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table 6 evaluating adverse events

| V5.0        | CTCAE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Grade 1                                                                                                    | Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.   |
|-------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|
| Grading     | Grade 2                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. |                                                                                                              |
| Grade 3     | Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; limiting  self-care ADL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |                                                                                                            |                                                                                                              |
| Grade 4     | Life threatening consequences; urgent intervention indicated.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                                            |                                                                                                              |
| Grade 5     | Death related to AE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                                                            |                                                                                                              |
| Seriousness | A serious adverse event is any adverse event occurring at any dose or during any use of pembrolizumab that: †Results in death; or †Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an  adverse event that, had it occurred in a more severe form, might have caused death.); or †Results in a persistent or significant disability/incapacity (substantial disruption of one's ability to conduct normal life functions); or †Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the  hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting  condition which has not worsened does not constitute a serious adverse event.); or †Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or |                                                                                                            |                                                                                                              |  
An investigator who is a qualified physician, will evaluate all adverse events as to:
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This document is confidential and the property of the University of Pennsylvania. No part of it may be transmitted, reproduced, published, or used by other  
 persons without prior written authorization from the regulatory sponsor.  
| Is a new cancer; (that is not a condition of the study) or Is an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not  associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when,  based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes  listed previously (designated above by a †).   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Duration                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| Action taken                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Did the adverse event cause pembrolizumab to be discontinued? Did pembrolizumab cause the adverse event? The determination of the likelihood that pembrolizumab caused the adverse event will be provided by an investigator                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Relationship to  test drug                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | who is a qualified physician. The investigator's signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures  that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are  intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the  available information.  The following components are to be used to assess the relationship between pembrolizumab and the AE; the greater the correlation with the components and  their respective elements (in number and/or intensity), the more likely pembrolizumab caused the adverse event (AE): Exposure Is there evidence that the subject was actually exposed to pembrolizumab such as: reliable history, acceptable compliance assessment (pill count,  diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? Time Course Did the AE follow in a reasonable temporal sequence from administration of pembrolizumab?  Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors |  
| Relationship                  | The following components are to be used to assess the relationship between the test drug and the AE: (continued)                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |
|-------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| to  Pembrolizumab (continued) | Dechallenge                                                                                                                                                                                                                                                                                                                                                                          | Was pembrolizumab discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge. (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation  of pembrolizumab; or (3) the trial is a single-dose drug trial); or (4) pembrolizumab is/are only used one time.) |
| Rechallenge                   | Was the subject re-exposed to pembrolizumab in this study? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge. (Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or  (3) pembrolizumab is used only one time). |                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |  
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| NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN  CAUSED BY PEMBROLIZUMAB, OR IF REEXPOSURE TO PEMBROLIZUMAB POSES ADDITIONAL POTENTIAL SIGNIFICANT  RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL MONITOR AS  PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                                                                                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| Consistency  with Trial  Treatment  Profile                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding pembrolizumab or drug class pharmacology or  toxicology? |
| The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including  consideration of the above elements. Record one of the following Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a pembrolizumab relationship). Yes, there is a reasonable  possibility of pembrolizumab relationship. There is evidence of exposure to pembrolizumab. The temporal sequence of the AE onset relative to the administration of pembrolizumab is  reasonable. The AE is more likely explained by pembrolizumab than by another cause. No, there is not a reasonable  possibility pembrolizumab relationship Subject did not receive pembrolizumab OR temporal sequence of the AE onset relative to administration of pembrolizumab is not reasonable OR  there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.) |                                                                                                                                                           |  
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 persons without prior written authorization from the regulatory sponsor.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
  
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7.3.3 modification of ctc grading

