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6.3 response criteria

Response rate of pembrolizumab in patients with relapsed/refractory gray-zone lymphomas (GZL) and extranodal diffuse large B-cell lymphomas (DLBCL) will be assessed according to the International Working Group (IWG) response criteria and the International PCNSL workshop response criteria. In addition, we will also look at overall response rate according to the 5-point Lugano classification for interpreting FDG-PET scans. When appropriate, for patients with disease involvement of the bone marrow at baseline, repeat assessment will be done to confirm response. 6.3.1 Response Criteria for Lymphoma Lymphoma - GZL and DLBCL (not PCNSL) The following will be used to assess response in subjects with GZL and extranodal ABC, with the exception of PCNSL (see Section **6.3.2**).  
6.3.1.1 International Working Group (IWG) response criteria The International Working Group (IWG) response criteria will be used (Cheson et al.):  
| Response                  | Examination              | Lymph Nodes              | Lymph Node             |               |
|---------------------------|--------------------------|--------------------------|------------------------|---------------|
| Physical                  | Masses                   | Bone Marrow              |                        |               |
| Category CR               | Normal                   | < 1 cm                   | < 1 cm                 | Normal        |
| CRu                       | Normal                   | > 1 cm                   | > 75% decrease         | Indeterminate |
| Normal                    | Normal                   | Normal                   | Positive               |               |
| PR                        | Normal                   | ≥50% decrease            | ≥50% decrease          | Irrelevant    |
| Decrease in  liver/spleen | ≥50% decrease            | ≥50% decrease            | Irrelevant             |               |
| Enlarging                 |                          |                          |                        |               |
| Progression               | liver/spleen;  new sites | New or  increased  > 50% | New or increased > 50% | Reappearance  |  
6.3.1.2 The Five-Point Scale (5-PS) Deauville criteria The five-point scale (5-PS) has been validated for use at interim staging and at the end of treatment and was adopted as the preferred reporting method at the First International Workshop on PET in Lymphoma in Deauville, France (i.e., Deauville criteria), and in several international trials. The 5-PS scores the most intense uptake in a site of initial disease:
1. if present, as follows:no uptake or no residual uptake (when used at interim)  
2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation)  
6.3.1.3 Lugano Classification of Response Lugano classification of response criteria with PET (Cheson et al., 2014).  
| Lugano classification of response criteria with PET (Cheson et al., 2014). Response and Site PET-CT Based Response CT-Based Response Complete Complete metabolic response Complete radiologic response All of the following: - Target nodes/nodal masses must regress to ≤1.5  cm in LDi - No extralymphatic sites of disease NOTE: It is recognized that in Waldeyer's ring or extranodal sites with high physiologic uptake or  with activation within spleen or marrow (e.g., with chemotherapy or myeloid colony-stimulating  factors), uptake may be greater than normal mediastinum and/or liver. In this circumstance, complete  metabolic response may be inferred if uptake at sites of initial involvement is no greater than  surrounding normal tissue even if the tissue has high physiologic uptake. Nonmeasured lesions Not applicable Absent Organ enlargement Not applicable Regress to normal New lesions None None Score 1, 2, or 3* with or without a  residual mass on 5PS† Lymph nodes and extralymphatic sites Bone marrow No evidence of FDG-avid disease in  Normal by morphology; if indeterminate, IHC  marrow negative Partial Partial metabolic response Partial remission All of the following: Score 4 or 5† with reduced uptake  compared with baseline and residual  mass(es) of any size At interim, these findings suggest  responding disease. At end of treatment, these findings indicate  residual disease. - ≥50% decrease in SPD of up to 6 target  measureable nodes and extranodal sites Lymph nodes and  extralymphatic sites When a lesion is too small to measure on CT, assign 5  mm x 5 mm as the default valve; when no longer visible, 0  x 0 mm. For a node >5 mm x 5 mm, but smaller than  normal, use actual measurement for calculation. Nonmeasured lesions Not applicable Absent/normal, regressed, but no increase Organ enlargement Not applicable Spleen must have regressed by >50% in length  beyond normal New lesions None None Residual uptake higher than uptake in  normal marrow but reduced compared  with baseline (diffuse uptake  compatible with reactive changes from  chemotherapy allowed). If there are  persistent focal changes in the marrow  in the context of a nodal response,  consideration should be given to  further evaluation with MRI or biopsy or an interval scan. Bone marrow Not applicable No response or  stable disease No metabolic response Stable disease Target nodes/nodal  masses, extranodal  lesions <50% decrease from baseline in SPD of up to 6  dominant, measurable nodes and extranodal sites;  no criteria for progressive disease are met Nonmeasured lesions Not applicable No increase consistent with progression Organ enlargement Not applicable No increase consistent with progression New lesions None None Bone marrow No change form baseline Not applicableScore 4 or 5 with no significant  change in FDG uptake from baseline  at interim or end of treatment   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
| Response and Site                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | PET-CT Based Response                              | CT-Based Response                                                                                                                                                                                                                                                                                                                                            |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Progressive disease                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Progressive metabolic disease                      | Progressive disease                                                                                                                                                                                                                                                                                                                                          |
| Requires at least 1 of the following:                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                    |                                                                                                                                                                                                                                                                                                                                                              |
| An individual node/lesion must be abnormal with:  - LDi >1.5 cm, and - Increase by ≥ 50% from PPD nadir, and - An increase in LDi or SDi from nadir: o 0.5 cm for lesions ≤2 cm o 1.0 cm for lesions >2 cm                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                    |                                                                                                                                                                                                                                                                                                                                                              |
| Score 4 or 5 with an increase in intensity of uptake from baseline; and/or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                    |                                                                                                                                                                                                                                                                                                                                                              |
| Individual target nodes/nodal masses                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | -                                                  | In the setting of splenomegaly, the splenic length  must increase by >50% of the extent of its prior  increase beyond baseline (e.g., a 15-cm spleen  must increase to >16 cm). If no prior splenomegaly, must increase by at least 2 cm  from baseline.                                                                                                     |
| -                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | New or recurrent splenomegaly                      |                                                                                                                                                                                                                                                                                                                                                              |
