untitled h1
7.1.2 xelox dose modifications

| Toxicity Gradea   | Occurrence   | Oxaliplatin   | Capecitabine   |
|-------------------|--------------|---------------|----------------|
| DIARRHEA Grade 1  | Any          | Maintain dose | Maintain dose  |  
| If tolerable: Maintain dose                                                                | If tolerable: Maintain dose                                                                                                                                                                                 |                                                                          |                                  |
|--------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------|----------------------------------|
| Grade 2                                                                                    | Any                                                                                                                                                                                                         | If intolerable: Hold until grade ≤1,  then resume at 80% of current dose | If intolerable: Hold until       |
| grade ≤1,then resume at 80% of  current dose b                                             |                                                                                                                                                                                                             |                                                                          |                                  |
| rd                                                                                         | Hold until grade ≤1, then resume at                                                                                                                                                                         | Hold until grade ≤1, then resume at                                      |                                  |
| 1 st - 3                                                                                   | 80% of current dose                                                                                                                                                                                         | 80% of current dose                                                      |                                  |
| Grade 3                                                                                    | Hold until grade ≤1, –obtain                                                                                                                                                                                |                                                                          |                                  |
| 4 th and higher                                                                            | permission of PI to resume at  80% of current dose                                                                                                                                                          | Hold until grade ≤1, obtain                                              |                                  |
| permission of PI to resume at  80% of current dose–                                        |                                                                                                                                                                                                             |                                                                          |                                  |
| st                                                                                         | Hold until grade ≤1, then resume at                                                                                                                                                                         | Hold until grade ≤1, then resume at                                      |                                  |
| 1                                                                                          | 60% of current dose                                                                                                                                                                                         | 60% of current dose                                                      |                                  |
| Grade 4                                                                                    | Hold until grade ≤1, obtain                                                                                                                                                                                 |                                                                          |                                  |
| nd and higher 2                                                                            | permission of PI to resume at 60%  of current dose b                                                                                                                                                        | Hold until grade ≤1, obtain                                              |                                  |
| permission of PI to resume at  60% of current dose b                                       |                                                                                                                                                                                                             |                                                                          |                                  |
| VOMITING Grade 1                                                                           | Any                                                                                                                                                                                                         | Maintain dose                                                            | Maintain dose                    |
| Grade 2                                                                                    | Any                                                                                                                                                                                                         | Maintain dose                                                            | Maintain dose                    |
| Grade 3                                                                                    |                                                                                                                                                                                                             |                                                                          |                                  |
| [occurring within 3  days of Oxaliplatin  dosing despite  optimal anti-emetic prophylaxis] | st                                                                                                                                                                                                          | Hold until grade ≤1, then resume                                         |                                  |
| 1                                                                                          | at 80% of current dose c                                                                                                                                                                                    | Maintain dose                                                            |                                  |
| nd and higher                                                                              | Hold until grade ≤ 1, then                                                                                                                                                                                  |                                                                          |                                  |
| 2                                                                                          | resume at current dose. c                                                                                                                                                                                   | Maintain dose                                                            |                                  |
| Grade 4                                                                                    |                                                                                                                                                                                                             |                                                                          |                                  |
| (TPN, intensive care  or hemodynamic  collapse) [occurring  within 3 days of Oxaliplatin dosing  despite optimal antiemetic prophylaxis]                                                                                            | st                                                                                                                                                                                                          | Hold until grade ≤1 c , then                                             | Hold until grade ≤1, then resume |
| 1                                                                                          | resume at 60% of current dose                                                                                                                                                                               | at 60% of current dose                                                   |                                  |
| Hold until grade ≤1, obtain                                                                |                                                                                                                                                                                                             |                                                                          |                                  |
| 2 nd and higher                                                                            | Discontinue                                                                                                                                                                                                 | permission of PI to resume at 60%  of current dose                       |                                  |
| a.                                                                                         | National Cancer Institute Common Terminology Criteria Version 3.                                                                                                                                            |                                                                          |                                  |
| b.                                                                                         | Continue treatment if it is considered to be in the best interest of the patient                                                                                                                            |                                                                          |                                  |
| c.                                                                                         | NOTE: After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to  grade ≤1, the treating physician may choose, to hold oxaliplatin and continue capecitabine and |                                                                          |                                  |  
2  
nd and higher Discontinue  
Hold until grade ≤1, obtain  
permission of PI to resume at 60%  
of **current** dose  
a. National Cancer Institute Common Terminology Criteria Version 3. b. Continue treatment if it is considered to be in the best interest of the patient  
c. **NOTE:** After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to  
grade ≤1, the treating physician may choose, to hold oxaliplatin and continue capecitabine and pembrolizumab at current dose as clinically indicated. If the treating physician chooses to restart oxaliplatin later in the patient's treatment course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on which patient was treated. The specific treatment approach used and dose modifications that occur are required to be reported in the Case Report Forms.  
| OTHER CLINICALLY SIGNIFICANT* NON-HEMATOLOGIC ADVERSE EVENTS ToxicityGradea Occurrence Oxaliplatin   | Capecitabine   |                                 |                                                           |
|------------------------------------------------------------------------------------------------------|----------------|---------------------------------|-----------------------------------------------------------|
| Grade 1                                                                                              | Any            | Maintain dose                   | Maintain dose                                             |
| Hold until grade ≤1, then                                                                            |                |                                 |                                                           |
| Grade 2                                                                                              | 1 st           | resume at 80% of current dose c | Hold until grade ≤1, then  resume at 80% of current  dose |  
| OTHER CLINICALLY SIGNIFICANT* NON-HEMATOLOGIC ADVERSE EVENTS ToxicityGradea Occurrence Oxaliplatin   | Capecitabine                                                                       |                                                           |
|------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|-----------------------------------------------------------|
| Hold until grade ≤1, then  resume at 80% of current  dose                                            |                                                                                    |                                                           |
| nd and higher                                                                                        | Hold until grade ≤ 1, then                                                         |                                                           |
| 2                                                                                                    | resume at current dose. b,c Hold until grade ≤1, then                              |                                                           |
| 1 st                                                                                                 | resume at 80% of current dose c                                                    | Hold until grade ≤1, then  resume at 80% of current  dose |
| Grade 3                                                                                              | Hold until grade ≤1, then  resume at 80% of current  dose                          |                                                           |
| nd and higher                                                                                        | Hold until grade ≤ 1, then                                                         |                                                           |
| 2                                                                                                    | resume at current dose. b,c Hold until grade ≤1, then                              |                                                           |
| st                                                                                                   | resume at 60% of current                                                           |                                                           |
| 1                                                                                                    | dose c                                                                             | Hold until grade ≤1, then  resume at 60% of current dose  |
| Grade 4                                                                                              | Hold until grade ≤1,                                                               |                                                           |
| obtainpermission of PI to                                                                            |                                                                                    |                                                           |
| 2 nd and higher                                                                                      | resume at 60% of current dose b                                                    | Hold until grade ≤1, obtain                               |
| permission of PI to resume at  60% of current dose b                                                 |                                                                                    |                                                           |
| a.                                                                                                   | National Cancer Institute Common Terminology Criteria Version 3.0                  |                                                           |
| b.                                                                                                   | Continued treatment if it is considered to be in the best interest of the patient. |                                                           |  
a. National Cancer Institute Common Terminology Criteria Version 3.0 b. Continued treatment if it is considered to be in the best interest of the patient.  
c. **NOTE:** After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade
≤1, the treating physician may choose, instead of lowering the dose of capecitabine, to hold oxaliplatin and continue capecitabine and pembrolizumab at current dose as clinically indicated. If toxicity recurs, follow original dose modification instructions for capecitabine. If the treating physician chooses to restart oxaliplatin later in the patient's treatment course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on which patient was treated. The specific treatment approach used and dose modifications that occur are required to be reported in the Case Report Forms.  
* Dose adjustments only for clinically significant toxicities (e.g. asymptomatic lab abnormalities do not necessarily require dose modifications) If non-hematologic toxicities can be attributed solely to either oxaliplatin, capecitabine, or pembrolizumab then no dose adjustments of the other agents are needed.  
| HEMATOLOGIC ADVERSE EVENTS ToxicityGradea Occurrence       | Oxaliplatin                                          | Capecitabine                                                                                           |                              |
|------------------------------------------------------------|------------------------------------------------------|--------------------------------------------------------------------------------------------------------|------------------------------|
| NEUTROPENIA Grade 1                                        | Any                                                  | Maintain dose                                                                                          | Maintain dose                |
| Grade 2                                                    | Any                                                  | Maintain dose                                                                                          | Maintain dose                |
| st                                                         | Hold until grade 1, then                            |                                                                                                        |                              |
| 1                                                          | resume at current dose                               | Maintain dose                                                                                          |                              |
| Grade 3(≥0.5 - <1x109 /L)                                  | Hold until grade 1, then                            |                                                                                                        |                              |
| nd and higher 2                                            | resume at 80% of current                             | Maintain dose                                                                                          |                              |
| dose d                                                     |                                                      |                                                                                                        |                              |
| Hold until grade  1, then                                 |                                                      |                                                                                                        |                              |
| 1 st                                                       | resume at 80% of current dose.b,c,d                  | Hold until grade ≤1, then                                                                              |                              |
| resume at 80% of the current dose b,c                      |                                                      |                                                                                                        |                              |
| Grade 4 (< 0.5  x109 /L)                                   | Hold until grade ≤1, obtain                          |                                                                                                        |                              |
| permission of PI to resume at  60% of current dose         |                                                      |                                                                                                        |                              |
| FEBRILE NEUTROPENIA                                        | Hold until grade ≤1, obtain                          |                                                                                                        |                              |
| 2 nd and higher                                            | permission of PI to resume  at 60% of current dose d | Hold until resolution of fever  and neutropenia to grade ≤1,  then resume at 60% of current dose b,c,d |                              |
| Hold until resolution of fever  and neutropenia to grade ≤ |                                                      |                                                                                                        |                              |
| 1 st - 2 nd                                                | 1, then resume at 60% of  current dose d             |                                                                                                        |                              |
| Grade 3                                                    |                                                      |                                                                                                        |                              |
| (neutropenia and  fever  38.5C)                           | rd                                                   | Discontinue Protocol                                                                                   |                              |
| 3                                                          | Therapy                                              | Discontinue Protocol Therapy                                                                           |                              |
| Grade 4                                                    | Any                                                  | Discontinue Protocol                                                                                   | Discontinue Protocol Therapy |
| (neutropenia and                                           | Therapy                                              |                                                                                                        |                              |
| fever > 38.5 C)                                            |                                                      |                                                                                                        |                              |
| THROMBOCYTOPENIA Grade 1 (< LLN - <75.0 x 109 /L)          | Any                                                  | Maintain dose                                                                                          | Maintain dose                |
| Hold until grade ≤1, then                                  |                                                      |                                                                                                        |                              |
| 1 st                                                       | resume at 80% of current                             | Maintain dose                                                                                          |                              |
| dose d                                                     |                                                      |                                                                                                        |                              |
| Grade 2(50.0 - <  75.0 x 109 /L)                          | nd and higher                                        | If stable grade 2, maintain                                                                            |                              |
| 2                                                          | current dose                                         | Maintain dose                                                                                          |                              |
| Hold until grade ≤1, then                                  |                                                      |                                                                                                        |                              |
| 1st                                                        | resume at 80% current dose  d                        | Hold until grade ≤1, then                                                                              |                              |
| resume at 80% of the current dose                          |                                                      |                                                                                                        |                              |
| Grade 3(25.0 - <  50.0 x 109 /L)                          | Hold until grade ≤1, then                            |                                                                                                        |                              |
| 2nd and higher                                             | resume at 80% current  dose d                        | Hold until grade ≤1, then                                                                              |                              |
| resume at 80% of the current dose b                        |                                                      |                                                                                                        |                              |
| Hold until grade ≤1, then                                  |                                                      |                                                                                                        |                              |
| 1st                                                        | resume at 60% of the  current dose b,d               | Hold until grade ≤1, then                                                                              |                              |
| resume at 60% of the current dose b                        |                                                      |                                                                                                        |                              |
| Grade 4(< 25.0 x  109 /L)                                  | 2nd                                                  | Discontinue Protocol  Therapy                                                                          | Discontinue Protocol Therapy |  
| HEMOGLOBIN Grade 1 < LLN - 10.0 g/dL <  LLN - 100 g/L <  LLN - 6.2mmol/L   | Any                                                                                    | Maintain dose   | Maintain doseb   |
|----------------------------------------------------------------------------|----------------------------------------------------------------------------------------|-----------------|------------------|
| Grade 2                                                                    |                                                                                        |                 |                  |
| 8.0 - < 10.0 g/dL 80 - < 100 g/L 4.9 - < 6.2 mmol/L                        | Any                                                                                    | Maintain dose   | Maintain dose    |
| Grade 3                                                                    |                                                                                        |                 |                  |
| 6.5 - < 8.0 g/dL 65 - < 80 g/L                                             |                                                                                        |                 |                  |
| 4.0 - < 4.9 mmol/L                                                         | Any                                                                                    | Maintain dose   | Maintain dose    |
| Grade 4 < 6.5 g/dL < 65 g/L                                                |                                                                                        |                 |                  |
| < 4.0 mmol/L                                                               | Hold until < grade 2; then                                                             |                 |                  |
| Any                                                                        | resume at current dose, may                                                            | Maintain dose b |                  |
| transfuse b                                                                |                                                                                        |                 |                  |
| OTHER HEMATOLOGIC TOXICITY Grades 1 - 4 Any                                | Maintain dose                                                                          | Maintain dose   |                  |
| a.                                                                         | National Cancer Institute Common Terminology Criteria Version 3.0                      |                 |                  |
| b.                                                                         | Continued treatment only if it is considered to be in the best interest of the patient |                 |                  |  
a. National Cancer Institute Common Terminology Criteria Version 3.0 b. Continued treatment only if it is considered to be in the best interest of the patient c. Consider growth factor support if continuing treatment is felt to be in the patient's best interest.  
d. **NOTE:** After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade ≤1, the treating physician may choose, to hold oxaliplatin and continue capecitabine and pembrolizumab at current dose as clinically indicated. If the treating physician chooses to restart oxaliplatin later in the patient's treatment course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on which patient was treated. The specific treatment approach used and dose modifications that occur are required to be reported in the Case Report Forms.
untitled h1
7.1.2.1 special guidelines related to

