obtained from primary tumor sites and metastatic sites (if applicable). No more than 4 cores may be obtained per site. When possible, the same site of disease should be biopsied on repeat evaluation. Specimens are used for the following studies conducted in the LTIB, CCR, NCI:  
5.1.1.2.1 Level of PD-L1 expression will be assessed by immunohistochemistry staining (IHC).  
Of note, further techniques to evaluate the expression of PD-L1 and/or marker candidates impacting the targeting or contributing to improve its expression may be also investigated if needed.  
5.1.1.2.2 Frequency and localization of tumor-infiltrated leukocytes (e.g., CD8, CD4 T-cells, Treg, NK cells, macrophage (M1/2 profile) by IHC
70 Version Date:10*.30.2019* 5.1.1.2.3 Gene expression-based subtyping Analysis to be performed in an outside lab, to be determined, using the methods described in Guinney, et al.75. We will evaluate the clinical and immunologic effects of treatment in the standard and combination arms by subtype. Additional analysis may be performed to evaluate the expression of immune-related genes in tumor tissue pre- and post-treatment in each arm.  
5.1.1.3 Sample Processing 5.1.1.3.1 Blood samples will be processed at:
Clinical Services Program NCI Frederick Cancer Research and Development Center PO Box B Frederick, MD 21702 301-846-1000 On days samples are drawn, Jennifer Bangh at CSP should be notified (phone: [301] 846-5893; fax [301] 846-6222). She will arrange courier delivery of the specimens to the processing lab. Couriers are assigned to CCR and Georgetown and this mechanism is in place. The weekly patient lists of samples drawn will be emailed to Caroline Jochems at jochemscm@mail.nih.gov, Jen Bangh at jb478s@nih.gov, and Theresa Burks at burkst@mail.nih.gov. 5.1.1.3.2 Tissue samples will be processed immediately after acquisition by a member of the clinical staff. Core biopsy material will be separated (if necessary) into 3 samples. One sample will be placed in formalin and taken to the Laboratory of Pathology and stored as FFPE (formalin fixed paraffin embedded) for IHC examination at a later time. The second sample will be placed in a 1-2mL cryovial and snap-frozen in liquid nitrogen. The third sample will be placed in OCT media for preservation and stored at –70˚C. Any additional samples, if available, will be flash frozen.  
After processing, all non-FFPE samples will be transferred for labeling and tracking at:
Clinical Services Program NCI Frederick Cancer Research and Development Center PO Box B Frederick, MD 21702 301-846-1000 On days samples are drawn, Jennifer Bangh at CSP should be notified (phone: [301] 8465893; fax [301] 846-6222). She will arrange courier delivery of the specimens to the processing lab. Couriers are assigned to CCR and Georgetown and this mechanism is in place.  
The weekly patient lists of samples drawn will be emailed to Caroline Jochems at jochemscm@mail.nih.gov, Jen Bangh at jb478s@nih.gov and Theresa Burks (burkst@mailnih.gov).
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5.1.2 omics studies

Coded, linked, formalin-fixed, paraffin-embedded tissue and blood samples will be sent to NantOmics per the Genomic and Proteomic Sample Collection Manual under an existing CRADA
71 Version Date:10*.30.2019* agreement for analysis of genetic mutations, RNA expression profiling, and proteomic profiling of patient tumor samples from baseline and on treatment.  
5.1.2.1 Rationale Genomic sequencing of tumor cells relative to non-tumor cells from whole blood will be profiled to identify the genomic variances that may contribute to response or disease progression and provide an understanding of molecular abnormalities. RNA sequencing will be conducted to provide expression data and give relevance to DNA mutations. Quantitative proteomics will be conducted to determine the exact amounts of specific proteins and to confirm expression of genes that are correlative of response and disease progression. All genomic, transcriptomic, and proteomic molecular analysis will be retrospective and exploratory, and used for future hypothesis generation.
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5.1.2.2 sampling

Please follow the instructions in the Genomics and Proteomic Sample Collection Manual to become familiar with the materials provided, to register and to create a patient order. For additional questions, please contact the study coordinator as listed on the title page. Exploratory genomics and proteomics molecular profiling will be performed on formalin-fixed, paraffin embedded (FFPE) tumor tissue and whole blood (subject matched normal comparator against the tumor tissue) by next-generation sequencing and mass spectrometry-based quantitative proteomics. Collection of whole blood at baseline is mandatory for this study. Tumor samples may be collected at baseline and any time after completion of C4 per PI discretion if the patient is willing. 5.1.2.2.1 General Information for Collection of Tumor Tissues and Whole Blood Tumor tissue and whole blood samples are to be collected according to the instruction cards included in the Tissue Specimen Kit and Blood Specimen Kit. The kits include the materials necessary to collect and ship FFPE tumor tissue samples and whole blood samples. The Investigational Site is responsible for obtaining the subject's written Informed Consent Form for genomic and proteomic molecular profiling; the Investigator is to confirm that the written informed consent was obtained before collection of genomic and proteomic samples.  
The Investigational Site is responsible for completing the P152525 Clinical Trial Requisition Form with the following information:
- Clinical Site Information  
- Patient Information
- Specimen Information - Specimen Collection Information
The Investigational Site will return the completed Clinical Trial Requisition Form via Fax per the instructions provided on the form.  
72 Version Date:10*.30.2019* Detailed specimen requirements and procedural instructions for FFPE tumor tissue samples and whole blood samples are provided in the P152525 Genomic and Proteomic Sample Collection Manual.  
5.1.2.3 Genomic and Proteomic Analysis of Tumor Tissue and Whole Blood A single FFPE tumor tissue block is required for the extraction of tumor DNA, tumor RNA, and tumor protein. A whole blood sample is required for the extraction of subject normal DNA. Tumor tissue and whole blood will be processed in the NantOmics, LLC CLIA-registered and CAP accredited/CLIA certified laboratories.  
5.1.2.4 Genomic and Proteomic Analysis Results The individual subject's summary report of cancer-related genomic and proteomic data can be provided to the investigator upon request after the individual subject has completed or discontinued the clinical study. Procedural instructions for requesting the cancer-related genomic and proteomic summary report are provided in the P152525 Genomic and Proteomic Sample Collection Manual.  
| 5.2                                                                                                                   | SAMPLE COLLECTION SUMMARY                                                                          |             |                                       |             |
|-----------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|-------------|---------------------------------------|-------------|
| Test/assay                                                                                                            | Sample/ volume                                                                                     | Type of     | Collection point                      | Location of |
| blood                                                                                                                 | tube                                                                                               | (+/- 48hrs) | specimen analysis                     |             |
| Baseline (from  optional fresh or  archival samples  collected); any  time after  completion of C4  per DI discretion |                                                                                                    |             |                                       |             |
| Tissue analysis                                                                                                       | Optional core  biopsy                                                                              | N/A         | Clinical Services  Program, Frederick |             |
| (5.1.1.2)                                                                                                             | Single block FFPE  with tissue surface  area 25 mm2, 75  µm thick, at least  30% malignant  tissue | N/A         | NantOmics                             |             |
| Omics studies (5.1.2)                                                                                                 | leftover samples  from biopsies  collected on  study will be  utilized                             |             |                                       |             |
| Optional biopsy                                                                                                       | N/A                                                                                                | NantOmics   |                                       |             |  
| Version Date:10.30.2019 Test/assay Sample/ volume   | Type of                                                 | Collection point                                        | Location of       |
|-----------------------------------------------------|---------------------------------------------------------|---------------------------------------------------------|-------------------|
| blood                                               | tube                                                    | (+/- 48hrs)                                             | specimen analysis |
| PAXgene  Blood  DNA  Tube  (provided  in kit)       |                                                         |                                                         |                   |
| 2. 5 mL blood                                       | Baseline                                                | NantOmics                                               |                   |
| Two 10  mL  Sodium  heparin                         | C1D1, C3D1,  C5D1, C9D1 and  every 4 cycles  thereafter |                                                         |                   |
| CEA-specific T  cell response                       | Clinical Services  Program, Frederick                   |                                                         |                   |
| 15 mL blood                                         |                                                         |                                                         |                   |
| (5.1.1.1.2)                                         | Two 10  mL  Sodium  heparin                             | C1D1, C3D1,  C5D1, C9D1 and  every 4 cycles  thereafter |                   |
| PMBC subset  correlation                            | Clinical Services  Program, Frederick                   |                                                         |                   |
| 15 mL blood                                         |                                                         |                                                         |                   |
| (5.1.1.1.1)                                         | One 10  mL  Sodium  heparin                             | C1D1, C3D1,  C5D1, C9D1 and  every 4 cycles  thereafter |                   |
| T cell clonality                                    | Clinical Services  Program, Frederick                   |                                                         |                   |
| 4 mL blood                                          |                                                         |                                                         |                   |
| (5.1.1.1.4)  Cytokine analysis                      | C1D1, C3D1,  C5D1, C9D1 and  every 4 cycles  thereafter | Clinical Services  Program, Frederick                   |                   |
| 8 mL blood                                          | One SST                                                 |                                                         |                   |
| (5.1.1.1.3,  5.1.1.1.5)                             |                                                         |                                                         |                   |
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5.3 sample storage tracking disposition

Samples collected at NIH 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. At participating sites, samples will be ordered and tracked per local SOPs. Samples will not be sent outside NIH without IRB notification and an executed MTA. All data associated with the patient samples is protected by using a secure database. All samples drawn at the NIH Clinical Center and the Georgetown Lombardi Cancer Center will be transported to the NCI Frederick Central Repository by couriers. Samples will be tracked and managed by the Central Repository database. All samples will be stored in liquid nitrogen. These freezers are located at NCI Frederick Central Repository in Frederick, Maryland.  
74 Version Date:10*.30.2019* NCI Frederick Central Repositories store, among other things, biological specimens in support of NIH clinical studies. All specimens are stored in secure, limited access facilities with sufficient security, back-up and emergency support capability and monitoring to ensure long-term integrity of the specimens for research. It is the intent and purpose of ATCC to accept only coded, linked, samples and sample information. To the best of our ability, every effort will be made to ensure that protected information is not sent electronically or by hard copy or on vial labels. Sample data is stored in the BioSpecimen Inventory (BSI) System II. This inventory tracking system is used to manage the storage and retrieval of specimens as well as maintain specimen data. BSI is designed for controlled, concurrent access. It provides a real-time, multi-user environment for tracking millions of specimens. The system controls how and in what order database updates and searches are performed. This control prevents deadlocks and race conditions. For security, BSI has user password access, 3 types of user access levels, and 36 user permissions (levels of access) that can be set to control access to the system functions. BSI provides audit tracking for processes that are done to specimens including shipping, returning to inventory, aliquoting, thawing, additives, and other processes. BSI tracks the ancestry of specimens as they are aliquoted, as well as discrepancies and discrepancy resolution for specimens received by the repository. If a specimen goes out of the inventory, the system maintains data associated with the withdrawal request. Vials are labeled with a unique BSI ID which is printed in both eye-readable and barcoded format. No patient-specific information is encoded in this ID.  
Investigators are granted view, input and withdrawal authority only for their specimens. They may not view specimen data or access specimens for which they have not been authorized. Access to specimen storage is confined to repository staff. Visitors to the repositories are escorted by repository staff at all times.
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5.3.1 protocol completion/sample destruction