| New FDG-avid foci consistent with                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                    |                                                                                                                                                                                                                                                                                                                                                              |
| Extranodal lesions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | lymphoma at interim or end of treatment assessment |                                                                                                                                                                                                                                                                                                                                                              |
| Nonmeasured lesions                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | None                                               | New or clear progression of preexisting nonmeasured lesions - Regrowth of previously resolved lesions - A new node >1.5 cm in any axis - A new extranodal site >1.0 cm in any axis; if  <1.0 cm in any axis, its presence must be unequivocal and must be attributable to  lymphoma - Assessable disease of any size unequivocally  attributable to lymphoma |
| Bone marrow                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | New or recurrent FDG-avid foci                     | New or recurrent involvement                                                                                                                                                                                                                                                                                                                                 |
| Abbreviations: 5PS, 5-point scale; CT computed tomography; FDG, fluorodeoxyglucose; IHC, immunohistochemistry;  LDi, longest transverse diameter of a lesion; MRI, magnetic resonance imaging; PET, positron emission tomography;  PPD, cross product of the LDi and perpendicular diameter; SDi, shortest axis perpendicular to the LDi; SPD, sum of the  product of the perpendicular diameters for multiple lesions. *A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim  scan. However, in trails involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as  inadequate response (to avoid under treatment). Measured dominant lesions: Up to 6 of the largest dominant nodes, nodal  masses, and extranodal lesions selected to be clearly measurable in 2 diameters. Nodes should preferably be from  disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal  lesions include those in solid organs (eg, liver spleen, kidneys, and lungs), GI involvement, cutaneous lesions, or those  noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable  disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected  as dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as  well as truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with  measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other  lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver,  bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no  higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy of myeloid  growth factors).  †PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake  moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related  to lymphoma.New FDG-avid foci consistent with lymphoma rather than another etiology  (e.g., infection, inflammation). If  uncertain regarding etiology of new lesions, biopsy or interval scan may be  considered. New lesions |                                                    |                                                                                                                                                                                                                                                                                                                                                              |  
| 2005) will be used for subjects on study with PCNSL:  Response Brain Imaging Corticosteroid  dose Eye examination                                         | CSF cytology             |                                       |                           |          |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|---------------------------------------|---------------------------|----------|
| CR                                                                                                                                                        | No contrast  enhancement | None                                  | Normal                    | Negative |
| No contrast  enhancement                                                                                                                                  | Any                      | Normal                                | Negative                  |          |
| abnormality                                                                                                                                               | Any                      | Minor RPE                             |                           |          |
| Minimal                                                                                                                                                   | abnormality              | Negative                              |                           |          |
| CRu                                                                                                                                                       | Minor RPE                |                                       |                           |          |
| 50% decrease in  enhancing tumor                                                                                                                          | Irrelevant               | abnormality or                        | Negative                  |          |
| normal                                                                                                                                                    |                          |                                       |                           |          |
| PR                                                                                                                                                        | Decrease in              |                                       |                           |          |
| No contrast  enhancement                                                                                                                                  | Irrelevant               | vitreous cells or  retinal infiltrate | Persistent or  suspicious |          |
| 25% increase in  lesion                                                                                                                                   | Irrelevant               | Recurrent or new                      | Recurrent or              |          |
| PD                                                                                                                                                        | ocular disease           | positive                              |                           |          |
| Any new site of disease: CNS or systemic                                                                                                                  |                          |                                       |                           |          |
| Abbreviations: CR, complete response; CRu, unconfirmed complete response; RPE, retinal pigment  epithelium; PR, partial response; PD, progressive disease |                          |                                       |                           |          |  
6.3.2 Response Criteria for Lymphoma - PCNSL The following response criteria as per the CNS lymphoma working group (Abrey et al. JCO 2005) will be used for subjects on study with PCNSL: 6.3.3 Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. 6.3.4 Duration of Response The duration of response (DOR) is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started), death, or, in the absence of PD, date of last assessment. 6.3.5 Progression-Free Survival Progression-free survival (PFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, or death, whichever occurs first. 6.3.6 Event-Free Survival Event-free survival (EFS) is defined as the duration of time from the date of study enrollment until time of disease relapse, disease progression, alternative therapy for lymphoma given (such as radiation), or death, whichever occurs first. 6.3.7 Other Evaluable for toxicity: All patients who receive at least 1 dose of pembrolizumab will be evaluable for toxicity.  
Evaluable for objective response: Only those patients who have measurable or evaluable disease present at baseline, have received at least two doses of therapy, and have had their disease reevaluated with radiographic imaging will be considered evaluable for response. These patients will have their response classified according to the definitions stated below. (NOTE: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
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6.4 toxicity criteria