The CTCAE grading system was developed to capture a cytokine release syndrome occurring during infusional therapy and is inadequate to capture the delayed CRS that occurs after CART-19 infusions. We propose to modify the CTC grading specifically to capture toxicity for protocols using CART-19 cells (Table 7.2.5a). Related definitions can be found in **Table**
7.2.5b.  
Recipients of CART-19 cells may develop a cytokine release syndrome. Data from small numbers of patients show marked elevations in IL6, IFN-g, and less intensely TNF among other cytokines. Elevations in clinically available markers of inflammation including ferritin and CRP have also been observed to correlate with the clinical CRS syndrome. Symptoms usually occur 1-14 days after cell infusion, but the syndrome is not defined by the timing of the reaction. Patients developing any symptoms attributable by the investigator as related to cytokine release should be reported as having had a CRS. Symptoms may include:
High fevers Rigors Sweating Nausea Vomiting Anorexia Fatigue Headache Myalgia/arthralgia Hypotension Dyspnea Tachypnea Hypoxia Altered mental status End organ dysfunction Signs of macrophage activation syndrome including hemophagocytosis and hemolysis For the purposes of reporting and grading on clinical trials using CART-19 cells, we will use the following grading for CRS Toxicity. The start date of CRS is a retrospective assessment of the date of onset of persistent fevers and/or myalgia consistent with CRS and not explained by other events (i.e. sepsis). The stop date of CRS is defined as the date when the patient has been afebrile for 24 hours and off vasopressors for 24 hours.  
  
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| Table 7.2.5a - CRS Toxicity Grading                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                 |                       |    |       |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------|----|-------|
| 1                                                                                                                                                                                                                                                                                                                      | 2                                                                                                                                                                                                                                                                                                                                                               | 3                     | 4  | 5     |
| Mild  reaction:  Treated  with  supportive  care such  as antipyretics,  antiemetics                                                                                                                                                                                                                                                                                                                        | Moderate reaction  requiring IV  fluids or  parenteral  nutrition; some  signs of organ  dysfunction (i.e.  grade 2 creatinine  or grade 3 liver  function tests  ([LFTs] related to  CRS and not  attributable to any  other condition).                                                                                                                       | More severe reaction: | Life-threatening  complications  such as  hypotension  requiring highdose pressors  (see Table  7.2.5b) or hypoxia  requiring  mechanical  ventilation    | Death |
| Hospitalization required for  management of symptoms  related to organ dysfunction  including:  grade 4 LFTs  grade 3 creatinine related to  CRS and not attributable to  any other conditions  hypotension requiring  multiple fluid boluses for  blood pressure support or  low-dose pressors (see  Table 7.2.5b) |                                                                                                                                                                                                                                                                                                                                                                 |                       |    |       |
| Hospitalization  for management  of CRS related  symptoms  including fevers  with associated  neutropenia.                                                                                                                                                                                                             |  coagulopathy requiring  fresh frozen plasma or cryoprecipitate  hypoxia requiring  supplemental oxygen (nasal  cannula oxygen, high flow  oxygen, Continuous  Positive Airway Pressure  [CPAP] or Bilateral  Positive Airway Pressure  [BiPAP]) Patients admitted for  management of suspected  infection due to fevers and/or  neutropenia may have grade 2 |                       |    |       |
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Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
  
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| Table 7.2.5a - CRS Toxicity Grading CRS and this excludes  management of fever or  myalgias   |
|-----------------------------------------------------------------------------------------------|  
| Definition of "High-Dose" Vasopressors Vasopressor Dose for ≥ 3 hours Norepinephrine monotherapy ≥ 20 mcg/kg/min Dopamine monotherapy ≥ 10 mcg/kg/min Phenylephrine monotherapy ≥ 200mcg/min Epinephrine monotherapy ≥ 10 mcg/min If on vasopressin High-dose if vaso + Norepinephrine Equivalent (NE) of  >10 mcg/min (using Vasopressin and Septic Shock Trial  (VASST) formula) If on combination  Norepinephrine equivalent of ≥ 20 mcg/min (using VASST  vasopressors (not vasopressin) formula) Vasopressin and Septic Shock Trial (VASST) Equivalent Equation:   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
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table 7.2.5b high dose vasopressor

Norepinephrine equivalent dose = [norepinephrine (mcg/min)] + [dopamine (mcg/kg/min) ÷ 2] + [epinephrine (mcg/min)] + [phenylephrine (mcg/min) ÷10]
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7.3.4 sponsor responsibility for reporting

All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.  
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reportable events