All specimens obtained in the protocol are used as defined in the protocol. Any specimens remaining at the completion of the protocol will be stored in the conditions described above. The study will remain open as long as sample or data analysis continues. Samples from consenting subjects will be stored until they are no longer of scientific value or until a subject withdraws consent for their continued use, at which time they will be destroyed. Once primary research objectives for the protocol are achieved, intramural researchers can request access to remaining samples, provided they have an IRB-approved protocol and patient consent or an exemption from OHSRP. The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be per the requirements of section Error! Reference source not found..
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5.4.2 certificate of confidentiality

As part of study efforts to provide confidentiality of subject information, this study has obtained a Certificate of Confidentiality which helps to protect personally identifiable research information.  
75 Version Date:10*.30.2019* The Certificate of Confidentiality allows investigators on this trial to refuse to disclose identifying information related to the research participants, should such disclosure have adverse consequences for subjects or damage their financial standing, employability, insurability or reputation. The informed consent includes the appropriate coverage and restrictions of the Certificate of Confidentiality.
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5.4.3 management of results

Subjects at NIH and at participating sites will not be contacted with information about their gene variant changes because NantOmics will provide the individual subject's report of genomic data to the investigator only after subject has completed or discontinued the clinical study.
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6 data collection and evaluation

Data will be entered in C3D at all study sites. All data will be kept secure. The PI will be responsible for overseeing entry of data into an in-house password protected electronic system and ensuring data accuracy, consistency and timeliness. The principal investigator, associate investigators/research nurses and/or a contracted data manager will assist with the data management efforts. All human subjects personally identifiable information (PII) as defined in accordance to the Health Insurance Portability and Accountability Act, eligibility and consent verification will be recorded. Primary 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. Document AEs from the first study intervention, Study Day 1 through 30 days after removal from study treatment or until off-study, whichever comes first. Adverse events that are serious need to be recorded through 30 days after the last intervention. Beyond 30 days after the last intervention and through long term follow up (survival of subject), only adverse events which are serious and related to the study intervention need to be recorded.  
An abnormal laboratory value will be recorded in the database as an AE **only** if the laboratory abnormality is characterized by any of the following:
- Results in discontinuation from the study  
- Is associated with clinical signs or symptoms - Requires treatment or any other therapeutic intervention - Is associated with death or another serious adverse event, including hospitalization. - Is judged by the Investigator to be of significant clinical impact - If any abnormal laboratory result is considered clinically significant, the investigator will provide details about the action taken with respect to the test drug and about the patient's outcome.
Exceptions to data collection: Grade 1 adverse events will not be recorded.  
76 Version Date:10*.30.2019* 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, this will be reported expeditiously per requirements in section Error! Reference source not found...
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6.2 data sharing plans 6.2.1

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_ Identified or coded, linked data with approved outside collaborators under appropriate agreements.
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how and where will the

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.
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when will the data be

_X_ Before publication.  
_X_ At the time of publication or shortly thereafter.
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6.3 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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6.4 response criteria

For the purposes of this study, patients should be re-evaluated for response every 8 weeks. In addition to a baseline scan, confirmatory scans should also be obtained up to 6 (not less than 4) weeks following initial documentation of objective response. 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 77 Version Date:10*.30.2019*
(version 1.1).  
76 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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6.4.1 definitions

Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first treatment with avelumab. Evaluable for DLT: The first 6 subjects enrolled will be evaluable for DLT from the time of their first treatment with avelumab until 28 days have passed. Subjects who do not complete the DLT observation period for reasons other than a DLT will be replaced. Evaluable for objective response: Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. Evaluable Non-Target Disease Response: Patients who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease. The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
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6.4.2 disease parameters

Measurable disease: Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as:
- By chest x-ray: >20 mm; - By CT scan:  
o Scan slice thickness 5 mm or under as >10 mm with CT scan o Scan slice thickness >5 mm: double the slice thickness
- With calipers on clinical exam: >10 mm.
All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. Non-measurable disease. All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardia l 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.  
78 Version Date:10*.30.2019*
'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if non-cystic lesions are present in the same patient, these are preferred for selection as target lesions. Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, representative of all involved organs, should be identified as **target lesions** and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance the next largest lesion which can be measured reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the short axis is added into the sum. The baseline sum diameters will be used as reference to further characterize any objective tumor regression in the measurable dimension of the disease. Non-target lesions. All other lesions (or sites of disease) including any measurable lesions over and above the 5 target lesions should be identified as **non-target lesions** and should also be recorded at baseline. Measurements of these lesions are not required, but the presence, absence, or in rare cases unequivocal progression of each should be noted throughout follow-up.
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6.4.3 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. Clinical lesions: Clinical lesions will only be considered measurable when they are superficial
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations (e.g. for body scans). Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal resolution; however, there are many image acquisition variables involved in MRI, which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the availability of MRI is variable globally. As with CT, if an MRI is performed, the technical specifications of the scanning sequences used should be optimized for the evaluation of the type and site of disease. Furthermore, as with CT, the modality used at follow-up should be the same as was used at baseline and the 79 Version Date:10*.30.2019* lesions should be measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type of scanner should be used and the image acquisition protocol should be followed as closely as possible to prior scans. Body scans should be performed with breath-hold scanning techniques, if possible. PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is not always of optimal diagnostic CT quality for use with RECIST measurements. However, if the site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements and can be used interchangeably with conventional CT in accurately measuring cancer lesions over time. Note, however, that the PET portion of the CT introduces additional data which may bias an investigator if it is not routinely or serially performed. Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not advised. However, such techniques may be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response (CR) or surgical resection is an endpoint. Tumor markers: Tumor markers alone cannot be used to assess response. If markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been published77-79. In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer80.  
Cytology, Histology: These techniques can be used to differentiate between partial responses (PR)
and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known residual benign tumors can remain). The cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment when the measurable tumor has met criteria for response or stable disease is mandatory to differentiate between response or stable disease (an effusion may be a side effect of the treatment) and progressive disease. FDG-PET: While FDG-PET response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in assessment of progression (particularly possible 'new' disease). New lesions on the basis of FDG-PET imaging can be identified according to the following algorithm:
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD
based on a new lesion.  
80 Version Date:10*.30.2019*  
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDGPET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDGPET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the basis of the anatomic images, this is not PD.  
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR
due to limitations of FDG-PET and biopsy resolution/sensitivity.
Note: A 'positive' FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice that of the surrounding tissue on the attenuation corrected image.
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6.4.4 response criteria

6.4.4.1 Evaluation of Target Lesions Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters while on study.  
6.4.4.2 Evaluation of Non-Target Lesions Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Note: If tumor markers are initially above the upper normal limit, they must normalize for a patient to be considered in complete clinical response. Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.  
Progressive Disease (PD): Appearance of one or more new lesions and/or *unequivocal progression* of existing non-target lesions. *Unequivocal progression* should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.  
81 Version Date:10*.30.2019* Although a clear progression of "non-target" lesions only is exceptional, the opinion of the treating physician should prevail in such circumstances, and the progression status should be confirmed at a later time by the review panel (or Principal Investigator).  
6.4.4.3 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| For Patients with Measurable Disease (i.e., Target Disease) Target  Non-Target  New  Overall  Best Overall Response when  Lesions Lesions Lesions Response Confirmation is Required* CR CR No CR >4 wks. Confirmation** CR NonCR/Non-PD No PR CR Not  No PR evaluated >4 wks. Confirmation** PR NonCR/NonPD/not  evaluated No PR SD NonCR/NonPD/not  evaluated No SD Documented at least once >4  wks. from baseline** PD Any Yes or  PD No Any PD*** Yes or 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. *** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as  disease progression. Note: Patients with a global deterioration of health status requiring discontinuation of treatment without  objective evidence of disease progression at that time should be reported as "symptomatic   |
|---|  
82 Version Date:10.30.2019 deterioration." Every effort should be made to document the objective progression even after discontinuation of treatment.  
For Patients with Non-Measurable Disease (i.e., Non-Target Disease)  
| Non-Target Lesions                                                                                                                                                                                                                             | New Lesions   | Overall Response   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------|--------------------|
| CR                                                                                                                                                                                                                                             | No            | CR                 |
| Non-CR/non-PD                                                                                                                                                                                                                                  | No            | Non-CR/non-PD*     |
| Not all evaluated                                                                                                                                                                                                                              | No            | not evaluated      |
| Unequivocal PD                                                                                                                                                                                                                                 | Yes or No     | PD                 |
| Any                                                                                                                                                                                                                                            | Yes           | PD                 |
| * 'Non-CR/non-PD' is preferred over 'stable disease' for non-target disease since SD is increasingly used  as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be  measured is not advised |               |                    |
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6.4.5 duration of response

Duration of overall response: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (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. 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.
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6.4.6 progression-free survival (pfs)

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
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6.4.7 response review

An independent review of CT scans and MRIs used in determining response will be undertaken at the end of the study by a collaborator in the Radiology and Imaging Sciences. Images will be reviewed using RECIST 1.1. Initial evaluation of progression should be confirmed with a follow up scan in 4-6 weeks, if clinically reasonable. Date of progression should be the initial date of progression when confirmation is obtained. If no confirmation scan is performed, the initial scan demonstrating progression will determine progression. The image data which is collected from the sites outside the NIH LAN, will be using the NIH provided secure e-mail system or FEDEX of a CD with images. The system provides the ability to 83 Version Date:10*.30.2019* e-mail large attachments which would include the dicom images collected at the remote sites collaborating with the clinical trial. When a remote site has an image data set which is ready to be transferred to the NCI site for central storage, they should send a non-secure e-mail to a designated e-mail recipient in the NCI informing them that data is ready to be transferred. The recipient of that e-mail will send an NIH secure email to the offsite person requesting that they send the data. The offsite person will then, by replying to the NIH secure e-mail, attach the DICOM image data set to the replied too e-mail. The NCI person will receive the replied too e-mail with the data attached. The NCI person will extract the attachment and upload the offset dicom image data set to the NCI PACS for final storage and archival. Alternatively, the images can be loaded to a CD and FEDEX to the NCI designated person.  
NCI designated recipients:
Chrisa Thomas 10 Center Drive, Building 10 Room 13N210 Bethesda, MD 20892.
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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_40).
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7 nihreporting requirements/data and safety