Capecitabine can cause diarrhea, and should be *stopped at diarrhea grade*  2, and treated symptomatically (recommend IV hydration and use of loperamide for diarrhea, observing loperamide dosage recommendation and treatment start, see below). If control takes longer than 2 days, medical evaluation including relevant diagnostic procedures, alternative treatment and possible investigation of Dihydropyrimidine Dehydrogenase Deficiency (DPD) deficiency should be considered.  
Capecitabine cannot be re-started until diarrhea has resolved to baseline or grade < 2. The recommended dosage regimen for loperamide: 4 mg at the first onset of late diarrhea and then 2 mg every 2 hours until the patient is diarrhea-free for at least 12 hours. During the night, the patient may take 4 mg of loperamide every 4 hours. Note: This dosage regimen exceeds the usual dosage recommendations for loperamide. Premedication with loperamide is not recommended.  
The use of drugs with laxative properties should be avoided because of the potential for exacerbation of diarrhea. Patients should be advised to contact their physician to discuss any laxative use.  
Patients with ≥ grade 3 diarrhea should also be evaluated for c-difficile. Patients with neutropenia and diarrhea should be considered for empiric use of prophylactic antibiotics, such as oral quinolones.  
| Toxicity Gradea           | Occurrence                                                                             | Oxaliplatin              | Capecitabine   |
|---------------------------|----------------------------------------------------------------------------------------|--------------------------|----------------|
| 1                         | Any                                                                                    | Maintain dose            | Maintain dose  |
| Hold until grade ≤1, then |                                                                                        |                          |                |
| st - 3 rd                 | Maintain dose                                                                          |                          |                |
| 1                         | resume 80% of current                                                                  |                          |                |
| 2                         | dose                                                                                   |                          |                |
| th and higher             | Discontinue Protocol                                                                   | Discontinue Protocol     |                |
| 4                         | Therapy                                                                                | Therapy                  |                |
| Hold until grade ≤1, then |                                                                                        |                          |                |
| 1 st - 2 nd               | Maintain dose                                                                          | resume at 80% of current |                |
| 3                         | dose                                                                                   |                          |                |
| rd and higher             | Discontinue Protocol                                                                   | Discontinue Protocol     |                |
| 3                         | Therapy                                                                                | Therapy                  |                |
| a.                        | National Cancer Institute Common Terminology Criteria Version 3.0                      |                          |                |
| b.                        | Continued treatment only if it is considered to be in the best interest of the patient |                          |                |  
a. National Cancer Institute Common Terminology Criteria Version 3.0 b. Continued treatment only if it is considered to be in the best interest of the patient c. **NOTE:** After Cycle 1, at the discretion of the treating physician, once there is recovery of the toxicity to grade ≤1, the treating physician may choose, to hold oxaliplatin and continue capecitabine and pembrolizumab at current dose as clinically indicated. If the treating physician chooses to restart oxaliplatin later in the patient's treatment course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on which patient was treated. The specific treatment approach used and dose modifications that occur are required to be reported in the Case Report Forms.  
*Applies only for grading hand–foot syndrome and should not be used to describe any other skin event and/or other cutaneous area.  
In the case of a discrepancy between the clinical domain and the functional domain, the assigned grade should correspond to the domain with the higher grade.
untitled h1
grade 2-3 hand-foot skin reaction

Treat symptomatically (recommended use of emollients) and according to above table. The use of vitamin B6 (Pyridoxine) has been reported to be of possible benefit for symptomatic or secondary prophylactic treatment, but due to a possible interaction with cisplatin (and thus possibly oxaliplatin)
the use of B6 is not permitted in this trial.  
7.1.2.1.3 Stomatitis/Oral Mucositis/Mouth Ulcers Stomatitis/oral mucositis/mouth ulcers due to capecitabine should be treated using local supportive care. Please follow the paradigm below for treatment of stomatitis/oral mucositis/mouth ulcers:  
For mild toxicity (grade 1), use conservative measures such as non-alcoholic mouth wash or salt water (0.9%) mouth wash several times a day until resolution.
For more severe toxicity (grade 2 in which case patients have pain but are able to maintain adequate oral alimentation, or grade 3 in which case patients cannot maintain adequate oral alimentation), the suggested treatments are topical analgesic mouth treatments (i.e., local anesthetics such as, benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol, or phenol) with or without topical corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog in Orabase®). For patients with grade 2 and above stomatitis, capecitabine may be held or dose reduced according to dose reduction table for non-hematologic toxicities (Section 3.3.4).  
Agents containing hydrogen peroxide, iodine, and thyme derivatives may tend to worsen mouth ulcers. It is preferable to avoid these agents. The ingredient list of used toothpastes and mouthwashes should be checked for these agents.  
Antifungal agents must be avoided unless a fungal infection is diagnosed. Topical antifungal agents are preferred if an infection is diagnosed. Similarly, antiviral agents such as acyclovir should be avoided unless a viral infection is diagnosed.
Note: Stomatitis/oral mucositis should be appropriately graded using the functional grading given on the NCI-CTC for Adverse Events, version 3.0.
untitled h1
7.2.1.2 special guidelines related to

| 7.2.1.2.1 Dose Modifications for Neurological Toxicity Related to Oxaliplatin Toxicity Grade Duration of Toxicity   | Persistent                                                  |                                                             |                                                             |
|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------|-------------------------------------------------------------|-------------------------------------------------------------|
| Between Cyclesa                                                                                                     |                                                             |                                                             |                                                             |
| 1-7 Days                                                                                                            | > 7 Days                                                    |                                                             |                                                             |
| Grade 1                                                                                                             |                                                             |                                                             |                                                             |
| Paresthesias/dysesthesiasb that do not interfere                                                                    | Maintain dose                                               | Maintain dose                                               | Maintain dose                                               |
| with function                                                                                                       |                                                             |                                                             |                                                             |
| Grade 2 Tolerable                                                                                                   | Continue to dose                                            |                                                             |                                                             |
| Paresthesias/dysesthesiasb interfering with                                                                         | Maintain dose                                               | Maintain dose                                               | but reduce to 80%                                           |
| function, but not activities of daily living (ADL)                                                                  | of current dose c                                           |                                                             |                                                             |
| Grade 2 Intolerable                                                                                                 |                                                             |                                                             |                                                             |
| Paresthesias/dysesthesiasb interfering with  function, but not activities of daily living (ADL)                     | Hold until grade ≤1;  then resume at 80%  of current dose d |                                                             |                                                             |
| Grade 3                                                                                                             |                                                             |                                                             |                                                             |
| Paresthesias/dysesthesiasb with pain or with  functional impairment that also interfere with  ADL                   | Hold until grade ≤1;  then resume at 80%  of current dose d | Hold until grade ≤1;  then resume at 80%  of current dose d |                                                             |
| Hold until grade ≤1;  then resume at 80%  of current dose d                                                         | Hold until grade ≤1;  then resume at 80%  of current dose d | Hold until grade ≤1;  then resume at 80%  of current dose d |                                                             |
| Grade 4                                                                                                             |                                                             |                                                             |                                                             |
| Persistent paresthesias/dysesthesiasb that are  disabling or life-threatening                                       | Hold until grade ≤1;  then resume at 60%  of current dose d | Hold until grade ≤1;  then resume at 60%  of current dose d | Hold until grade ≤1;  then resume at 60%  of current dose d |
| 1 st occurrence:                                                                                                    |                                                             |                                                             |                                                             |
| Increase duration of  next infusion to 4  hoursd 2 nd and higher  occurrence: Increase infusion to  6 hours         |                                                             |                                                             |                                                             |
| ACUTE                                                                                                               |                                                             |                                                             |                                                             |
| (during or after the 2 hour infusion)  laryngopharyngeal dysesthesiasb                                              | N/A                                                         | N/A                                                         |                                                             |
| a.                                                                                                                  | Not resolved by the beginning of the next cycle.            |                                                             |                                                             |
| b.                                                                                                                  | May be cold-induced.                                        |                                                             |                                                             |  
a. Not resolved by the beginning of the next cycle. b. May be cold-induced. c. If grade 2 *tolerable* neurologic toxicity persists longer than 6 weeks, despite oxaliplatin dose adjustments, oxaliplatin should be held and therapy with capecitabine and pembrolizumab can be continued. If neurologic toxicity subsequently resolves to < Grade 1, oxaliplatin therapy may resume at 80% of current dose.  
d. **NOTE:** After Cycle 1, the treating physician may choose to hold oxaliplatin and continue capecitabine and pembrolizumab at current dose as clinically indicated. If toxicity resolves to grade 1 or less the treating physician may chooses to restart oxaliplatin later in the patient's treatment course, the dose of oxaliplatin at which the patient restarts should be one dose level lower than last dose level on which patient was treated. The specific treatment approach used and dose modifications that occur are required to be reported in the Case Report Forms.  
If grade 2 intolerable, grade 3 or grade 4 neurological toxicity (see Table 3E) is evident at the time of the next planned administration of oxaliplatin, then oxaliplatin administration will be held until the next treatment cycle. Capecitabine and pembrolizumab will be administered if otherwise appropriate.  
Missed doses will not be made up. If toxicity resolves to grade 1 or less at next treatment cycle, resume oxaliplatin per instructions provided in Table 3E. If neurological toxicity is still present and has not resolved to grade 1 or less at the next treatment cycle, oxaliplatin will continue to be held. Patients may continue to receive capecitabine and pembrolizumab on study if otherwise appropriate. Oxaliplatin may be repeatedly temporarily discontinued and then re-initiated in this fashion unless the patient has disease progression, whereby the patient will be removed from the study. However, if the patient is not receiving oxaliplatin at the time of progression, if it is appropriate and safe as determined by the treating physician that oxaliplatin can be restarted, oxaliplatin may be restarted and the patient may continue on treatment. If the patient has disease progression on oxaliplatin or it is not safe or appropriate to restart oxaliplatin, the patient will be removed from the study.  
Dose escalations of oxaliplatin are not permitted at any time.
untitled h1
laryngopharyngeal dysesthesia