The following adverse event management guidelines are intended to ensure the safety of each patient while on the study. The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All appropriate treatment areas should have access to a copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm\#ctc_40).
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7 nih reporting /data and

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

7.2.1 Expedited Reporting Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 802 Non-Compliance Human Subjects Research found here. 7.2.2 IRB Requirements for PI Reporting at Continuing Review Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.
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7.3 nci clinical director reporting

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

7.4.1 Principal Investigator/Research Team The clinical research team will meet on a regular basis (i.e., approximately weekly) when patients are being actively treated on the trial to discuss each patient. Decisions about trial continuation will be made based on the efficacy data from prior patients at appropriate time points per the statistical plan.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead associate investigator. Events meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure safety and data accuracy. The principal investigator will personally conduct or supervise the investigation and provide appropriate delegation of responsibilities to other members of the research staff.
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8 sponsor protocol/safety reporting 8.1

8.1.1 General Information and Summary Merck is providing pembrolizumab for participants in this clinical trial. As part of the agreement, information about the trial, including adverse events will be shared with them. Unless otherwise agreed to with Merck, Merck-provided/-specific forms will be used to report events to Merck during the course of this study. These will be provided to the Principal Investigator and study team, and maintained in the regulatory files. 8.1.2 Reporting Timeframes/Requirements For the purposes of reporting:
- From the time that the consent form is signed but before initiation of treatment:  
o All adverse events that occur must be reported if they cause the subject to be excluded from the trial, or are the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
o Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study that occurs to any subject must be reported within 2 working days to Merck Global Safety if it causes the subject to be excluded from the trial, or is the result of a protocol-specified intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.  
NOTE: These same reporting requirements and windows apply to Events of Clinical Interest (see Section **8.1.4**).  
- From the time after treatment allocation through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier:
o Any serious adverse event, or follow up to a serious adverse event, including death due to any cause other than progression of the cancer under study, whether or not related to the Merck product, must be reported within 2 working days to Merck Global Safety.  
o Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to Merck product that is brought to the attention of the investigator at any time following consent through the end of the specified safety follow-up period specified in the paragraph above, or at any time outside of
the time period specified in the previous paragraph also must be reported immediately to Merck Global Safety.  
NOTE: These same reporting requirements and windows apply to Events of Clinical Interest (see Section **8.1.4**).  
All patients with serious adverse events must be followed up for outcome. SAE reports and any other relevant safety information are to be forwarded to the Merck Global Safety facsimile **number: +1-215-993-1220.** See **APPENDIX B** for the specific criteria and categories of information that require documentation and reporting to Merck with each event. 8.1.3 Serious Adverse Events In addition to the serious adverse events listed in Section **7.1.1** , the following are also required to be reported as "serious" events to Merck:
- Is a new cancer (that is not a condition of the study)
- Is associated with an overdose (see additional information in Section **8.1.4.1**)
8.1.4 Reporting Requirements for Events of Clinical Interest Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).  
All ECI reporting time frames are indicated above in Section **8.1.2**.  
8.1.4.1 Overdose of a Merck Product 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 a reportable event of special interest. 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. Appropriate supportive treatment should be provided if clinically indicated. If an adverse event(s) is associated with ("results from") the overdose of a Merck product, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met. If a dose of Merck's product meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a nonserious Event of Clinical Interest (ECI), using the terminology "accidental or intentional overdose without adverse effect." 8.1.4.2 Liver Function Tests (LFTs) An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined by way of protocol-specified laboratory testing or unscheduled laboratory testing, are also to be reported as events of clinical interest to Merck in an expedited fashion.  
NOTE: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology.  
8.1.4.3 Reporting of Pregnancy and Lactation to Merck Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them) that occurs during the trial. Pregnancies and lactations that occur from the time of treatment allocation through 120 days following cessation of pembrolizumab, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported by the investigator. All reported pregnancies 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 within 2 working days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 8.1.5 Protocol-Specific Exceptions to Serious Adverse Event Reporting Efficacy endpoints as outlined in this section will not be reported to Merck as described in Section 8.1.2, unless there is evidence suggesting a causal relationship between the drug and the event.  
Any such event will be submitted to Merck Global Safety within 2 working days either by electronic or paper media. Specifically, the suspected/actual events covered in this exception include any event that is disease progression of the cancer under study. The PI will monitor unblinded aggregated efficacy endpoint events and safety data to ensure the safety of the patients in the trial. Any suspected endpoint which upon review is not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE within 2 working days of determination that the event is not progression of the cancer under study. In addition, hospitalization related to convenience (e.g., transportation issues etc.) will not be considered a SAE or a Protocol Deviation.
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9 statistical considerations 9.1 statistical