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

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. Note: Only IND Safety Reports that meet the definition of an unanticipated problem will need to be reported per these policies.
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7.2.2 irb requirements for pi

Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical Director. A separate submission is not necessary as reports in iRIS will be available to the Clinical Director. In addition to those reports, all deaths that occur within 30 days after receiving a research intervention should be reported via email to the Clinical Director unless they are due to progressive disease. To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut at NCICCRQA@mail.nih.gov within one business day of learning of the death
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7.4 .nciguidance for reporting expedited

Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802: Non-compliance in Human Subjects Research, found here. Until such time as direct electronic reporting mechanisms are available to participating sites, the site PI must immediately report to the coordinating center PI any deaths possibly related to the research within 24 hours of PI awareness of the event. The Site PI must also report any other events required by Policy 801 to the coordinating center PI within 7 days of PI awareness using the CCR Problem Report Form
(See **Appendix C**).  
Once direct electronic reporting mechanisms are available, these will be utilized. Please also notify the coordinating center PI and study coordinator of your submission at the time you make it. For IND studies, the site PI will also directly submit reports to the CCR as IND sponsor per section 8.3.
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7.5 institutional biosafety committee (ibc)reporting

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

Within 60 days after the one-year anniversary of the date on which the IBC approved the initial protocol, and after each subsequent anniversary until the trial is completed, the Principal Investigator (or delegate) shall submit the information described below. Alternatively, the IRB continuing review report can be sent to the IBC in lieu of a separate report. Please include the IBC
protocol number on the report.  
85 Version Date:10.30.2019 7.5.2.1 Clinical Trial Information A brief summary of the status of the trial in progress or completed during the previous year. The summary is required to include the following information:
- the title and purpose of the trial;
- clinical site;
- the Principal Investigator;
- clinical protocol identifiers; - participant population (such as disease indication and general age group, e.g., adult or pediatric);  
- the total number of participants planned for inclusion in the trial; the number entered into the trial to date whose participation in the trial was completed; and the number who dropped out of the trial with a brief description of the reasons;
- the status of the trial, e.g., open to accrual of subjects, closed but data collection ongoing, or fully completed;
- if the trial has been completed, a brief description of any study results.  
7.5.2.2 Progress Report and Data Analysis Information obtained during the previous year's clinical and non-clinical investigations, including:
- a narrative or tabular summary showing the most frequent and most serious adverse experiences by body system;
- a summary of all serious adverse events submitted during the past year;  
- a summary of serious adverse events that were expected or considered to have causes not associated with the use of the gene transfer product such as disease progression or concurrent medications;
- if any deaths have occurred, the number of participants who died during participation in the investigation and causes of death;
- a brief description of any information obtained that is pertinent to an understanding of the gene transfer product's actions, including, for example, information about dose-response, information from controlled trials, and information about bioavailability.
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7.6 nihrequired data and safety

The clinical research team will meet on a regular basis (every two weeks by teleconference with participating sites) when patients are being actively treated on the trial to discuss each patient, enrollment and data management issues. Decisions about dose level enrollment and dose escalation (NCI site only) will be made based on the toxicity data from prior patients.  
86 Version Date:10*.30.2019* All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section Error! Reference source not found. will be submitted within the appropriate timelines. The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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7.6.2 safety monitoring committee (smc)

This protocol will require oversight from the Safety Monitoring Committee (SMC). Initial review will occur as soon as possible after the annual NIH Intramural IRB continuing review date. Subsequently, each protocol will be reviewed as close to annually as the quarterly meeting schedule permits or more frequently as may be required by the SMC. For initial and subsequent reviews, protocols will not be reviewed if there is no accrual within the review period. Written outcome letters will be generated in response to the monitoring activities and submitted to the Principal investigator and Clinical Director or Deputy Clinical Director, CCR, NCI.
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8 sponsor safety reporting 8.1

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

An adverse event or suspected adverse reaction is considered serious if in the view of the investigator or the sponsor, it results in any of the following:
- Death,  
- A life-threatening adverse event (see section **8.1.3**)
- Inpatient hospitalization or prolongation of existing hospitalization o A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery arranged prior to the start of the study), a planned hospitalization for pre-existing condition, or a procedure required by the protocol, without a serious deterioration in health, is not considered a serious adverse event.  
o A hospitalization/admission that is solely driven by non-medical reasons (e.g.,
hospitalization for patient convenience) is not considered a serious adverse event.
87 Version Date:10*.30.2019* o Emergency room visits or stays in observation units that do not result in admission to the hospital would not be considered a serious adverse event. The reason for seeking medical care should be evaluated for meeting one of the other serious criteria.  
- Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions
- A congenital anomaly/birth defect - Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.
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8.1.3 life-threatening

An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. (21CFR312.32)
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8.1.4 severity

The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.0.
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8.1.5 relationship to study product

All AEs will have their relationship to study product assessed using the terms: related or not related.  
- Related - There is a reasonable possibility that the study product caused the adverse event. Reasonable possibility means that there is evidence to suggest a causal relationship between the study product and the adverse event.  
- Not Related - There is not a reasonable possibility that the administration of the study product caused the event.
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8.2 assessment of safety events

AE information collected will include event description, date of onset, assessment of severity and relationship to study product and alternate etiology (if not related to study product), date of resolution of the event, seriousness and outcome. The assessment of severity and relationship to the study product will be done only by those with the training and authority to make a diagnosis and listed on the Form FDA 1572 as the site principal investigator or sub-investigator. AEs occurring during the collection and reporting period will be documented appropriately regardless of relationship. AEs will be followed through resolution.
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saes will be

- Assessed for severity and relationship to study product and alternate etiology (if not related to study product) by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  
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- Recorded on the appropriate SAE report form, the medical record and captured in the clinical database.  
- Followed through resolution by a licensed study physician listed on the Form FDA 1572 as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section Error! Reference source not found.. All serious adverse events recorded from the time of first investigational product administration must be reported to the sponsor with the exception of any listed in section 8.4.
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8.3 reporting of serious adverse

Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of Special Interest that require expedited reporting must be submitted immediately (within 24 hours of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited reporting requirements are found in section 8.4. All SAE reporting must include the elements described in section 8.2.  
SAE reports will be submitted to the Center for Cancer Research (CCR) at: OSROSafety@mail.nih.gov and to the CCR PI and study coordinator. CCR SAE report form and instructions can be found at: https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=157942842 Following the assessment of the SAE by OSRO, other supporting documentation of the event may be requested by the OSRO Safety and should be provided as soon as possible.
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8.4 waiver of expedited reporting

As hospitalization due to disease progression is part of the secondary objective, and captured as an endpoint in this study, hospitalization due to disease progression will not be reported in expedited manner to the sponsor. However, if there is evidence suggesting a causal relationship between the study drug and the event, report the event in an expedited manner according to section Error! Reference source not found..
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8.5 safety reporting criteria to

The following reportable events must be submitted to EMD Serono within 2 business days or 3 calendar days (whichever comes first) using the applicable safety report form provided. 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.  
- Serious Adverse Events  
- Exposure during Pregnancy or Breastfeeding (even if not associated with an adverse event)
- Occupational exposure (even if not associated with an adverse event)
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- Potential drug-induced liver injury (Hy's Law cases): These events are considered important medical events and should be reported as SAEs.
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contact information for submission of

Fax: +49 6151 72 6914 OR E-mail: GlobalDrugSafety@merckgroup.com Specifying: PROTOCOL Number and/or Title EMD Serono assigned Study Number SUBJECT Number SITE Number/PI Name SAE/ONSET DATE.
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8.5.2 etubics corporation (ad-cea vaccine)

In the event of any new SAE (of any Grade) occurring during the reporting period, the Manufacturer (Etubics Corporation) or designee must immediately (i.e., within a maximum 24 hours after becoming aware of the event) be informed by telephone, by fax, or by email. When an event (or follow-up information) is reported by telephone, a written report must be sent immediately thereafter by fax or email. Reporting procedures and timelines are the same for any new information on a previously reported SAE (follow-up). Joseph Balint Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 Telephone: +1-206-838-5110 ext. 107 Email: joe@etubics.com OR
Frank Jones Address: 410 West Harrison Street, Suite 100, Seattle, WA 98119 Telephone: +1-206-838-5110 ext. 101 (office)
+1-206-818-2857 (cell)
Email: frank@etubics.com All Medwatch 3500a forms and written reports should be transmitted, which must be completed by the investigator following specific completion instructions. Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant drugs). In all cases, the information provided in the SAE Report Form must be consistent with the data on the event that is recorded in the corresponding sections of the CRF.  
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8.5.3 reporting pregnancy 8.5.3.1 maternal

If a patient becomes pregnant during the course of the study, the study treatment should be discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later than 24 hours of when the outcome of the Pregnancy becomes known, Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects and spontaneous miscarriages that meet serious criteria (section **8.1.2**) should be reported as SAEs. The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) should be followed up and documented.  
8.5.3.2 Paternal exposure Male patients should refrain from fathering a child or donating sperm during the study and for 4 months after the last treatment with avelumab or 6 months after the last administration of bevacizumab, whichever occurs later. Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital abnormality) occurring from the date of the first dose until 4 months after the last treatment with avelumab or 6 months after the last administration of bevacizumab, whichever occurs later should, if possible, be followed up and documented.
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8.6 regulatory reporting for studies

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

As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring program. The CCR's program allows for confirmation of: study data, specifically data that could affect the interpretation of primary and secondary study endpoints; adherence to the protocol, regulations, ICH E6, and SOPs; and human subjects protection. This is done through independent verification of study data with source documentation focusing on:
- Informed consent process
- Eligibility confirmation - Drug administration and accountability
- Adverse events monitoring
- Response assessment.  
91 Version Date:10*.30.2019* The monitoring program also extends to multi-site research when the CCR is the coordinating center. This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified by training and experience to monitor the progress of clinical trials. Personnel monitoring this study will not be affiliated in any way with the trial conduct.
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10 statistical considerations