An unusual laryngopharyngeal dysesthesia (LPD), a loss of *sensation* of breathing without any objective evidence of respiratory distress (laryngospasm, bronchospasm or hypoxia) has also been observed. This neurotoxicity may be induced or exacerbated upon exposure to cold and should be distinguished from a hypersensitivity reaction. If a patient develops LPD, the patient's oxygen saturation should be evaluated via a pulse oximeter and, if normal, reassurance, a benzodiazepine or other anxiolytic agent should be considered and the patient should be observed in the clinic until the episode has resolved. The oxaliplatin infusion may then be continued at a reduced rate, 33% of the original rate. Because this syndrome may be associated with the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin should be administered as 4-6-hour infusions. To minimize the risk of LPD, patients will be instructed to avoid ice and cold drinks the day of treatment.
untitled h1
hypersensitivity reactions

Oxaliplatin, as is the case with all platinum-containing compounds, is associated with a measurable
(approximately 11%) incidence of hypersensitivity reactions, usually after multiple doses of treatment. This may present as bronchospasm, hypotension, and even hemolytic anemia. Pre-treatment with glucocorticoids and anti-histamines may be useful for some patients, but may not always prevent the development of anaphylactoid reactions, especially in patients with a prior history of hypersensitivity to this agent. For patients who have experienced a Grade 1 or 2 acute hypersensitivity reaction that is assessed as related to oxaliplatin administration, the following premedication is recommended prior to each subsequent dose of oxaliplatin:
Dexamethasone 20 mg PO or IV, 12 and 6 hours prior to the oxaliplatin dose;
untitled h1
or

Dexamethasone 20 mg PO or IV, as well as diphenhydramine 50 mg IV, and one of the following:
cimetidine 300 mg IV, ranitidine 50 mg IV, or famotidine 20 mg IV 30-60 minutes prior to oxaliplatin administration. If these prophylactic measures fail to prevent oxaliplatin-related hypersensitivity, therapy with oxaliplatin should be discontinued. Patients who have grade 3 or 4 acute hypersensitivity reactions should discontinue oxaliplatin therapy.
untitled h1
pulmonary fibrosis

In the case of unexplained respiratory symptoms such as nonproductive cough, dyspnea or radiological pulmonary infiltrates, oxaliplatin should be discontinued until further investigation excludes interstitial pulmonary fibrosis. If interstitial pulmonary fibrosis is confirmed, oxaliplatin therapy should be terminated.
untitled h1
7.2 toxicity management

Subjects should receive appropriate supportive care measures as deemed necessary by the Investigator. It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of evaluation of the event. Suggested supportive care measures for the management of adverse events with potential immunologic etiology are outlined below. Where appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might require additional supportive care. The treatment guidelines are intended to be applied when the Investigator determines the events to be related to pembrolizumab.
untitled h1
7.2.1 pneumonitis

For **Grade 2 events**, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
For recurrent **Grade 2 events**, discontinue treatment with pembrolizumab.  
For **Grade 3-4 events**, immediately treat with intravenous steroids. Administer additional antiinflammatory measures, as needed.  
For first occurrence of **Grade 3-4 events**, discontinue treatment with pembrolizumab.  
Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration.
untitled h1
7.2.2 diarrhea/colitis

Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).  
All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.  
For **Grade 2 or higher diarrhea**, consider GI consultation and endoscopy to confirm or rule out colitis.  
For **Grade 2** diarrhea/colitis that persists greater than 3 days, administer oral corticosteroids.  
For **Grade 3 or 4** diarrhea/colitis that persists > 1 week, treat with intravenous steroids followed by high dose oral steroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
untitled h1
7.2.3 diabetes mellitus

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or Grade 3-4 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA)
Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and C-peptide.
untitled h1
7.2.4 hypophysitis

For **Grade 2** events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
For **Grade 3-4** events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.
untitled h1
7.2.5 hyperthyroidism or hypothyroidism

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.  
**Grade 2** hyperthyroidism events (and **Grade 2-4** hypothyroidism):  
o In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy.  
o In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated per standard of care.
**Grade 3-4** hyperthyroidism o Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.
untitled h1
7.2.6 hepatic

For **Grade 2** events, monitor liver function tests more frequently until returned to baseline values
(consider weekly).  
Treat with IV or oral corticosteroids For **Grade 3-4** events, treat with intravenous corticosteroids for 24 to 48 hours.  
When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over no less than 4 weeks.
untitled h1
7.2.7 renal failure or nephritis

For **Grade 2** events, treat with corticosteroids.  
For **Grade 3-4** events, treat with systemic corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
untitled h1
7.2.8 infusion reactions

Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. Table 7.2.8 below shows treatment guidelines for subjects who experience an infusion reaction associated with administration of pembrolizumab.
untitled h1
table 7.2.8 infusion reaction treatment

| NCI-CTCAE Grade                                                                          | Treatment                                                                                                                                     | Premedication at Subsequent  Dosing   |
|------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| Grade 1 Mild reaction; infusion  interruption not indicated;  intervention not indicated | Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion  of the investigator. | None                                  |  
| NCI-CTCAE Grade                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Treatment                                                           | Premedication at Subsequent  Dosing                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|--------------------------------------------------------------------------------------------|
| Grade 2 Requires infusion interruption  but responds promptly to  symptomatic treatment (e.g.,  antihistamines, NSAIDS,  narcotics, IV fluids);  prophylactic medications  indicated for < =24 hrs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Stop Infusion and monitor symptoms.                                 | Subject may be premedicated 1.5hr (± 30 minutes) prior to infusion of  pembrolizumab with: |
| Additional appropriate medical therapy  may include but is not limited to:  IV fluids  Antihistamines  NSAIDS  Acetaminophen  Narcotics Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion  of the investigator. If symptoms resolve within 1hr of  stopping drug infusion, the infusion may  be restarted at 50% of the original  infusion rate (e.g., from 100 mL/hr to 50  mL/hr). Otherwise dosing will be held  until symptoms resolve and the subject  should be premedicated for the next  scheduled dose. Subjects who develop Grade 2  toxicity despite adequate  premedication should be permanently  discontinued from further trial  treatment administration. |                                                                    | Diphenhydramine 50 mg po (or  equivalent dose of  antihistamine).                          |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | Acetaminophen 500-1000 mg  po (or equivalent dose of  antipyretic). |                                                                                            |
| Grades 3 or 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Stop Infusion.                                                      | No subsequent dosing                                                                       |
| Additional appropriate medical therapy  may include but is not limited to:  IV fluids  Antihistamines  NSAIDS  Acetaminophen  Narcotics  Oxygen  Pressors  Corticosteroids  Epinephrine Increase monitoring of vital signs as  medically indicated until the subject is  deemed medically stable in the opinion  of the investigator. Hospitalization may be indicated. Subject is permanently discontinued  from further trial treatment  administration.                                                                                                                                                                                                                                                                                  |                                                                     |                                                                                            |
| Grade 3: Prolonged (i.e., not  rapidly responsive to  symptomatic medication  and/or brief interruption of  infusion); recurrence of  symptoms following initial  improvement; hospitalization  indicated for other clinical  sequelae (e.g., renal  impairment, pulmonary  infiltrates) Grade 4: Life-threatening;  pressor or ventilatory support  indicated                                                                                                                                                                                                                                                                                                                                                                                       |                                                                     |                                                                                            |
untitled h1
8.0 correlatives