Any accidental or unintentional deviation from the approved protocol, identified retrospectively, that in the opinion of the investigator or as defined by the protocol, placed one or more participants at increased risk, compromises the rights or welfare of subjects, and/or disrupts the study design, is considered a reportable event and must be reported to the Study Principal Investigator, Study Medical Monitor, IRB, and ACC DSMC within 10 working days of notification. Principal Investigator and Medical Monitor approval/acknowledgement must be received first and included in with the IRB/DSMC submission. Deviations to protect subjects from immediate harm/danger should be reported immediately following the event to the entities outlined above.
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exceptions (prospective action)

An exception is defined as a one-time, intentional action or process that departs from the IRB and CTSRMC approved study protocol, intended for one occurrence. If this action disrupts the study progress, such that the study design or outcome (endpoints) may be compromised, or the action compromises the safety and welfare of study subjects (i.e., requests to enroll and/or treat subjects outside of the current protocol criteria), advance documentation of Medical Monitor, IRB, and DSMC approval is required. Principal Investigator and Medical Monitor approval must be received first and included in with the IRB/DSMC submission. All entities should be given sufficient time to evaluate this request. Deviations (Retrospective action): A one time, unintentional action or process that departs from the IRB and CTSRMC approved study protocol, involving one incident and identified retrospectively, after the event occurred. If the impact on the protocol disrupts the study design, may affect the outcome (endpoints) or compromises the safety and welfare of the subjects, the deviation must be reported to the DSMC within 5 business days and the IRB within 10 business days. For reportable deviations, documentation of the Medical Monitor response must be submitted to the DSMC **with** the report. Deviations that do not meet the definition above of "reportable" will be explained in a memo to file or recorded on a deviation log and will contain documentation of the **PI's assessment** of the impact of the deviation on safety and study outcomes.  
  
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8.0 statistical analysis plan 8.1

(1) **Objective:** To determine the safety of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas. Safety will be assessed by adverse event monitoring. Patients who have received at least one dose of pembrolizumab will be considered evaluable for safety. In this trial, success will be defined as receiving at least one dose of pembrolizumab and the lack at least possibly related adverse events leading to permanent discontinuation of pembrolizumab. Patients who experience Grade 3 or higher non-hematologic toxicity leading to permanent pembrolizumab discontinuation or any Grade 4 non-hematologic toxicity or cytokine release syndrome at least possibly related to pembrolizumab will be considered toxicity failures. Methodology: We will use a Bayesian monitoring rule to assure that the failure rate is no greater than 30%. Monitoring will begin with the first patient. Because little information is available on the safety of this drug in lymphoma, we will assume a noninformative Beta(1, 1) prior distribution for the failure rate. We will denote the rate of pembrolizumab discontinuation as failure rate, FR, and will use the following monitoring rule in the interest of patient safety: we will stop the trial if at any time: Pr[FR > 0.30 | data from the trial] >= 97.5%
That is, if at any time during the study, we can conclude that there is at least a 97.5% chance that the failure rate is greater than 30%, we will stop the study. The stopping boundaries corresponding to this probability criterion are to terminate the trial if: (\# of patients that experience failure) / (\# of patients evaluated) ≥ 3/3, 3/4, 4/5, 4/6, 5/7, 5/8, 6/9, 6/10, 7/11, 7/12. Any patient who has received at least one dose of pembrolizumab will be included in this denominator for evaluable patients if they have received at least 4 doses of pembrolizumab and not experienced toxicity OR if they have experienced any toxicity with any dose of pembrolizumab. If the study is not terminated early, it will continue until all patients have been treated with pembrolizumab and completed all follow up evaluations. Hypothesis: Pembrolizumab will be safely tolerated with ≤ 30% of patients experiencing toxicities resulting in discontinuation of pembrolizumab  
  
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8.1.2 secondary objectives & hypotheses