Following an initial 6 patient safety evaluation, the primary objective of the trial is to determine if there is a difference in progression free survival among patients with metastatic or unresectable colorectal cancer who are treated with standard of care vs. standard of care + anti-PD-L1+ AdCEA vaccine monoclonal antibody. A secondary hypothesis (objective) will be to obtain preliminary data on ratio of patients that are hospitalized because of adverse events attributed to disease progression. Based upon results in the literature, patients who would be eligible to be randomized on this trial would be expected to have an estimated 10-month median progression free survival with standard of care alone. The goal of this study will be to determine if the use of the anti-PD-L1 monoclonal antibody + the Ad-CEA vaccine along with standard of care will result in patients having an increased median progression free survival of 18 months. Kaplan-Meier curves and a two-tailed log-rank test will be the primary analysis methods. Assuming exponential progression free survival curves, the hazard rate for standard of care alone is 0.0693 or approximately a 7% probability of progressing each month when the median progression free survival is 10 months. If we assume that the combination arm will be associated with a median progression free survival of 18 months, this corresponds to a hazard rate of 0.0385 and the resulting hazard ratio for the comparison of the two overall actuarial curves would be 1.80. Following the principals of a phase 2.5 design, to compare these curves and detect a difference with a 0.10 one-tailed log-rank test, a total of 35 evaluable subjects per arm (70 total) will need to be randomized over a one year period and a maximum follow-up of three years, with occurrence of 52 total progressions, in order to have 80% power to compare the curves.  
In addition, during the randomized portion of the trial, beginning with the 4th patient on a given arm, if the cumulative fraction of patients at any point who experience a grade 3 or 4 toxicity on either arm is greater than or equal to 1/3, then accrual to the randomized trial will be suspended and will only resume following modifications to the treatment on the appropriate arm, detailed in an amendment created for that purpose. Thus, for example, one patient with a DLT in the first 3 randomized patients on an arm would be permitted, but if there are 2 patients with a DLT in the first 4 on either arm, this would be considered excessive. It is expected that all 76 patients (6 for safety lead-in plus 70 for phase 2.5) can be accrued onto this trial in three to four years. In order to allow for a number of inevaluable patients, due to screen failures at the other sites, the accrual ceiling will be set at 97 patients.
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11 collaborative agreements 11.1 crada

A CRADA (02666) is in place between the Laboratory of Tumor Immunology and Biology (LTIB), CCR NCI and EMD Serono, the manufacturer of avelumab.
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11.1.2 etubics corporation

A CRADA (02997) is in place between the Laboratory of Tumor Immunology and Biology (LTIB), CCR NCI and Etubics Corporation, the manufacturer of Ad-CEA vaccine.
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11.1.3 nantomics

The studies referenced in section **5.1.2** will be conducted under a CRADA (03063) agreement between the Laboratory of Tumor Immunology and Biology (LTIB), CCR NCI and NantOmics.
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11.2 mta 11.2.1 emd serono

A MTA (41326-16) is in place between the CCR NCI and EMD Serono
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11.3 multi-institutional guidelines 11.3.1 irb

Subjects from all racial and ethnic groups are eligible for this trial if they meet the eligibility criteria. Efforts will be made to extend the accrual to a representative population.
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12.2 participation of children 12.3

The age group for enrollment on this trial is ≥ 18 years of age. Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent may be necessary and there is a possibility, though unlikely, that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (section **12.4**), all subjects will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance The PI will provide the NIH Intramural IRB with a copy of the participating institution's approved yearly continuing review. Registration will be halted at any participating institution in which a current continuing approval is not on file at the NIH Intramural IRB. The CCR PI will provide the NIH Intramural IRB with copies of all amendments, consents and approvals from each participating institution. 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 consent; assistance in identifying and assessing an appropriate surrogate when indicated; and/or an assessment of the capacity to appoint a surrogate. For those subjects that become incapacitated and do not have pre-determined substitute decision maker, the procedures described in NIH HRPP SOP 14E for appointing a surrogate decision maker for adult subjects who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed.
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12.4 evaluation of benefits and

Patients will receive evaluation of their disease at the National Cancer Institute's Clinical Center and/or MedStar Georgetown University Hospital (Lombardi Cancer Center). This protocol may or may not benefit an individual, but the results may help the investigators learn more about the disease and develop new treatments for patients with this disease. Potential adverse reactions attributable to the administration of avelumab and the chemotherapeutic agents utilized in this trial are discussed in section 13. All care will be taken to minimize side effects, but they can be unpredictable in nature and severity. Patients will be examined and evaluated prior to enrollment. All evaluations to monitor the treatment of patients will be recorded in the patient chart. If patients suffer any physical injury as a result of the participation in this study, immediate medical treatment is available at the Clinical Center, National Cancer Institute, Bethesda, Maryland and/or MedStar Georgetown University Hospital (Lombardi Cancer Center). In addition, the study may involve up to two CT guided biopsies (optional) collected for research purposes only. Subjects undergoing two optional biopsy collection will be exposed to 1.5 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.  
Although no compensation is available, any injury will be evaluated and treated in keeping with the benefits or care to which patients are entitled under applicable regulations. In all publications and presentations resulting from this trial, patients' anonymity will be protected to the maximum extent possible. Authorized personnel from the National Cancer Institute (NCI) and Food and Drug Administration (FDA) or other regulatory authorities may have access to research files in order to verify that patients' rights have been safeguarded. In addition, patient names will be given to the Central Registration to register and verify patients' eligibility.
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12.5 consent and assent process

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 will be carefully explained to the patient, and a signed informed consent document will be obtained by a study investigator prior to entry onto the study.  
94 Version Date:10*.30.2019* 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. If there is an optional biopsy for research in the protocol, then the patient will consent at the time of the procedure. If the patient refuses the optional biopsy at that time, the refusal will be documented in the medical record.
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12.5.1 telephone re-consent procedure

Re-consent on this study may be obtained via telephone according to the following procedure: the informed consent document will be sent to the subject. An explanation of the study will be 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. A fully executed copy will be returned via mail for the subject's records. The informed consent process will be documented in the medical record.
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12.5.2 request for waiver of

Prior to the subject signing the consent for this study pre-screening activities listed in section 2.2.1 may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the subjects. A waiver will not adversely affect the rights and welfare of the subjects given that the activities are only intended to determine suitability for screening for participation in research protocols. These activities could not practicably be carried out without the wavier as central recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies and obtaining consent for each one is beyond their resources. The subjects will be provided with additional pertinent information after participation as they will be informed whether or not they are eligible to sign a consent for additional screening.
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13 pharmaceutical information

All commercial agents are used as indicated, therefore these agents will not be included in the IND.
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13.1 avelumab (bb ind# 17056)

Avelumab will be supplied by the manufacturer, EMD Serono, Inc., through a Cooperative Research and Development Agreement (CRADA). The Clinical Trial Supplies department of the manufacturer will supply the trial medication of avelumab, which will be distributed to the sites by EMD Serono, the manufacturer of avelumab.  
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13.1.2 toxicity

The available safety data for current EMR100070-001 trial are summarized below based on the safety data cut-off date, 05 November 2014. In addition to subjects treated during dose escalation, a total of 480 subjects were enrolled during the dose expansion (NSCLC: 184; metastatic breast cancer: 169; gastric cancer: 47; colorectal cancer: 22; castrate-resistant prostate cancer: 11; ovarian cancer: 37, melanoma: 5; mesothelioma: 1; adrenocortical carcinoma: 1; and urothelial carcinoma: 3), treated with the recommended dose of 10 mg/kg avelumab once every 2 weeks and followed up for at least 4 weeks up to the cut-off date. For all subjects treated during the dose expansion, the most frequently affected System Organ Classes (with an incidence > 30%) were general disorders and administration site conditions (59.6%), gastrointestinal disorders (57.3%), respiratory, thoracic and mediastinal disorders (39.8%), musculoskeletal and connective tissue disorders (38.8%), and metabolic and nutrition disorders (32.3%).  
| Most Frequently Reported Treatment-related TEAEs During Dose Expansion (≥ 5% of Subjects) Treatment-emergent Adverse Eventsa Subjects (Safety Population, N = 480) Preferred Term (MedDRA) N (%) Fatigue 97 (20.2%) Nausea 62 (12.9%) Infusion-related reaction 47 (9.8%) Chills 33 (6.9%) Diarrhea 33 (6.9%) Decreased appetite 30 (6.3%) Pyrexia 27 (5.6%) Influenza like illness 25 (5.2%) Arthralgia 24 (5.0%) MedDRA = Medical Dictionary for Regulatory Activities.   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
a Only treatment-emergent adverse events started during the on-treatment period are summarized.
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treatment-related teaes grade >= 3

Of the Grade ≥ 3 treatment-related TEAEs (59 subjects; 12.3%), the following occurred in more than 2 subjects: fatigue (5 subjects, 1.0%), anemia (5 subjects, 1.0%), infusion-related reaction, lipase increased, and GGT increased (each in 4 subjects, 0.8%).  
Of the 59 subjects who had Grade ≥ 3 treatment-related TEAEs, 44 (9.2%) had Grade 3 treatmentrelated TEAEs, 11 (2.3%) had Grade 4 treatment-related TEAEs, and 4 (0.8%) had Grade 5 96 Version Date:10*.30.2019* treatment-related TEAEs. One Grade 3 event of encephalopathy (Subject 101-0032), which was initially considered as posterior reversible encephalopathy syndrome, was assessed as related to trial medication with an alternative explanation of hypertension.
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serious adverse events

Overall, 176 of the 480 subjects (36.7%) treated during the dose expansion had serious TEAEs. Of these, 22 (4.6%) subjects reported dyspnea, which was the most frequent serious TEAE in this group, followed by 19 subjects (4.0%) reporting disease progression, 12 subjects (2.5%) reporting pleural effusion, 11 subjects (2.3%) reporting pneumonia, and 7 subjects (1.5%) reporting anemia. All other serious TEAEs were each reported in less than 1.5% of subjects. Of the serious TEAEs considered treatment-related by the investigator (31 subjects; 6.5%), the following were reported for 2 or more subjects: infusion-related reaction (4 subjects, 0.8%), pneumonitis (3 subjects, 0.6%), and disease progression, dyspnea, and hypercalcemia (each in 2 subjects, 0.4%).
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deaths

In total, 134 subjects (27.9%) treated during the dose expansion died up to the cut-off date (05 November 2014). Of these, the majority of deaths (101 deaths; 21.0%) were due to disease progression. An additional 8 deaths (1.7%) were due to TEAEs unrelated to trial treatment, 4 deaths (0.8%) were due to TEAEs related to trial treatment, and the reason for 8 deaths (1.7%)
was labeled as other. The reason for 13 deaths (2.7%) was unknown at the time of the data cutoff. Of the 134 subjects who died, 53 subjects (11.0%) died within 30 days of the last administration of trial treatment. Among these deaths, 39 (8.1%) were due to disease progression, 7 (1.5%) were due to TEAEs unrelated to trial treatment, 4 (0.8%) were due to TEAEs related to trial treatment, and 3 (0.6%) were due to other reasons. No death of unknown reason was reported in the 30-day period.
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immune-related adverse events