- Primary Endpoint:
o Overall response rate (ORR); this will be assessed at up to 24 months.  
- Secondary Endpoints:
o Type, grade, and frequency of toxicities o Duration of response o Progression-free survival (PFS) o Event-free survival (EFS) o Overall survival (OS)
NOTE: Each of the above will be assessed definitively when 24 months have passed since the last patient has been enrolled.
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9.2 sample size determination

The trial will be conducted in two cohorts using a single stage design for evaluating efficacy in each cohort since modestly high clinical response rates are expected in both cohorts.  
In the GZL cohort, results from a prior study indicate that 3 of 3 patients had a complete response when treated with (authors data, manuscript accepted for publication). With 20 evaluable patients, there would be 91% power to rule out 50% and be consistent with 80% who may be able to experience a clinical response, using an exact binomial test with a 0.10 one-sided significance level. As an illustration, if 20 evaluable patients are enrolled, 14 of 20 (70.0%) who experience a clinical response would have an associated one-sided lower 90% confidence interval bound of 53.3%, and simultaneously an associated one-sided upper 90% confidence interval bound of 83.4%. This demonstrates that 14 responses in 20 patients would be a desirable result based on the parameters selected. In the PCNSL and extranodal DLBCL cohort, newly published results in 5 patients suggest the overall response rate will be moderately high.38 With 20 evaluable patients, there would be 88%
power to rule out 40% and be consistent with 70% who may be able to experience a clinical response, using an exact binomial test with a 0.10 one-sided significance level. As an illustration, if 20 evaluable patients are enrolled, 12 of 20 (60.0%) who experience a clinical response would have an associated one-sided lower 90% confidence interval bound of 43.3%, and simultaneously an associated one-sided upper 90% confidence interval bound of 75.1%. This demonstrates that 12 responses in 20 patients would be a desirable result based on the parameters selected. Within the PCNSL and extranodal DLBCL cohort, the goal will be to enroll a total of 10 PCNSL patients and 10 extranodal DLBCL patients. By doing so, at the conclusion of the trial, there will potentially be adequate patients to make an approximate estimate of the response rate for each group, which could provide information that may guide future development in these patient subsets. While 20 patients may be needed for evaluation per cohort, in order to allow for a small number of inevaluable patients, we intend to initiate treatment in 48 eligible subjects. In order to also account for ineligible patients (i.e., screen failures who do not initiate treatment), the accrual ceiling will be set at 52 patients. If 18-20 patients may be accrued onto this trial per year, accrual should be completed within 2 to 2.5 years.
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9.3 populations for analyses

All patients who receive at least 2 doses of pembrolizumab, and who have both a baseline and follow-up scan at the appropriate time to assess response will be considered evaluable and included in the analyses.
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9.4 statistical analyses 9.4.1 general

The response rate will be determined and reported along with a 95% confidence interval. Other time-to-event outcomes will be reported using Kaplan-Meier curves. 9.4.2 Analysis of the Primary Endpoints The ORR in each cohort will be determined and reported along with a 95% confidence interval.  
9.4.3 Analysis of the Secondary Endpoints The duration of response (DOR; beginning at the date clinical response is first identified), overall survival (OS), event free survival (EFS), and progression free survival (PFS) will be estimated for each of the two types of lymphoma individually using Kaplan-Meier curves with appropriate confidence intervals reported. 9.4.4 Safety Analyses The type, grade and frequency of toxicities will be reported. 9.4.5 Planned Interim Analyses No interim analyses are planned because of the single stage design of the trial. 9.4.6 Sub-Group Analyses None.  
9.4.7 Tabulation of Individual Participant Data None. 9.4.8 Exploratory Analyses The exploratory objectives such as seeking to identify potential biomarkers or T-cell and B-cell clones in peripheral blood which are associated with response, will be assessed using descriptive statistics as well as non-parametric methods such as exact Wilcoxon rank sum tests. The analyses will be done without formal adjustment for multiple comparisons, but in the context of the number of tests performed.
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10 collaborative agreements 10.1 clinical

There will be a CTA between the National Cancer Institute and Merck, Inc. (CTA \#01043-17) A CRADA is also being discussed and will be added in an amendment, if finalized.
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11 human subjects protections 11.1

Gray-zone lymphomas (GZL) affect all races and genders, but certain subsets such as mediastinal gray-zone lymphomas occur preferentially in young adults with a slight male predominance. Extranodal DBCL and other ABC-like subtypes of DLBCL including PCNSL are more likely to occur in older patients. Across both cohorts, we anticipate an even gender distribution. This trial is directed at assessing a novel therapy using single agent pembrolizumab in patients with either previously treated GZL and patients with previously treated extranodal DLBCL. Pregnant or nursing mothers are excluded because of the potential teratogenic effects of therapy.
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11.2 participation of children