Any patient who receives at least one dose of pembrolizumab will be included in efficacy analyses.  
(1) **Objective:** To describe the overall response rate (ORR) to pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas.  
Methodology: For efficacy, a sample size of 12 patients achieves an 80% power to detect a difference (P1 0.35 - P0 0.05) of 0.30 using a one-sided binomial test for ORR. The target of significance level is 0.05. This response rate prediction of 35% is based on the reported 28% response rate reported for nivolumab, another anti-PD1 blocking antibody, in patients with B cell lymphoma. This also assumes that a 5% response rate would be seen if pembrolizumab does not have efficacy in this population. If the response rate is 3 or more, the hypothesis that the ORR is ≤ 0.05 is rejected. If the number of responses is 2 or less, the hypothesis that ORR is ≥ 0.35. Hypothesis: The response rate after pembrolizumab will be 3 or more, allowing us to reject the null hypothesis that pembrolizumab after CTL019/CTL119 has an ORR ≤ 0.05
(2) **Objective**: To describe the clinical efficacy of pembrolizumab, including progressionfree survival, disease-free survival, event-free survival, response duration, and overall survival (Cheson, 2007) in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas. Efficacy comparisons will be made with both most recent prior therapy as well as with CTL019/CTL119.  
Methodology: Kaplan Meier survival analysis will be used to estimate progression-free survival, event-free survival, response duration, and overall survival. For patients with initial responses to both CTL 019 and pembrolizumab, progression-free survival, eventfree survival, and response duration, patients' response to CTL 019 therapy will be compared to their response to pembrolizumab using the log-rank test, with p ≤ 0.05 considered statistically significant. Hypothesis: Pembrolizumab will enhance the efficacy of CTL019/CTL119 in patients failing to respond to or relapsing after chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas.  
  
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8.1.3 exploratory objectives

(1) **Objective**: To describe the immunophenotypic and cytokine profiles of chimeric antigen receptor modified T cells in these patients before and after therapy with pembrolizumab Hypothesis: Immunophenotypic profiles of tumor cells and chimeric antigen receptor modified T cells obtained pre and post pembrolizumab therapy will identify patients for whom pembrolizumab will enhance efficacy.  
(2) Objective: For immunologic correlative studies, within subject comparisons of baseline to post pembrolizumab measures will be conducted. These analyses will be descriptive and considered exploratory; thus, power will not be considered for these paired comparisons.
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9.0 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. Clinical Supplies will be provided by Merck as summarized in Table 7. Table 7 Product Descriptions  
| Product Name & Potency    | Dosage Form                      |
|---------------------------|----------------------------------|
| Pembrolizumab 50 mg       | Lyophilized Powder for Injection |
| Pembrolizumab 100 mg/ 4mL | Solution for Injection           |
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9.2 packaging and labeling information

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.  
  
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9.3 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.
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9.4 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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9.5 returns and reconciliation

The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 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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10.0 administrative and regulatory details

Information about study subjects will be kept confidential and managed according to the requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those regulations require a signed subject authorization informing the subject of the following: - What protected health information (PHI) will be collected from subjects in this study  
- Who will have access to that information and why - Who will use or disclose that information
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- The rights of a research subject to revoke their authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains the ability to use all information collected prior to the revocation of subject authorization. For subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period.
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10.2 compliance with law and

The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the supporter, government regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory documents, data collection instruments, study data etc.). The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). Participation as an investigator in this study implies acceptance of potential inspection by government regulatory authorities and applicable University compliance and quality assurance offices.
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10.3 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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10.4 quality and safety management

It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site. This safety monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well as the construction and implementation of a site data and safety-monitoring plan. This will include a regular assessment of the number and type of serious adverse events. The investigator will permit study-related monitoring, audits, and inspections by the DSMC, IRB, government regulatory bodies, and University compliance and quality assurance groups of all study related documents (e.g. source documents, regulatory documents, data collection  
  
transmitted, reproduced, published, or used by other persons without prior written authorization from the regulatory sponsor.  
instruments, study data etc.). The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). Interim analyses of toxicity are to be performed quarterly or every three patients on-study. The Abramson Cancer Center Data and Safety Monitoring Committee will conduct in-house safety audits as per their guidelines.  
During the course of the trial, safety and data quality monitoring will be performed in an ongoing manner by the Principal Investigator. The principal investigator will monitor data integrity. This includes ensuring that all source documents exist for the data on the case report forms, ensuring that all fields are competed appropriately, all corrections are done according to GCPs and any inconsistencies / deviations are documented. The Principal Investigator will also review all Adverse Event forms in "real-time" to ensure appropriateness of the data and timeliness of reporting.  
The Medical monitor for this study will be Alfred L. Garfall, M.D., who is not directly involved in the trial and is not collaborating with the sponsor or study supported in any other trial. In this role, the medical monitor will review all AEs including grading, toxicity assignments, all other safety data and activity data. The medical monitor may recommend reporting of adverse events and relevant safety data not previously reported and may recommend suspension or termination of the trial. The Medical Monitor will be asked to review study data at least quarterly (every 3 months) or more frequently depending on enrollment.
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10.5 ethical considerations