As of 05 November 2014, a cumulative review revealed 56 cases of potential immune-related AEs out of 480 subjects (11.7%) treated in the dose expansion part of trial EMR 100070-001 and 4 cases out of 50 subjects (8.0%) treated in the dose escalation part of trial EMR 100070-001. A customized Medical Dictionary for Regulatory Activities (MedDRA) query was used for data retrieval from the clinical database with predefined Preferred Terms of potential immune-related AEs (irAEs). Of 69 potential irAEs reported, 13 were SAEs (18.8%) and 56 were non-serious AEs (81.1%). In the majority of the cases, there was a plausible temporal association between the event onset and the drug administration. Of these 69 events, 46 events (66.7%) were assessed as treatment related by the investigator and 23 events (33.3%) were assessed as not treatment-related by the investigator. Twenty-six events were assessed as Grade 1, 29 events as Grade 2, 11 events as Grade 3, 2 events as Grade 4, and 1 event (pneumonitis) as Grade 5 (Please note: 2 more events of autoimmune hepatitis had a fatal outcome; however, they were assessed as Grade 3 with a consequent fatal liver failure).
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infusion-related reactions

Two suspected unexpected serious adverse reactions (SUSARs; anaphylactic reaction and infusion-related reaction) involving 2 subjects were reported in December 2013 and triggered a cumulative review of serious and non-serious cases of infusion-related reactions / hypersensitivity across the avelumab program. Following evaluation of safety signals, infusion related reactions / hypersensitivity have been classified as a newly identified risk (previously classified as a potential risk) and a mandatory premedication regimen of histamine H1 receptor (H1) blockers plus acetaminophen was implemented for all trial subjects as of 28 January 2014. As of 05 November 2014, 49 (10.2%) of the 480 subjects in the expansion cohort experienced at least 1 episode of an infusion-related reaction when receiving avelumab monotherapy. Most of the events were Grade 1 (8 subjects, 1.7%) or Grade 2 (36 subjects, 7.5%) in intensity, and Grade 3 (3 subjects, 0.6%) or Grade 4 events (2 subjects, 0.4%) were less frequent. No Grade 5 events were reported. Most of the infusion-related reaction events had an onset after the first (30 subjects, 6.3%) or second (16 subjects, 3.3%) avelumab infusion. In 8 subjects (1.7%), avelumab treatment was discontinued because of infusion-related reaction events. In addition, 1 subject (2.0%) in the dose escalation cohort reported an infusion-related reaction event (Grade 2). In addition to the aforementioned 49 subjects, 1 case of Grade 4 cardiac arrest occurred 1.5 hours after the third infusion of avelumab (10 mg/kg). The subject died due to an anoxic brain injury 7 days later; no autopsy was performed. Starting from 29 January 2014, the Sponsor has implemented a mandatory premedication with H1 blockers plus acetaminophen for all subjects who are to receive avelumab. This premedication procedure was applied to 28 and 440 subjects in the dose escalation and the pooled treatment expansion cohort, respectively. Under this premedication procedure, 33 of 440 subjects (7.5%) in the expansion cohort experienced infusion-related reaction events, with 6 subjects (1.4%) having Grade 1, 26 subjects (5.9%) having Grade 2, and 1 subject (0.2%) having Grade 3 events. No infusion-related reaction events were reported in the 28 subjects in the dose escalation cohort.
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13.1.3 formulation and preparation

Avelumab is formulated as a 10.0 mg/mL solution in single-use glass vials, with a rubber stopper. Packaging and labeling will be in accordance with applicable local regulatory requirements and applicable Good Manufacturing Practice (GMP) guidelines. Avelumab will be packed in boxes containing a suitable number of vials. The information on the medication will be in accordance with approved submission documents. Avelumab will be shipped in transport cool containers (2°C to 8°C) that are monitored with temperature control devices. Prior to preparation, the day of usage, avelumab must be allowed to warm to room temperature (15-25°C) for 30 minutes. The calculated dose of avelumab must be diluted with 0.9% sterile sodium chloride injection to a total volume of 250 mL in an infusion bag. Prior to the addition of avelumab, an equal volume of 0.9% sodium chloride injection must be removed from the infusion bag and must be discarded.
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13.1.4 stability and storage

Avelumab drug product must be stored at 2°C to 8°C until use, with a temperature log maintained daily. All medication boxes supplied to each study center must be stored carefully, safely, and separately from other drugs. Avelumab drug product stored at room temperature (15°C to 25°C) or at elevated temperatures (38°C to 42°C) for extended periods is subject to degradation. Avelumab must not be frozen. Rough shaking of avelumab must be avoided. Chemical and physical in-use stability has been demonstrated for 24 h at 25°C for the diluted medication in the approved infusion bags. However, from a microbiological point of view, the diluted solution should be used immediately and is not intended to be stored unless dilution has taken place in controlled and validated aseptic conditions.
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13.1.6 incompatibilities the following treatments

- Immunotherapy, immunosuppressive drugs (i.e., chemotherapy or systemic corticosteroids except for short term treatment of allergic reactions, for the treatment of irAEs, or for management of radiation induced tumor swelling), or other experimental pharmaceutical products. Short term administration of systemic steroid (i.e., for allergic reactions, the management of irAEs, and management of radiation induced tumor swelling) is allowed. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.  
- Any vaccine therapies for the prevention of infectious disease (e.g., seasonal flu vaccine, human papilloma virus vaccine) except administration of the inactive influenza vaccine.
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13.2 ad-cea vaccine (bb ind#

Ad-CEA will be supplied by the manufacturer, Etubics Corporation, through a Cooperative Research and Development Agreement (CRADA). The manufacturing department of Etubics will supply the vaccine, which will be distributed to the sites by Etubics Corporation.
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13.2.2 toxicity

A Phase I/II clinical trial of ETBX-011 (Ad5 [E1-, E2b-]-CEA(6D)) (IND\#14325) that expresses the tumor-associated antigen carcinoembryonic antigen (CEA) has been performed. A summary of the study results on the clinical trial is presented below.  
Schedule, Dosing, and Safety: The primary objective of the Phase I/II dosing trial was to assess safety and a secondary objective was to evaluate CEA-specific immune responses to CEA and to obtain preliminary data on response rate. The study was performed under an FDA-approved IND (IND14325) and registered at ClinicalTrials.gov (NCT01147965). Participants were recruited from oncology clinics at Duke University Medical Center and Medical Oncology Associates, 99 Version Date:10*.30.2019* Spokane, WA and provided informed consent that was approved by IRB's. Patients with a histological confirmed diagnosis of metastatic malignancy who were previously treated with standard therapy known to have a possible survival benefit were enrolled into the study. For this study, the carcinoma must have had over expression of CEA as defined by immunohistochemical staining (at least 50% of the tumor with at least moderate intensity of staining) or a carcinoma known to be universally CEA positive *i.e.* colorectal adenocarcinoma). Patients were not treated until 4 or more weeks after any prior chemotherapy or radiation therapy. They could not have a history of autoimmune disease, serious intercurrent chronic or acute illness, active hepatitis, serologic evidence for HIV infection, or be receiving steroid or immunosuppressive therapy. All patients were >21 years old and had a Karnofsky Performance Score of 70% or higher and a life expectancy of at least 3 months. Pregnant women and nursing mothers were excluded. Dose Limiting Toxicities (DLTs) were defined as any Grade 3 or 4 immediate hypersensitivity reactions, Grade 3 or 4 fever that may possibly be associated with the immunization, Grade ≥2 autoimmune events except for vitiligo or fever for less than 2 days and less than 101.5 ºF, Grade ≥2 allergic reactions (Grade 2 is defined as generalized urticaria as defined by NCI Common Terminology Criteria for Adverse Events (CTCAE version 5.0), or Grade ≥3 non-hematologic toxicity. The Ad5 [E1-, E2b-]-CEA(6D) injections were given subcutaneously in the same thigh. The doses were administered every 3 weeks for 3 treatments as follows: Cohort 1 (3 patients) 109 VP in 0.5 ml; Cohort 2 (3 patients): 1010 VP; Cohort 3 (6 patients) 1011 VP. Following establishment of safety in Phase I, 12 additional patients were entered into a Phase II using the 1011 VP/dose. To evaluate a higher dose, 6 additional patients (cohort 5) received 5x1011 VP/dose.  
Patient Demographics: One patient with CEA expressing bladder and one patient with lung carcinoma was enrolled. Thirty two patients, median age 57.5 (range 38-77) with metastatic colorectal cancer, who had failed a median of three prior chemotherapeutic regimens (range: 2–5), had a median performance status of 90% (range 70-100%), and had a median of three sites of metastatic disease (range 1-5), were enrolled. The majority was able to receive all three immunizations. Five patients who stopped immunizations early did so due to significant disease progression. The colorectal adenocarcinoma patient demographics compares favorably with previously published studies of patients with chemotherapy-refractory colorectal cancer [44-46].  
Adverse Effects: A total of 94 immunization treatments were administered to all patients.  
There was no dose limiting toxicity and no serious adverse events that resulted in treatment discontinuation at any dose level. The most common toxicity was a self-limited, injection site reaction. Other reactions that occurred at a low frequency include fever, flu-like symptoms, anorexia, chills, nausea, and headache. These symptoms were also self-limiting and did not require intervention other than symptomatic measures such as acetaminophen. There were no SAE associated with immunizations. A summary of the adverse events reported on 34 patients treated and evaluated for safety are presented below.  
| Incidence %  (based on 94  total  treatments)   |        |                    |          |           |
|-------------------------------------------------|--------|--------------------|----------|-----------|
| Adverse Events as                               | # of   | Unrelated/Unlikely | Possible | Probably/ |
| of 07/31/12                                     | Events | Definite           |          |           |  
| Version Date:10.30.2019 Injection Site  Reaction   | 21   | 2   | 21   | 22.3   |      |
|----------------------------------------------------|------|-----|------|--------|------|
| Flu-like symptoms                                  | 10   | 4   | 5    | 3      | 10.6 |
| Fever                                              | 9    | 6   | 1    | 4      | 9.5  |
| Fatigue                                            | 8    | 6   | 2    | 8.5    |      |
| Shortness of Breath                                | 6    | 6   | 6.3  |        |      |
| Pain                                               | 6    | 4   | 6.3  |        |      |
| Anorexia                                           | 5    | 1   | 5.3  |        |      |
| Chills                                             | 5    | 5   | 1    | 4      | 5.3  |
| Constipation                                       | 5    | 5   | 5.3  |        |      |
| Edema                                              | 5    | 4   | 5.3  |        |      |
| Nausea                                             | 5    | 4   | 1    | 5.3    |      |
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grade 3 and grade 4

| Percent (Based  on 34 patients  evaluated for  safety)   |              |           |
|----------------------------------------------------------|--------------|-----------|
| Pain (all types)                                         | 2            | 5.6       |
| Fatigue                                                  | 1            | 2.9       |
| Anemia                                                   | 1            | 2.9       |
| Pleural effusion                                         | 1            | 2.9       |
| Alkaline Phosphatase Increase                            | 1            | 2.9       |
| Abdominal Bloating                                       | 1            | 2.9       |
| Bowel obstruction                                        | 1            | 2.9       |
| GI disorder                                              | 1            | 2.9       |
| Acute renal failure                                      | 1            | 2.9       |
| Adverse Events                                           | Number of    | Number of |
| Grade 3 (G3)                                             | Grade 4 (G4) |           |  
*Represents reported adverse events whether or not related to ETBX-011 vaccine Of 34 total patients entered into the trial, 28 received all three treatments and the blood hematology, chemistry, and ANA values at week 0 (prior to first treatment) were compared with those obtained at week 9 (three weeks after the third treatment). There were no biologically significant changes in chemistry, hematology, or ANA values.
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13.2.3 formulation and preparation

