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5.8 retreatment

Patients will be eligible for retreatment with pembrolizumab and/or copanlisib after completion of the trial treatment IF they achieved a complete response during the treatment phase AND remained in a complete remission until completion of the trial phase (36 cycles) **AND** experience a documented relapse within one year after completion of the trial phase. Retreatment will have to be discussed with the sponsor and will at most be for another 18 cycles. Prior to retreatment the patient will have to fulfill all the initial eligibility criteria as outlined in Section 5.1 Entry Criteria.  
| 6.0 TRIAL FLOW CHART                     | Induction Phase   | Treatment Cycles A              | End  of  Treat ment   | Post-Treatment                |     |     |     |     |     |     |    |    |    |
|------------------------------------------|-------------------|---------------------------------|-----------------------|-------------------------------|-----|-----|-----|-----|-----|-----|----|----|----|
| (Day -21 to -1)                          |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Trial Period:                            | Screening Phase   | To be  repeated  after Cycle  8 | At  time  of  Disco n |                               |     |     |     |     |     |     |    |    |    |
| Main  Study  Screeni ng                  | 1                 | 2                               | 3                     | 4                             |     |     |     |     |     |     |    |    |    |
| Pre                                          |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| screenin g                               | Follow            |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| 5-8                                      | Up Visits         | Survival                        |                       |                               |     |     |     |     |     |     |    |    |    |
| B                                        | Follow-Up         |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Safety  Followup                                          |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Treatment Cycle/Title:                   | Day               | Day                             | Day                   | Every 12  weeks  post  discon |     |     |     |     |     |     |    |    |    |
| 30 days  post  discon                    |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| -21                                      | -14               | -7                              | D1                    | D8o                           | D8  |     |     |     |     |     |    |    |    |
| ± 3 D1                                   | D1                | D8                              | D1                    | D8                            | D1  | D8  |     |     |     |     |    |    |    |
| -50 to -                                 |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Scheduling Window (Days):                | 22                | ± 3                             | ± 3                   | ± 3                           | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 |    |    |    |
| Administrative Procedures                |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Informed Consent                         | X                 |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Inclusion/Exclusion Criteria             | X                 |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Demographics and Medical  History        | X                 |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Prior and Concomitant  Medication Review | X                 | X                               | X                     | X                             | X   | X   | X   |     |     |     |    |    |    |
| Pembrolizumab AdministrationQ            | X                 | X                               | X                     | X                             | X   |     |     |     |     |     |    |    |    |
| Copanlisib AdministrationM, Q            | X N               | X                               | X                     | X                             | X   | X   | X   | X   | X   | X   | X  | X  |    |
| Post-study anticancer therapy            | X                 | X                               |                       |                               |     |     |     |     |     |     |    |    |    |
| status Survival Status                   | X                 |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Clinical Procedures/Assessments          |                   |                                 |                       |                               |     |     |     |     |     |     |    |    |    |
| Review Adverse Events                    | X                 | X                               | X                     | X                             | X   | X   | X   | X   | X   | X   | X  | X  | X  |
| Full Physical Examination                | X                 | X                               | X                     | X                             | X   | X   | X   | X   | X   |     |    |    |    |
| Vital Signs I and Weight                 | X                 | X                               | X                     | X                             | X   | X   | X   | X   | X   | X   | X  | X  | X  |  
| 15-1020                                                                   | Page 42 of 94      |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
|---------------------------------------------------------------------------|--------------------|---------------------------------|-----------------------|-------------------------------|-----|-----|-----|-----|-----|-----|----|----|----|----|
| Induction Phase                                                           | Treatment Cycles A | End  of  Treat ment             | Post-Treatment        |                               |     |     |     |     |     |     |    |    |    |    |
| (Day -21 to -1)                                                           |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Trial Period:                                                             | Screening Phase    | To be  repeated  after Cycle  8 | At  time  of  Disco n |                               |     |     |     |     |     |     |    |    |    |    |
| Main  Study  Screeni ng                                                   | 1                  | 2                               | 3                     | 4                             |     |     |     |     |     |     |    |    |    |    |
| Pre                                                                           |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| screenin g                                                                | Follow             |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| 5-8                                                                       | Up Visits          | Survival                        |                       |                               |     |     |     |     |     |     |    |    |    |    |
| B                                                                         | Follow-Up          |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Safety  Followup                                                                           |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Treatment Cycle/Title:                                                    | Day                | Day                             | Day                   | Every 12  weeks  post  discon |     |     |     |     |     |     |    |    |    |    |
| 30 days  post  discon                                                     |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| -21                                                                       | -14                | -7                              | D1                    | D8o                           | D8  |     |     |     |     |     |    |    |    |    |
| ± 3 D1                                                                    | D1                 | D8                              | D1                    | D8                            | D1  | D8  |     |     |     |     |    |    |    |    |
| -50 to -                                                                  |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Scheduling Window (Days):                                                 | 22                 | ± 3                             | ± 3                   | ± 3                           | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 |    |    |    |    |
| Height                                                                    | X                  |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| ECOG Performance Status                                                   | X                  | X                               | X                     | X                             | X   | X   | X   | X   | X   |     |    |    |    |    |
| Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Pregnancy Test - Urine or Serum  B-HCG                                    | X H                |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| PT/INR and aPTT                                                           | X G                |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| CBC with Differential                                                     | X G                | X                               | X                     | X                             | X   | X   | X   | X   | X   | X   | X  | X  | X  | X  |
| Comprehensive Serum Chemistry                                             | X                  | X                               | X                     | X                             |     |     |     |     |     |     |    |    |    |    |
| Panel J                                                                   | X G                | X                               | X                     | X                             | X   | X   | X   | X   | X   | X   |    |    |    |    |
| LDH                                                                       | X G                | X                               | X                     | X                             | X   | X   | X   | X   | X   |     |    |    |    |    |
| Uric Acid                                                                 | X G                | X                               | X                     | X                             |     |     |     |     |     |     |    |    |    |    |
| Phophorus                                                                 | X G                | X                               | X                     | X                             |     |     |     |     |     |     |    |    |    |    |
| Magnesium                                                                 | X G                |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Urinalysis                                                                | X G                |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Lipase and amylase                                                        | X G                | X                               | X                     | X                             | X   | X   |     |     |     |     |    |    |    |    |
| T3, FT4 and TSH C                                                         | X G                | X                               | X                     | X                             | X   | X C | X   | X   |     |     |    |    |    |    |
| CMV monitoring P                                                          | X G                | X                               | X                     | X                             | X   | X   |     |     |     |     |    |    |    |    |
| Efficacy Measurements                                                     |                    |                                 |                       |                               |     |     |     |     |     |     |    |    |    |    |
| Tumor Imaging D,L                                                         | X                  | X D                             | X                     | X E                           |     |     |     |     |     |     |    |    |    |    |  
| 15-1020                                                             | Page 43 of 94      |                                 |                       |                               |     |        |     |     |     |     |
|---------------------------------------------------------------------|--------------------|---------------------------------|-----------------------|-------------------------------|-----|--------|-----|-----|-----|-----|
| Induction Phase                                                     | Treatment Cycles A | End  of  Treat ment             | Post-Treatment        |                               |     |        |     |     |     |     |
| (Day -21 to -1)                                                     |                    |                                 |                       |                               |     |        |     |     |     |     |
| Trial Period:                                                       | Screening Phase    | To be  repeated  after Cycle  8 | At  time  of  Disco n |                               |     |        |     |     |     |     |
| Main  Study  Screeni ng                                             | 1                  | 2                               | 3                     | 4                             |     |        |     |     |     |     |
| Pre                                                                     |                    |                                 |                       |                               |     |        |     |     |     |     |
| screenin g                                                          | Follow             |                                 |                       |                               |     |        |     |     |     |     |
| 5-8                                                                 | Up Visits          | Survival                        |                       |                               |     |        |     |     |     |     |
| B                                                                   | Follow-Up          |                                 |                       |                               |     |        |     |     |     |     |
| Safety  Followup                                                                     |                    |                                 |                       |                               |     |        |     |     |     |     |
| Treatment Cycle/Title:                                              | Day                | Day                             | Day                   | Every 12  weeks  post  discon |     |        |     |     |     |     |
| 30 days  post  discon                                               |                    |                                 |                       |                               |     |        |     |     |     |     |
| -21                                                                 | -14                | -7                              | D1                    | D8o                           | D8  |        |     |     |     |     |
| ± 3 D1                                                              | D1                 | D8                              | D1                    | D8                            | D1  | D8     |     |     |     |     |
| -50 to -                                                            |                    |                                 |                       |                               |     |        |     |     |     |     |
| Scheduling Window (Days):                                           | 22                 | ± 3                             | ± 3                   | ± 3                           | ± 3 | ± 3    | ± 3 | ± 3 | ± 3 | ± 3 |
| Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood |                    |                                 |                       |                               |     |        |     |     |     |     |
| Archival or Newly Obtained  Tissue Collection                       | X                  |                                 |                       |                               |     |        |     |     |     |     |
| Correlative Studies Blood                                           | X F, K             | X F                             | X F                   | X F                           | X K | X F, K | X K |     |     |     |
| Collection F, K A Total of 36 treatment cycles                      |                    |                                 |                       |                               |     |        |     |     |     |     |  
A Total of 36 treatment cycles B Patients should be assessed every 12 weeks (84 ± 7 days) for the first 2 years (or until disease progression) clinically for disease status - see section 7.1.5.4. Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy they move into survival follow-up C Check during treatment phase once every cycle.  
D Preferably FDG PET/CT at baseline, but if unavailable a contrast-enhanced CT scan is allowed. If PET CT is performed, the CT component must be of diagnostic quality. Subsequent imaging should be of the same modality as the imaging at baseline - see Sections 7.1.2.6 and 12.3. Once a patient achieved at PET-negative CR after completion of treatment, subsequent imaging can be a contrast-enhanced CT scan only. The first imaging during the treatment phase will be within 1 week prior to or on the day of starting treatment cycle 5; subsequent imaging will be every 12 weeks (± 3days) thereafter during the treatment phase (i.e. within 1 week prior to or on the day of starting treatment C9D1, C13D1, C17D1,…etc). Scan at the end of treatment should be performed within 14 days of the visit.  
E Radiologic imaging to monitor disease status will be performed every 12 weeks (84 ± 7 days) for the first 24 months (year 1&2 of follow-up), then every 26 weeks (182 ± 14 days) for the next year after completing therapy (year 3 of follow-up). After 3 years, patient will be followed clinically every 3-6 months with diagnostic imaging only as clinically indicated.  
F Peripheral blood samples will be collected immediately prior to the induction phase on day -21 (time 1); induction on day -7 (time 2); cycle 2 day 1, immediately prior to dose 2 (time 3); prior to dose 3, cycle 3 day 1
(time 4); prior to dose 5, cycle 5 day 1 (time 5); prior to dose 9, cycle 9 day 1 (time 6); and at time of progression (time 7) or end of treatment due to toxicity. Blood for correlative studies must be collected from MonThurs so that it can be processed immediately at Fox Chase Cancer Center. Also, blood for correlative must not be collected a day before a holiday. Blood must reach Fox Chase Cancer Center on a working day.  
G Within 10 days of treatment initiation H Within 72 hours of treatment initiation if participant is a woman of child bearing potential. After that as per institutional practice. I Vital signs consist of temperature, pulse, respiration, and blood pressure and will be monitored every 15 minutes during the pembrolizumab infusion and for 60 minutes after completion of each infusion. Copanlisib administration will have blood pressure measured through observation period.  
J A direct bilirubin must be performed if the total bilirubin is above the upper limit of normal. Serum chemistry includes test for albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, sodium, total protein, SGOT [AST], SGPT [ALT].  
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| Induction Phase           | Treatment Cycles A                                                                                                                                               | End  of  Treat ment             | Post-Treatment        |                               |     |     |     |     |     |     |
|---------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|-----------------------|-------------------------------|-----|-----|-----|-----|-----|-----|
| (Day -21 to -1)           |                                                                                                                                                                  |                                 |                       |                               |     |     |     |     |     |     |
| Trial Period:             | Screening Phase                                                                                                                                                  | To be  repeated  after Cycle  8 | At  time  of  Disco n |                               |     |     |     |     |     |     |
| Main  Study  Screeni ng   | 1                                                                                                                                                                | 2                               | 3                     | 4                             |     |     |     |     |     |     |
| Pre                           |                                                                                                                                                                  |                                 |                       |                               |     |     |     |     |     |     |
| screenin g                | Follow                                                                                                                                                           |                                 |                       |                               |     |     |     |     |     |     |
| 5-8                       | Up Visits                                                                                                                                                        | Survival                        |                       |                               |     |     |     |     |     |     |
| B                         | Follow-Up                                                                                                                                                        |                                 |                       |                               |     |     |     |     |     |     |
| Safety  Followup                           |                                                                                                                                                                  |                                 |                       |                               |     |     |     |     |     |     |
| Treatment Cycle/Title:    | Day                                                                                                                                                              | Day                             | Day                   | Every 12  weeks  post  discon |     |     |     |     |     |     |
| 30 days  post  discon     |                                                                                                                                                                  |                                 |                       |                               |     |     |     |     |     |     |
| -21                       | -14                                                                                                                                                              | -7                              | D1                    | D8o                           | D8  |     |     |     |     |     |
| ± 3 D1                    | D1                                                                                                                                                               | D8                              | D1                    | D8                            | D1  | D8  |     |     |     |     |
| -50 to -                  |                                                                                                                                                                  |                                 |                       |                               |     |     |     |     |     |     |
| Scheduling Window (Days): | 22                                                                                                                                                               | ± 3                             | ± 3                   | ± 3                           | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 | ± 3 |
| K                         | Cell free DNA/ImmunoSeq TCR at baseline and every 12 weeks for 2 yrs then every 6 months for 1 yr and at time of progression or end of treatment due to toxicity |                                 |                       |                               |     |     |     |     |     |     |  
L For patients undergoing PET/CT, response will also be assessed using the 5-point scale (Deauville criteria).2 Refer to section 13 for measurements of effect.  
M Blood glucose levels and Blood pressure measurement (not more than 4 per visit) must be done before copanlisib administration on day -21 and day -14 and conditions as described in section 5.2.2.2 must be met for drug administration during the induction phase alone. During copanlisib administration, blood pressure should be measured at 30 min (during infusion), and 60 min (end of infusion) from start of the infusion, 1 hr and 2 hr (after the infusion).  
N. Patients in cohort 2 who will receive copanlisib must be fasting for at least 8 hours before the drug administration on Day -21 of the induction phase. Blood glucose level should be monitored and copanlisib may not be given if blood glucose level is higher than 160 mg/dl. Follow guidelines as described in section 5.2.2.2 for copanlisib administration.  
O. Day 8 treatment of each cycle with copanlisib may not take place (see section 4.2.3.1) if RP2D is dose level -1. If Day 8 treatment does not take place all visit related activities on day 8 will also not happen. P. Before starting copanlisib, all patients should have CMV status assessed. For seropositive patients, CMV quantitative polymerase chain reaction (PCR) testing with every cycle. Interrupt Copanlisib in patients with evidence of active CMV infection of any grade or viremia until the viremia has resolved. Ganciclovir or valganciclovir should be preemptively initiated in patients with positive CMV PCR and symptoms consistent with CMV infection, patients presenting with fever and no clear source in whom quantitative CMV testing is unavailable, and asymptomatic patients with increasing viral load. Patients can continue with pembrolizumab while copanlisib is being held.  
Q In cohort 2, on the days when patients receive both the drugs, sequence of administration must be copanlisib, followed by pembrolizumab.
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7.0 trial procedures 7.1 trial