The original intent was for the study to include participation of children. Specifically, that subjects who are at least 14 years old will be included because mediastinal gray zone lymphomas do occasionally affect younger age subjects and because there is no adequate treatment at this time. The age cut-off is based on the rarity of this disease in younger children. However, given the difficulty in recruitment and decision to close the study to accrualearly, and that no children were enrolled to the study prior to the decision to close, children were ultimately not included. Due to required protocol updates at the request of the NIH IRBO (made in early 2021), the study was revised to note enrollment and inclusion of only adults in the study.
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11.3 participation of subjects unable

Adults who are unable to consent are included in this protocol because the protocol offers a prospect of direct benefit and should therefore exclude participants only when scientifically necessary or participants with this condition are at risk of losing capacity at least temporarily and enrollment might be compromised without their involvement. In addition, re-consent on this protocol may be necessary and there is a possibility that subjects could become decisionally impaired. For this reason and because there is a prospect of direct benefit from research participation (Section **11.4**), all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for research and care, and assign a substitute decision maker on the "NIH Advance Directive for Health Care and Medical Research Participation" form so that another person can make decisions about their medical care in the event that they become incapacitated or cognitively impaired during the course of the study.  
NOTE: The PI or AI will contact the NIH Ability to Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify an LAR, as needed. Please see section **11.5** for consent procedure.
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11.4 evaluation of benefits and

Patients may obtain direct benefit from treatment with pembrolizumab. The most common adverse reactions (≥10%) observed in clinical trials were rash, fatigue, nausea, diarrhea, cough, pruritus, dyspnea, musculoskeletal pain, decreased appetite, headache, vomiting, asthenia, pyrexia, back pain, anemia, peripheral edema and constipation. Although the potential for serious adverse events exists for these patients, the incidence of them is decidedly lower and management algorithms have been developed. The potential toxicity of pembrolizumab is reasonable in relation to the potential benefit to this group of patients who have few treatment options. The risks associated with research procedures (i.e., research blood and tissue collection, including planned analyses and risks associated with genetic research) are described in detail in the informed consent document.
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11.4.1 risks 11.4.1.1 imaging

In addition to the radiation risks discussed below, scans often use a contrast agent and may include the risks of an allergic reaction to the contrast. Participants might experience hives, itching, headache, difficulty breathing, increased heartrate and swelling.
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11.4.1.2 ct and pet scans

CT and PET scans often use a contrast agent. There is a small risk of having a reaction to the contrast and most often include nausea, pain in the vein where the contrast is given, headache, metallic and/ or bitter taste in the mouth and a warm, flushing feeling. Rarely, some people have more severe allergic reactions to the contrast which may include skins rashes, shortness of breath, wheezing or low blood pressure.
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11.4.1.3 mri

People are at risk for injury from the MRI magnet if they have some kinds of metal in their body. People with fear of confined spaces may become anxious during an MRI. Those with back  
problems may have back pain or discomfort from lying in the scanner. The noise from the scanner is loud enough to damage hearing, especially in people who already have hearing loss. There are no known long-term risks of MRI scans.  
11.4.1.4 Gadolinium enhanced MRI (Required in patients with PCNSL)
During part of the MRI patient will receive gadolinium, a contrast agent, through an intravenous (IV) catheter (small tube). It will be done for research purposes. The risks of an IV catheter include bleeding, infection, or inflammation of the skin and vein with pain and swelling. Participants undergoing gadolinium enhanced MRIs may also be at risk for kidney damage. Most of the gadolinium contrast is eliminated in the urine. However, recent studies have found very small amounts of residual gadolinium in the body, including the brain and bone, by imaging and at autopsy. Macrocyclic gadolinium-containing contrast agents are substantially less likely to leave gadolinium behind than linear agents. There is presently no evidence that the retained gadolinium is associated with any adverse effects or other health risks. Participants undergoing gadolinium enhanced MRIs may also be at risk for kidney damage. 11.4.1.5 Radiation Exposure The procedures for performing the CT and 18F-FDG PET/CT scans will follow clinical policies, no special procedures apply to these additional assessments for research purposes. In summary, subjects may receive additional radiation exposure from up to five (5) additional CT scans of the chest, abdomen, and pelvis and two (2) additional 18F-FDG PET/CT scans maximum in an annual period. The total additional radiation dose for research purposes will be approximately 7.9 rem. This amount is more than would be expected from everyday background radiation. Being exposed to excess radiation can increase the risk of cancer. 11.4.1.6 Blood sampling Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 11.4.1.7 Bone marrow aspirate and/or biopsy Bone marrow biopsy is minimally invasive and is typically a very safe procedure. Usually hipbone is numbed with anesthesia. Using a needle, the solid and liquid portion of bone marrow is taken out. This procedure causes some pain. Very rarely, infection or bleeding may occur at the needle site. 11.4.1.8 Biopsy (optional) All care will be taken to minimize risks that may be incurred by tumor sampling. However, there are procedure-related risks (such as bleeding, infection, and injury) that will be explained fully during informed consent 11.4.1.9 Urine collection There is no physical risk involved with urine collection. 11.4.1.10 Lumbar puncture Risks of lumbar puncture include headache, dizziness, infection, back discomfort, minor radicular numbness and brainstem herniation. 11.4.1.11 Opthalmalogic evaluation There are no anticipated long-term physical risks expected with the eye exams planned in patients in PCNSL. 11.5 CONSENT PROCESS AND D**OCUMENTATION** The informed consent document will be provided to the participant or consent designee(s) as applicable for review prior to consenting. A designated study investigator will carefully explain the procedures and tests involved in this study, and the associated risks, discomforts and benefits. In order to minimize potential coercion, as much time as is needed to review the document will be given, including an opportunity to discuss it with friends, family members and/or other advisors, and to ask questions of any designated study investigator. A signed informed consent document will be obtained prior to entry onto the study. The initial consent process as well as re-consent, when required, may take place in person or remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the designated study investigator and with the agreement of the participant/consent designee(s). Whether in person or remote, the privacy of the subject will be maintained. Consenting investigators (and participant/consent designee, when in person) will be located in a private area (e.g., clinic consult room). When consent is conducted remotely, the participant/consent designee will be informed of the private nature of the discussion and will be encouraged to relocate to a more private setting if needed. 11.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation For participants addressed in section **11.3**, an LAR will be identified consistent with Policy 403 and informed consent obtained from the LAR, as described in Section **11.5**.  
11.6 INCLUSION OF WOMEN AND M**INORITIES** Both men and women and members of all races are eligible for this trial.
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12 regulatory and operational considerations