The protocol for this study has been designed in accordance with the general ethical principles outlined in the Declaration of Helsinki. This study is to be conducted according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), applicable government regulations and Institutional research policies and procedures. All subjects for this study will be provided a consent form describing this study and providing sufficient information for subjects to make an informed decision about their participation in this study. See Appendix I for a copy of the Subject Informed Consent Form. This consent form will be submitted with the protocol for review and approval by the EC/IRB for the study. The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained before that subject is submitted to any study procedure. This consent form must be signed by the subject or legally acceptable surrogate, and the investigator-designated research professional obtaining the consent. Documentation of the informed consent process should be Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas  
  
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recorded in the subject's source documents. The original consent form signed and dated by the subject and by the person consenting the subject prior to the subject's entry into the study, must be maintained in the Investigator's study files.
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10.6 conflict of interest

Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly constituted Conflict of Interest Committee with a Committeesanctioned conflict management plan that has been reviewed and approved by the study supporter prior to participation in this study. All University of Pennsylvania investigators will follow the University conflict of interest policy.
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10.7 records retention

It is the investigator's responsibility to retain study essential documents for at least 2 years after the last approval of a marketing application in their country and until there are no pending or contemplated marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period if required by an agreement. In such an instance, it is the responsibility of the sponsor to inform the institution as to when these documents no longer need to be retained. The Investigator agrees to adhere to the document/records retention procedures by signing the protocol.  
  
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11.0 references

Cheson, B. P. (2007). Revised response criteria for malignant lymphoma. *Journal of Clinical* Oncology, 25, 579-586.  
Garon, E., Rizvi, N., Hui, R., Leighl, N., Balmanoukian, A., & al, e. (2015). Pembrolizumab for the treatment of non-small cell lung cancer. *New England Journal of Medicine*, 111.  
Grupp, S. K. (2013). Chimeric antigen receptor-modified T cells for acute lymphoid leukemia.  
New England Journal of Medicine, 368(16), 1509-1518.  
Hamid, O., Robert, C., Daud, A., Hodi, S., Hwu, W., & al, e. (2013). Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. *New England Journal of* Medicine, 369(2), 134-144.  
John, L. D. (2013). Anti-PD-1 antibody therapy potently enhances the eradication of established tumors by gene-modified T cells. *Clinical Cancer Research, 19*(20), 56365646.  
Lesokhin, A., Ansell, S., Armand, P., Scott, E., Halwani, A., & al, e. (2014). Preliminary Results of a Phase I Study of Nivolumab (BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. *Blood, 124*(21), Abstract \#291.  
Maude, S. F. (2014). Chimeric antigen receptor T cells for sustained remissions in leukemia.  
New England Journal of Medicine, 371(16), 1507-1517.  
Porter, D. L. (2011). Chimeric antigen receptor-modified T cells in chronic lymphocytic leukemia. New England Journal of Medicine, 365(8), 725-733.  
  
transmitted, reproduced, published, or used by other persons without prior written authorization from the regulatory sponsor.
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12.0 appendices 12.1 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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12.2 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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12.3 response evaluation criteria

The Revised Response Criteria for Malignant Lymphoma will be utilized for response assessment in this study (Cheson, 2007).
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12.4 events of clinical interest

Events of Clinical Interest (ECI) Guidance Document Version 5 will guide pembrolizumab administration, discontinuation, and specific event reporting. Please refer to attached document.  
Version 12, October 21, 2018. UPCC 46415: Phase I/II study of pembrolizumab in patients failing to respond to or relapsing after anti-CD19 chimeric antigen receptor modified T cell therapy for relapsed or refractory CD19+ lymphomas