The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit. Individual trial procedures are described in detail below. It may be necessary to perform these procedures at unscheduled time points if deemed clinically necessary by the investigator. Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or Merck, Bayer for reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed consent be obtained from the subject. In these cases, such evaluations/testing will be performed in accordance with those regulations.
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7.1.1 administrative procedures 7.1.1.1 informed

The Investigator must obtain documented consent from each potential subject prior to participating in a clinical trial.
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7.1.1.1.1 general informed consent

Consent must be documented by the subject's dated signature or by the subject's legally acceptable representative's dated signature on a consent form along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent form should be given to the subject before participation in the trial. The initial informed consent form, any subsequent revised written informed consent form and any written information provided to the subject must receive the IRB's approval/favorable opinion in advance of use. The subject or his/her legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the trial. The communication of this information will be provided and documented via a revised consent form or addendum to the original consent form that captures the subject's dated signature or by the subject's legally acceptable representative's dated signature. Specifics about a trial and the trial population will be added to the consent form template at the protocol level. The informed consent will adhere to IRB requirements, applicable laws and regulations and Sponsor requirements.
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7.1.1.2 inclusion/exclusion criteria

All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the trial.
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7.1.1.3 medical history

A medical history will be obtained by the investigator or qualified designee. Medical history will include all active conditions, and any condition diagnosed within the prior 10 years that are considered to be clinically significant by the Investigator. Details regarding the disease for which the subject has enrolled in this study will be recorded separately and not listed as medical history.
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7.1.1.4 prior and concomitant medications

The investigator or qualified designee will review prior medication use, including any protocol-specified washout requirement, and record prior medication taken by the subject within 28 days before starting the trial. Treatment for the disease for which the subject has enrolled in this study will be recorded separately and not listed as a prior medication.
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7.1.1.4.2 concomitant medications

The investigator or qualified designee will record medication, if any, taken by the subject during the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in Section 8.0.
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7.1.1.5 disease details and treatments

The investigator or qualified designee will obtain prior and current details regarding disease status.
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7.1.1.5.2 prior treatment details

The investigator or qualified designee will review all prior cancer treatments including systemic treatments, radiation and surgeries.
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7.1.1.5.3 subsequent anti-cancer therapy status

The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.
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7.1.2 clinical procedures/assessments 7.1.2.1 adverse

The investigator or qualified designee will assess each subject to evaluate for potential new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to NCI CTCAE Version 5.0 (see Section 14.2). Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment. All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology (irAE). See Section 5.4 regarding the identification, evaluation and management of AEs of a potential immunological etiology. Please refer to section 8.0 for detailed information regarding the assessment and recording of AEs.
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7.1.2.2 full physical exam

The investigator or qualified designee will perform a complete physical exam during the screening period. Clinically significant abnormal findings should be recorded as medical history. A full physical exam will also be performed every 3 cycles during the treatment phase, 30 days post treatment, and every 3 months during follow-up.
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7.1.2.3 directed physical exam

For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or qualified designee will perform a directed physical exam as clinically indicated prior to trial treatment administration.
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7.1.2.4 vital signs

The investigator or qualified designee will take vital signs at screening, prior to the administration of each dose of trial treatment and at treatment discontinuation as specified in the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at screening only.
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7.1.2.5 eastern cooperative oncology group

The investigator or qualified designee will assess ECOG status (see Section 14.1) at screening, prior to the administration of each dose of trial treatment and discontinuation of trial treatment as specified in the Trial Flow Chart. After Cycle 8 assessment of ECOG status will be performed every other cycle in conjunction with the directed or full physical exam.
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7.1.2.6 tumor imaging and assessment

Scans will be performed at baseline, and thereafter every 12 weeks (± 3 days) while on treatment. Imaging during follow up is outlined in section 7.1.5.4. It is critical that all FDG PET/CT or CT scans be performed in an identical way to the baseline scan with the same scan direction and consistent arm pointing. The interval between FDG injection and initiation of emission scanning should be the same or similar to the baseline scan. If tumor flare is suspected, the patient must undergo a second scan within a month of the first scan and the case must be discussed with the principle investigator. If progression is documented at that time, patient must come off study. A scan should be performed within 14 days of the end of treatment visit.
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7.1.2.7 tumor tissue collection and

For details in regards to tumor tissue collection please see Section 7.1.3.1.2 Tumor tissue collection for central pathology review and correlative studies and the trial lab manual.  
Peripheral blood samples will be collected immediately prior to the first dose of pembrolizumab (time 1), at cycle 2 (immediately prior to dose 2; time 2) and cycle 3 (immediately prior to dose 3; time 3) and at time of progression (time 4) for correlative studies as outlined in Section 6.0 Trial Flow Chart. In evaluating the effect of the treatment on altering immunity, quantity of main interest is the change in the percentage of activated T cells and Natural Killer cells from Time 1 to Time 2, and from Time 2 or Time 3 to Time 4. The results of these studies are for the purposes of the trial only and will not be returned to the site or reported to the patient. Processing of blood samples will occur at FCCC as outlined in the Lab Manual. Blood samples will be shipped to Protocol Support Laboratory (PSL) at Fox Chase. Samples will be distributed from the PSL at Fox Chase to Kerry Campbell's lab. Remaining cells will be stored in the PSL.
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7.1.3 laboratory procedures/assessments

Details regarding specific laboratory procedures/assessments to be performed in this trial are provided below.
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7.1.3.1 laboratory safety evaluations (hematology

Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5. Laboratory tests for screening should be performed within 10 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of trial treatment.
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7.1.3.1 biomarker evaluations 7.1.3.1.1 blood

Sample collection, processing, storage, and shipment instructions for samples will be provided in the trial Lab Manual. The time points for blood sampling for correlative studies are described in Section 6.0 - Trial Flow Chart.  
| Table 5 Laboratory Tests Hematology                                                                                | Chemistry                      | Urinalysis           | Other                                  |
|--------------------------------------------------------------------------------------------------------------------|--------------------------------|----------------------|----------------------------------------|
| Hematocrit                                                                                                         | Albumin                        | Blood                | Serum β-human chorionic  gonadotropin† |
| Hemoglobin                                                                                                         | Alkaline phosphatase           | Glucose              | (β-hCG)†                               |
| Platelet count                                                                                                     | Alanine aminotransferase (ALT) | Protein              | PT (INR)                               |
| WBC (total and differential)                                                                                       | Aspartate aminotransferase     | Specific gravity     | aPTT                                   |
| (AST)                                                                                                              |                                |                      |                                        |
| Red Blood Cell Count                                                                                               | Lactate dehydrogenase (LDH)    | Microscopic exam (If | Total thriiodothyronine (T3)           |
| abnormal)                                                                                                          |                                |                      |                                        |
| Absolute Neutrophil Count                                                                                          | Carbon Dioxide                 | results are noted    | Free tyroxine (T4)                     |
| Confidential Limited Access                                                                                        |                                |                      |                                        |
| Copyright© 2018 Fox Chase Cancer Center® Office of Clinical Research. All rights reserved. Version Date 01/13/2020 |                                |                      |                                        |  
| 15-1020                                                                                                                                                                              | Page 49 of 94                 |                                    |       |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------|------------------------------------|-------|
| Hematology                                                                                                                                                                           | Chemistry                     | Urinalysis                         | Other |
| (CO2 or biocarbonate)                                                                                                                                                                | Urine pregnancy test †        | Thyroid stimulating hormone  (TSH) |       |
| Uric Acid Calcium Chloride                                                                                                                                                           | Blood for correlative studies |                                    |       |
| Glucose Phosphorus Potassium  Sodium Magnesium Total Bilirubin Direct Bilirubin (If total bilirubin  is elevated above the upper limit  of normal) Total protein Blood Urea Nitrogen |                               |                                    |       |
| † Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum  pregnancy test will be required.                             |                               |                                    |       |
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7.1.3.1.2 tumor tissue collection for

Pathology samples from the confirmatory relapse biopsies taken within 28 days of enrollment are to be submitted within one (1) month following registration or collection. Representative FFPE tumor tissue blocks from confirmatory relapse specimen (MANDATORY) are to be submitted to the Fox Chase Cancer Center PSL in addition to any available specimens and reports from the original tumor biopsy at diagnosis. The following pathology material needs to be submitted:
Paraffin embedded biopsy or cell block, and Any available pathology report related to that tumor sample, including flow cytometry, genetic and molecular reports.  
NOTE: If a block is unavailable for submission, slides are to be submitted. All slides must be adequately labeled, with slides numbered sequentially in the order cut. Alternative submission requirement:
One (1) H&E slide, and Fifteen (15) 4 μm unstained air-dried on plus slides.  
Original diagnostic material (from initial diagnostic material) will also be reviewed at Fox Chase if available. These include:
Pathology reports of the initial **tumor biopsy at diagnosis**, including flow cytometry reports, cytogenetic and molecular reports, and Any available H&E and IHC slides of the initial tumor biopsy at diagnosis.  
NOTE: Original material will be sent back to the referring institution.  
Shipment of pathology samples is outlined in the lab manual for this trial.
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7.1.4 other procedures 7.1.4.1 withdrawal/discontinuation

When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled for the final trial visit should be performed at the time of discontinuation. Any adverse events, which are present at the time of discontinuation/withdrawal, should be followed in accordance with the safety requirements outlined in Section 8.0 - Assessing and Recording Adverse Events. Subjects who a) attain a CR or b) complete 36 cycles of treatment with pembrolizumab may discontinue treatment with the option of restarting treatment if they meet the criteria specified in Section 5.1. After discontinuing treatment following assessment of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4).
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7.1.5 visit requirements

Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
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7.1.5.1 screening 7.1.5.1.1 screening period

Subjects will be screened within 28 prior to protocol treatment. Study procedures and information regarding the nature of the study will be reviewed with potential subjects and written informed consent will be obtained prior to any study related procedures. Screening procedures are described in Section 6.0 - Trial Flow Chart.
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7.1.5.2 treatment period

Subjects will be treated every 3 weeks of pembrolizumab for up to 36 cycles. During the treatment phase patients will be evaluated prior to any treatment dose of pembrolizumab for toxicities and every 3 months for disease progression as outlined in detail in Section 6.0 - Trial Flow Chart.
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7.1.5.3 post-treatment visits 7.1.5.3.1 safety

The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with a study drug attributable AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first. Events of Clinical Interest that occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should also be followed and recorded.
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7.1.5.4 follow-up visits

Subjects who discontinue trial treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) for the first 2 years clinically for disease progression. Radiologic imaging (see Section 14.3 Measurement of Effect) to monitor disease status will be performed every 12 weeks (84 ± 7 days) for the first 24 months (year 1 & 2 of follow-up), then every 26 weeks (182 ± 14 days) for the next year after completing therapy (year 3 of follow-up). After 3 years patient will be followed clinically every 3-6 months with diagnostic imaging only as clinically indicated. Every effort should be made to collect information regarding disease status until the start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 5.8. Information regarding post-study antineoplastic treatment will be collected if new treatment is initiated.
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7.1.5.4.1 survival follow-up

Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase. Survival follow-up will take place approximately every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. This contact can be done by telephone, medical record search, office visit, etc. After 3 years of follow-up this contact can go to every 6 month.
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8.0 assessing and recording adverse

Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, treatment or procedure regardless of whether it is considered related to the medical treatment or procedure *(NCI CTEP Guidelines March 28, 2011)*
Serious Adverse Event (SAE) is an AE that results in the following outcomes-
Death Life threatening adverse event Requires inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours),
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, Congenital anomaly/ birth defect.  
A "life**-threatening**" adverse event places the patient at immediate risk of death in the judgment of the investigator or sponsor.  
NOTE: Important medical event that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, may jeopardize the subject and may require medical or surgical intervention to prevent any of the above outcomes.
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8.1 severity rating

The investigator will evaluate the severity of each adverse event. NCI Common Terminology Criteria for Adverse Events (CTCAE v.5.0) or study specific toxicity tables provided in the protocol define severity. If not included in CTCAE v.5.0, severity is expressed in numerical grade using the following definitions:
Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.  
Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL.  
Grade 3: Severe-severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.  
Grade 4: Life-threatening consequences; urgent intervention indicated. Grade 5: Death related to AE
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8.2 attribution/relationship to study drug

Definite - clearly related Probable - likely related Possible - may be related Unlikely - doubtfully related Unrelated - clearly not related
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8.3 expectedness

An Expected Adverse Event is one where the specificity or severity is consistent with the current information available from the resources. An Unexpected Adverse Event is one where the nature, severity, or frequency of the event is related to participation in the research is not consistent with either:
1. The known or foreseeable risk of adverse events associated with the procedures involved in the research that are described in (a) the protocol-related documents, such as the IRB-approved research protocol, any applicable investigator brochure, and the current IRB-approved informed consent document, and (b) other relevant sources of information, such as product labeling and package inserts: or 2. The expected natural progression of any underlying disease, disorder, or condition of the subject (s) experiencing the adverse event and the subjects(s) predisposing risk factor profile for the adverse event.  
(OHRP Guidance on reviewing unanticipated problems 2007)
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9.0 recording and reporting responsibilities

1. Upon identification of an AE or SAE, the site investigator will utilize the above definitions to properly classify attribution and expectedness of the event. These must be recorded for each event.
2. All AEs and SAEs will be recorded in the "AE case report forms" (CRF) and in progress reports with details about the grade and attribution of each episode, action taken with respect to the study drug, and the patient's outcome will be recorded in the CRF. All events will be recorded on case report forms for the duration of the study until they resolve.  
3. All SAEs will be recorded on the FDA MedWatch form 3500a. The attribution and expectedness must be recorded on the MedWatch form. If this information is not available at the time of initial reporting, a final report must be documented with attribution and expectedness. It may be necessary to submit follow up reports to the Sponsor should the event require further investigation. All subsequent SAEs must be recorded for up to 30 days after the last treatment.  
4. All patient data must be recorded in eCRFs by the investigative site within 7 days of the patient's visit. eCRFs will be available through Oncore electronic data capture system.
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9.1.2 investigative site reporting responsibilities

1. The investigator/ site is responsible to report all SAEs that occur on or after the first day of study treatment to the sponsor within 24 hours of becoming aware of the event. It may be necessary to submit a final SAE report if the initial report did not have the complete information. All subsequent SAEs must be recorded for up to 30 days after the last treatment. Each investigator is responsible to report all AEs/SAEs to their local IRB following guidelines set by that IRB. The FCCC OCR reserves the right to request an event be reported to the IRB at their discretion. Copies of events reviewed by the IRB must be sent by email to **SAE.FCCC@fccc.edu.**
2. If the investigator or IRB feels the event warrants a revision to the informed consent that was not already initiated by the ISRU, draft revisions will be made in track changes and submitted to the ISRU for consideration. Any consent revisions must receive ISRU approval **prior** to submission to the IRB.  
3. Any investigator who is in doubt of whether a particular AE needs to be reported is directed to call the Study Monitor for confirmation with the Sponsor-Investigator
4. If the results of an investigator or ISRU investigation show an adverse event not initially determined to be reportable is so reportable (to IRB or FDA), the investigator will report the event following the above guidelines based on the date the determination is made.  
5. Investigative site should report Reportable New Information (RNI) to their local IRB
according to the local IRB guidelines. This information should also be sent to ISRU. At minimum serious unexpected events that are associated with the treatment are considered to be reportable. Expected AEs that are experienced at a higher frequency or severity than expected in the patient population according to the investigator brochure are considered to be reportable.  
6. Copies of all related correspondence and reporting documents must be submitted to the ISRU and will be maintained in the trial master file.
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participating sites should report events

Investigator-Sponsored Research Unit Office of Clinical Research Fox Chase Cancer Center SAE.FCCC@fccc.edu
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9.1.3 sponsor reporting responsibilities

Adverse events which meet **all of the following criteria** must be reported to all participating institutions for IRB submission within 2 weeks of notification of the event.  
Unexpected (in terms of nature, severity, or frequency) given i. (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and ii. (b) the characteristics of the subject population being studied; Possibly related to participation in the research (possibly related means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and Serious (refer to above definition) or otherwise one that suggests that the research places subjects or others at a greater risk of physical or psychological harm than was previously known or recognized.  
If the adverse event requires modification of the study protocol and informed consent, these changes will be provided to all participating institutions in the form of an amendment from the ISRU for each site's IRB of record along with the report of the adverse event.  
All participating sites must be notified of all amendments approved by FCCC IRB; or if the study is suspended such that the participating sites cannot accrue patients in the study until further notification.  
All participating sites must be notified when the study is closed by IRB.  
Copies of all related correspondence and reporting documents will be maintained in a centralized regulatory file for this study at ISRU.  
SAEs that are fatal or life threatening are reportable through the Food and Drug Administration (FDA) MedWatch program by telephone or fax no later than 7 calendar days after initial receipt of the information. Further information on the timing of submissions are as directed by FDA guidelines can be found in the following link: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedan dApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm362555 .htm. SAEs that are serious, unexpected and at least possibly related to the study drug (**unexpected suspected adverse events**) or events that suggest significant clinical risk will be submitted to FDA within 15 calendar days after initial receipt of this information. The 15 day report has to be submitted by in paper format (or electronic submission if that is available) to the IND as described in the "safe to proceed" letter. The FAX number for reporting SAE to FDA (7-day reporting) can be found in the FDA "Study may proceed" letter. The SAE report can also be submitted by email to the Regulatory Project Manager and/or the Chief, Project Management Staff described in the "Study May Proceed" letter.  
As soon as there is reasonable suspicion of the following AE, the investigator should immediately notify Bayer (within 24 hours) regardless of whether the event is assessed as causally related/not related to the study drug, or as serious/non-serious. The AESI should be entered on a Medwatch form and if the event is assessed as non-serious, the non-serious assessment should be noted in the form.  
Non-infectious pneumonitis (NIP)
The following should be reported within 24 hours after the initial receipt of information to BAYER by fax and/or e-mail: (973) 709-2185; DrugSafety.GPV.US@bayer.com Reportable New Information (RNI) to IRB according to the IRB guidelines. This information should also be sent to all participating sites if associated with safety concern. At minimum serious unexpected events that are associated with the treatment are considered to be reportable. Expected AEs that are experienced at a higher frequency or severity than expected in the patient population according to the investigator brochure are considered to be reportable.  
All SAEs and reports of overdose with and without an adverse event will be reported to Merck Global Safety within 2 working days of receipt. (Attn: Worldwide Product Safety; FAX 215 993-1220)
A copy of all Annual Progress Reports submitted as required by FDA and nonserious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in the same manner as SAEs.  
All Serious Adverse Events occurring after start of administration of BAYER
product, independent of their causal relationship to the STUDY DRUG
Any other relevant safety information including but not limited to:
i. reports of drug exposure via mother / father with and without adverse events (exposure during conception, pregnancy, childbirth and breastfeeding) including their outcome; ii. if linked to a serious adverse event, reports of misuse, abuse, overdose, medication error and other uses outside what is foreseen in the protocol, drug dependency, occupational exposure suspected transmission of an infectious agent, withdrawal syndrome, drug interactions with respect to the STUDY DRUG;
and Any communication concerning safety related information to regulatory authorities or ethics committees including but not limited to:  
Development Safety Update Reports / relevant parts of IND reports for the STUDY;
Any other safety related reports, issues and queries that are either raised by or communicated to regulatory authorities or ethics committees (e.g., reportable non-serious cases);
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9.2 definition of an overdose

For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed dose for pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab should be discontinued and 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 non-serious Event of Clinical Interest (ECI), using the terminology "accidental or intentional overdose without adverse effect."
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9.3 events of clinical interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 24 hours to the Sponsor, who will report this information within 2 working days to Merck Global Safety. Events of clinical interest for this trial include: 1. An overdose of Merck product, as defined in Section 9.2, that is not associated with clinical symptoms or abnormal laboratory results. 2. 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. 3. In the event a subject develops any of the following AEs, a detailed narrative of the event should be reported as an ECI to the Sponsor within 24 hours, who will report this information within 2 working days to Merck Global Safety:
a. Grade ≥ 3 diarrhea b. Grade ≥ 3 colitis c. Grade ≥ 2 pneumonitis d. Grade ≥ 3 hypo- or hyperthyroidism A comprehensive list of ECI is also provided in the appendix (Appendix 13.4 - Events of Clinical Interest (ECI) guidance). This appendix provides guidance regarding identification, evaluation and management of ECIs and irAEs. Additional ECIs are identified in this guidance document and also need to be reported to the Sponsor within 24 hours, who will report this information within 2 working days to Merck Global Safety. Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and subjects should be asked for signs and symptoms suggestive of an immune-related event. Subjects who develop an ECI thought to be immune-related should have additional testing to rule out other etiologic causes. If lab results or symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out other etiologic causes. If no other cause is found, then it is assumed to be immune-related. ECIs that occur in any subject from the date of first dose through 90 days following cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to the Merck's product, must be reported within 24 hours to the Sponsor, who will report this information within 2 working days to Merck Global Safety.
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9.4 reporting of pregnancy and

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 or within 120 days of completing the trial completing the trial, or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported to Merck and Bayer.
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10.0statistical analysis plan 10.1 statistical

The primary endpoint is based on the median progression free survival (PFS). Estimates are based on historical controls from published data.31,33,34,78 We will test the null hypothesis that median PFS is at most 3 months versus the alternative that it is at least 6 months. We will use a two-stage design with early stopping rules79 and enroll an initial cohort of 13 patients. We will terminate the study for futility unless more than 6 patients are progression-free (as defined alive and achieving SD, PR or CR as per revised Cheson response criteria) at 3 months. Otherwise we will recruit an additional 11 patients and evaluate these 11 plus all eligible patients from the initial cohort (n=13) who were progression-free at 3 months at 6 months. If at least 10 out of 24 patients have not progressed at 6 months we will reject the null hypothesis. Only those patients who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for response. (Note: Patients who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.) Patients who are not evaluable for response will be replaced. However, all patients who received at least 1 dose of the study drug will be included in the safety analysis. The study has 80% power and 4.7% type I error. The chance of early stopping, after 13 patients, is 50% under the null and 5.5% in error.
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early stopping rules for safety/adverse

Adverse events will be assessed continuously throughout the study. If ever during evaluation of the first cohort of 13 eligible patients, 3 patients have to discontinue study treatment due to treatment related adverse events the study will be interrupted for consideration of dose reduction or termination. If ever 4 of the 24 eligible patients have to discontinue study treatment due to treatment related adverse events the study will be suspended and early termination for excess toxicity will be considered after careful investigation of the causes of the higher than expected toxicities. Once the root of the higher than anticipated toxicities has been determined, the study team will confer with the FCCC DSMC and IRB to make a determination whether accrual can be resumed or the study will be terminated early. The chance of early termination with a true toxicity of 25% is 67%. The chance of early termination when true toxicity is 5% is 2.5%. The overall chance of study termination under the null of 5% true toxicity is 4.2% and is 89% if true toxicity is 25%. Correlative studies: Due to this limited sample size, all exploratory analyses of associations of biomarkers with outcomes and changes in marker levels pre- and during treatment will be largely descriptive in nature. Multiple imputation will be used to account for missing data in order to provide an unbiased estimate.
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10.2 statistical analyses plan (cohort

There will be a phase 1 part (cohort 2a), during which the recommended phase 2 dose (RPTD) of the combination of pembrolizumab and copanlisib will be determined, followed by a phase 2 portion (cohort 2b), which will explore safety and efficacy of the combination. The phase 1 portion will follow a standard '3+3' escalation/de-escalation design as outlined above. A minimum of 4 and a maximum of 12 patients will be included in the phase 1 portion. For the phase 2 portion, an optimal Simon's two-stage design will be used. The null hypothesis that the true response rate is 30% will be tested against the alternative hypothesis of a true response rate ≥60%. Response is defined as either a partial or complete response by Revised Cheson criteria (see 13.3) by 4 cycles of treatment. All eligible and evaluable patients who received at least 1 dose of the combination regimen will be included in this response analysis. Patients who come off study prior to second clinic visit for reasons other than progressive disease will be replaced. Patients who are lost to follow-up after re-evaluation will be counted as failures and will not be replaced. For the first stage, 8 patients will be treated at the RPTD of the combination. If at least 4 patients achieve a response, we will accrue 16 more for a total of 24 patients treated at the RPTD (including those patients treated during the phase 1 portion at the RPTD). If of the first 8 patients, 3 or less respond, the trial will be stopped. The null hypothesis will be rejected if 11 or more responses are observed in 24 patients and the combination deemed worthy of further consideration. This design yields a power of 80% with a type I error of 5% when the true response rate is ≥60% ORR. The probability of early stopping under the null hypothesis is 80%. Early stopping rules for safety/adverse events: A discontinuation rate for toxicities related to study treatment of ≤30% will be deemed acceptable, while a ≥50% discontinuation rate for toxicities related to study treatment will be considered unacceptable. An interim analysis will be conducted when 8 patients have accrued to determine safety by the Principal Investigator and the statistician. If ≥4 of the initial 8 treated patients at the RPTD discontinue due to study related toxicities, the study will be stopped for safety. If after 24 patients have been enrolled, or at any time point during the study with treatment at the RPTD, 11 or more patients discontinue due to study related toxicities, the study will also be stopped for safety. With this design, the probability of stopping early with a ≥50% true toxicity rate is 64%, and 19% if the true toxicity is ≤30%. The probability of stopping at any point due to a ≥50% true toxicity rate is 82%, while it is ≤22% if the true toxicity is 30%. Accrual: The expected monthly accrual rate is 1-2 patients. Thus, accrual is anticipated to take approximately 2.5 years.
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11.0 labeling packaging storage and

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 protocol and any applicable laws and regulations. Pembrolizumab will be provided by Merck and copanlisib will be provided by Bayer as summarized in Table 6. Table 6 Product Descriptions  
| Product Name & Potency     | Dosage Form            |
|----------------------------|------------------------|
| Pembrolizumab 100 mg/ 4 mL | Solution for Injection |
| Copanlisib 60 mg/vial      | Solution for Injection |
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11.2 packaging and labeling information

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.
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11.3 clinical supplies disclosure

This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or lists are not provided.
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11.4 storage and handling requirements

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label.  
Receipt and dispensing of trial medication 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.
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11.5 returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck, Bayer or designee, the amount dispensed to and returned by the subjects 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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12.0 administrative regulatory data monitoring

FCCC ISRU will monitor the medical and study records of each participant accrued throughout the course of the study. In addition, the ISRU will collect and report data to the study Sponsor Investigator who will review these data on a regular basis at a rate dependent on subject accrual. All serious adverse events (SAEs) will be reviewed on a real time basis first by the study site PI and subsequently by the ISRU and Sponsor Investigator as applicable.
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12.2 data safety monitoring committee

Interim analysis of toxicity, outcome and ongoing scientific investigations will be performed at least every 3 months by the Fox Chase Cancer Center Data Safety Monitoring Committee (FCCCDSMC). In this capacity the FCCCDSMC will serve as an advisory committee to the OCR. The FCCCDSMC will review those aspects of this trial that are outlined in the responsibilities section of the Data and Safety Monitoring Plan (DSMP). If the committee decides that changes should be made to this trial, it will make recommendations in writing to the Study Principal Investigator, the Associate Director of Clinical Research, and the Protocol Management Executive Committee, which, in turn, have the authority to approve or disapprove these recommendations. These changes will be discussed with the Study Principal Investigator before they are implemented. These changes may include early termination of accrual. Other changes might include altering the accrual goals or changing the eligibility criteria for the trial.
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12.3 compliance with law audit

This study will be conducted in accordance will local, state and Federal regulations and according to accepted good clinical practice guidelines.
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12.4 compliance with trial registration

Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for determining whether the trial and its results are subject to the requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate trial locations and trial site contact information.
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12.5 retention of records

Time points for the retention of records are described in detail in the contract between the grantor and the CTO and passed on to the participating site. Please refer to the study specific terms for specific time points. In all cases the QA Specialist / Study Monitor must be notified of any plans to move records to an offsite location prior to doing so.
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12.6 study agents

Any study agent supplied through the CTO from the manufacturer or a third party distributor may not be used for any purpose outside the scope of this protocol. The agent may not be transferred to any party not participating in the clinical trial.
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12.7 informed consent

The IRB approved informed consent documents must be signed by the patient, or the patient's legally authorized representative, before his or her participation in the study. The case history for each patient shall document that informed consent was obtained prior to participation in the study. A copy of the informed consent documents must be provided to the patient or the patient's legally authorized representative. If applicable, they will be provided in a certified translation of the local language. Original signed consent forms must be filed in each patient's study file or medical record with a copy in the study file.
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12.8 data reporting

The FCCC Study Monitor will request case report forms to be completed within 2 weeks of the protocol visit. Participating sites are responsible to respond to queries prior to the next scheduled monitoring visit. The ISRU staff is responsible for compiling and submitting data to the Sponsor Investigator and statistician on an ongoing basis for monitoring as described in the data safety monitoring plan and reporting to the Data and Safety Monitoring Committee. All patient information will be stored in an EDC system accessible only to the study team members for the purpose of entering, reviewing and analyzing data. Any paper records, such as case report files, produced will be stored in a secure location.
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13.0 list of references

1. Cheson BD, Pfistner B, Juweid ME, et al: Revised Response Criteria for Malignant Lymphoma. Journal of Clinical Oncology 25:579-586, 2007 2. Barrington SF, Mikhaeel NG, Kostakoglu L, et al: Role of Imaging in the Staging and Response Assessment of Lymphoma: Consensus of the International Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol, 2014 3. Disis ML: Immune regulation of cancer. J Clin Oncol 28:4531-8, 2010 4. Dong H, Strome SE, Salomao DR, et al: Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793-800, 2002 5. Sharpe AH, Freeman GJ: The B7-CD28 superfamily. Nat Rev Immunol 2:116-26, 2002 6. Brown JA, Dorfman DM, Ma FR, et al: Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170:1257-66, 2003 7. Francisco LM, Sage PT, Sharpe AH: The PD-1 pathway in tolerance and autoimmunity.  
Immunol Rev 236:219-42, 2010 8. Thompson RH, Dong H, Lohse CM, et al: PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 13:175761, 2007 9. Talmadge JE, Donkor M, Scholar E: Inflammatory cell infiltration of tumors: Jekyll or Hyde. Cancer Metastasis Rev 26:373-400, 2007 10. Usubutun A, Ayhan A, Uygur MC, et al: Prognostic factors in renal cell carcinoma. J Exp Clin Cancer Res 17:77-81, 1998 11. Al-Shibli KI, Donnem T, Al-Saad S, et al: Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 14:5220-7, 2008 12. Deschoolmeester V, Baay M, Van Marck E, et al: Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC Immunol 11:19, 2010 13. Diez M, Pollan M, Enriquez JM, et al: Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 18:689-94, 1998 14. 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Lee HE, Chae SW, Lee YJ, et al: Prognostic implications of type and density of tumourinfiltrating lymphocytes in gastric cancer. Br J Cancer 99:1704-11, 2008 21. Leffers N, Gooden MJ, de Jong RA, et al: Prognostic significance of tumor-infiltrating Tlymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 58:449-59, 2009 64 of 94 22. Nishimura H, Honjo T, Minato N: Facilitation of beta selection and modification of positive selection in the thymus of PD-1-deficient mice. J Exp Med 191:891-8, 2000 23. Liotta F, Gacci M, Frosali F, et al: Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int 107:1500-6, 2011 24. Morton LM, Wang SS, Devesa SS, et al: Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 107:265-76, 2006 25. A clinical evaluation of the International Lymphoma Study Group classification of nonHodgkin's lymphoma. The Non-Hodgkin's Lymphoma Classification Project. Blood 89:3909-18, 1997 26. Rizvi MA, Evens AM, Tallman MS, et al: T-cell non-Hodgkin lymphoma. Blood 107:1255-64, 2006 27. Abouyabis AN, Shenoy PJ, Lechowicz MJ, et al: Incidence and outcomes of the peripheral T-cell lymphoma subtypes in the United States. Leuk Lymphoma 49:2099-107, 2008 28. Swerdlow SH, Campo E, Harris NL, et al: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer: Lyon, 2008., 2008 29. Turner JJ, Morton LM, Linet MS, et al: InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood 116:e90-8, 2010 30. Savage KJ, Chhanabhai M, Gascoyne RD, et al: Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 15:1467-75, 2004 31. Mak V, Hamm J, Chhanabhai M, et al: Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol 31:1970-6, 2013 32. Kewalramani T, Zelenetz AD, Teruya-Feldstein J, et al: Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma. Br J Haematol 134:202-7, 2006 33. O'Connor OA, Pro B, Pinter-Brown L, et al: Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study. Journal of Clinical Oncology 29:1182-1189, 2011 34. Coiffier B, Pro B, Prince HM, et al: Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy. Journal of Clinical Oncology 30:631-636, 2012 35. Chen BJ, Chapuy B, Ouyang J, et al: PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies. Clin Cancer Res 19:3462-73, 2013 36. Kozako T, Yoshimitsu M, Fujiwara H, et al: PD-1/PD-L1 expression in human T-cell leukemia virus type 1 carriers and adult T-cell leukemia/lymphoma patients. Leukemia 23:375-82, 2009 37. Andorsky DJ, Yamada RE, Said J, et al: Programmed death ligand 1 is expressed by nonhodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res 17:4232-44, 2011 38. Munir S, Andersen GH, Woetmann A, et al: Cutaneous T cell lymphoma cells are targets for immune checkpoint ligand PD-L1-specific, cytotoxic T cells. Leukemia 27:2251-3, 2013 39. Prochazka V, Novak M, Pikalova Z, et al: Number of PD-1+/CD8+ Cells in Peripheral Blood of Patients with Lymphoma Reflects Tumor Burden, Lymphoma Subtype, Disease Phase and Is Significantly Higher Compared to Healthy Volunteers. ASH Annual Meeting Abstracts 120:2670-, 2012 65 of 94 40. Goldberg JD, Chou JF, Horwitz S, et al: Long-term survival in patients with peripheral Tcell non-Hodgkin lymphomas after allogeneic hematopoietic stem cell transplant. Leuk Lymphoma 53:1124-9, 2012 41. Hamadani M, Abu Kar SM, Usmani SZ, et al: Management of Relapses After Hematopoietic Cell Transplantation in T-Cell Non-Hodgkin Lymphomas. Seminars in Hematology 51:7386, 2014 42. Berger R, Rotem-Yehudar R, Slama G, et al: Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14:3044-51, 2008 43. Armand P, Nagler A, Weller EA, et al: Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial. Journal of Clinical Oncology 31:4199-4206, 2013 44. Westin JR, Chu F, Zhang M, et al: Safety and activity of PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed follicular lymphoma: a single group, open-label, phase 2 trial. The Lancet Oncology, 2013 45. Tabernero J, Powderly JD, Hamid O, et al: Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors. ASCO Meeting Abstracts 31:3622, 2013 46. Ansell SM, Hurvitz SA, Koenig PA, et al: Phase I study of ipilimumab, an anti-CTLA-4 monoclonal antibody, in patients with relapsed and refractory B-cell non-Hodgkin lymphoma. Clin Cancer Res 15:6446-53, 2009 47. Xerri L, Chetaille B, Serriari N, et al: Programmed death 1 is a marker of angioimmunoblastic T-cell lymphoma and B-cell small lymphocytic lymphoma/chronic lymphocytic leukemia. Hum Pathol 39:1050-8, 2008 48. Dorfman DM, Brown JA, Shahsafaei A, et al: Programmed death-1 (PD-1) is a marker of germinal center-associated T cells and angioimmunoblastic T-cell lymphoma. Am J Surg Pathol 30:80210, 2006 49. Roncador G, Garcia Verdes-Montenegro JF, Tedoldi S, et al: Expression of two markers of germinal center T cells (SAP and PD-1) in angioimmunoblastic T-cell lymphoma. Haematologica 92:1059-66, 2007 50. Brody J, Kohrt H, Marabelle A, et al: Active and Passive Immunotherapy for Lymphoma:
Proving Principles and Improving Results. Journal of Clinical Oncology 29:1864-1875, 2011 51. Lesokhin AM, Ansell SM, Armand P, et al: Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. Journal of Clinical Oncology 34:2698-2704, 2016 52. Dreyling M, Morschhauser F, Bouabdallah K, et al: Phase II study of copanlisib, a PI3K
inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. Ann Oncol 28:2169-2178, 2017 53. Sai J, Owens P, Novitskiy SV, et al: PI3K Inhibition Reduces Mammary Tumor Growth and Facilitates Antitumor Immunity and Anti-PD1 Responses. Clinical Cancer Research 23:3371-3384, 2017 54. Kaneda MM, Messer KS, Ralainirina N, et al: PI3Kgamma is a molecular switch that controls immune suppression. Nature 539:437-442, 2016 55. Peng W, Chen JQ, Liu C, et al: Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy. Cancer Discov 6:202-16, 2016 56. De Henau O, Rausch M, Winkler D, et al: Overcoming resistance to checkpoint blockade therapy by targeting PI3Kgamma in myeloid cells. Nature 539:443-447, 2016 66 of 94 57. Liu N, Haike K, Glaeske S, et al: COPANLISIB IN COMBINATION WITH ANTI-PD-1 INDUCES REGRESSION IN ANIMAL TUMOR MODELS INSENSITIVE OR RESISTANT TO THE MONOTHERAPIES OF PI3K AND CHECKPOINT INHIBITORS. Hematological Oncology 35:257258, 2017 58. Wartewig T, Kurgyis Z, Keppler S, et al: PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 552:121-125, 2017 59. Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 60. Karim R, Jordanova ES, Piersma SJ, et al: Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma. Clin Cancer Res 15:6341-7, 2009 61. Nomi T, Sho M, Akahori T, et al: Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res 13:2151-7, 2007 62. Hamanishi J, Mandai M, Iwasaki M, et al: Programmed cell death 1 ligand 1 and tumorinfiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S
A 104:3360-5, 2007 63. Topalian SL, Hodi FS, Brahmer JR, et al: Safety, Activity, and Immune Correlates of Anti–
PD-1 Antibody in Cancer. New England Journal of Medicine 366:2443-2454, 2012 64. MacFarlane AWt, Jillab M, Plimack ER, et al: PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. Cancer Immunol Res 2:320-31, 2014 65. Logan AC, Zhang B, Narasimhan B, et al: Minimal residual disease quantification using consensus primers and high-throughput IGH sequencing predicts post-transplant relapse in chronic lymphocytic leukemia. Leukemia 27:1659-65, 2013 66. Roschewski M, Dunleavy K, Pittaluga S, et al: Circulating tumour DNA and CT
monitoring in patients with untreated diffuse large B-cell lymphoma: a correlative biomarker study. Lancet Oncol 16:541-9, 2015 67. Kurtz DM, Green MR, Bratman SV, et al: Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing. Blood 125:3679-87, 2015 68. Carlotti E, Wrench D, Rosignoli G, et al: High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution. PLoS One 10:e0134833, 2015 69. Weng WK, Armstrong R, Arai S, et al: Minimal residual disease monitoring with highthroughput sequencing of T cell receptors in cutaneous T cell lymphoma. Sci Transl Med 5:214ra171, 2013 70. Wu D, Sherwood A, Fromm JR, et al: High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia. Sci Transl Med 4:134ra63, 2012 71. Logan AC, Vashi N, Faham M, et al: Immunoglobulin and T cell receptor gene highthroughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplantation relapse and survival. Biol Blood Marrow Transplant 20:1307-13, 2014 72. Timakhov RA, Tan Y, Rao M, et al: Recurrent chromosomal rearrangements implicate oncogenes contributing to T-cell lymphomagenesis in Lck-MyrAkt2 transgenic mice. Genes Chromosomes Cancer 48:786-94, 2009 73. Tan Y, Timakhov RA, Rao M, et al: A novel recurrent chromosomal inversion implicates the homeobox gene Dlx5 in T-cell lymphomas from Lck-Akt2 transgenic mice. Cancer Res 68:1296-302, 2008 74. O'Leary MN, Schreiber KH, Zhang Y, et al: The ribosomal protein Rpl22 controls ribosome composition by directly repressing expression of its own paralog, Rpl22l1. PLoS Genet 9:e1003708, 2013 75. Rao S, Lee SY, Gutierrez A, et al: Inactivation of ribosomal protein L22 promotes transformation by induction of the stemness factor, Lin28B. Blood 120:3764-73, 2012 76. Stadanlick JE, Zhang Z, Lee SY, et al: Developmental arrest of T cells in Rpl22-deficient mice is dependent upon multiple p53 effectors. J Immunol 187:664-75, 2011 77. Beachy SH, Onozawa M, Chung YJ, et al: Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma. Blood 120:104859, 2012 78. Piekarz RL, Frye R, Prince HM, et al: Phase 2 trial of romidepsin in patients with peripheral T-cell lymphoma. Blood 117:5827-5834, 2011 79. Litwin S, Wong YN, Hudes G: Early stopping designs based on progression-free survival at an early time point in the initial cohort. Stat Med 26:4400-15, 2007
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14.0 appendices 14.1 ecog performance

| Grade                                                                                                                                                                                                                                                                                                                        | Description                                                                                                                                                                                     |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0                                                                                                                                                                                                                                                                                                                            | Normal activity. Fully active, able to carry on all pre-disease  performance without restriction. Symptoms, but ambulatory. Restricted in physically strenuous                                  |
| 1                                                                                                                                                                                                                                                                                                                            | activity, but ambulatory and able to carry out work of a light or  sedentary nature (e.g., light housework, office work). In bed <50% of the time. Ambulatory and capable of all self-care, but |
| 2                                                                                                                                                                                                                                                                                                                            | unable to carry out any work activities. Up and about more than 50%  of waking hours.                                                                                                           |
| 3                                                                                                                                                                                                                                                                                                                            | In bed >50% of the time. Capable of only limited self-care, confined  to bed or chair more than 50% of waking hours.                                                                            |
| 4                                                                                                                                                                                                                                                                                                                            | 100% bedridden. Completely disabled. Cannot carry on any self-care.  Totally confined to bed or chair.                                                                                          |
| 5                                                                                                                                                                                                                                                                                                                            | Dead.                                                                                                                                                                                           |
| * As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,  McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology  Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D.,  Group Chair. |                                                                                                                                                                                                 |
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14.2 common terminology criteria for

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html)
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14.3 measurement of effect revised

NOTE: These criteria are based upon the criteria from the Revised Response Criteria for Malignant Lymphoma, (Cheson et al.), Journal of Clinical Oncology, 2007, Vol. 25:579-586. The criteria use the following categories of response: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Relapse and Progression (PD). In the case of stable disease, follow-up assessments must have met the SD criteria at least once after study entry at a minimum interval of six weeks. The following guidelines are to be used for establishing tumor measurements at baseline and for subsequent comparison:
The six largest dominant nodes or extranodal masses must be identified at baseline.  
If there are 6 or fewer nodes and extranodal masses, all must be listed as dominant If there are more than 6 involved nodes or extranodal masses, the 6 largest dominant nodes or extranodal masses should be selected according to the following features: a) they should be clearly measurable in at least two perpendicular measurements; b) they should be from as disparate regions of the body as possible; and c) they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.  
Measurements for all dominant nodes and extranodal masses will be reported at baseline.  
Measurements on non-dominant nodes are not required.  
The lymph nodes or extranodal masses selected for measurement should be measured in two perpendicular diameters, one of which is the longest perpendicular diameter. The lymph nodes should be measured in centimeters to the nearest one tenth of a centimeter (e.g.,2.0 cm, 2.1cm, 2.2 cm, etc.)
The two measured diameters of each lymph node site or extranodal mass should be multiplied giving a product for each nodal site or extranodal mass. The product of each nodal site should be added, yielding the sum of products of the diameters (SPD). The SPD will be used in determining the definition of response for those who have less than a complete response.  
Patients should be assessed with PET/CTs. Where PET is not available, response should be assessed as above, but only using CT scans. However, residual masses should not be assigned CRu status, but should be considered partial responses.  
For patients undergoing PET/CT, tumor assessment at all timepoints should also include the 5point scale (Deauville criteria) as an adjunct to the Cheson criteria.  
2 Scoring guidelines for the 5point scale are below. A score of 1, 2, or 3 indicates a complete metabolic response. Refer to section 14.3.1 for further definition of complete response.  
| 1   | No uptake                                                          |
|-----|--------------------------------------------------------------------|
| 2   | ≤ Mediastinal blood pool                                           |
| 3   | > Mediastinum and ≤ liver                                          |
| 4   | Moderately > liver at any site                                     |
| 5   | Markedly increased uptake above liver and/or  new sites of disease |
| X   | New areas of uptake unlikely to be related to  lymphoma            |
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14.3.1 complete response

Complete disappearance of all detectable clinical evidence of disease, and disease-related symptoms if present prior to therapy. In patients with a typically FDG-avid lymphoma with no pre-treatment PET scan, or for lymphomas for which the PET scan was positive prior to therapy: a post-treatment residual mass of any size is permitted as long as it is PET-negative. For variably FDG-avid lymphomas without a pretreatment PET scan, or if a pretreatment PET scan was negative: all lymph nodes and extranodal masses must have regressed on CT to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy). Previously involved nodes that were 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to treatment must have decreased to ≤ 1 cm in their short axis after treatment The spleen and/or liver, if considered enlarged prior to therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination, and nodules related to lymphoma should disappear. However, no normal size can be specified because of the difficulties in accurately evaluating splenic and hepatic size and involvement. For instance, a spleen considered normal size may contain lymphoma, whereas an enlarged spleen may not necessarily reflect the presence of lymphoma, but variations in anatomy, blood volume, the use of hematopoietic growth factors, or other causes. NOTE: Complete Remission/unconfirmed (CRu): Using the above definition for CR and that below for PR eliminates the category of CRu.
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14.3.2 partial response (pr)

The designation of PR requires all of the following: A ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or extranodal masses. No increase in the size of other nodes, liver or spleen. No new sites of disease. For a typically FDG-avid lymphoma with no pretreatment PET scan or one that was PET-positive prior to therapy, the post-treatment PET should be positive at any previously involved sites. For variably FDG-avid lymphomas/FDG-avidity unknown, without a pre-treatment PET scan, or if a pretreatment PET scan was negative, CT scan criteria should be used. Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
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14.3.3 stable disease (sd)

Failing to attain the criteria needed for a PR or CR, but not fulfilling those for progressive disease (see below). Typically FGD-avid lymphomas: The PET should be positive at prior sites of disease with no new areas of involvement on the post-treatment CT or PET.  
For variably FDG-avid lymphomas/FDG-avidity unknown: For patients without a pretreatment PET scan or if the pre-treatment PET was negative, there must be no change in the size of the previous lesions on the post-treatment CT scan.
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14.3.4 progression (pd) and relapse

For determination of relapsed and progressive disease, lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if the short axis is more than 1 cm. Lymph nodes ≤ 1 x ≤ 1 cm will not be considered as abnormal for relapse or progressive disease. Treatment decisions in patients with presumed refractory, relapsed or progressive disease should not be made solely on the basis of a single PET scan without histologic confirmation. Appearance of any new lesion more than 1.5 cm in any axis during or at the end of therapy, even if other lesions are decreasing in size. Increased FDG uptake in a previously unaffected site should only be considered relapsed or progressive disease after confirmation with other modalities. In patients with no prior history of pulmonary lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic decision should not be made solely on the basis of the PET without histologic confirmation. At least a 50% increase from nadir in the SPD of any previously involved nodes or extranodal masses, or in a single involved node or extranodal mass, or the size of other lesions (e.g. splenic or hepatic nodules). To be considered progressive disease, a lymph node or extranodal mass with a diameter of the short axis of less than 1.0 cm must increase by ≥ 50% and to a size of 1.5 cm x 1.5 cm or more than 1.5 cm in the long axis. At least a 50% increase in the longest diameter of any single previously identified node or extranodal mass more than 1 cm in its short axis. Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems (< 1.5 cm in its long axis by CT). Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these response criteria, the spleen is considered nodal disease. Disease that is only assessable (e.g.,
pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or physical examination, it is found to be histologically negative.
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14.3.5 response endpoints

All tumor assessments will be made using Revised Response (Cheson) criteria. Pembrolizumab is expected to trigger immune-mediated responses, which require activation of the immune system prior to the observation of clinical responses. Such immune activation may take weeks to months to be evident. Some patients may experience tumor flare with objective volume increase of tumor lesions or other disease parameters (based on study indication, ie, hematologic malignancies) within 12 weeks following the start of pembrolizumab dosing. Such patients may not have had sufficient time to develop the required immune activation or, in some patients, tumor volume or other disease parameter increases may represent infiltration of lymphocytes into the original tumor or blood. In conventional studies, such tumor volume or relevant laboratory parameter increases during the first 12 weeks of the study would constitute PD and lead to discontinuation of imaging to detect response, thus disregarding the potential for subsequent immune-mediated clinical response. Therefore if at the first imaging time point (12 weeks after initiating treatment) patients demonstrate up to 2 new lesions, with sum of all lesions < 70% greater than baseline by SPD, or decreasing in size, and stable without evidence of rapid clinical deterioration, patients may be continue to be treated with pembrolizumab and clinically observed with imaging repeated after 1 month. If, at that time, there is Progression of Disease (POD) by standard Revised Response Criteria patients will be removed from study. For patients in whom investigators consider that tumor flare may be playing a role in the response seen on initial imaging, this must be documented at time of scan, and discussed with Study Chair. This may improve the overall assessment of the clinical activity of pembrolizumab and more likely capture its true potential to induce clinical responses. In regards to PFS analysis, the date of progression for patients who were initially considered to have tumor flare, but had further progression of disease (POD) on the repeat image after 1 month, will be the time of first imaging in which new lesions were originally detected.
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14.3.6 duration of response

This is measured from the documented beginning of response (CR or PR) to the time of relapse. This is measured in responders.
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14.3.7 overall survival

Overall survival is defined as the date of study entry to the date of death.
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14.3.8 progression-free survival

Progression-free Survival (PFS) is defined as the time from entry onto study until lymphoma progression or death from any cause. PFS is often considered the preferable endpoint in lymphoma clinical trials. PFS reflects tumor growth and, therefore, occurs prior to the endpoint of overall survival. In addition, PFS is not confounded by the administration of subsequent therapy. Whether a prolongation of PFS represents direct clinical benefit or a surrogate for clinical benefit depends on the magnitude of the effect and the risk-benefit ratio of the therapy under investigation. Unlike survival, the precise date of progression is generally unknown. It may be defined as the first date of documentation of a new lesion or enlargement of a previous lesion, or the date of the scheduled clinic visit immediately after radiologic assessment has been completed. Where there is missing information, censoring of the data may be defined as the last date at which progression status was adequately assessed or the first date of unscheduled new antilymphoma treatment.
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14.4 events of clinical interest

This appendix offers specific guidance for investigators for the management of ECI based on the "PEMBROLIZUMAB PROGRAM (MK-3475) EVENT OF CLINICAL INTEREST GUIDANCE DOCUMENT Version 5.0". These recommendations should be seen as guidelines and the treating physician should exercise individual clinical judgment based on the patient. For any question of dose modification or other treatment options, the specific language in the protocol should be followed. The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab for each immune related adverse event. Of note, when the guidance states to "discontinue" pembrolizumab this is the permanent discontinuation of treatment with pembrolizumab. "Hold" means to stop treating with pembrolizumab but resumption of treatment may be considered assuming the patient meets the criteria for resumption of treatment.
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14.4.1 list of eci

| 14.4.1  List of ECI                                                                                                             |                                                                                    |                                          |
|---------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------|------------------------------------------|
| Pneumonitis (reported as ECI if  > Grade 2)                                                                                     |                                                                                    |                                          |
| Acute interstitial pneumonitis                                                                                                  | Interstitial lung disease                                                          | Pneumonitis                              |
| Colitis (reported as ECI if > Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  |                                                                                    |                                          |
| Intestinal Obstruction                                                                                                          | Colitis microscopic                                                                |                                          |
| Colitis                                                                                                                         |                                                                                    |                                          |
| Enterocolitis                                                                                                                   | Enterocolitis hemorrhagic                                                          | Gastrointestinal perforation             |
| Necrotizing colitis                                                                                                             | Dismhes                                                                            |                                          |
| Endocrine (reported as ECI if > Grade 3 or > Grade 2 and resulting in dose modification or use of systemic steroids to treat    |                                                                                    |                                          |
| te AE)                                                                                                                          |                                                                                    |                                          |
| Adrenal Insufficiency                                                                                                           | Hyperthyroidism                                                                    | Hypophysitis                             |
| Hypopituitarism                                                                                                                 | Hypothyroidism                                                                     | Thyroid disorder                         |
| Thyroidin's                                                                                                                     | Hyperglycemia, if >Grade 3 and associated with ketosis or metabolic acidosis (DKA) |                                          |
| Endocrine (reported as ECI)                                                                                                     |                                                                                    |                                          |
| Type 1 diabetes mellitus (if new onset)                                                                                         |                                                                                    |                                          |
| Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the |                                                                                    |                                          |
| AE)                                                                                                                             | Thrombotic Thrombocytopenic Purpura                                                |                                          |
| Autoimmune hemolytic anemia                                                                                                     | Aplastic anemia                                                                    | (TTP)                                    |
| Idiopathic (or immune) Thrombocytopenia                                                                                         | Disseminated Intravascular Coagulation                                             | Haemolytic Uraemic Syndrome (HUS)        |
| Purpura (ITP)                                                                                                                   | (DIC)                                                                              |                                          |
| Any Grade 4 anemia regardless of underlying mechanism                                                                           |                                                                                    |                                          |
| Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) |                                                                                    |                                          |
| Hepatitis                                                                                                                       | Autoimmune hepatitis                                                               | Transaminase elevations (ALT and/or AST) |
| Infusion Reactions (reported as ECI for any grade)                                                                              |                                                                                    |                                          |
| Allergic reaction                                                                                                               | Anaphylaxis                                                                        | Cytokine release syndrome                |
| Serum sickness                                                                                                                  | Infusion reactions                                                                 | Infusion-like reactions                  |
| Neurologic (reported as ECI for any grade)                                                                                      |                                                                                    |                                          |
| Autoimmune neuropathy                                                                                                           | Guillain-Barre syndrome                                                            | Demyelinating polyneuropathy             |
| Myasthenic syndrome                                                                                                             |                                                                                    |                                          |
| Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)     |                                                                                    |                                          |
| Uveitis                                                                                                                         | Iritis                                                                             |                                          |
| Renal (reported as ECI if  > Grade 2)                                                                                           |                                                                                    |                                          |
| Nephritis                                                                                                                       | Nephritis autoimmune                                                               | Renal Failure                            |
| Creatinine elevations (report as ECI if >Grade 3 or any grade resulting in dose                                                 |                                                                                    |                                          |
| Renal failure acute                                                                                                             | modification or use of systemic steroids to treat the AE)                          |                                          |
| Skin (reported as ECI for any grade)                                                                                            |                                                                                    |                                          |
| Dermatitis exfoliative                                                                                                          | Erythema multiforme                                                                | Stevens-Johnson syndrome                 |
| Toxic epidermal necrolysis                                                                                                      |                                                                                    |                                          |
| Skin (reported as ECI if > Grade 3)                                                                                             |                                                                                    |                                          |
| Prunitus                                                                                                                        | Rash                                                                               | Rash generalized                         |
| Rash maculo-papular                                                                                                             |                                                                                    |                                          |
| Any rash considered clinically significant in the physician's judgment                                                          |                                                                                    |                                          |
| Other (reported as ECI for any grade)                                                                                           |                                                                                    |                                          |
| Myocarditis                                                                                                                     | Pancreatitis                                                                       | Penicarditis                             |
| Any other Grade 3 event which is considered immune-related by the physician                                                     |                                                                                    |                                          |
| 14.4.2  Pneumonitis                                                                                                             |                                                                                    |                                          |  
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Pneumonitis
- Interstitial lung disease Confidential Limited Access
- Acute interstitial pneumonitis If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a cardiology consultation should be considered. All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral infection. It is important that patients with a suspected diagnosis of pneumonitis be managed as per the guidance below until treatment-related pneumonitis is excluded. Treatment of both a potential infectious etiology and pneumonitis in parallel may be warranted. Management of the treatment of suspected pneumonitis with steroid treatment should not be delayed for a therapeutic trial of antibiotics. If an alternative diagnosis is established, the patient does not require management as below; however, the AE should be reported regardless of etiology.
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course of action grade 2

- Report as ECI - Hold pembrolizumab. - Consider pulmonary consultation with bronchoscopy and biopsy/BAL. - Consider ID consult - Conduct an in person evaluation approximately twice per week - Consider frequent Chest X-ray as part of monitoring - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - Second episode of pneumonitis - discontinue pembrolizumab if upon re-challenge the patient develops a second episode of Grade 2 or higher pneumonitis.
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grade 3 and 4 events

- Report as ECI - Discontinue pembrolizumab. - Hospitalize patient - Bronchoscopy with biopsy and/or BAL is recommended. - Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When symptoms improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks. - If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional antiinflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-inflammatory measures, as needed - Add prophylactic antibiotics for opportunistic infections.
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14.4.3 colitis

The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Colitis - Colitis microscopic - Enterocolitis - Enterocolitis hemorrhagic - Gastrointestinal perforation - Intestinal obstruction - Necrotizing colitis - Diarrhea All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by examination for stool leukocytes, stool cultures, a Clostridium difficile titer and endoscopy. However the AE should be reported regardless of etiology.
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course of action

Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, abdominal pain, mucus or blood in stool):
- Report as ECI - Hold pembrolizumab. - Symptomatic Treatment - For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or mucus, o Consider GI consultation and endoscopy to confirm or rule out colitis o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) - When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - If symptoms worsen or persist > 3 days treat as Grade 3 Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week):
- Report as ECI - Hold pembrolizumab. - Rule out bowel perforation. Imaging with plain films or CT can be useful. - Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. - Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 hours, consider treatment with additional anti-inflammatory measures as described in the literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-inflammatory measures as needed.  
- Report as ECI - Permanently discontinue pembrolizumab. - Manage as per Grade 3.
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14.4.4 endocrine

The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Adrenal insufficiency - Hyperthyroidism - Hypophysitis - Hypopituitarism - Hypothyroidism - Thyroid disorder - Thyroiditis All attempts should be made to rule out other causes such as brain metastases, sepsis and/or infection. However, the AE should be reported regardless of etiology. Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism Grade 2-4 events:
- Report as ECI if appropriate - Hold pembrolizumab - Rule out infection and sepsis with appropriate cultures and imaging. - Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until returned to baseline values. - Pituitary gland imaging should be considered (MRIs with gadolinium and selective cuts of the pituitary can show enlargement or heterogeneity and confirm the diagnosis). - Treat with prednisone 40 mg p.o. or equivalent per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered.  
- Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - Hypophysitis with clinically significant adrenal insufficiency and hypotension, dehydration, and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis. - Consultation with an endocrinologist may be considered.
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14.4.5 hyperthyroidism and hypothyroidism

Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events:
- Report as ECI if appropriate (see Table 1) - Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until returned to baseline values. - Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. - Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is instituted. - In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. - In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated per standard of care. - Consultation with an endocrinologist may be considered.
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grade 3 hyperthyroidism events

- Report as ECI - Hold pembrolizumab. - Rule out infection and sepsis with appropriate cultures and imaging. - Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral prednisone 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid dose is tapered. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Grade 4 hyperthyroidism events:
- Report as ECI - Discontinue pembrolizumab. - Manage as per Grade 3
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14.4.6 type 1 diabetes mellitus

The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA)
- Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA). Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of preexisting diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but events meeting the above criteria should be reported as ECIs regardless of etiology. The patients may present with hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic acidosis, or low or undetected c-peptide.
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course of action

T1DM should be immediately treated with insulin. T1DM or Grade 3-4 Hyperglycemia events:
- Report as ECI if appropriate (see Table 1) - Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia associated with evidence of beta cell failure, and resume pembrolizumab when patients are clinically and metabolically stable. - Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. - Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and C-peptide. - Consultation with an Endocrinologist is recommended. - Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin may be obtained.
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14.4.7 hematologic

The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event:
- Autoimmune hemolytic anemia - Aplastic anemia - Disseminated Intravascular Coagulation (DIC) - Haemolytic Uraemic Syndrome (HUS) - Idiopathic (or immune) Thrombocytopenia Purpura (ITP) - Thrombotic Thrombocytopenic Purpura (TTP) - Any Grade 4 anemia regardless of underlying mechanism All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy or Coomb's test, etc., should be considered to confirm the diagnosis. However the AE should be reported regardless of etiology.
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course of action

Grade 2 events:
- Report as ECI - Hold pembrolizumab - Prednisone 1-2 mg/kg daily may be indicated - Consider Hematology consultation. Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Report as ECI - Hematology consultation. - Hold pembrolizumab Discontinuation should be considered as per specific protocol guidance. - Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Report as ECI - Hematology consultation - Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic malignancies. - Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate
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14.4.8 hepatic

The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or use of systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Autoimmune hepatitis - Hepatitis - Transaminase elevations All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic diseases. However, the AE should be reported regardless of etiology.  
-Drug Induced Liver Injury (DILI)
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the laboratory criteria for potential DILI defined as:
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than or equal to three times (3X) the upper limit of normal (ULN) and
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course of action grade 2

- Report as ECI - Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times ULN. - Monitor liver function tests more frequently until returned to baseline values (consider weekly).  
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for opportunistic infections, and resume pembrolizumab per protocol - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. - Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative to baseline and lasts ≥1 week.
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grade 3 events - report

- Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times ULN. - Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary - Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks. - If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to its potential for hepatotoxicity. - Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Report as ECI - Permanently discontinue pembrolizumab - Manage patient as per Grade 3 above An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN,
As a result of within-protocol-specific testing or unscheduled testing. Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI
event.
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14.4.9 neurologic

The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Autoimmune neuropathy - Demyelinating polyneuropathy - Guillain-Barre syndrome - Myasthenic syndrome All attempts should be made to rule out other causes such as metastatic disease, other medications or infectious causes. However, the AE should be reported regardless of etiology.
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course of action grade 2

- Report as ECI - Moderate (Grade 2) - consider withholding pembrolizumab. - Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate - Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.
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grade 3 and 4 events

- Report as ECI - Discontinue pembrolizumab - Obtain neurology consultation. Consider biopsy for confirmation of diagnosis - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. If condition worsens, consider IVIG or other immunosuppressive therapies as per local guidelines. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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14.4.10 ocular

The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event:
- Uveitis - Iritis All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular disease (e.g. glaucoma or cataracts). However, the AE should be reported regardless of etiology.
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course of action grade 2

- Evaluation by an ophthalmologist is strongly recommended. - Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. - Discontinue pembrolizumab as per protocol if symptoms persist despite treatment with topical immunosuppressive therapy.  
- Evaluation by an ophthalmologist is strongly recommended - Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. - Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Evaluation by an ophthalmologist is strongly recommended - Permanently discontinue pembrolizumab. - Treat with corticosteroids as per Grade 3 above
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14.4.11 renal

The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Nephritis - Nephritis autoimmune - Renal failure - Renal failure acute Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to treat the AE. All attempts should be made to rule out other causes such as obstructive uropathy, progression of disease, or injury due to other chemotherapy agents. A renal consultation is recommended. However, the AE should be reported regardless of etiology.
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course of action

Grade 2 events:
- Hold pembrolizumab - Treatment with prednisone 1-2 mg/kg p.o. daily. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
- Discontinue pembrolizumab - Renal consultation with consideration of ultrasound and/or biopsy as appropriate - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once per day. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Pembrolizumab Event of Clinical Interest Guidance Document
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14.4.12 skin rash and pruritus

The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor within 24 hours of the event:
- Pruritus - Rash - Rash generalized - Rash maculo-papular - In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and could possibly include rashes such as the following:
o rash with a duration >2 weeks; OR
o rash that is >10% body surface area; OR o rash that causes significant discomfort not relieved by topical medication or temporary cessation of study drug.
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other skin ecis

The following AEs should always be reported as ECIs, regardless of grade, and should be reported to the Sponsor within 24 hours of the event:
- Dermatitis exfoliative - Erythema multiforme - Steven's Johnson syndrome - Toxic epidermal necrolysis Please note, the AE should be reported regardless of etiology.
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course of action

Grade 2 events:
- Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral antipruritics (e.g., diphenhydramine HCl or hydroxyzine HCl).  
- Treatment with oral steroids is at physician's discretion for Grade 2 events.  
- Hold pembrolizumab. - Consider Dermatology Consultation and biopsy for confirmation of diagnosis. - Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks.  
Grade 4 events:
- Permanently discontinue pembrolizumab. - Dermatology consultation and consideration of biopsy and clinical dermatology photograph. - Initiate steroids at 1 to 2 mg/kg prednisone or equivalent. When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.
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14.4.12.1 immediate evaluation for potential

A. Photographs: Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as possible. Obtain appropriate consent for subject photographs if a consent form addendum is required by your IRB/ERC.  
- Take digital photographs of: o the head (to assess mucosal or eye involvement), o the trunk and extremities, and o a close-up of the skin lesion/rash.  
- If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of distance.  
- The time/date stamp should be set in the 'ON' position for documentation purposes. - Photographs should be stored with the subject's study records. - The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will provide guidance to the site, if needed.  
B. Past Medical History: Collect past medical history relevant to the event, using the questions in Appendix 1 (Past Medical History Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical History eCRF. C. Presentation of the Event: Collect information on clinical presentation and potential contributing factors using the questions in Appendix 2 (Presentation of the Dermatologic Event) as a guide. This information should be summarized and entered in narrative format in the AE eCRF. Please use the available free-text fields, such as Signs and Symptoms. Note pertinent negatives where applicable to reflect that the information was collected. Any treatments administered should be entered on the Concomitant Medication eCRF. D. Vitals Signs and Standard Laboratory Tests: Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital Signs in eCRF. Perform standard laboratory tests (CBC with manual differential and serum chemistry panel, includingLFTs). E. Focused Skin Examination: Perform a focused skin examination using the questions in Appendix 3 (Focused Skin Examination) as a guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the narrative.  
F. Dermatology Consult Refer the subject to a dermatologist as soon as possible. - For a "severe rash", the subject must be seen within 1-2 days of reporting the event. - For clinically significant rash, the subject should be seen within 3-5 days. The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a pathologist experienced in reviewing skin specimens. The site should provide the dermatologist with all relevant case history, including copies of clinical photographs and laboratory test results.
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14.4.13 other

The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 hours of the event:
- Myocarditis - Pericarditis - Pancreatitis - Any additional Grade 3 or higher event which the physician considers to be immune related All attempts should be made to rule out other causes. Therapeutic specialists should be consulted as appropriate. However, the AE should be reported regardless of etiology.
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course of action

Grade 2 events or Grade 1 events that do not improve with symptomatic treatment:
- Withhold pembrolizumab. - Systemic corticosteroids may be indicated. - Consider biopsy for confirmation of diagnosis. - If pembrolizumab held and corticosteroid required, manage as per grade 3 below.  
- Hold pembrolizumab - Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. - When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. - Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may be restarted and the dose modified as specified in the protocol  
- Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. - Discontinue pembrolizumab
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14.4.14 follow-up to resolution

Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with information regarding duration and clinical course of the event. Information obtained from the consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-text fields should be used to record narrative information:
- Clinical course of the event - Course of treatment - Evidence supporting recovery - Follow-up to the clinical course Any treatments administered for the event should also be entered in the Concomitant Medication eCRF.  
Page 89 of 94 14.4.15 ECI APPENDIX 1 - Past Medical History Related to Dermatologic Event Past Medical History:
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical History eCRF.  
1. Does the subject have any allergies? □ Yes □ No If yes, please obtain the following information:
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc):
__
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? □ Yes □
No Describe the agent and type of allergic response:  
c. Any allergy to food? □ Yes □ No Describe the food and type of allergic response: _
Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may b d. Any allergy to animals, insects? □ Yes □ No Describe the allergen and type of allergic response: _
__
e. Any other allergy? □ Yes □ No Describe the allergen and type of allergic response: _  
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No If so what kind? _
3. Has the subject ever been treated for a skin condition? □ Yes □ No If so what kind?  
__
4. Is the current finding similar to a past experience? □ Yes □ No Confidential Limited Access
eci appendix 2 - presentation
14.4.14 follow-up to resolution

Presentation of the event:
Collect information on clinical presentation and potential contributing factors. Key information should be summarized and entered on the Adverse Experience eCRF. Any treatments administered should be entered on the Concomitant Medication eCRF.  
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug?  
2. Has the subject contacted any known allergens? □ Yes □ No If so what kind? _
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, personal care product, poison ivy, etc.)? □ Yes □ No If so what kind? _
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)?  
If so what kind?  
__
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No If so what kind?  
Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may b 6. Does the subject have or had in the last few days any illness? □ Yes □ No If so what kind?  
__
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No If so who and what?  
__
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. Molluscum Contagiosum)?  □ Yes □ No 9. Has the subject had recent sun exposure? □ Yes □ No 10. For the current rash, have there been any systemic clinical signs? □ Yes □ No Testing to the content of the content to the content of the content of the content of the content of the content of the content of the content of the content of the content a i. Anaphylaxis? □ Yes □ No i. Signs of hypotension? □ Yes □ No ii. Signs of dyspnea? □ Yes □ No iv. Fever, night sweats, chills? □ Yes □ No 1. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine therapy? □ Yes □ No If so what kind?  
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No List medication(s) and dose(s):
__
13. Is the rash pruritic (itchy)? □ Yes □ No 14.4.17 ECI APPENDIX 3 - Focused Skin Examination Focused Skin Examination:
Key information should be summarized and entered on the Adverse Experience eCRF.  
Primary Skin Lesions Description Color:  
General description:
__
__
Describe the distribution of skin reaction, skin eruption, or rash on the body:
__  
Is skin reaction, skin eruption, or rash resolving or continuing to spread?  
__
Any associated signs on physical examination?  
Page 92 of 94
eci appendix 2 - presentation
14.4.18 appendix 4- low glycemic

The average Glycemic Index of common foods derived from multiple studies by different
eci appendix 2 - presentation
laboratories

Foods are categorized as having a low-glycemic index if the glucose reference index is ≤ 55. High-Glycemic Index foods have a glucose reference index >55. The summary table below contains glucose reference for common foods.  
| Hgh-carbohydrate foods                                                                       | Breakfast cereals   | Fruit and fruit products   | Vegetables   |                 |        |                       |         |
|----------------------------------------------------------------------------------------------|---------------------|----------------------------|--------------|-----------------|--------|-----------------------|---------|
| White wheat bread*                                                                           | 75 ± 21             | Comflakes                  | 81 ± 6       | Apole, raw t    | 36 ± 2 | Potato, boiled        | 78 ± 4  |
| Whole wheat/whole meal bread                                                                 | 74 ± 2              | Wheat flake biscuits       | 69 ± 2       | Orange, raw?    | 43 ± 3 | Potato, instant mash  | 87 ± 3  |
| Specialty grain bread                                                                        | 53 ± 2              | Porridge, rolled cats      | 5±2          | Banana, raw?    | 51±3   | Potato, french fries  | 63 £ 5  |
| Unleavened wheat bread                                                                       | 70 ± 5              | Instant cat porridge       | 79 ± 3       | Pineapple, raw  | 59 ± 8 | Carrots, boiled       | 39 ± 4  |
| Wheat roti                                                                                   | 62 ± 3              | Rce porridge/congee        | 78 £ 9       | Mango, rawf     | 51 ± 5 | Sweet potato, boiled  | 63 £ 6  |
| Chapatti                                                                                     | 52 ± 4              | Millet porridge            | 67±5         | Watermelon, raw | 76±4   | Pumpkin, boiled       | 64 ± 7  |
| Com tortilla                                                                                 | 4 ± +               | Muesli                     | 57±2         | Dates, raw      | 42 ± 4 | Plantain/green banana | 55 ± 6  |
| White rice, boiled*                                                                          | 73 ± 4              | Peaches, cannedt           | 43 ± 5       | Taro, boiled    | 5 ± 2  |                       |         |
| Brown rice, boiled                                                                           | 68 ± 4              | Strawberry jam/jelly       | 4 ± 3        | Vegetable soup  | 48 ± 5 |                       |         |
| Barley                                                                                       | 28 ± 2              | Apple juice                | 41 ± 2       |                 |        |                       |         |
| Sweet com                                                                                    | 52 ± 5              | Orange juice               | 50 ± 2       |                 |        |                       |         |
| Spaghetti, white                                                                             | 49 ± 2              |                            |              |                 |        |                       |         |
| Spaghetti, whole meal                                                                        | 48 ± 5              |                            |              |                 |        |                       |         |
| Rce noodles*                                                                                 | 53 ± 7              |                            |              |                 |        |                       |         |
| Udon noodles                                                                                 | 5 ± 7               |                            |              |                 |        |                       |         |
| Couscoust                                                                                    | 65 ± 4              |                            |              |                 |        |                       |         |
| Dairy products and                                                                           | Legumes             | Snack products             | Sugars       |                 |        |                       |         |
| alternatives                                                                                 |                     |                            |              |                 |        |                       |         |
| Mlilk, full fat                                                                              | 39 ± 3              | Chickpeas                  | 28 - 9       | Chocolate       | 40 ± 3 | Fructose              | 15 ± 4  |
| Mkilk, skim                                                                                  | 37 ± 4              | Kidney beans               | 24 2 4       | Popcom          | 65±5   | Sucrose               | 65±4    |
| lce cream                                                                                    | 51 ± 3              | Lentils                    | 32 £ 5       | Potato crisps   | 56 ± 3 | Glucose               | 103 ± 3 |
| Yogurt, fruit                                                                                | 41 ± 2              | Soya beans                 | 16 ± 1       | Soft drink/soda | 59 ± 3 | Honey                 | 61 ± 3  |
| Soy milk                                                                                     | 3 ± 4               | Rice crackers/crisps       | 87 ± 2       |                 |        |                       |         |
| Rice milk                                                                                    | 86  7               |                            |              |                 |        |                       |         |
| Data are means + SEM. *Low-GI vaneties were also identified. *Average of all available data: |                     |                            |              |                 |        |                       |         |
eci appendix 2 - presentation
14.4.19 appendix 5- prohibited medications

| Category                                                                             | Drug name                                                                                                                                                                                                                                                                                                                                                                   |                |           |                |
|--------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|-----------|----------------|
| Strong CYP3A Inhibitors                                                              | Voriconazole, boceprevir, clarithromycin, cobicistat,  conivaptan, danoprevir/ritonavir, eltegravir/ritonavir,  grapefruit juice, indinavir/ritonavir, itraconazole,  ketoconazole, lopinavir/ritonavir, mibefradil,  nefazodone, nelfinavir, posaconazole, ritonavir,  saquinavir, saquinavir/ritonavir, telaprevir,  telithromycin, tipranavir/ritonavir, troleandomycin, |                |           |                |
| Moderate CYP3A Inhibitors                                                            | Grapefruit, grapefruit hybrids, pummelos, star-fruit, and  Seville oranges (citrus paradisi fruit juice)                                                                                                                                                                                                                                                                    |                |           |                |
| Strong CYP3A Inducers                                                                | Avasimibe,                                                                                                                                                                                                                                                                                                                                                                  | carbamazepine, | mitotane, | phenobarbital, |
| phenytoin, rifabutin, rifampin (rifampicin), St. John's wort  (hypericum perforatum) |                                                                                                                                                                                                                                                                                                                                                                             |                |           |                |
| CYP3A Substrates with NTI                                                            | Alfentanil, apixaban (doses >2.5 mg only), aprepitant,  astemizole, cisapride, cyclosporine, diergotamine,  dihydroergotamine, ergotamine, fentanyl, lovastatin,  nicardipine, nisoldipine, pimozide, quinidine, rivaroxaban,  simvastatin, sirolimus, tacrolimus, terfenadine, thioridazine,                                                                               |                |           |                |
| Other Investigational and                                                            | Other investigational therapies must not be used while the                                                                                                                                                                                                                                                                                                                  |                |           |                |
| Antineoplastic Therapies                                                             | patient is on the study. Anticancer therapy (chemotherapy,  biologic or radiation therapy, and surgery) other than the study  treatments must not be given to patients while the patient is on  the study medication. If such agents are required for a patient  then the patient must be discontinued from the study.                                                      |                |           |                |
| Herbal Preparations/ Medications                                                     | Herbal preparations/medications are prohibited throughout the  study. These herbal medications include, but are not limited  to: St. John's wort, Kava, ephedra (ma huang), ginkgo biloba,  dehydroepiandrosterone (DHEA), yohimbe, saw palmetto,  and ginseng. Patients should stop using these herbal  medications 7 days prior to first dose of study drug               |                |           |                |