Tissue and blood based biomarker studies will be performed to better understand the role of factors that may be associated with efficacy or toxicity from study treatment and/or cancer biology. Additional markers related to efficacy, toxicity, and/or cancer biology may be analyzed. Anticipated analyses are listed below and focus on factors associated with angiogenesis, inflammation, immunity, and tumor growth. However, final analyte lists and technology platforms will be based upon best science and available funding at the time of analysis. External vendors and collaborators may conduct or participate in these analyses, provided sampels are de-identified. All collaborations will be subject to Duke policies on sample and data sharing.  
8.1 **Tumor Tissue Biomarkers**
Archived formalin fixed paraffin embedded (FFPE) tumor tissue will be collected for all subjects (if available). Refer to *Study Manual* for collection, processing, and submission details.  
For patients accrued to the dose expansion cohort, pre-treatment and on-treatment tumor biopsies will be performed only on patients who have a tumor lesion that is amenable to safe biopsy. In the biomarker cycle, patients will undergo tumor biopsy up to 1 week before starting treatment (i.e., pre-treatment)
and will undergo a second tumor biopsy on Day 7 or 8 prior to start of oxaliplatin and capecitabine (i.e.,
on-treatment). The preferred type of biopsy is a core biopsy: five 18-gauge core needle biopsies
(diameter about 2 mm) with a throw length of approximately 2 cm will provide adequate tissue for study.  
Refer to *Study Manual* for collection, processing, and submission details. Note: Those patients accrued to the dose expansion cohort who do not have a tumor lesion that is amenable to safe biopsy will only have blood-based biomarker collections in the biomarker cycle (ie. Cycle 1). We will interrogate these tissue specimens using whole exomic sequencing studies, spacial transcriptomic analysis, and proximity ligation assays to spatially resolve the impact of pembrolizumab on tumor T cell/PMN-MDSC infiltration and NLRP3 inflammasome activation. These data will be correlated with mutations associated with this resistance pathway as well as with clinical response. This work will leverage a rare tissue bank of pre- and post-pembro tumor specimens to reveal a series of novel pharmacologic targets and potential biomarkers capable of overcoming immunotherapy resistance and improving the management of patients with gastrointestinal maligancies.  
Archived FFPE tumor tissue and pre-treatment/on-treatment tumor biopsy samples will be tested by IHC for CD8 and PDL1 staining, the primary biomarker endpoints for this study. Expression of additional proteins that may be associated with sensitivity or resistance to pembrolizumab or XELOX and pembrolizumab, including but, not limited to, TGF1, STAT3, and various immune cell populations, including CD3, CD4, CD8, Treg, (FoxP3), Th17 T-cells and monocyte/macrophage and neutrophil populations. RNA Seq or PCR may also be performed for analyses of factors that may be associated with sensitivity or resistance to these agents including but not limited to CD3, CD4, CD8, EOMES, IFNγ, FOXP-3, Granzyme-A, Granzyme-B, Perforin, IL1β, IL6, IL7, IL10, IL11, IL12, IL17A, IL17E, IL22, and IL23. Micro-satellite instability (MSI) by IHC and/or polymerase chain reaction (PCR) may also be assessed. Genetic alterations, including both gene mutation and copy number alteration, may be characterized using a customized Next Gen Sequencing platform. Samples evaluated will be archived FFPE tumor samples. Further refinement of these approaches can be made depending on interest.
untitled h1
8.2 circulating immune cells (pbmc)

Peripheral blood will be collected for peripheral blood mononuclear cells (PBMCs) from each subject at the following timepoints: baseline, end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), first restaging only, disease progression or treatment discontinuation, and for complete responders on long term follow-up. Refer to *Study Manual* for collection and submission details. PBMCs will be processed and stored by the Duke Immune Profiling Core facility under the direction of Dr. Kent Weinhold. Polychromatic flow cytometry (PFC) panels will be used to compare treatment related changes in both tumor and peripheral immune cell compartments. Up to 50 markers may be analyzed using 3 PFC panels: 1) a 12-color 'Exhaustion Panel', 2) a 12-color 'Tumor Reactive T Cell Panel', and 3) a 14-color regulatory T cell (Treg) and myeloid-derived suppressor cells (MDSC) panel. This analysis will be overseen by Dr. Weinhold.  
8.3 Protein Multiplex Arrays **(Plasma)**
Peripheral blood will be collected for plasma from each subject at the following timepoints: baseline, end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), every restaging, disease progression or treatment discontinuation, off treatment follow-up, and for complete responders on long term follow-up. Refer to *Study Manual* for collection, processing, and submission details.  
Plasma will be stored by the Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew Nixon. Markers of inflammation will be analyzed in the Duke Phase I Biomarker lab. Analyses will be performed on pre-treatment and on-treatment samples. Analyte levels, and changes in analyte levels, will be correlated with clinical outcome (PFS, OS). Plasma and serum samples will be evaluated by ELISA for protein markers that may be associated with sensitivity or resistance to pembrolizumab. These may include CRP and other markers of inflammation, including but not limited to IFNγ, IL1β, IL4, IL6, IL7, IL10, IL12, IL17A, IL17E, and IL23.
untitled h1
8.4 pharmacogenomics (whole blood)

Subjects will have whole blood collected at baseline. Refer to *Study Manual* for collection, processing, and submission details. Whole blood will be stored for possible future analysis of HLA type and other candidate markers of efficacy and toxicity by the Duke Phase I Biomarker Laboratory under the direction of Dr. Andrew Nixon with the consent of the patient.  
8.5 **Future Use of Patient Samples**
Any remaining biological materials at the end of the study will be deidentified and deidentified samples may be retained for possible use in biomarker research with the consent of the patient.
untitled h1
8.6 correlative collaborations 8.6.1. duke-personalis

In order to identify potential mechanisms of sensitivity and resistance to pembrolizumab in gastric cancer and to better characterize the changes of key tumor and immune factors in response to pembrolizumab therapy, we plan to collaborate with Personalis, Inc. for both tissue- and bloodbased biomarker analyses using their comprehensive, state-of-the-art technology platforms
(https://www.personalis.com/).  
8.6.1.1 The following samples for the specified assays and analytic pipelines will be shared with Personalis.  
Sample Type Sample Format/Quantity **Assay Type**  
FFPE tumor tissue  
50 samples  
4 x 5um unstained slides or 2 x 10um  
curls, 25mm2 surface area per sample ImmunoID NeXT  
PBMC  
36 samples 2-4 million frozen PBMC per sample ImmunoID NeXT  
Plasma  
150 samples Up to 8 ml per sample NeXT Liquid Biopsy  
8.6.1.2 The following clinical data will be shared with Personalis in order to utilize pre-existing  
biomarker analytic pipelines. Duke statisticians will work with both teams in a collaborative  
fashion to analyze and interpret the data from each project.  
Deidentified patient metadata.  
o Patient age, gender, race/ethnicity, prior therapies, treatment duration,  
treatment dosage, smoking status, tumor size, tumor site  
RECIST and iRECIST response data for each patient case per timepoint  
Deidentified patient outcomes data.  
o OS, PFS and response to therapy
untitled h1
no personal health information will

In order to identify potential mechanisms of sensitivity and resistance to pembrolizumab in gastric cancer and to better characterize the changes of key tumor and immune factors in response to pembrolizumab therapy, we plan to collaborate with Olink for both tissue- and blood-based biomarker analyses using their comprehensive, state-of-the-art technology platforms (https://www.olink.com/)
8.6.2.2 The following clinical data will be shared with Olink in order to utilize pre-existing biomarker analytic pipelines. Duke statisticians will work with both teams in a collaborative fashion to analyze and interpret the data from each project.  
Deidentified patient metadata.  
o Patient age, gender, race/ethnicity, prior therapies, treatment duration, treatment dosage, smoking status, tumor size, tumor site RECIST and iRECIST response data for each patient case per timepoint Deidentified patient outcomes data.  
o OS, PFS and response to therapy  
| Olink.                               |                                    |                    |
|--------------------------------------|------------------------------------|--------------------|
| Sample Type                          | Sample Format/Quantity             | Assay Type         |
| Fresh frozen tumor tissue 25 samples | Tissue lysate, 20 ug per sample    | Olink Explore 1536 |
| PBMC 150 samples                     | Cell lysate, 1000 PBMCs per sample | Olink Explore 1536 |
| Plasma 150 samples                   | 100 µl per sample                  | Olink Explore 1536 |  
No personal health information will be shared with Olink.
untitled h1
9.1.1 primary endpoint

The primary endpoint will be progression-free survival (PFS) measured from study entry until documented progression or death from any cause. Patients who have not experienced progression will be censored at the date of the last radiographic assessment. Based on the results of the AVAGAST and ToGA trials a median PFS of approximately 5.5 months is expected for patients treated with oxaliplatin and capecitabine alone. Also, observed PFS hazard ratios of 0.80 and 0.71 were reported for AVAGAST and ToGA, respectively. With 35 patients enrolled, the difference between a historical median PFS of 5.5 months and experimental median of 7.3 months, a hazard ratio of 0.75, can be detected with 80% power (1-sided test of single exponential mean, α=0.2). PFS and median PFS will be estimated using the Kaplan-Meier method. The 95% confidence interval estimate for median PFS will be computed using the variance estimate proposed by Brookmeyer and Crowley. Under the alternative hypothesis, 32 PFS events are expected at the end of the follow-up period.  
The primary analysis of PFS will be intention-to-treat in that all patients who have undergone at least one scheduled restaging on-treatment, or who have had unequivocal progression prior to the first scheduled restaging will be followed for progression. These patients will be followed for PFS, even if they are removed from treatment due to unacceptable toxicity or because they withdrew consent. As a secondary analysis, these patients will be censored at the time they were removed from treatment.  
The magnitude of reduction in tumor burden will be summarized descriptively (such as a waterfall plot) based on change in the sum of the longest diameters of target lesions relative to baseline.
untitled h1
9.1.2 secondary endpoints

Secondary endpoints include the safety and tolerability of the XELOX/pembro regimen and response rate (RR). Adverse events will be described and presented by Type and Grade according to NCI-CTCAE
version 4.03 criteria and descriptively compared with historical controls.  
Radiographic imaging will be repeated every three cycles (approximately every 9 weeks) as described in Section 5.0. Tumor response defined as complete response (CR) or partial response (PR) will be assessed using RECIST 1.1 (see Section 5.6).  
RR will be estimated by the 90% confidence interval for the binomial proportion. With 35 patients studied
(5 in the safety validation and 30 in the expanded cohort), RR can be estimated to within at most +/- 0.14 with 90% confidence.  
The magnitude of reduction in tumor burden will be summarized descriptively (such as with a waterfall plot) based on change in the sum of the longest diameters of target lesions relative to baseline. Overall survival (OS) will be described.
untitled h1
9.1.3 exploratory endpoints

CD8 and PDL1 staining measured by IHC are the primary biomarker endpoints for this study.  
Descriptive statistics will be provided for each of these endpoints at each time point (pre-, P, and ontreatment, OT) and for the change P vs OT.  
For continuous CD8 and PDL1 expression measures (e.g., percentages), the paired t-test will be used to compare change in P vs OT. We expect approximately 25 patients to have paired measurements. With 25 patients studied a difference of 0.53 standard deviation (SD) can be detected with 90% power
(1-sided α=0.1). With this sample size differences of 13%, 27%, and 40% can be detected with 80%
power assuming SDs of 0.25, 0.5, and 0.75, respectively. For dichotomous paired proportions (e.g., <2+ versus >2+ by IHC) McNemar's test will be used to test the null hypothesis that the difference in P and OT proportions is 0 versus the alternative that it is > 0 or < 0. With 25 paired patient samples studied 79% power is achieved to detect the difference illustrated in Table 1a below and 86% power is achieved to detect the difference illustrated in Table 1b (2-sided α=0.1).  
Table 1a: Alternative hypothesis resulting in 79% power using McNemar's test (2-sided α=0.1).  
Post Treatment Total  
Pre Treatment <2+ >2+  
<2+ 0.15 0.45 0.60 >2+ 0.10 0.30 0.40  
Total 0.25 0.75 1.00  
Table 1b. Alternative hypothesis resulting in 86% power using McNemar's test (2-sided α=0.1).  
Post Treatment Total  
Pre Treatment <2+ >2+  
<2+ 0.10 0.50 0.60 >2+ 0.10 0.30 0.40  
Total 0.20 0.80 1.00  
Similar analyses will be conducted for other biomarkers as described in Section 8.0. No adjustments will be made for multiple comparisons. Data transformations or non-parametric methods will be used as appropriate. Associations between changes in immune infiltrates and outcomes (PFS, RR, OS) will be explored using Cox regression (PFS), 2-sample t-tests or non-parametric Wilcoxon rank-sum tests, or the Chisquare test (6-month PFS, RR) based on the distribution and structure of the data (i.e., either parametric or non-parametric methods will be used as appropriate).
untitled h1
10.1 adverse events