ETBX-011 is a clear colorless liquid filled in a 2-mL amber vial containing 1.0 mL of extractable vaccine. There are total of 5x1011 total virus particles in 1.0 mL of the product. Each vial is sealed with a rubber stopper and has a white flip off seal. End user of the product will need to flip the white plastic portion of the cap up/off with their thumb to expose the rubber stopper, 101 Version Date:10*.30.2019* and then puncture the stopper with an injection needle to withdraw the liquid. The rubber stopper is secured to the vial with an aluminum crimped seal.
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13.2.4 stability and storage

Individual vials (in the desired number) of ETBX-011 will be packaged in a cardboard box and will be shipped over dry ice (<-80 °C) by overnight courier with a temperature monitoring device included. Upon receipt, one will inspect contents of package for any noticeable damages or defects. Unpack the shipment contents and place the cardboard box containing ETBX-011 vials into a freezer with a temperature control of ≤-20 °C. Receiver must stop the temperature monitoring device by turning off the power switch (instructions for handling and operation of temperature monitoring device will be provided with the package).
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13.2.6 incompatibilities

ETBX-011 is administered as a separate subcutaneous injection, with no known incompatibilities.
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13.3.1 source

Bevacizumab will be supplied by the local pharmacy using supply purchased from commercial sources.
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13.3.2 toxicity

The most common adverse reactions observed in bevacizumab patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis Some of the adverse reactions are commonly seen with chemotherapy; however, bevacizumab may exacerbate these reactions when combined with chemotherapeutic agents. Examples include palmar-plantar erythrodysaesthesia syndrome with pegylated liposomal doxorubicin or capecitabine peripheral sensory neuropathy with paclitaxel or oxaliplatin, and nail disorders or alopecia with paclitaxel.  
13.3.2.1 Gastrointestinal Perforations and Fistulae Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in bevacizumab treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 3.2% across clinical studies. From a clinical trial in patients with persistent, recurrent, or metastatic cervical cancer (Study 9), gastrointestinal perforations were reported in 3.2% of bevacizumab treated patients, all of whom had a history of prior pelvic radiation. Fatal outcome was reported in <1% of bevacizumab-treated patients. In a platinum-resistant ovarian cancer trial (Study 10), the incidence of GI perforation was 1.7% (3/179). In this trial, patients with evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction were excluded.  
102 Version Date:10.30.2019 13.3.2.2 Non-Gastrointestinal Fistulae Serious and sometimes fatal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in bevacizumab -treated patients compared to controls. Uncommon (<1%) reports of fistulae that involve areas of the body other than the gastrointestinal tract were observed in clinical trials across various indications and have also been reported in post-marketing experience. Most events occurred within the first 6 months of bevacizumab therapy.
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13.3.2.3 surgery and wound healing

Bevacizumab impairs wound healing in animal models. In clinical trials, administration of bevacizumab was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of bevacizumab treatment was 15% and in patients who did not receive bevacizumab, was 4%.
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13.3.2.4 hemorrhage

Bevacizumab can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving bevacizumab compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving bevacizumab ranged from 0.4 to 6.9 %.
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13.3.2.5 arterial thromboembolic events

Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving bevacizumab compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the bevacizumab containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving bevacizumab in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years.
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13.3.2.6 hypertension

The incidence of severe hypertension is increased in patients receiving bevacizumab as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.  
13.3.2.7 Posterior Reversible Encephalopathy Syndrome (PRES)
PRES has been reported with an incidence of < 0.5% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of bevacizumab. PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.
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13.3.2.8 proteinuria

The incidence and severity of proteinuria is increased in patients receiving bevacizumab as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving bevacizumab 103 Version Date:10*.30.2019* in clinical trials, in some instances with fatal outcome. In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.  
13.3.2.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of bevacizumab were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.  
13.3.2.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving bevacizumab in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which bevacizumab is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with bevacizumab
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13.3.3 formulation and preparation

Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid ready for parenteral administration in vials of two sizes:
- 100 mg/4 mL, single use vial  
- 400 mg/16 mL, single use vial
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Withdraw necessary amount of bevacizumab and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP. Discard any unused portion left in a vial, as the product contains no preservatives.
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do not administer or mix

Bevacizumab vials should be stored according to FDA-approved labeling. Do not freeze or shake. Diluted bevacizumab solutions may be stored at 2−8°C (36−46°F) for up to 24 hours, per site pharmacy guidelines. Store in the original carton until time of use. No incompatibilities between bevacizumab and polyvinylchloride or polyolefin bags have been observed.
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13.3.6 incompatibilities

A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without bevacizumab. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.  
104 Version Date:10*.30.2019* In a study assessing the safety and efficacy of bevacizumab as first line therapy in non-small cell lung cancer, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with bevacizumab. However, 3 of the 8 patients receiving bevacizumab plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without bevacizumab had a greater paclitaxel exposure at Day 63 than at Day 0.
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13.4.1 source

Capecitabine will be supplied by the local pharmacy using supply purchased from commercial sources.
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13.4.2 toxicity

Most common adverse reactions (≥30%) were diarrhea, hand-and-foot syndrome, nausea, vomiting, abdominal pain, fatigue/weakness, and hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported.
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pooled phase 3 colorectal trials

| Patients Adverse Event                       | Capecitabine (n=596)   |         |    |
|----------------------------------------------|------------------------|---------|----|
| Total                                        | Grade 3                | Grade 4 |    |
| %                                            | %                      | %       |    |
| Number of Patients With > One Adverse Event  | 96                     | 52      | 9  |
| Body System/Adverse Event GI Diarrhea        | 55                     | 13      | 2  |
| Nausea                                       | 43                     | 4       | -  |
| Vomiting                                     | 27                     | 4       | <1 |
| Stomatitis                                   | 25                     | 2       | <1 |
| Abdominal Pain                               | 35                     | 9       | <1 |
| Gastrointestinal Motility Disorder           | 10                     | <1      | -  |
| Constipation                                 | 14                     | 1       | <1 |
| Oral Discomfort                              | 10                     | -       | -  |
| Upper GI Inflammatory Disorders              | 8                      | <1      | -  |
| Gastrointestinal Hemorrhage                  | 6                      | 1       | <1 |
| Ileus                                        | 6                      | 4       | 1  |
| Skin and Subcutaneous Hand-and-Foot Syndrome | 54                     | 17      | NA |
| Dermatitis                                   | 27                     | 1       | -  |  
105  
Version Date:10*.30.2019*  
| Version Date:10.30.2019 Adverse Event        | Capecitabine (n=596)   |         |    |
|----------------------------------------------|------------------------|---------|----|
| Total                                        | Grade 3                | Grade 4 |    |
| %                                            | %                      | %       |    |
| Number of Patients With > One Adverse Event  | 96                     | 52      | 9  |
| Body System/Adverse Event Skin Discoloration | 7                      | <1      | -  |
| Alopecia                                     | 6                      | -       | -  |
| General Fatigue/Weakness                     | 42                     | 4       | -  |
| Pyrexia                                      | 18                     | 1       | -  |
| Edema                                        | 15                     | 1       | -  |
| Pain                                         | 12                     | 1       | -  |
| Chest Pain                                   | 6                      | 1       | -  |
| Neurological Peripheral Sensory Neuropathy   | 10                     | -       | -  |
| Headache                                     | 10                     | 1       | -  |
| Dizziness*                                   | 8                      | <1      | -  |
| Insomnia                                     | 7                      | -       | -  |
| TasteDisturbance                             | 6                      | 1       | -  |
| Metabolism Appetite Decreased                | 26                     | 3       | <1 |
| Dehydration                                  | 7                      | 2       | <1 |
| Eye Eye Irritation                           | 13                     | -       | -  |
| Vision Abnormal                              | 5                      | -       | -  |
| Respiratory Dyspnea                          | 14                     | 1       | -  |
| Cough                                        | 7                      | <1      | 1  |
| Pharyngeal Disorder                          | 5                      | -       | -  |
| Epistaxis                                    | 3                      | <1      | -  |
| Sore Throat                                  | 2                      | -       | -  |
| Musculoskeletal Back Pain                    | 10                     | 2       | -  |
| Arthralgia                                   | 8                      | 1       | -  |  
| Version Date:10.30.2019 Adverse Event                   | Capecitabine (n=596)   |         |    |
|---------------------------------------------------------|------------------------|---------|----|
| Total                                                   | Grade 3                | Grade 4 |    |
| %                                                       | %                      | %       |    |
| Number of Patients With > One Adverse Event             | 96                     | 52      | 9  |
| Body System/Adverse Event Vascular Venous Thrombosis    | 8                      | 3       | <1 |
| Psychiatric Mood Alteration                             | 5                      | -       | -  |
| Depression                                              | 5                      | -       | -  |
| Infections Viral                                        | 5                      | <1      | -  |
| Blood and Lymphatic Anemia                              | 80                     | 2       | <1 |
| Neutropenia                                             | 13                     | 1       | 2  |
| Hepatobiliary Hyperbilirubinemia                        | 48                     | 18      | 5  |
| - Not observed  * Excluding vertigo NA = Not Applicable |                        |         |    |
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13.4.3 formulation and preparation tablets

Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. Each light peach-colored tablet contains 150 mg capecitabine and each peach-colored tablet contains 500 mg capecitabine. The inactive ingredients in capecitabine include: anhydrous lactose, croscarmellose sodium, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate and purified water. The peach or light peach film coating contains hydroxypropyl methylcellulose, talc, titanium dioxide, and synthetic yellow and red iron oxides.
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13.4.4 stability and storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). KEEP TIGHTLY CLOSED. Care should be exercised in the handling of capecitabine. Capecitabine tablets should not be cut or crushed. Procedures for the proper handling and disposal of anticancer drugs should be considered. Any unused product should be disposed of in accordance with local requirements, or drug take back programs. Several guidelines on the subject have been published.
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13.4.6 incompatibilities

- Anticoagulants: Monitor anticoagulant response (INR or prothrombin time) frequently in order to adjust the anticoagulant dose as needed.  
- Phenytoin: Monitor phenytoin levels in patients taking capecitabine concomitantly with phenytoin. The phenytoin dose may need to be reduced.  
- Leucovorin: The concentration of 5-fluorouracil is increased and its toxicity may be enhanced by leucovorin.  
- CYP2C9 substrates: Care should be exercised when capecitabine is coadministered with CYP2C9 substrates.
- Food reduced both the rate and extent of absorption of capecitabine.  
13.5 **5-FLUOROURACIL (5-FU)** (Please see package insert for complete information) 13.5.1 **Source** 5-FU will be supplied by the local pharmacy using supply purchased from commercial sources.
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13.5.2 toxicity

5-FU should be used with extreme caution in poor risk patients with a history of high-dose pelvic irradiation or previous use of alkylating agents, those who have a widespread involvement of bone marrow by metastatic tumors or those with impaired hepatic or renal function. Rarely, unexpected, severe toxicity (e.g., stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to deficiency of dipyrimidine dehydrogenase activity. A few patients have been rechallenged with 5-fluorouracil and despite 5-fluorouracil dose lowering, toxicity recurred and progressed with worse morbidity. Absence of this catabolic enzyme appears to result in prolonged clearance of 5-fluorouracil. The administration of 5-fluorouracil has been associated with the occurrence of palmar-plantar erythrodysesthesia syndrome, also known as hand-foot syndrome. Interruption of therapy is followed by gradual resolution over 5 to 7 days. Although pyridoxine has been reported to ameliorate the palmar-plantar erythrodysesthesia syndrome, its safety and effectiveness has not been established. Stomatitis and esophagopharyngitis (which may lead to sloughing and ulceration), diarrhea, anorexia, nausea and emesis are commonly seen during therapy. Leukopenia usually follows every course of adequate therapy with fluorouracil. The lowest white blood cell counts are commonly observed between the 9th and 14th days after the first course of treatment, although uncommonly the maximal depression may be delayed for as long as 20 days. By the 30th day the count has usually returned to the normal range. Alopecia and dermatitis may be seen in a substantial number of cases. The dermatitis most often seen is a pruritic maculopapular rash usually appearing on the extremities and less frequently on the trunk. It is generally reversible and usually responsive to symptomatic treatment. Other adverse reactions are:
108 Version Date:10*.30.2019*  
- Hematologic: pancytopenia, thrombocytopenia, agranulocytosis, anemia. - Cardiovascular: myocardial ischemia, angina. - Gastrointestinal: gastrointestinal ulceration and bleeding. - Allergic Reactions: anaphylaxis and generalized allergic reactions. - Neurologic: acute cerebellar syndrome (which may persist following discontinuance of treatment), nystagmus, headache.  
- Dermatologic: dry skin; fissuring; photosensitivity, as manifested by erythema or increased pigmentation of the skin; vein pigmentation; palmar-planter erythrodysesthesia syndrome, as manifested by tingling of the hands and feet followed by pain, erythema and swelling.  
- Ophthalmic: lacrimal duct stenosis, visual changes, lacrimation, photophobia. - Psychiatric: disorientation, confusion, euphoria. - Miscellaneous: thrombophlebitis, epistaxis, nail changes (including loss of nails)
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13.5.3 formulation and preparation 13.5.3.1

Fluorouracil injection, USP an antineoplastic antimetabolite, is a sterile, nonpyrogenic injectable solution for intravenous administration. Each 10 mL contains 500 mg fluorouracil; pH is adjusted to approximately 9.2 with sodium hydroxide. For intravenous use. Fluorouracil injection, USP is available at a concentration of 50mg/mL. The 50 mL and 100 mL pharmacy bulk packages are packaged 5 vials per shelf pack. 13.5.3.2 Preparation No dilution is required.
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13.5.4 stability and storage

Store at room temperature 15° to 30°C (59° to 86°F). Protect from light. Retain in carton until time of use. 13.5.5 **Administration procedures**
Please see section **3.4.1.1.**
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13.6.1 source

Leucovorin will be supplied by the local pharmacy using supply purchased from commercial sources. In the event of a leucovorin drug shortage, levoleucovorin may be substituted using equivalent doses at the investigator's discretion and administered according to FDA-approved labeling.  
109 Version Date:10*.30.2019*
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13.6.2 toxicity

Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following the administration of both oral and parenteral leucovorin. No other adverse reactions have been attributed to the use of leucovorin per se.  
Table 1 below summarizes significant adverse events occurring in 316 patients treated with the leucovorin/5-fluorouracil combinations compared against 70 patients treated with 5-fl uorouracil alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen.  
| Reporting Adverse Experiences or Hospitalized for Toxicity (High LV) /5-FU   | (Low LV) /5-FU   | 5-FU Alone   |         |          |         |          |
|------------------------------------------------------------------------------|------------------|--------------|---------|----------|---------|----------|
| (N=155)                                                                      | (N=161)          | (N=70)       |         |          |         |          |
| Toxicity                                                                     | Any (%)          | Grade 3+     | Any (%) | Grade 3+ | Any (%) | Grade 3+ |
| (%)                                                                          | (%)              | (%)          |         |          |         |          |
| Leukopenia                                                                   | 69               | 14           | 83      | 23       | 93      | 48       |
| Thrombocytopenia                                                             | 8                | 2            | 8       | 1        | 18      | 3        |
| Infection                                                                    | 8                | 1            | 3       | 1        | 7       | 2        |
| Nausea                                                                       | 74               | 10           | 80      | 9        | 60      | 6        |
| Vomiting                                                                     | 46               | 8            | 44      | 9        | 40      | 7        |
| Diarrhea                                                                     | 66               | 18           | 67      | 14       | 43      | 11       |
| Stomatitis                                                                   | 75               | 27           | 84      | 29       | 59      | 16       |
| Constipation                                                                 | 3                | 0            | 4       | 0        | 1       | -        |
| Lethargy/Malaise/Fatigue                                                     | 13               | 3            | 12      | 2        | 6       | 3        |
| Alopecia                                                                     | 42               | 5            | 43      | 6        | 37      | 7        |
| Dermatitis                                                                   | 21               | 2            | 25      | 1        | 13      | -        |
| Anorexia                                                                     | 14               | 1            | 22      | 4        | 14      | -        |
| Hospitalization for                                                          | 5%               | 15%          | 7%      |          |         |          |
| Toxicity                                                                     |                  |              |         |          |         |          |  
| (High LV) /5-FU   | (Low LV) /5-FU   | 5-FU Alone   |         |          |         |          |
|-------------------|------------------|--------------|---------|----------|---------|----------|
| (N=155)           | (N=161)          | (N=70)       |         |          |         |          |
| Toxicity          | Any (%)          | Grade 3+     | Any (%) | Grade 3+ | Any (%) | Grade 3+ |
| (%)               | (%)              | (%)          |         |          |         |          |  
High LV = Leucovorin 200 mg/m2, Low LV = Leucovorin 20 mg/m2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of Grade 3 or higher
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13.6.3 formulation and preparation 13.6.3.1

Leucovorin Calcium Injection USP is a sterile, preservative-free solution indicated for intramuscular (IM) or intravenous (IV) administration in a 50 mL single-dose vial. Each mL contains leucovorin calcium equivalent to 10 mg Leucovorin, USP; 8 mg sodium chloride; sodium hydroxide and/or hydrochloric acid for pH adjustment pH 7.8 (6.5 to 8.5). There is 0.004 mEq of calcium per mg of leucovorin. Solution contains no bacteriostat or antimicrobial agents. Leucovorin Calcium for Injection is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, and 350 mg vials. Each 50 mg vial of Leucovorin Calcium for Injection, when reconstituted with 5 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 100 mg vial of Leucovorin Calcium for Injection, when reconstituted with 10 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 200 mg vial of Leucovorin Calcium for Injection, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 350 mg vial of Leucovorin Calcium for Injection, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL.  
In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium.
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13.6.3.2 preparation

These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, USP, added to adjust tonicity. Because of the benzyl alcohol contained in certain diluents used for reconstituting Leucovorin Calcium for Injection, when doses greater than 10 mg/m2 (as in this study) are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately.  
111 Version Date:10*.30.2019*
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13.6.4 stability and storage

Store at 20°C to 25°C (68° to 77° F). [See USP Controlled Room Temperature.] Protect from light. Retain in carton until time of use.  
Reconstituted form should be used immediately.
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13.6.6 incompatibilities

Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible pediatric patients. Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin may reduce the efficacy of intrathecally administered methotrexate. Leucovorin may enhance the toxicity of 5-fluorouracil
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13.7.1 source

Oxaliplatin will be supplied by the local pharmacy using supply purchased from commercial sources.
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13.7.2 toxicity