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

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

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

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

This clinical investigation of a marketed drug is exempt from the IND requirements because all of the criteria for an exemption in 21CFR 312.2(b) are met:
- The drug product is lawfully marketed in the United States. - The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.  
- In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.  
- The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product.  
- The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).  
- The investigation is conducted in compliance with the requirements of 21 CFR 312.7, i.e.,
the drug may not be represented as safe or effective, nor may it be commercially distributed, for the purposes for which it is under investigation.
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13.1 pembrolizumab

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the approved, marketed product label and information, this clinical protocol, and any applicable laws and regulations. It has been confirmed with Merck prior to activation that commercial drug lots (i.e., not research/investigational lots) will be provided for this clinical trial. A summary of protocol-specific information is included here: 13.1.1 Source Pembrolizumab will be supplied by Merck, Inc. for use by subjects in this clinical trial. 13.1.2 Toxicity Please refer to the Package Insert for pembrolizumab (KEYTRUDA®) for toxicity information. 13.1.3 Formulation and Preparation Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.  
The formulations to be supplied are as follows:  
| Product Name & Potency    | Dosage Form                      |
|---------------------------|----------------------------------|
| Pembrolizumab 50 mg       | Lyophilized Powder for Injection |
| Pembrolizumab 100 mg/ 4mL | Solution for Injection           |  
Preparation for infusion should follow current clinical practice for marketed pembrolizumab.  
NOTE: This trial is open-label; therefore, the subject and the trial site personnel are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided. 13.1.4 Stability and Storage Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of trial supplies must be recorded by an authorized person at the trial site. Clinical supplies may not be used for any purpose other than that stated in the protocol. 13.1.5 Administration procedures Pembrolizumab should be administered per the FDA-approved labeling instructions as is applicable for the commercial lots of drug being supplied for this study. 13.1.6 Returns and Reconciliation The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed and the amount remaining at the conclusion of the trial. Upon completion or termination of the study, all unused and/or partially used investigational product will be destroyed at the site per institutional policy. It is the investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
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14 references