An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the supporting company product(s), is also an AE. Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered AEs. Examples of this may include, but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time.  
Supporting company product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by the supporting company for human use. AEs may occur during the course of the use of supporting company product(s) in clinical trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.  
Progression of the cancer under study is not considered an AE unless it is considered to be drug related by the Investigator. AEs will be documented from the date of first dose of study drug through 30 days after the last dose of study drug. All Grade 2-5 AEs as well as special reporting circumstances, such as exposure via a parent during pregnancy or breast-feeding, overdose, medication error, misuse, abuse, off-label use or occupational exposure must be recorded on the CRF.
untitled h1
10.2 serious adverse events

A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose:
1. Results in death.  
2. Is immediately life-threatening (ie, in the opinion of the Investigator, the AE places the subject at immediate risk of death; it does not include a reaction that, had it occurred in a more severe form, might have caused death).  
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 4. Results in persistent or significant disability or incapacity. (Note: The term "disability" refers to events that result in a substantial disruption of a subject's ability to conduct normal life function.)
5. Is a congenital anomaly or birth defect. 6. Is an important medical event (Note: The term "important medical event" refers to an event that, based upon appropriate medical judgment, may not be immediately life-threatening or result in death or hospitalization, but may jeopardize the subject or require intervention to prevent one of the other serious outcomes listed under the definition of SAE. Examples of important medical events include intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in hospitalization; or development of product dependency or product abuse.)
SAEs and/or follow up to SAEs including death due to any cause other than progression of the cancer under study, that occurs from the date of the first dose of study drug through 30 days following the last dose of study drug, whether or not related to study drug(s), must be recorded on the CRF and must be reported within 2 business days supporting companies. External sites should report SAEs to the Duke study team within 24 hours. Reporting instructions for external sites can be found in the REDCap study eManual. All SAEs must be followed until resolution, return to baseline condition, or stabilization. Any SAEs that are ongoing at the time the clinical database is closed will be reported to supporting companies as unresolved. The initial report for each SAE or death should include at minimum the following information:
The Investigator should report a diagnosis or a syndrome rather than individual signs or symptoms. The Investigator should also try to separate a primary AE considered as the foremost untoward medical occurrence from secondary AEs which occurred as complications. Whenever possible, the Investigator should also provide the batch or lot number of the study drug(s).
untitled h1
sae reporting procedure

Immediately upon awareness of a SAE, the Investigator (or designee) completes the DCI SAE Report Form and will submit the form within 2 business days of knowledge of the event to the funding company.  
External sites should submit the form within 24 hours to the Duke study team via the REDCap SAE reporting tool. In accordance with applicable regulations, Investigators must report SAEs to their local IRB according to their institutional guidelines. Note: It is imperative that initial SAE reports are submitted as soon as possible (within 2 business days of knowledge of the event) with available information to the supporting company. Missing and/or clarified event information may be provided in a follow-up report. Follow-up information including severity, action taken, concomitant medications, and outcome should be communicated to the funding company as soon as possible using the same forms mentioned above. :
The Lead PI will review the report form with accompanying source document, sign page 5, and then the PI or designee will promptly submit it to the supporting company. If the event meets the Duke University Health System (DUHS) IRB reporting requirements, the Duke GI
Oncology regulatory coordinator will submit information about the SAE including the Lead PI's  
protocol number and title patient initials, study identification number, sex, age date the event occurred description of the event seriousness criteria event causality or causal relationship study drug name(s)
dose level and cycle number at the time the event occurred description of the patient's condition study status of patient at time of report responsible investigator name and contact details
assessment as a safety event to the DUHS IRB within 5 business days. Any study-related death must be reported to the IRB within 24 hours of discovery. Within two business days of receipt, the Duke study team will also submit the SAE report form and other relevant safety information to the following supporting companies:
Merck Global Safety ATTN: Worldwide Product Safety Fax: 215-993-1220
untitled h1
expedited reporting procedure for duke

Duke Cancer Institute as the coordinating center for this study is responsible for reporting SAEs to the FDA in accordance with 21CFR 312.32. Any SAE that is possibly related and unexpected must be submitted to the FDA attached to the IND. If the SAE meets criteria for reporting to the FDA, the Duke study team will complete the Form FDA 3500A (MedWatch) and send to the Lead PI and the supporting companies that are noted above. This submission of the Form FDA 3500A to the FDA attached to the IND will be completed by the Duke GI Oncology Clinical Trials Regulatory Coordinator.  
All unexpected, drug related SAEs that are fatal or life-threatening will be reported to the FDA by phone or fax within 7 calendar days of initial receipt of the information and will provide a complete report within 8 days of the initial report submission (by calendar day 15).  
All unexpected, treatment-related SAEs that are not fatal or life-threatening will be reported in a written report to the FDA within 15 days of initial receipt of the information.
The Duke study team will forward all expedited reports to all participating investigators in the form of an Investigator Alert. The Investigator Alert template is available on the DCI intranet titled "Safety Reporting for Multi-site IITs Notification Email".
untitled h1
10.3 events of clinical interest

Select (non-serious and serious) adverse events called Events of Clinical Interest (ECI) that occur from the date of the first dose of study drug through 30 days following the last dose of study drug, must be recorded on the CRF and must be reported within 2 working days to Merck Global Safety. An ECI for this study is any hepatic toxicity that is ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to the adverse event. Such adverse events include but are not limited to; hepatitis, autoimmune hepatitis, and transaminase elevations (ALT and/or AST). Any overdose of pembrolizumab (1,000 mg or greater) is also considered an ECI for this study and should be reported as such, regardless of the outcome.
untitled h1
eci reporting procedure

Immediately upon awareness of an ECI, the Investigator (or designee) completes the **DCI SAE Report**
Form and will submit the form within 2 business days of knowledge of the event to the funding company.  
External sites should submit the form within 24 hours to the Duke study team via the REDCap SAE reporting tool. Note: It is imperative that initial ECI reports are submitted as soon as possible (within 2 business days of knowledge of the event) with available information to the supporting company. Missing and/or clarified event information may be provided in a follow-up report.  
Follow-up information including severity, action taken, concomitant medications, and outcome should be communicated to the funding company as soon as possible using the same form mentioned above. The Lead PI will review the report form with accompanying source document, sign page 5, and the PI or designee will then promptly submit it to the funding company. Within two business days of receipt, the study team will also submit the SAE report form and other relevant safety information to the following supporting company:
Merck Global Safety ATTN: Worldwide Product Safety Fax: 215-993-1220
untitled h1
10.4 other safety considerations

The Investigator must also report in the same timelines as SAEs any incidence of medication error, occupational exposure, abuse or misuse that is associated with or result in an adverse event. All related fatal outcomes must also be reported in the same timeline as a SAE. Refer to SAE reporting procedures in Section 10.2.
untitled h1
10.4.1 pregnancy and lactation

Although pregnancy and lactation are not considered adverse events, it is the responsibility of Investigator or designee to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 120 days of following cessation of treatment. All subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (important medical events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported reported in the same procedure as an SAE. Refer to SAE reporting procedures in Section 10.2.
untitled h1
10.4.2 medication overdose and error

For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 times the indicated dose) and is an event of clinical interest (see Section 10.3 for reporting instructions). No specific information is available on the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the subject should be observed closely for signs of toxicity. Monitoring should be based upon good medical judgment, taking into account the level of overdose, evolving toxicities, and other relevant medical and social factors specific to the patient. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with ("results from") the overdose of study drug(s), the adverse event(s) is reported as a SAE, even if no other seriousness criteria are met. Refer to SAE reporting procedures in Section 10.2.  
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as an ECI, using the terminology "accidental or intentional overdose without adverse effect." Refer to ECI reporting procedures in Section 10.3.
untitled h1
11.0 administrative responsibilities 11.1 institutional

Before study initiation, the Investigator must have written and dated approval/favorable opinion from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the protocol, consent form, subject recruitment materials/process (e.g., advertisements), and any other written information to be provided to subjects.  
The Investigator should provide the IRB/IEC with reports, updates, and other information (e.g., Safety Updates, Amendment IRB/IECs, and Administrative Letters) according to regulatory requirements and institution procedures. Copies of all IRB/IEC approvals, as well as annual re-approvals and approved/stamped informed consent forms must be submitted to Duke GI Oncology Clinical Trials Office.
untitled h1
11.2 protocol and protocol revisions

All revisions to the protocol will be provided to the supporting companies by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office. The Lead PI must have written and dated approval/favorable opinion from the Duke University Health System (DUHS) IRB of revised protocol prior to distribution to Investigators at external participating sites.  
Investigators must obtain written and dated and approval/favorable opinion from the IRB/IEC before conducting any updated protocol version. Study must be conducted as described in the approved protocol. The Investigator must not implement changes of the approved protocol without prior written agreement by the Lead PI and prior review and documented approval/favorable agreement by the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) to study subjects, or when the changes involve only logistical or administrative aspects of the study (e.g.,
changes in research personnel or change in phone numbers). Documentation of approval(s) from the IRB/IEC must be sent to Duke GI Oncology Clinical Trials Office.
untitled h1
11.3 protocol deviations and violations

A protocol deviation is non-adherence to protocol specific study procedures or schedules that does not involve inclusion/exclusion criteria, primary objective evaluation criteria, and/or Good Clinical Practice
(GCP) guidelines. A protocol violation is any significant divergence from the protocol such as non-adherence on the part of the subject, the Investigator, or the sponsor to protocol specific inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines. As a matter of policy, the Lead PI (ie. sponsor) will not grant exceptions to protocol specific entry criteria to allow subjects to enter a study. If it is found that a subject who did not meet protocol eligibility criteria was entered in a study (a protocol violation), the Lead PI and/or designee(s) at the Duke GI Oncology Clinical Trials Office must be informed immediately. Such subjects will be discontinued from the study, except in an exceptional instance following review and written approval by the Lead PI and the responsible IRB/IEC. Protocol deviations and violations must be documented and reported to the Lead PI and/or designee(s) at the Duke GI Oncology Clinical Trials Office. In accordance with applicable regulations, Investigators must report protocol deviations and violations to their local IRB/IEC according to their institutional guidelines.
untitled h1
11.4 informed consent

The Investigator must ensure that subjects or their legally acceptable representatives are clearly and fully informed about the purpose, potential risks and other critical issues regarding clinical trials in which they volunteer to participate. Preparation of the consent form is the responsibility of the Investigator and must include all elements required by CFR 21 Part 50.25 and their IRB. A copy of the proposed informed consent document must be submitted to the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office for review and comment prior to submission to the local IRB/IEC. Informed consent must be obtained prior to performing any study-related procedures that are not part of normal subject care, including screening and changes in medications. A copy of the signed informed consent form must be given to the study subject.
untitled h1
11.5 source and study documentation

Source documents include all original recordings of observations or notations of clinical activities and all reports and records necessary for the evaluation and reconstruction of the clinical study.  
Accordingly, source documents include, but are not limited to, laboratory reports (including normal and abnormal results), radiology reports, subject diaries, biopsy reports, ultrasound photographs, subject progress notes, hospital charts or pharmacy records and any other similar reports or records of any procedure performed in accordance with the protocol. Whenever possible, the original recording of an observation should be retained as the source document; however, a photocopy is acceptable provided that it is a clear, legible, and exact duplication of the original certified document. When clinical observations are entered directly into an electronic medical record system (i.e. in lieu of original hardcopy records), the electronic record can serve as the source document if the system has must be validated to meet the FDA requirements for electronic records and signatures (i.e. meets 21 CFR Part 11 compliant).  
Regulations require that Investigators maintain information in the study subject's medical records which corroborate data recorded on the CRF. In order to comply with these regulatory requirements, the following information will be maintained and made available as required by the Lead PI or designee(s), monitors, and/or regulatory inspectors:  
Medical history/physical condition of the study subject prior to involvement in the study sufficient to verify protocol entry criteria.  
Dated note that informed consent was obtained for the subject's participation in the study.  
Dated and signed notes for each subject visit including results of examinations. Notations on abnormal lab results and their resolution. Dated reports of special assessments (e.g., ECG reports).  
Dated and signed notes regarding adverse events (includng event description, severity, onset date, duration, relation to study treatment, outcome and treatment for adverse event).  
Dated notes regarding concomitant medications taken during the study (including start and stop dates).  
Subject condition upon completion of or withdrawal from the study.
Study documentation includes all CRFs, data correction forms, source documents, monitoring logs and appointment schedules, sponsor-investigator correspondence and regulatory documents (e.g., protocol and amendments, IRB/IEC correspondence and approvals, approved and signed subject consent forms, Statement of Investigator form, and clinical study supplies receipts and distribution records).  
The Investigator will prepare and maintain complete and accurate study documentation in compliance with GCP guidelines and applicable federal, state, and local laws, rules and regulations; and, for each subject participating in the study, promptly complete all CRFs and such other reports as required by this protocol following completion or termination of the clinical study or as otherwise required pursuant to any agreement with the Lead PI and Duke Cancer Institute (DCI). The Investigator acknowledges that, within legal and regulatory restrictions and institutional and ethical considerations, study documentation will be promptly and fully disclosed to Lead PI or designee(s) by the Investigator upon request and also shall be made available at the Investigator's site upon request for inspection, copying, review and audit at reasonable times by representatives of the Lead PI and DCI
or responsible government agencies as required by law.  
The Investigator agrees to promptly take any reasonable steps that are requested by the Lead PI or designee(s) as a result of an audit to cure deficiencies in the study documentation and case report forms.
untitled h1
11.6 case report forms

Subject data will be entered (ie. CRFs completed) into an electronic data capture (EDC) system called Medidata RAVE. This database is maintained on a secure Duke University server and is accessible via internet with login and password. CRFs should be completed by trained study personnel according to guidelines provided by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office. The Investigator or qualified designee is responsible for recording and verifying the accuracy of subject data. The Investigator acknowledges that his/her electronic signature is the legally binding equivalent of a written signature.  
By entering his/her electronic signature, the Investigator confirms that all recorded data have been verified as accurate. In the event of discrepant data, the study monitor or study designee will request data clarification from the Investigator or designee for which may be resolved electronically in the EDC system. Accurate and reliable data collection will be ensured through verification and crosscheck of the CRFs against the Investigator's study records (source document verification) by the study monitor or study designee.
untitled h1
11.7 monitoring and audits/inspections

The study will be monitored both internally by the Lead PI and externally by the Duke Cancer Institute
(DCI) Monitoring Team in accordance with their NCI-approved "Institutional Protocol Monitoring Procedures and Guidelines for NIH-sponsored Research Involving Human Subjects".  
In terms of internal review, the Lead PI and/or designee(s) will continuously monitor and tabulate adverse events. Appropriate reporting to the DUHS IRB will be made. If an unexpected frequency of Grade 3 or 4 adverse events occurs, depending on their nature, action appropriate to the nature and frequency of these adverse events will be taken. This may require a protocol amendment, dose deescalation, or potentially closure of the study. The Lead PI of this study will also continuously monitor the conduct, data, and safety of this study to ensure that:
Interim analyses occur as scheduled (if applicable);
Stopping rules for toxicity and/or response are met; Risk/benefit ratio is not altered to the detriment of the subjects; Appropriate internal monitoring of adverse events and outcomes is done;  
Over-accrual does not occur; Under-accrual is addressed with appropriate amendments or actions; Data are being appropriately recorded on the CRF in a reasonably timely manner.
The Duke Cancer Institute (DCI) Monitoring Team will conduct monitoring visits to ensure subject safety and to ensure that the protocol is conducted, recorded, and reported in accordance with the protocol, standard operating procedures, GCP, and applicable regulatory requirements. As specified in the DCI Data and Safety Monitoring Plan, the DCI Monitoring Team will conduct routine monitoring after the third subject is enrolled, followed by annual monitoring of 1-3 subjects until the study is closed to enrollment and subjects are no longer receiving study interventions that are more than minimal risk. An external site monitoring plan addendum describes monitoring at participating sites. Additional monitoring may be prompted by findings from monitoring visits, unexpected frequency of serious and/or unexpected toxicities, or other concerns and may be initiated upon request of DUHS and DCI leadership, the DCI Cancer Protocol Committee, the Safety Oversight Committee (SOC), the sponsor, the Principal Investigator, or the IRB. All study documents must be made available upon request to the DCI Monitoring Team and other authorized regulatory authorities, including but not limited to the National Institute of Health, National Cancer Institute, and the FDA. Every reasonable effort will be made to maintain confidentiality during study monitoring.  
The DCI Safety Oversight Committee (SOC) will perform annual reviews on findings from the DCI Monitoring Team visit and additional safety and toxicity data submitted by the Principal Investigator. DCI Quality Assurance personnel, or designee, may conduct audits at sites. Audits will include, but not be limited to: audit trail of data handling and processes, SOPs, drug supply, presence of required documents, the informed consent process, and comparison of case report forms/database with source documents. The Investigator agrees to accommodate and participate in audits conducted at a reasonable time in a reasonable manner, as needed. Regulatory authorities may also audit an Investigator during or after the study. The Investigator should contact the Lead PI and designee(s) at the Duke GI Oncology Clinical Trials Office as well as their local IRB, immediately if this occurs, and must fully cooperate with governmental (e.g., FDA) audits conducted at a reasonable time in a reasonable manner. The Duke University Compliance Program - Human Subject Research Compliance (HSRC) section may conduct confidential audits to evaluate compliance with the protocol and the principles of GCP. The Lead PI agrees to allow the HSRC auditor(s) direct access to all relevant documents and to allocate his/her time and the time of the study team at the Duke GI Oncology Clinical Trials Office to the CTQA auditor(s) in order to discuss findings and any relevant issues.
untitled h1
11.8 study closeout

Upon completion of the study (defined as all subjects have completed all follow-up visits, all CRFs are complete, and all queries have been resolved) the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office will notify the Investigator of closeout and a study closeout visit will be performed.  
The study monitor or study designee will ensure that the Investigator's regulatory files are up to date and complete, and that any outstanding issues from previous visits have been resolved. Other issues to be reviewed at the closeout visit include: retention of study files, possibility of site audits, publication policy, and study closure with local IRB.
untitled h1
11.9 records retention

The Investigator will maintain the records of study drug disposition, worksheets and all other studyspecific documentation (e.g., study files, source documentation) until notified by the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office that records may be destroyed. If the application is not filed or is withdrawn, the Investigator will maintain the records for at least two (2) years after the formal discontinuation of the clinical development program for this product(s). To avoid error, the Investigator will contact the Lead PI or designee(s) at the Duke GI Oncology Clinical Trials Office before the destruction of any records pertaining to the study to ensure they no longer need to be retained. In addition, the Lead PI or designee(s) will be contacted if the Investigator plans to leave the institution so that arrangements can be made for the transfer of records.
untitled h1
12.0 references

1. Kamangar, F., G. M. Dores, et al. (2006). "Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world." J
Clin Oncol 24(14): 2137-2150.  
2. Altekruse, S., C. Kosary, et al. (2010). SEER Cancer Statistics Review, 1975-2007.  
Bethesda, MD, National Cancer Institute.  
3. Glimelius, B., K. Ekstrom, et al. (1997). "Randomized comparison between chemotherapy plus best supportive care with best supportive care in advanced gastric cancer." Ann Oncol 8(2): 163-168.  
4. Cutsem, E. V., Y. Kang, et al. (2009). Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy (CT) in first-line human epidermal growth factor receptor 2 (HER2)- positive advanced gastric cancer (GC). ASCO Annual Meeting. Orlando, FL, J Clin Oncol. 27: suppl; abstr LBA4509.  
5. Kang, Y., A. Ohtsu, et al. (2010). AVAGAST: A randomized, double-blind, placebocontrolled, phase III study of first-line capecitabine and cisplatin plus bevacizumab or placebo in patients with advanced gastric cancer (AGC). ASCO Annual Meeting. Chicago, IL, J Clin Oncol. 28: suppl; abstr LBA4007.  
6. Van Cutsem, E., V. M. Moiseyenko, et al. (2006). "Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group." J Clin Oncol 24(31): 4991-4997.  
7. Wagner, A. D., W. Grothe, et al. (2006). "Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data." J Clin Oncol 24(18): 2903-2909.  
8. Cunningham, D., N. Starling, et al. (2008). "Capecitabine and oxaliplatin for advanced esophagogastric cancer." N Engl J Med 358(1): 36-46.  
9. Saito H, Kuroda H, Matsunaga T, Osaki T, Ikeguchi M. (2013). "Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer."J Surg Oncol 107(5):517-22.  
10. 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.* Jun 28 2012;366(26):2455-2465.  
11. Blank C, Gajewski TF, Mackensen A. Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. *Cancer Immunol Immunother.*
Apr 2005;54(4):307-314.  
12. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. *Annu Rev* Immunol. 2008;26:677-704.  
13. Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: an update on implications for chronic infections and tumor evasion. Cancer *Immunol Immunother.* May 2007;56(5):739745.  
14. Exolatin(R) [package insert]. Sanofi-aventis U.S. LLC., Bridgewater, NJ; October 2015.  
http://pi.lilly.com/us/byetta-pi.pdf. Accessed January 4, 2017.  
15. Xeloda(R) [package insert]. Hoffmann-La Roche, Inc., San Francisco, CA; December 2016.  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/020896s039lbl.pdf. Accessed January 4, 2017.  
16. Muro, K., Chung, H. C., et al. (2016). Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. The Lancet Oncology, 17(6), 717-726.  
17. NCCN Guidelines National Comprehensive Cancer Network. Bone Cancer (Version I - March 21, 2017).  
https://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed April 5, 2017.  
18. Al-Batran, Salah-Eddin, et al. "Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: a study of the Arbeitsgemeinschaft Internistische Onkologie." *Journal of Clinical Oncology* 26.9 (2008): 1435-1442.  
19. Enzinger, Peter C., et al. "CALGB 80403 (Alliance)/E1206: A randomized phase II study of three chemotherapy regimens plus cetuximab in metastatic esophageal and gastroesophageal junction cancers." Journal of Clinical Oncology 34.23 (2016): 2736-2742.  
20. Kim, Gun Min, et al. "A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in advanced gastric cancer." European Journal of Cancer 48.4 (2012): 518-526.  
21. Cunningham, David, et al. "Capecitabine and oxaliplatin for advanced esophagogastric cancer." New England Journal of Medicine 358.1 (2008): 36-46.  
22. A Study to Evaluate the Efficacy and Safety of Trastuzumab in Combination With Capecitabine and Oxaliplatin as First-line Chemotherapy for Inoperable, Locally Advanced or Recurrent and/or Metastatic 23. Gastric Cancer https://clinicaltrials.gov/ct2/show/NCT01364493 24. Phase 3 Study of Xelox Followed by Maintenance Capecitabine in the Advanced Gastric Cancer https://clinicaltrials.gov/ct2/show/NCT02289547?term=capecitabine+oxaliplatin+gastric&recr=Open&rank=1 1 25. Chemotherapy Options for the First Line Chemotherapy in Elderly Patient With Advanced Gastric Cancer https://clinicaltrials.gov/ct2/show/NCT02114359?term=capecitabine+oxaliplatin+gastric&recr=Open&rank=3 6 26. Study of Oxaliplatin and Xeloda and Cetuximab as First Line Treatment for Metastatic or Unresectable Gastric or Gastroesophageal Junction Cancer https://clinicaltrials.gov/ct2/show/NCT00183898 27. A Study of Pazopanib With CAPEOX in AGC Patients https://clinicaltrials.gov/ct2/show/NCT01130805 28. Wang, Weiwei, et al. "Chemoimmunotherapy by combining oxaliplatin with immune checkpoint blockades reduced tumor burden in colorectal cancer animal model." Biochemical and Biophysical Research Communications (2016).  
29. Hato, Stanleyson V., et al. "Molecular pathways: the immunogenic effects of platinum-based chemotherapeutics." Clinical Cancer Research 20.11 (2014): 2831-2837.  
30. Hirsch, Bradford R., and S. Yousuf Zafar. "Capecitabine in the management of colorectal cancer." Cancer Manag Res 3 (2011): 79-89.  
31. Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol. 2008;26(13):2118–2123.  
32. Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol. 2008;26(21):3523–3529.
untitled h1
appendix a. recist 1.1

RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. **E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M.*
Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.
untitled h1
definitions

Response and progression will be evaluated in this study using the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (version 1.1). Changes in only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria provided below. The term "evaluable" in reference to measurability will not be used because it does not provide additional meaning or accuracy.
untitled h1
measurable disease

Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the plane of measurement is to be recorded) with a minimum size of:  
10mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness and a minimum of 10mm)
10mm caliper measurement by clinical exam (when superficial) 20mm by chest X-ray (if clearly defined and surrounded by aerated lung)
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be ≥15mm 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.
untitled h1
non-measurable disease

All other lesions (or sites of disease), including small lesions (longest diameter ≥10 to <15 mm with conventional techniques or <10 mm using spiral CT scan), are considered non-measurable disease. Leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques are all nonmeasurable.  
Bone lesions:  
- Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure bone lesions. However, these techniques can be used to confirm the presence or disappearance of bone lesions.  
- Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as measurable lesions if the soft tissue component meets the definition of measurability described above.  
- Blastic bone lesions are non-measurable.
Cystic lesions:  
- Lesions that meet the criteria for radiographically defined simple cysts should not be considered as malignant lesions (neither measurable nor non-measurable) since they are, by definition, simple cysts.  
- 'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same patient, these are preferred for selection as target lesions.
Lesions with prior local treatment:
- Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. Study protocols should detail the conditions under which such lesions would be considered measurable.
untitled h1
target lesions

All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 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 organ, but in addition should be those that lend themselves to reproducible repeated measurements.  
Lymph nodes merit special mention since they are normal anatomical structures which may be visible by imaging even if not involved by tumor. Pathological nodes which are defined as measurable and may be identified as target lesions must meet the criterion of a short axis of ≥15mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). The smaller of these measures is the short axis. For example, an abdominal node which is reported as being 20mm x 30mm has a short axis of 20mm and qualifies as a malignant, measurable node. In this example, 20mm should be recorded as the node measurement. All other pathological nodes (those with short axis ≥10mm but <15 mm) should be considered non-target lesions. Nodes that have a short axis <10mm are considered nonpathological and should not be recorded or followed.  
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 as noted above, 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.
untitled h1
non-target lesions

All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as 'present', 'absent', or in rare cases 'unequivocal progression' (more details to follow). In addition, it is possible to record multiple non-target lesions involving the same organ as a single item on the case record form (e.g. 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
untitled h1
guidelines for evaluation of measurable

All measurements should be recorded in metric notation, using calipers if clinically assessed. All baseline evaluations should be performed as close as possible to the treatment start 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 should always be done rather than 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 and
>10mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study.  
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for response assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice thickness is 5mm or less. When 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).  
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 from 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, they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in trials where recurrence following complete response or surgical resection is an endpoint.  
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers are initially above the upper normal limit, however, they must normalize for a patient to be considered in complete response. Because tumor markers are disease specific, instructions for their measurement should be incorporated into protocols on a disease specific basis. Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be integrated with objective tumor assessment for use in first-line trials in ovarian cancer.  
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or stable disease in order to differentiate between response (or stable disease) and progressive disease.  
Response Criteria 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 diameters of target lesions, taking as reference the baseline sum diameters.  
Progressive Disease (PD): At least a 20% increase in the sum of 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 progression).  
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Lymph nodes. Lymph nodes identified as target lesions should always have the actual short axis measurement recorded (measured in the same anatomical plane as the baseline examination), even if the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, the 'sum' of lesions may not be zero even if complete response criteria are met, since a normal lymph node is defined as having a short axis of <10 mm. Case report forms or other data collection methods may therefore be designed to have target nodal lesions recorded in a separate section where, in order to qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.  
Target lesions that become 'too small to measure'. While on study, all lesions (nodal and nonnodal) recorded at baseline should have their actual measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable assigning an exact measure and may report them as being 'too small to measure'. When this occurs it is important that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement should be recorded as 0mm. If the lesion is believed to be present and is faintly seen but too small to measure, a default value of 5mm should be assigned (Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this circumstance as well). This default value is derived from the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore providing this default value will prevent false responses or progressions based upon measurement error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be recorded, even if it is below 5 mm.  
Lesions that split or coalesce on treatment. When non-nodal lesions 'fragment', the longest diameters of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the longest diameter in this instance should be the maximal longest diameter for the 'coalesced lesion'.  
Evaluation of Non-target Lesions While some non-target lesions may actually be measurable, they need not be measured and instead should be assessed only qualitatively at the time points specified in the protocol.  
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10mm short axis).  
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): Unequivocal progression (see comments below) of existing nontarget lesions. (Note: the appearance of one or more new lesions is also considered progression).
When the patient also has measurable disease. In this setting, to achieve 'unequivocal progression' on the basis of the non-target disease, there must be an overall level of substantial worsening in non-target disease such that, even in presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 'increase' in the size of one or more non-target lesions is usually not sufficient to quality for unequivocal progression status. The designation of overall progression solely on the basis of change in non-target disease in the face of SD or PR of target disease will therefore be extremely rare.  
When the patient has only non-measurable disease. This circumstance arises in some phase III
trials when it is not a criterion of study entry to have measurable disease. The same general concept apply here as noted above, however, in this instance there is no measurable disease assessment to factor into the interpretation of an increase in non-measurable disease burden.  
Because worsening in non-target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for unequivocal progression is to consider if the increase in overall disease burden based on the change in nonmeasurable disease is comparable in magnitude to the increase that would be required to declare PD for measurable disease: i.e. an increase in tumor burden representing an additional 73% increase in 'volume' (which is equivalent to a 20% increase diameter in a measurable lesion). Examples include an increase in a pleural effusion from 'trace' to 'large', an increase in lymphangitic disease from localized to widespread, or may be described in protocols as 'sufficient to require a change in therapy'. If 'unequivocal progression' is seen, the patient should be considered to have had overall PD at that point. While it would be ideal to have objective criteria to apply to nonmeasurable disease, the very nature of that disease makes it impossible to do so, therefore the increase must be substantial.
untitled h1
new lesions

The appearance of new malignant lesions denotes disease progression; therefore, some comments on detection of new lesions are important. There are no specific criteria for the identification of new radiographic lesions; however, the finding of a new lesion should be unequivocal: i.e. not attributable to differences in scanning technique, change in imaging modality or findings thought to represent something other than tumor (for example, some 'new' bone lesions may be simply healing or flare of pre-existing lesions). This is particularly important when the patient's baseline lesions show partial or complete response. For example, necrosis of a liver lesion may be reported on a CT scan report as a 'new' cystic lesion, which it is not. A lesion identified on a follow-up study in an anatomical location that was not scanned at baseline is considered a new lesion and will indicate disease progression. An example of this is the patient who has visceral disease at baseline and while on study has a CT or MRI brain ordered which reveals metastases. The patient's brain metastases are considered to be evidence of PD even if he/she did not have brain imaging at baseline.  
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new lesion, then progression should be declared using the date of the initial scan.  
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:
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a new lesion.  
No FDG-PET at baseline and a positive FDG-PET at follow- up: If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT scans are needed to determine if there is truly progression occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDGPET 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.  
Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the study treatment until the end of treatment taking into account any requirement for confirmation. On occasion a response may not be documented until after the end of therapy so protocols should be clear if post-treatment assessments are to be considered in determination of best overall response. Protocols must specify how any new therapy introduced before progression will affect best response designation. The patient's best overall response assignment will depend on the findings of both target and non-target disease and will also take into consideration the appearance of new lesions. Furthermore, depending on the nature of the study and the protocol requirements, it may also require confirmatory measurement. Specifically, in non-randomised trials where response is the primary endpoint, confirmation of PR or CR is needed to deem either one the "best overall response." The best overall response is determined once all the data for the patient is known. Best response determination in trials where confirmation of complete or partial response IS NOT required: Best response in these trials is defined as the best response across all time points (for example, a patient who has SD at first assessment, PR at second assessment, and PD on last assessment has a best overall response of PR). When SD is believed to be best response, it must also meet the protocol specified minimum time from baseline. If the minimum time is not met when SD is otherwise the best time point response, the patient's best response depends on the subsequent assessments. For example, a patient who has SD at first assessment, PD at second and does not meet minimum duration for SD, will have a best response of PD. The same patient lost to follow-up after the first SD assessment would be considered inevaluable.
untitled h1
appendix b. immune-related response criteria

The immune related response criteria* (irRC) has been developed to adequately characterize additional patterns of response and progression specific to patients treated with immunotherapy, that cannot be captured by the conventional criteria such as such as Response Evaluation Criteria in Solid Tumors (RECIST).  
*Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R,
Hodi FS. et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–7420.
untitled h1
antitumor response based on total

For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion measurements in the characterization of evolving tumor burden). At the baseline tumor assessment, the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions per organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent tumor assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide the total tumor burden:
Tumor Burden = SPDindex lesions + SPDnew, measurable lesions
untitled h1
time-point response assessment using irrc.

Percentage changes in tumor burden per assessment time point describe the size and growth kinetics of both conventional and new, measurable lesions as they appear. At each tumor assessment, the response in index and new, measurable lesions is defined based on the change in tumor burden (after ruling out irPD). Decreases in tumor burden must be assessed relative to baseline measurements (i.e., the SPD of all index lesions at screening).
untitled h1
overall response using the irrc.

The overall response according to the irRC is derived from time-point response assessments (based on tumor burden) as follows:  
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions)
- confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented
irPR, decrease in tumor burden ≥50%relative to baseline
- confirmed by a consecutive assessment at least 4 wk after first documentation irSD, not meeting criteria for irCR or irPR, in absence of irPD irPD, increase in tumor burden ≥25% relative to nadir (minimum recorded tumor burden)
- confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented
untitled h1
appendix c. ecog performance status

The ECOG Scale of Performance Status, developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair*, describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.).  
**Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response* Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.  
| Grade   | Description                                                                                                                                                                                 |
|---------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous                              |
| 1       | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, |
| 2       | but unable to carry out any work activities. Up and about more than  50% of waking hours.                                                                                                   |
| 3       | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                        |
| 4       | 100% bedridden. Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.                                                                                                                                                                                             |
| 5       | Dead.                                                                                                                                                                                       |
untitled h1
appendix d. study calendar

| Screening Period1          | Treatment Period2                                                                                                                      | Follow-up Period3                 |                       |      |
|----------------------------|----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|-----------------------|------|
| Study Procedures           | Weekly                                                                                                                                 | Every 3                           |                       |      |
| Days -28 to -1             | Day 125                                                                                                                                | C1 Only                           | cycles (+/-1  week)21 | Long |
| 30 (±7)                    | Term                                                                                                                                   |                                   |                       |      |
| Days22                     |                                                                                                                                        |                                   |                       |      |
| Informed Consent           | X4                                                                                                                                     |                                   |                       |      |
| Demographics               | X                                                                                                                                      |                                   |                       |      |
| Medical and Cancer History | X                                                                                                                                      |                                   |                       |      |
| Concomitant Medications    | X                                                                                                                                      | X --- (throughout study5 ) --- X  |                       |      |
| Physical Examination       | X                                                                                                                                      | X                                 | X                     | X    |
| Height                     | X                                                                                                                                      |                                   |                       |      |
| Vital Signs and Weight6    | X                                                                                                                                      | X                                 | X                     | X    |
| ECOG Performance Status7   | X                                                                                                                                      | X                                 | X                     | X    |
| CBC with Differential      | X8                                                                                                                                     | X10                               | X                     | X    |
| Chemistries including LFTs | X8                                                                                                                                     | X10                               | X                     | X    |
| Thyroid Function Tests     | X                                                                                                                                      | X                                 | X                     |      |
| Serum Pregnancy Test9      | X8, 9                                                                                                                                  | X26                               | X9                    | X9   |
| Pembrolizumab              | X11                                                                                                                                    |                                   |                       |      |
| Oxaliplatin                | X12                                                                                                                                    |                                   |                       |      |
| Capecitabine               | X13                                                                                                                                    |                                   |                       |      |
| Adverse Event Assessment   | X                                                                                                                                      | X --- (throughout study 5 ) --- X |                       |      |
| Tumor Assessment14         | X                                                                                                                                      | X                                 | X23                   |      |
| Blood Tumor Markers15      | X                                                                                                                                      | X                                 | X23                   |      |
| Archived Tumor Tissue16    | X16                                                                                                                                    | X16                               |                       |      |
| Tumor Biopsy17             | X17                                                                                                                                    | X17                               |                       |      |
| PBMC18                     | X18                                                                                                                                    | X18                               | X18                   | X27  |
| Plasma19                   | X19                                                                                                                                    | X19                               | X19                   | X27  |
| Whole Blood20              | X20                                                                                                                                    |                                   |                       |      |
| Survival                   | X24                                                                                                                                    |                                   |                       |      |
| 1.                         | Refer to Section 5.1.                                                                                                                  |                                   |                       |      |
| 2.                         | Refer to Section 5.2. Cycle length is 21 days. However, for dose expansion cohort, the first cycle (ie. biomarker cycle) is 28 days in |                                   |                       |      |  
Informed Consent X4  
Demographics X  
Medical and Cancer History X  
Concomitant Medications X X --- (throughout study5) --- X  
Physical Examination X X X X  
Height X  
Vital Signs and Weight6 X X X X ECOG Performance Status7 X X X X  
CBC with Differential X8 X10 X X Chemistries including LFTs X8 X10 X X  
Thyroid Function Tests X X X  
Serum Pregnancy Test9 X8, 9 X26 X9 X9 Pembrolizumab X11  
Oxaliplatin X12  
Capecitabine X13  
Adverse Event Assessment X X --- (throughout study 5) --- X  
Tumor Assessment14 X X X23  
Blood Tumor Markers15 X X X23  
Archived Tumor Tissue16 X16 X16  
Tumor Biopsy17 X17 X17  
PBMC18 X18 X18 X18 X27 Plasma19 X19 X19 X19 X27  
Whole Blood20 X20  
Survival X24  
1. Refer to Section 5.1.  
2. Refer to Section 5.2. Cycle length is 21 days. However, for dose expansion cohort, the first cycle (ie. biomarker cycle) is 28 days in  
length and subsequent cycles are 21 days in length. Visits for each cycle are Day 1 except for Cycle 1 when visits are weekly (ie.  
C1D8, C1D15 and for dose expansion cohort only, C1D22) and as clinically indicated.  
3. Refer to Section 5.3. 4. May be completed more than 28 days prior to Cycle 1 Day 1.  
5. Document this data throughout study when changes or events occur.  
6. Obtain temperature (OC), blood pressure, heart rate, and weight (kg).  
7. At screening, obtain within 7 days to first dose of study treatment. Refer to Appendix C.  
8. Must perform within 7 days prior to Cycle 1 Day 1. If completed within 7 days of Cycle 1 Day 1, no need to repeat. If repeated on  
Cycle 1 Day 1, must wait for results to confirm eligibility prior to starting study drug.  
9. Only for women of childbearing potential.  
10. After Cycle 1, may perform up to 3 days prior to Day 1. 11. Pembrolizumab (see Section 6.2) is administered on Day 1 of each cycle.  
12. Oxaliplatin (see Section 6.3) is administered on Day 1 of each cycle except for first cycle (ie. biomarker) cycle of dose expansion cohort  
only when administered on Day 8 (ie. pembrolizumab monotherapy lead-in period).  
13. Capecitabine (see Section 6.4) is taken on Days 1-14 of each cycle except for first cycle (ie. biomarker) cycle of dose expansion cohort  
only when taken on Days 8-22 (ie. pembrolizumab monotherapy lead-in period).  
14. Radiographic assessments (ie. restaging scans) include CT and/or MRI of chest, abdomen and pelvis after every 3 cycles (9 weeks).  
Same method for tumor assessment should be employed at every assessment.  
15. If clinically indicated (ex. CEA and/or CA19-9).  
16. If FFPE tumor tissue is available, refer to Section 8.1 and Study Manual.  
17. For patients accrued to the dose expansion cohort with tumor lesion that is amenable to safe biopsy, pre-treatment (up to 1 week prior to pembrolizumab monotherapy lead-in) and on-treatment (C1 D7 or D8, prior to oxaliplatin and capecitabine/end of one week pembrolizumab monotherapy lead-in in Cycle 1) tumor biopsies will be performed in the first cycle (ie. biomarker cycle). Refer to Section 8.1 and Study Manual.  
18. Peripheral blood collection for PBMCs (see Section 8.2 and Study Manual) at the following time points: baseline (may be obtained on Cycle 1 Day 1 prior to the first dose of study drug); end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), first restaging only (ie. after Cycle 3), and disease progression or treatment discontinuation. Note - There is no PBMC collection at 30-day off treatment follow-up.  
19. Peripheral blood collection for plasma (see Section 8.3 and Study Manual) at the following time points: baseline (may be obtained on Cycle 1 Day 1 prior to the first dose of study drug); end of monotherapy lead-in on Day 8 (biomarker cycle of dose expansion cohort only), end of first cycle of combination therapy on Day 29 (biomarker cycle of dose expansion cohort only), each restaging, disease progression or treatment discontinuation and 30-day off treatment follow-up.  
20. Peripheral blood collection for whole blood (see Section 8.4 and Study Manual at the following time point: baseline (may be obtained on Cycle 1 Day 1 prior to the first dose of study drug).  
21. After every 3 cycles. 22. After the last dose of study drug.  
23. Subjects discontinued from study treatment with no documented disease progression and no subsequent anti-cancer treatment should have disease status and blood tumor markers (if clinically indicated) followed per standard of care schedule until disease progression or start of new anti-cancer treatment regimen is documented. Disease status may be collected by personal interviews or review of medical records.  
24. Subjects are followed for survival up to 3 years after the last subject starts the study drug regimen or until the study is closed
(whichever comes first). Survival status may be collected by personal interviews or review of medical or public records.  
25. Treatment visits may occur within +/-3 days of D1 for C2 and all subsequent cycles.  
26. Cycle 1 day 1 only. After that, will redo at restaging visits.  
27. Only for subjects who achieved a complete response and have consented to the additional collection.
untitled h1
appendix e. laboratory tests

| CBC with differential   hematocrit   hemoglobin  platelet count                                                                                                                    |                                   | WBC (total and differential)   |                          | absolute neutrophil count   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|--------------------------------|---------------------------|-----------------------------|
|                                                                                                                                                                                      | red blood cell (RBC) count         |                               | absolute lymphocyte count |                             |
| Chemistries with liver function tests (LFTs)  albumin  alkaline phosphatase (ALP)  ALT  AST  Bicarbonate  blood urea nitrogen (BUN)  chloride  creatinine  glucose  calcium |                                   | potassium                      |                           |                             |
|                                                                                                                                                                                      | sodium                             |                                |                           |                             |
|                                                                                                                                                                                      | total bilirubin                    |                                |                           |                             |
|                                                                                                                                                                                      | total protein                      |                                |                           |                             |
| Thyroid Function Tests                                                                                                                                                                |                                   | total thriiodothyronine (T3)   |                          | free tyroxine (T4)          |
|                                                                                                                                                                                      | thyroid stimulating hormone  (TSH) |                                |                           |                             |
| Pregnancy Test  serum β-HCG pregnancy test                                                                                                                                           |                                    |                                |                           |                             |