The most common side effects of oxaliplatin include:  
- neutropenia, anemia, thrombocytopenia, hypertension, diarrhea, nausea, vomiting, constipation, oral mucositis, abdominal pain, anorexia, fatigue, injection site reactions, alopecia and dehydration
Potentially serious toxicities include:  
- **Grade 3/4 hypersensitivity,** including anaphylactic/anaphylactoid reactions, to oxaliplatin has been observed in 2-3% of colon cancer patients. These reactions are usually managed with standard epinephrine, corticosteroid, antihistamine therapy, and require discontinuation of therapy or desensitization protocol for continuation of therapy.  
- **Peripheral sensory neuropathy** (acute ≤ 14 days and persistent > 14 days) was reported in adjuvant patients treated with ELOXATIN as part of FOLFOX with a frequency of 92% (all grades) and 13% (grade 3). At the 28-day follow-up after the last treatment cycle, 60% of all patients had any grade (Grade 1=40%, Grade 2=16%, Grade 3=5%) peripheral sensory neuropathy decreasing to 39% at 6 months follow-up (Grade 1=31%, Grade 2=7%, Grade 3=1%) and 21% at 18 months of follow-up (Grade 1=17%, Grade 2=3%, Grade 3=1%).
Overall, neuropathy was reported in patients previously untreated for advanced colorectal cancer in 82% (all grades) and 19% (grade 3/4), and in the previously treated patients in 74% (all grades) and 7% (grade 3/4) events. Information regarding reversibility of neuropathy was not available from the trial for patients who had not been previously treated for colorectal cancer.  
- **Reversible Posterior Leukoencephalopathy Syndrome** (RPLS, also known as PRES,
Posterior Reversible Encephalopathy Syndrome) has been observed in clinical trials (< 0.1%) and postmarketing experience. Signs and symptoms of RPLS could be headache, altered mental functioning, seizures, abnormal vision from blurriness to blindness, associated or not with hypertension. Diagnosis of RPLS is based upon confirmation by brain imaging.  
- **Pulmonary Toxicity.** oxaliplatin has been associated with pulmonary fibrosis (<1% of study patients), which may be fatal. The combined incidence of cough and dyspnea was 7.4% (any grade) and < 1% (grade 3) with no grade 4 events in the oxaliplatin plus infusional 5-fluorouracil/leucovorin arm compared to 4.5% (any grade) and no grade 3 and 0.1% grade 4 events in the infusional 5- fluorouracil/leucovorin alone arm in adjuvant colon cancer patients. In this study, one patient died from eosinophilic pneumonia in the oxaliplatin combination arm. The combined incidence of cough, dyspnea and hypoxia was 43% (any grade) and 7% (grade 3 and 4) in the oxaliplatin plus 5-fluorouracil/leucovorin arm compared to 32% (any grade) and 5% (grade 3 and 4) in the irinotecan plus 5-fluorouracil/leucovorin arm of unknown duration for patients with previously untreated colorectal cancer. In case of unexplained respiratory symptoms such as non-productive cough, dyspnea, crackles, or radiological pulmonary infiltrates, ELOXATIN should be discontinued until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.  
- **Hepatotoxicity** as evidenced in the adjuvant study, by increase in transaminases (57% vs.  
34%) and alkaline phosphatase (42% vs. 20%) was observed more commonly in the oxaliplatin combination arm than in the control arm. The incidence of increased bilirubin was similar on both arms. Changes noted on liver biopsies include: peliosis, nodular regenerative hyperplasia or sinusoidal alterations, perisinusoidal fibrosis, and venoocclusive lesions. Hepatic vascular disorders should be considered, and if appropriate, should be investigated in case of abnormal liver function test results or portal hypertension, which cannot be explained by liver metastases
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13.7.3 formulation and preparation 13.7.3.1

Oxaliplatin is supplied in single-use vials containing 50 mg or 100 mg of oxaliplatin as a sterile, preservative-free lyophilized powder for reconstitution. Lactose monohydrate is also present as an inactive ingredient. 13.7.3.1.2 Solution 113 Version Date:10*.30.2019* Oxaliplatin is supplied in single-use vials containing 50 mg, 100 mg or 200 mg of oxaliplatin as a sterile, preservative-free, aqueous solution at a concentration of 5 mg/ml. Water for Injection, USP is present as an inactive ingredient.
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13.7.3.2 preparation 13.7.3.2.1 powder

Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions. The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. Oxaliplatin is not light sensitive.
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13.7.3.2.2 solution

Do not freeze and protect from light the concentrated solution. A final dilution must never be performed with a sodium chloride solution or other chloride containing solutions. The solution must be further diluted in an infusion solution of 250-500 mL of 5% Dextrose Injection, USP. After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.  
Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication.
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13.7.3.2.3 general

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present. Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.  
114 Version Date:10*.30.2019*
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13.7.4 stability and storage

13.7.4.1 Powder for solution for infusion:
Store under normal lighting conditions at 25°C (77°F); excursions permitted to 15-30°C (5986°F).  
13.7.4.2 Concentrate for solution for infusion:
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Do not freeze and protect from light (keep in original outer carton).
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13.7.6 incompatibilities

No specific cytochrome P-450-based drug interaction studies have been conducted. No pharmacokinetic interaction between 85 mg/m2 oxaliplatin and 5-fluorouracil/leucovorin has been observed in patients treated every 2 weeks. Increases of 5-fluorouracil plasma concentrations by approximately 20% have been observed with doses of 130 mg/m2 oxaliplatin dosed every 3 weeks. Because platinum-containing species are eliminated primarily through the kidney, clearance of these products may be decreased by co-administration of potentially nephrotoxic compounds; although, this has not been specifically studied.
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37. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nature immunology 2001;2:261-8. 38. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. 39. Lipson EJ, Sharfman WH, Drake CG, et al. Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clinical cancer research : an official journal of the American Association for Cancer Research 2013;19:462-8. 40. Herbst R, Gordon M, Fine G, et al. A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31 (suppl):abstr 3000. 41. N. Yamamoto YY, H. Nokihara, H. Asahina, T. Shibata, Y. Tamura, Y. Seki, K. Honda, Y. Tanabe, T. Tamura. Phase I study of ONO-4538 (BMS-936558), an anti PD-1 antibody, in Japanese patients with advanced solid tumors. ESMO Congress 2012 2012:Abstract 1174. 42. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2004;22:23-30. 43. Koopman M, Lieke HJ, Ten Tije AJ, et al. Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013;31 (suppl):abstr 3502.  
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Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC
Version Date:10.30.2019
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15 appendices

15.1 APPENDIX A: PRECLINICAL  MODEL EVALUATION  OF THE COMBINATION OF FOLFOX
WITH ANTI-PD-L1 Combination with FOLFOLX in the MC38 Tumor Model MSB0010718C
Study ID: IONC20042011CKH (TI10-079, TI11-001)
Pre-clinical Pharmacology - TA ImmunoOncology Non-clinical STUDY REPORT, In Vivo Combination of MSB0010718C (Anti-PD-L1) and FOLFOLX in a Subcutaneous MC38 Tumor Model in C57BL/6 Mice  
| Project name:                   | Anti-PD-L1                                     |
|---------------------------------|------------------------------------------------|
| Project code:                   | G10007001                                      |
| Study number:                   | IONC20012011CKH (TI10-079, TI11-001)           |
| Authors:                        | Huakui Yu, Robert Tighe, Ken Hance             |
| GLP Compliance :                | The study was not conducted in compliance with |
| Good Laboratory Practice (GLP). |                                                |
| Test facility:                  | Yan Lan, Director                              |
| Translational Immunology        |                                                |
| TA-Oncology-Immunotherapy       |                                                |
| EMD Serono Research Institute   |                                                |
| 45A Middlesex Turnpike          |                                                |
| Billerica, MA 01821             |                                                |
| April 20 th , 2011              |                                                |
| Date of report creation:        |                                                |  
122 Version Date:10*.30.2019*  
| 15.2                                                                                                                                                                                      | APPENDIX B-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  to carry on all pre-disease                                                                                                                          |                                                                        |                                                               |             |
| 0                                                                                                                                                                                         | performance without restriction.                                       | Able to carry on normal activity;  minor signs or symptoms of |             |
| 90                                                                                                                                                                                        | disease. Normal activity with effort;                                  |                                                               |             |
| 80                                                                                                                                                                                        | some 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). |                                                                        |                                                               |             |
| 1                                                                                                                                                                                         | Cares for self, unable to carry on                                     |                                                               |             |
| 70                                                                                                                                                                                        | normal activity or to do active  work.                                 |                                                               |             |
| In bed <50% of the time.  Ambulatory and capable of all  self-care, but unable to carry out  any work activities. Up and  about more than 50% of waking  hours.                           | Requires occasional assistance,                                        |                                                               |             |
| 60                                                                                                                                                                                        | but is able to care for most of  his/her needs.                        |                                                               |             |
| 2                                                                                                                                                                                         | 50                                                                     | Requires considerable assistance  and frequent medical care.  |             |
| 40                                                                                                                                                                                        | Disabled, requires special care  and assistance.                       |                                                               |             |
| In bed >50% of the time.  Capable of only limited self-care,  confined to bed or chair more  than 50% of waking hours.                                                                    |                                                                        |                                                               |             |
| 3                                                                                                                                                                                         | Severely disabled,                                                     |                                                               |             |
| 30                                                                                                                                                                                        | hospitalization indicated. Death  not imminent.                        |                                                               |             |
| 20                                                                                                                                                                                        | Very sick, hospitalization  indicated. Death not imminent.             |                                                               |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                  |                                                                        |                                                               |             |
| 4                                                                                                                                                                                         | 10                                                                     | Moribund, fatal processes  progressing rapidly.               |             |
| 5                                                                                                                                                                                         | Dead.                                                                  | 0                                                             | Dead.       |  
123 Version Date:10*.30.2019* 15.3 APPENDIX C:CCR **PROBLEM REPORT FORM**
CCR REPORTABLE EVENT FORM (REF)
NCI Protocol \#: Click or tap here to enter text. Protocol Title: Click or tap here to enter text.  
Report version: *(select one)*
☐ Initial Report
☐ Follow-up Site Principal Investigator: Click or tap here to enter text.  
Date site PI was notified of the problem: Click or tap to enter a date.  
Date of problem: Click or tap to enter a date.  
If delay in reporting to the coordinating center, please explain: Click or tap here to enter text.  
Location of problem: *(e.g., patient's home, doctor's office )*
Click or tap here to enter text. Description of Subject Does this problem apply to a subject?  
☐ yes ☐ not applicable (more than one subject is involved)
If yes, enter details below:
Subject ID: Click or tap here to enter text. (*do not use medical record number)*
Sex: ☐Male ☐ Female Age: Click or tap here to enter text.  
124 Version Date:10*.30.2019* Diagnosis: Click or tap here to enter text.  
Name the problem: *(select all that apply)*
☐ Specimen collection issue ☐ Informed consent issue ☐ Ineligible for enrollment ☐ Breach of PII ☐ Other, briefly state the nature of the problem: Click or tap here to enter text.  
Detailed Description of the problem: (Include any relevant treatment, outcomes or pertinent history): Click or tap here to enter text.  
What are you reporting?  
☐ **unanticipated problem** ☐ **non-compliance (other than a protocol deviation)** ☐ **protocol deviation** ☐ **new information that might affect the willingness of subjects to enroll or continue**
participation in this study If interventional or expanded access study, please answer the following questions about your site:
☐ **death**
125 Version Date:10*.30.2019* How many participants are still receiving the study intervention? Click or tap here to enter text. How many participants completed study interventions but remain in follow up? Click or tap here to enter text. How many participants are enrolled but not yet receiving study interventions? Click or tap here to enter text. Have similar problems occurred on this protocol at your site?  
☐ **Yes** ☐ No Describe what steps you have already taken or will be taking **as a result of this problem:** Click or tap here to enter text.  
INVESTIGATOR'S SIGNATURE: DATE:
Abbreviated Title: Chemo+antiPDL1+ vaccine in CRC
Version Date:10.30.2019 126