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clinico-pathological characteristics and outcomes of 99 patients from the Lymphoma Study Association. Haematologica 102:150-159, 2017 8. Joos S, Otano-Joos MI, Ziegler S, et al: Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood 87:1571-8, 1996 9. Green MR, Monti S, Rodig SJ, et al: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116:3268-77, 2010 10. Rui L, Emre NC, Kruhlak MJ, et al: Cooperative epigenetic modulation by cancer amplicon genes. Cancer Cell 18:590-605, 2010 11. Bryan LJ, Gordon LI: Blocking tumor escape in hematologic malignancies: The anti-PD-1 strategy. Blood Rev, 2014 12. Shiels MS, Pfeiffer RM, Besson C, et al: Trends in primary central nervous system lymphoma incidence and survival in the U.S. Br J Haematol 174:417-24, 2016 13. Ambady P, Holdhoff M, Bonekamp D, et al: Late relapses in primary CNS
lymphoma after complete remissions with high-dose methotrexate monotherapy. CNS Oncol 4:393-8, 2015 14. Gavrilovic IT, Hormigo A, Yahalom J, et al: Long-Term Follow-Up of HighDose Methotrexate-Based Therapy With and Without Whole Brain Irradiation for Newly Diagnosed Primary CNS Lymphoma. J Clin Oncol 24:4570-4574, 2006 15. DeAngelis LM, Seiferheld W, Schold SC, et al: Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10. J Clin Oncol 20:4643-8, 2002 16. Thiel E, Korfel A, Martus P, et al: High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, noninferiority trial. Lancet Oncol 11:1036-47, 2010 17. Rubenstein JL, Hsi ED, Johnson JL, et al: Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 31:3061-8, 2013 18. Ferreri AJ, Cwynarski K, Pulczynski E, et al: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol 3:e217-27, 2016 19. Ferreri AJ, Reni M, Foppoli M, et al: High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial. Lancet 374:1512-20, 2009 20. Nakamura T, Tateishi K, Niwa T, et al: Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol 42:279-90, 2016 21. Sung CO, Kim SC, Karnan S, et al: Genomic profiling combined with gene expression profiling in primary central nervous system lymphoma. Blood 117:1291-300, 2011 22. Rosenwald A, Wright G, Chan WC, et al: The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med 346:193747, 2002 23. Bruno A, Boisselier B, Labreche K, et al: Mutational analysis of primary central nervous system lymphoma. Oncotarget 5:5065-75, 2014 24. Fukumura K, Kawazu M, Kojima S, et al: Genomic characterization of primary central nervous system lymphoma. Acta Neuropathologica 131:865-875, 2016 25. Vater I, Montesinos-Rongen M, Schlesner M, et al: The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia 29:677-85, 2015 26. Braggio E, Van Wier S, Ojha J, et al: Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas. Clin Cancer Res 21:3986-94, 2015 27. Chapuy B, Roemer MG, Stewart C, et al: Targetable genetic features of primary testicular and primary central nervous system lymphomas. Blood 127:869-81, 2016 28. Nakamura T, Tateishi K, Niwa T, et al: Recurrent mutations of CD79B and MYD88 are the hallmark of primary central nervous system lymphomas. Neuropathol Appl Neurobiol, 2015 29. Wilson WH, Young RM, Schmitz R, et al: Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med 21:922-6, 2015 30. Dunleavy K, Lai CE, Roschewski M, et al: Phase I Study of Dose-AdjustedTeddi-R with Ibrutinib in Untreated and Relapsed/Refractory Primary CNS Lymphoma. Blood 126:472-472, 2015 31. Choquet S, Houillier C, Bijou F, et al: Ibrutinib Monotherapy in Relapse or Refractory Primary CNS Lymphoma (PCNSL) and Primary Vitreo-Retinal Lymphoma (PVRL). Result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network. Blood 128:784-784, 2016 32. Grommes C, Pastore A, Gavrilovic I, et al: Single-Agent Ibrutinib in Recurrent/Refractory Central Nervous System Lymphoma. Blood 128:783-783, 2016 33. Houillier C, Choquet S, Touitou V, et al: Lenalidomide monotherapy as salvage treatment for recurrent primary CNS lymphoma. Neurology 84:325-6, 2015 34. Armand P, Shipp MA, Ribrag V, et al: Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure. J Clin Oncol, 2016 35. Lesokhin AM, Ansell SM, Armand P, et al: Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 34:2698-704, 2016 36. Younes A, Santoro A, Shipp M, et al: Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol 17:1283-94, 2016 37. Ansell SM, Lesokhin AM, Borrello I, et al: PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med 372:311-9, 2015 38. Nayak L, Iwamoto FM, LaCasce A, et al: PD-1 blockade with nivolumab in relapsed/refractory primary central nervous system and testicular lymphoma. Blood, 2017 39. Kraan W, van Keimpema M, Horlings HM, et al: High prevalence of oncogenic MYD88 and CD79B mutations in primary testicular diffuse large B-cell lymphoma. Leukemia 28:719-20, 2014 40. Kraan W, Horlings HM, van Keimpema M, et al: High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immuneprivileged sites. Blood Cancer J 3:e139, 2013 41. Booman M, Douwes J, Glas AM, et al: Primary testicular diffuse large B-cell lymphomas have activated B-cell-like subtype characteristics. J Pathol 210:163-71, 2006 42. Booman M, Szuhai K, Rosenwald A, et al: Genomic alterations and gene expression in primary diffuse large B-cell lymphomas of immune-privileged sites: the importance of apoptosis and immunomodulatory pathways. J Pathol 216:209-17, 2008 43. Murase T, Yamaguchi M, Suzuki R, et al: Intravascular large B-cell lymphoma
(IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 109:478-85, 2007 44. Aviles A, Neri N, Nambo MJ: The role of genotype in 104 cases of diffuse large B-cell lymphoma primary of breast. Am J Clin Oncol 35:126-9, 2012 45. Pham-Ledard A, Prochazkova-Carlotti M, Andrique L, et al: Multiple genetic alterations in primary cutaneous large B-cell lymphoma, leg type support a common lymphomagenesis with activated B-cell-like diffuse large B-cell lymphoma. Mod Pathol 27:40211, 2014 46. Pham-Ledard A, Beylot-Barry M, Barbe C, et al: High frequency and clinical prognostic value of MYD88 L265P mutation in primary cutaneous diffuse large B-cell lymphoma, leg-type. JAMA Dermatol 150:1173-9, 2014 47. Kridel R, Telio D, Villa D, et al: Diffuse large B-cell lymphoma with testicular involvement: outcome and risk of CNS relapse in the rituximab era. Br J Haematol 176:210-221, 2017 48. Ishida Y, Agata Y, Shibahara K, et al: Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887-95, 1992 49. Kiyasu J, Miyoshi H, Hirata A, et al: Expression of programmed cell death ligand 1 is associated with poor overall survival in patients with diffuse large B-cell lymphoma. Blood, 2015 50. Blackburn SD, Shin H, Freeman GJ, et al: Selective expansion of a subset of exhausted CD8 T cells by alphaPD-L1 blockade. Proc Natl Acad Sci U S A 105:15016-21, 2008 51. Kamphorst AO, Pillai RN, Yang S, et al: Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients. Proc Natl Acad Sci U S A, 2017 52. Chen R, Zinzani PL, Fanale MA, et al: Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. J Clin Oncol:JCO2016721316, 2017 53. Rizvi NA, Hellmann MD, Snyder A, et al: Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124-8, 2015 54. Chen PL, Roh W, Reuben A, et al: Analysis of Immune Signatures in Longitudinal Tumor Samples Yields Insight into Biomarkers of Response and Mechanisms of Resistance to Immune Checkpoint Blockade. Cancer Discov 6:827-37, 2016
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15 appendix a performance status

| ECOG Performance Status Scale                                                                                                                                                             | Karnofsky Performance Scale                                       |                                                                           |                                                                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------|---------------------------------------------------------------------------|------------------------------------------------------------------------|
| Grade                                                                                                                                                                                     | Descriptions                                                      | Percent                                                                   | Description                                                            |
| 100                                                                                                                                                                                       | Normal, no complaints, no evidence  of disease.                   |                                                                           |                                                                        |
| Normal activity. Fully active, able to                                                                                                                                                    |                                                                   |                                                                           |                                                                        |
| 0                                                                                                                                                                                         | carry on all pre-disease performance  without restriction.        | 90                                                                        | Able to carry on normal activity;  minor signs or symptoms of disease. |
| Symptoms, but ambulatory. Restricted  in physically strenuous activity, but  ambulatory and able to carry out work  of a light or sedentary nature (e.g., light  housework, office work). | 80                                                                | Normal activity with effort; some  signs or symptoms of disease.          |                                                                        |
| 1                                                                                                                                                                                         | 70                                                                | Cares for self, unable to carry on  normal activity or to do active work. |                                                                        |
| In bed <50% of the time. Ambulatory  and capable of all self-care, but unable  to carry out any work activities. Up  and about more than 50% of waking  hours.                            | Requires occasional assistance, but is                            |                                                                           |                                                                        |
| 60                                                                                                                                                                                        | able to care for most of his/her  needs.                          |                                                                           |                                                                        |
| 2                                                                                                                                                                                         | 50                                                                | Requires considerable assistance and  frequent medical care.              |                                                                        |
| In bed >50% of the time. Capable of  only limited self-care, confined to bed  or chair more than 50% of waking  hours.                                                                    | 40                                                                | Disabled, requires special care and  assistance.                          |                                                                        |
| 3                                                                                                                                                                                         | 30                                                                | Severely disabled, hospitalization  indicated. Death not imminent.        |                                                                        |
| 20                                                                                                                                                                                        | Very sick, hospitalization indicated.  Death not imminent.        |                                                                           |                                                                        |
| 100% bedridden. Completely disabled.                                                                                                                                                      |                                                                   |                                                                           |                                                                        |
| 4                                                                                                                                                                                         | Cannot carry on any self-care. Totally  confined to bed or chair. | 10                                                                        | Moribund, fatal processes  progressing rapidly.                        |
| 5                                                                                                                                                                                         | Dead.                                                             | 0                                                                         | Dead.                                                                  |
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16 appendix b merck adverse

| The following information should be considered for each reportable event to Merck: V4.0 CTCAE  Grade 1 Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. Grading Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; limiting  self-care ADL. Grade 4 Life threatening consequences; urgent intervention indicated. Grade 5 Death related to AE Seriousness A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an adverse event  that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a  precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not worsened is not a serious adverse  event. A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the patient's medical history.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); or Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to Merck within 2 working days to meet certain local requirements);  or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An overdose  that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported to Merck within 2 working days. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, based upon  appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated  above by a †). Duration Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units Action taken Did the adverse event cause Merck product to be discontinued?   |
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16 appendix b merck adverse

| Relationship to                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Did Merck product cause the adverse event? The determination of the likelihood that Merck product caused the adverse event will be provided by an investigator who is a qualified                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
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| Merck Product                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | physician. The investigator's signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified  assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist  the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information. The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their respective  elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, diary,  etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from administration of Merck product?  Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors The following components are to be used to assess the relationship between the test drug and the AE: (continued) Dechallenge Was Merck product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of  the study drug; or (3) the trial is a single-dose drug trial); or (4) study drug is only used one time.) Rechallenge Was the subject re-exposed to Merck product in this study? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge. (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3)  study drug is used only one time). NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED  BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE  SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE PI AS PER DOSE MODIFICATION GUIDELINES  IN THE PROTOCOL. Consistency with Trial  Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or  Treatment Profile toxicology? |
| The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration  of the above elements. Record one of the following Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). Yes, there is a reasonable possibility of  There is evidence of exposure to Merck product. The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  Merck product relationship. The AE is more likely explained by Merck product than by another cause. No, there is not a reasonable possibility of  Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR  Merck product relationship the AE is more likely explained by another cause than the Merck product. (Also entered for a subject with overdose without an associated AE.) |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |