Clinical trial NCT03661723
Conditions: Glioblastoma
Keywords: Glioblastoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2018-09-28; Completion date: 2024-08-01
Enrollment: 60 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This research study is studying pembrolizumab and re-irradiation as possible treatments for glioblastoma.

The drugs involved in this study are:

* Pembrolizumab
* Radiation
* Bevacizumab, an FDA-approved drug for treating recurrent glioblastoma multiforme (GBM)

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

How the Study Interventions work:

Pembrolizumab: Pembrolizumab has been studied in lab experiments and in other types of cancer, and information from these studies suggests that it may be beneficial in this type of cancer. Pembrolizumab is a drug (an antibody) that may treat cancer by working with the immune system.

The FDA (the U.S. Food and Drug Administration) has not approved pembrolizumab for this specific disease but it has been approved for other uses.

Radiation (Re-irradiation): Radiotherapy destroys cancer cells using radiation aimed at a cancer from a machine.

The FDA (the U.S. Food and Drug Administration) has approved re-irradiation as a treatment option for this disease.

Bevacizumab: Bevacizumab (also known as "Avastin") is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels.

The FDA (the U.S. Food and Drug Administration) has approved bevacizumab as a treatment option for this disease.

In this research study, the investigators are looking to determine if this combination (pembrolizumab + re-irradiation) proves helpful in treating this cancer. If the participant has already been receiving bevacizumab, the participant will continue to receive this along with pembrolizumab and re-irradiation. By doing this, the investigators will look to determine if this combination (pembrolizumab and bevacizumab + re-irradiation) proves helpful in treating this cancer.

This study will also test the safety and tolerability of this combination (pembrolizumab + re-irradiation) when given alone or with bevacizumab

Arms: arm 1: * Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks. (De-escalation dosing frequencies = once every 4 weeks and once every 6 weeks.)
* Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks arm 2: * Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks. (De-escalation dosing frequencies = once every 4 weeks and once every 6 weeks.)
* Bevacizumab (15 mg/kg) will be administered intravenously (IV) once every 3 weeks
* Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks arm 3: * Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks
* Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks arm 4: * Pembrolizumab (200 mg) will initially be administered intravenously (IV) once every 3 weeks
* Bevacizumab (15 mg/kg) will be administered intravenously (IV) once every 3 weeks
* Re-irradiation (35 Gy) will be administered to patients 5 days per week for 2 weeks
Interventions: intervention 1: Pembrolizumab intervention 2: Bevacizumab intervention 3: Re-irradiation
Intervention descriptions: intervention 1: Pembrolizumab is a drug (an antibody) that may treat cancer by working with the immune system intervention 2: Bevacizumab (also known as "Avastin") is designed to prevent or slow down the growth of cancer cells by blocking the growth of blood vessels. intervention 3: Radiotherapy destroys cancer cells using radiation aimed at a cancer from a machine

Protocol documents:
Prot_SAP_000.pdf: 
Document Cover Page for ClinicalTrials.gov 
 
Official Study Title: 
Phase II Trial of Pembrolizumab and Reirradiation in Bevacizumab Naïve 
and Bevacizumab Resistant Recurrent Glioblastoma (DF/HCC #18-277) 
 
NCT Number: NCT03661723 
 
Document: Protocol 
 
Date of Document: July 26, 2021 (v. 6.0) 
 


 
 
Page 1 
NCI Protocol #: 
N/A 
 
DF/HCC Protocol #: 18-277  
 
Merck Protocol #: 
3475-787  
 
TITLE:   Phase II Trial of Pembrolizumab and Reirradiation in Bevacizumab Naïve and 
Bevacizumab Resistant Recurrent Glioblastoma 
 
 
Coordinating Center: 
 
 
Center for Neuro-Oncology, Dana-Farber Cancer Institute 
 
Principal Investigator (PI): 
David A. Reardon, M.D. 
 
Center for Neuro-Oncology, Dana-Farber Cancer Institute 
 
450 Brookline Avenue, D2134, Boston, MA 02215 
 
Telephone: 617-632-4750 
 
Fax: 617-632-4773 
 
E-mail: david_reardon@dfci.harvard.edu 
 
Other Investigators: 
Fabio Iwamoto, M.D. 
 
Columbia University Medical Center 
The Neurological Institute of New York, 710 West 168th Street, 
9th Floor, New York, NY 10032-3784 
 
Telephone – 212-342-0571 
 
Fax – 212-342-1246 
 
E-mail: fi2146@cumc.columbia.edu 
 
 
Tony J. Wang, M.D. 
 
Department of Radiation Oncology 
Columbia University Medical Center/Presbyterian Hospital and 
Vanderbilt Clinic 
 
622 West 168th Street 
 
New York, NY 10032 
 
Telephone – 212-305-5050 
 
Fax: 212-342-1246 
 
 
Shyam Tanguturi, M.D. 
 
Department of Radiation Oncology 
 
Dana-Farber Cancer Institute 
 
450 Brookline Avenue 
 
Boston, MA 02215 
 
Telephone: 617-732-6310 
 
Fax: 671-394-2668 
 
Biostatistician:  
 
 
Alona Muzikansky, MA 
Massachusetts General Hospital Biostatistics Center 
50 Staniford Street, Suite 560 
Boston, MA 
Phone: 617-724-6985 
Fax: 617-724-9878 
E-mail: amuzikansky@partners.org 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
2 
 
 
Sponsor Team  
 
 
Coordinator(s):  
 
Christine Sceppa McCluskey 
 
Responsible Research  
Jennifer Stefanik, NP; Lisa Doherty, NP; Chrissy Taubert, NP;  
Nurses / NPs / PA:   
Alexandra Torres, PA; Johny Chau, RN  
 
Investigational Agent:  Pembrolizumab (MK-3475), supplied by Merck & Co., Inc. 
 
IND #:  138489  
IND Sponsor: David A. Reardon, MD 
 
Protocol Type / Version # / Version Date: 
Original / v. #6.0 / July 26, 2021 


 
 
Page 3 
figure 1  STUDY SCHEMA 
Continue on study treatment until:
• 24 months on pembrolizumab therapy,
• confirmation of disease progression, 
• or unacceptable toxicity.
Recurrent glioblastoma
(N=60)
bevacizumab-resistant
Cohort A
(n=24)
•
RT (2W)
•
+ Pembrolizumab 
every 3 weeks
Cohort B
(n=24)
•
RT (2W)
•
+ Pembrolizumab every 3 weeks
•
+ continuation bevacizumab 
every 3 weeks
Overall 
survival
Progression–
free survival
bevacizumab-naïve
Follow for disease status until 
PD or initiation of new tx
Follow for overall survival via telephone or 
medical record review until death, 
withdrawal of consent, or end of study
Active 
Follow-up
Long-Term 
Follow-up
KEY
Cycles = 3 weeks
RT = Radiation Therapy
2W = 2 weeks
AEs = Adverse Events
Off-Tx = Off-Treatment
PD = Progressive Disease
Off-Tx for PD
Off-Tx for Reason Other Than PD
PD during Follow-Up
Follow AEs for 30 days or until initiation of new therapy
Cohort A
(n=6)
(may treat up to 18)
•
RT (2W)
•
+ Pembrolizumab 
every 3 weeks
Cohort B
(n=6)
(may treat up to 18)
•
RT (2W)
•
+ Pembrolizumab every 3 weeks
•
+ continuation bevacizumab 
every 3 weeks
Response assessed by MRI ev 6 wks for first year, then ev 9 wks thereafter.
bevacizumab-naïve
bevacizumab-resistant
S T R A T I F Y  ( 1 : 1 )
S T R A T I F Y  ( 1 : 1 )
Safety Lead-In
Phase II


 
 
Page 4 
TABLE OF CONTENTS 
figure 1  STUDY SCHEMA ..........................................................................................................3 
1. 
TRIAL SUMMARY ............................................................................................................7 
2. 
OBJECTIVES ......................................................................................................................8 
2.1 
Study Design ............................................................................................................8 
2.2 
Primary Objective ....................................................................................................9 
2.3 
Secondary Objectives...............................................................................................9 
2.4 
Exploratory Objectives ............................................................................................9 
3. 
BACKGROUND .................................................................................................................9 
3.1 
Study Disease(s).......................................................................................................9 
3.2 
Pembrolizumab ......................................................................................................10 
3.3 
Re-Irradiation .........................................................................................................11 
3.4 
Study Rationale ......................................................................................................12 
3.5 
Correlative Studies Background ............................................................................14 
4. 
PARTICIPANT SELECTION ...........................................................................................15 
4.1 
Eligibility Criteria ..................................................................................................15 
4.2 
Exclusion Criteria ..................................................................................................19 
4.3 
Inclusion of Women and Minorities ......................................................................22 
5. 
REGISTRATION PROCEDURES ...................................................................................23 
5.1 
General Guidelines for DF/HCC Institutions ........................................................23 
5.2 
Registration Process for DF/HCC Institutions .......................................................23 
5.3 
General Guidelines for Other Investigative Sites ..................................................23 
5.4 
Registration Process for Other Investigative Sites.................................................23 
6. 
TREATMENT PLAN ........................................................................................................24 
6.1 
Treatment Regimen ................................................................................................24 
6.2 
Allocation of accrual to two parallel non-comparative treatment arms .................27 
6.3 
Patient Evaluability and Replacement ...................................................................27 
6.4 
Agent Administration.............................................................................................27 
6.5 
Pre-Treatment Criteria ...........................................................................................29 
6.6 
General Concomitant Medication and Supportive Care Guidelines ......................29 
6.7 
Duration of Therapy and Criteria for Taking Participants Off Protocol 
Treatment ...............................................................................................................36 
6.8 
Post-Therapy Adverse Events ................................................................................37 
6.9 
End of Treatment Evaluation and 30-day Post Last Dose Follow-Up ...................37 
6.10 
Active Follow-Up ..................................................................................................37 
6.11 
Long-term Follow-Up ............................................................................................37 
6.12 
Criteria for Taking a Participant Off Study ...........................................................37 
6.13 
Participant Replacement Strategy ..........................................................................38 
6.14 
Beginning and End of the Trial ..............................................................................38 
6.15 
Criteria for Early Trial Termination ......................................................................39 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
5 
 
7. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................39 
7.1 
Dose Selection/Modification: General Information...............................................39 
7.2 
Pembrolizumab Dose Modifications......................................................................40 
7.3 
Re-Irradiation Dose Modification/Interruption/Discontinuation ...........................47 
7.4 
Bevacizumab Dose Modification/Interruption/Discontinuation (Cohort B) .........47 
8. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................50 
8.1 
Anticipated Toxicities ............................................................................................50 
8.2 
Definitions..............................................................................................................52 
8.3 
Evaluating Adverse Events ....................................................................................54 
8.4 
Procedures for AE and SAE Recording and Reporting .........................................58 
9. 
AGENT INFORMATION .................................................................................................65 
9.1 
Investigational Product:  Pembrolizumab ..............................................................65 
9.2 
Bevacizumab ..........................................................................................................68 
10. 
BIOMARKER STUDIES ..................................................................................................69 
10.1 
Archival Tumor PD-L1 Expression .......................................................................69 
11. 
STUDY CALENDAR  (Protocol Table 12).....................................................................71 
12. 
MEASUREMENT OF EFFECT........................................................................................74 
12.1 
Anti-Tumor Effect Definitions ..............................................................................74 
12.2 
Response/Progression Categories ..........................................................................74 
12.3 
Methods for Evaluation of Measurable Disease ....................................................77 
12.4 
Evaluation of Best Response .................................................................................77 
12.5 
Study Continuation Beyond Initial Progressive Disease .......................................78 
12.6 
Central Radiology Review .....................................................................................80 
12.7 
Neurologic Assessment in Neuro-Oncology (NANO) Scale .................................81 
13. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................81 
13.1 
Data Reporting .......................................................................................................81 
14. 
STATISTICAL ANALYSIS PLAN ..................................................................................83 
14.1 
Statistical Analysis Plan Summary ........................................................................83 
14.2 
Statistical Analysis Plan .........................................................................................83 
15. 
PUBLICATION PLAN .....................................................................................................89 
16. 
REFERENCES .................................................................................................................90 
APPENDIX A:  PERFORMANCE STATUS CRITERIA ...........................................................95 
APPENDIX B:  Study Safety Reporting Coversheet ....................................................................95 
APPENDIX C:   Pembro + Re-RT Tissue Requisition/Submission Form .....................................96 
APPENDIX D   NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) SCALE98 
APPENDIX E  Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety 
Monitoring Plan .............................................................................................................100 
APPENDIX F   Merck Drug Supply Request Form: Pembrolizumab ........................................116 
APPENDIX G   Quality of Life (QoL) Assessment: EORTC QLQ-C30 .................................117 
APPENDIX H   Radiation Therapy Guidelines (To be provided to Radiation Oncologist) 119 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
6 
 
LIST OF TABLES 
 
Table 1. Trial Summary 
Table 2. Adequate Organ Function Laboratory Values 
Table 3. Trial Treatment Overview 
Table 4. Pembrolizumab Infusion Reaction Treatment Guidelines 
Table 5. Pembrolizumab Dose Modification Guidelines for Pembrolizumab-related irAEs 
Table 6. Pembrolizumab Dose Modification Guidelines for Other Pembrolizumab-related AEs 
Table 7. Bevacizumab Dose Management Due to Adverse Events (Regardless of 
Attribution) 
Table 8. Merck Clarifications re: Evaluating Adverse Events 
Table 9. Reporting to Study’s Overall PI and DFCI Coordinating Center, Merck, and IRB 
Table 10. Pembrolizumab Nomenclature Details 
Table 11. Pembrolizumab Study Supply Information 
Table 12. Study Calendar 
Table 13. Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Table 14. Summary of the RANO Response Criteria 
Table 15. Imaging and Treatment After 1st Radiologic Evidence of Progression 
Table 16. Study Data Submission Table 
Table 17. Stopping Rule for Unacceptable Toxicity 
Table 18. Accrual Targets by Gender, ethnic category and racial category 
Table I-1. Radiation Therapy Target Coverage and Dose Limits 
Table I-2. Normal Tissue Dose Limits 
Table I-3. Standard structure names and reference doses. 
 
 
 
 
LIST OF FIGURES 
 
Figure 1. Study Schema 
Figure 2. iRANO Algorithm for Treatment Decision Making for Radiographic Progression 
 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
7 
 
1. TRIAL SUMMARY 
Table 1. Trial Summary 
Abbreviated Title 
Pembrolizumab plus re-irradiation in recurrent GBM (Phase II) 
Sponsor Product 
Identifiers 
Pembrolizumab (MK-3475) 
Trial Phase 
Phase II 
Clinical Indication 
Treatment of patients with recurrent glioblastoma (GBM) who have received 1 or 
more previous standard treatment(s). 
Trial Type 
Interventional 
Type of control 
Historical controls 
Route of 
administration 
Intravenous and external beam radiotherapy 
Trial Blinding 
Unblinded Open-label 
Treatment Groups 
 
Cohort A:  Pembrolizumab (MK-3475) 200 mg once every 3 weeks (Q3W) plus 
re-irradiation 35Gy/10fx  
Cohort B:  Pembrolizumab (MK-3475) 200 mg Q3W plus re-irradiation 
35Gy/10fx plus bevacizumab (or biosimilar) 15 mg/kg once every 3 weeks (Q3W) 
Number of trial 
participants 
Approximately 60 participants will be enrolled (up to 70 participants may be 
enrolled with the goal of treating 60 eligible participants). 
Estimated duration 
of trial 
The Sponsor estimates that the trial will require approximately 48 months from the 
time the first participant signs the informed consent until the last participant’s last 
study-related phone call or visit.  
Duration of 
Participation 
Each participant will participate in the trial from the time the participant signs the 
informed consent form (ICF) through the final protocol-specified contact.   
After a screening phase of up to 28 days, eligible participants will be assigned to 1 
of 2 cohorts based on history of prior bevacizumab treatment.  Participants who are 
bevacizumab-naïve will be assigned to Cohort A, and participants who have 
previously been treated with bevacizumab will be assigned to Cohort B.  A safety 
lead-in is included for each Cohort. All participants enrolled will receive 
pembrolizumab 200 mg on Day 1 of each 3-week (21 day) cycle until disease 
progression or study withdrawal.  All participants enrolled will also receive 1 
course of re-irradiation therapy (35 Gy/10fx) administered during Cycle 1.  In 
addition to pembrolizumab and re-irradiation, participants in Cohort B will receive 
bevacizumab (or biosimilar) 15 mg/kg on Day 1 of each treatment cycle.  
Treatment in both cohorts will continue until disease progression is confirmed by 
the site per the Response Assessment in Neuro-Oncology (RANO) criteria, 
unacceptable adverse event(s) (AE), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the participant, 
participant decides to withdraw from study, noncompliance with trial treatment or 
procedures requirements, administrative reasons requiring cessation of treatment, 
for a maximum of 24 months of treatment (up to 35 possible administrations) of 
pembrolizumab.   
After the end of treatment, each participant will be followed for 30 days for the 
occurrence of AEs and spontaneously reported pregnancy (described in Section 
7.2).  Participants with a Serious AE (SAE) will continue to be followed until 
death, SAE resolution, or SAE stabilization.  
Participants who discontinue for reasons other than disease progression will have 
post-treatment follow-up for disease status until disease progression is confirmed 
by the site, initiating a non-study cancer treatment, withdrawing consent, or 
becoming lost to follow-up.  All participants will be followed by telephone or 
medical record review for overall survival until death, withdrawal of consent, or 
the end of the study. 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
8 
 
2. OBJECTIVES 
 
2.1 
Study Design 
 
This is a multicenter, open-label, phase II trial of pembrolizumab plus re-irradiation among 
recurrent glioblastoma patients enrolled to two parallel, non-comparative treatment arms 
including patients who are bevacizumab naïve (Arm A, n=30) and patients who are 
bevacizumab-resistant (Arm B, n=30). The toxicity of the study regimen for each cohort has not 
been formally evaluated among recurrent glioblastoma patients; thus a safety lead-in is included 
for each cohort (Section 6.1) and will define the maximum tolerated dose (MTD)/recommended 
phase II dose (RP2D) of pembrolizumab for each cohort independently. 
 
Participants will be evaluated every 6 weeks with radiographic imaging to assess response to 
treatment in the first year and every 9 weeks thereafter. Modified Response Assessment in 
Neuro-Oncology (RANO) criteria1 will be used as the primary efficacy endpoint of response 
rate. RANO will be adapted as described in Section 12.0 due to the tumor response patterns seen 
with pembrolizumab treatment (e.g., tumor flare); these criteria will be used for treatment 
decisions by the sites. Adverse events will be monitored throughout the trial and graded in 
severity according to the guidelines outlined in the NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0. Treatment with study therapy will continue for a 
maximum of 24 months of treatment (up to 35 possible administrations) of pembrolizumab, or 
until documented disease progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the participant, 
participant withdraws consent, pregnancy of the participant, noncompliance with trial treatment 
or procedure requirements, or administrative reasons. After the end of treatment, each participant 
will be followed for 30 days for adverse event monitoring. Participants who discontinue 
treatment for reasons other than disease progression will have post-treatment follow-up of 
disease status until disease progression, initiation of a new anti-cancer treatment, withdrawing 
consent, or becoming lost to follow -up. All participants will be followed by telephone contact or 
medical record review for overall survival until death, withdrawal of consent or the end of the 
study, whichever comes first.  
 
The primary objective of the trial is to evaluate the anti-tumor activity of pembrolizumab when 
administered with re-irradiation versus the appropriate historical controls as measured by overall 
radiographic response (ORR) and overall survival at 12 months among participants with 
bevacizumab-naïve recurrent glioblastoma and at 6 months for those with bevacizumab-resistant, 
recurrent glioblastoma. Secondary objectives include safety and tolerability, progression-free 
survival (PFS), overall survival (OS), and ORR duration.  
 
This study will be conducted in conformance with Good Clinical Practices.  
 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Study Calendar Section 11.0.  
 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
9 
 
2.2 
Primary Objective 
 
2.2.1 Objective: To evaluate the efficacy of the combination of pembrolizumab and re-RT in 
bevacizumab naïve patients (Cohort A) and bevacizumab resistant patients (Cohort B) as 
measured by ORR per Response Assessment in Neuro-Oncology (RANO, for both 
cohorts) and OS at 12 months (cohort A) and OS at 6 months (Cohort B). 
 
Hypothesis: Administration of pembrolizumab with re-irradiation will result in a clinically 
meaningful benefit compared to the appropriate historical controls as measured by ORR or OS 
among participants with recurrent glioblastoma. 
 
2.3 
Secondary Objectives 
 
2.3.1 Objective: To evaluate the safety and tolerability of the therapy used in each cohort. 
2.3.2 Objective: To estimate duration of response in each cohort per RANO criteria.  
2.3.3 Objective: To estimate median PFS and PFS at 6 months in each cohort. 
2.3.4 Objective: To estimate median OS in each cohort. 
 
Hypothesis: Intravenous administration of pembrolizumab with re-irradiation will result in a 
clinically meaningful benefit compared to historical controls as measured by PFS, OS and ORR 
duration among participants with bevacizumab-naïve and bevacizumab-refractory, recurrent 
glioblastoma. 
 
2.4 
Exploratory Objectives 
 
2.4.1 Objective: To evaluate whether archival tumor expression of PD-L1, tumor infiltrating 
lymphocytes features, or T cell inflamed gene expression profile are associated with 
outcome.  
2.4.2 Objective: To evaluate Neurologic Assessment in Neuro-Oncology (NANO) in each 
cohort 
2.4.3 Objective: To evaluate the change of Patient Reported Outcome scores from baseline to 
post-baseline time-points using the EORTC QLQ-C30. 
2.4.4 Objective: To estimate ORR per iRANO 
 
 
3. BACKGROUND 
 
3.1 
Study Disease(s) 
 
Glioblastoma (GBM), the most common primary brain neoplasm in adults, remains incurable. 
Approximately 13,000 new cases of GBM are diagnosed in the US each year with an estimated 
global incidence of 3.5/100,000 people.2 Outcome following current standard of care therapy 
which includes surgery, radiation therapy and temozolomide remains poor with a median 
survival of 14.6 months and a five year survival rate of under 10%.3 Following recurrence, no 
therapy has been established to prolong survival and such patients represent a dire unmet need in 
modern day oncology.4 Although bevacizumab, a blocking antibody against vascular endothelial 
growth factor (VEGF), is FDA-approved for recurrent GBM, a recent phase 3 study 
demonstrated that it improves progression-free survival (PFS) but not overall survival (OS).5 
Furthermore, outcome following bevacizumab progression is dismal with a median OS of only 4 
months.6 Innovative treatment options are desperately needed. 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
10 
 
3.2 
Pembrolizumab 
 
Refer to the pembrolizumab Investigator’s Brochure for detailed information on pembrolizumab. 
 
3.2.1 Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
3.2.2 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades.7  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such 
as melanoma.8,9 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD-L1 and/or PD-L2).10,11 
 
The structure of murine PD-1 has been resolved.12  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the 
immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta 
(PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the CD3 T-cell 
signaling cascade.11,13  The mechanism by which PD-1 down-modulates T-cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping set 
of signaling proteins.14,15  PD-L1 has been shown to be upregulated by a number of aggressive 
cancers including glioblastoma16,17 and its expression has been associated with a poorer outcome 
among glioblastoma patients.17 As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in glioblastoma. 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
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3.2.3 Preclinical and Clinical Trial Data 
 
Refer to the pembrolizumab Investigator’s Brochure for preclinical and clinical data. 
 
3.3 
Re-Irradiation 
 
3.3.1 Background 
A hypofractionated course of reirradiation has been shown to provide modest therapeutic benefit 
for recurrent GBM patients18-21 including those who are bevacizumab-refractory22,23 and the 
safety of re-irradiation with concurrent bevacizumab for recurrent GBM patients has been 
previously established.24 Nonetheless, the primary goal of incorporating reirradiation in this 
study is to exploit the ability of radiation therapy to augment immune responses.25 Radiation 
therapy can enhance anti-tumor immune responses by two primary mechanisms including: 1) 
increasing exposure of tumor antigens through immunogenic cell death and; 2) generating 
immuno-adjuvant effects through induction of a wide array of immuno-activating modulators.  
The dose and fractionation of radiotherapy can affect the degree and type of cell death in a 
tissue-specific manner26 and immunogenic cell death from radiotherapy leads to enhanced 
efficiency of transfer of antigens from dendritic cells to T-cells, which in turn are capable of 
activating tumor-specific T cells resulting in increased therapeutic efficacy.27 In addition, 
radiotherapy can act as an immunoadjuvant by enhancing expression of several proinflammatory 
molecules to enhance anti-tumor immune responses including cytokines such as CXCL9, 
CXCL10, CXCL16, IL-1β, TNFα, type I interferons,28 as well as death receptors,29 MHC class I 
molecules,30 co-stimulatory molecules,31 adhesion molecules32 and stress-induced ligands.33 
Emerging clinical data supports the ability of radiotherapy to enhance anti-tumor activity both 
locally as well as systemically through induction of the abscopal effect.34 Furthermore, 
preclinical studies utilizing an immunocompetent orthotopic GBM model demonstrate that an 
abbreviated course of radiotherapy can enhance the therapeutic efficacy of immune checkpoint 
blockade including the induction of long-term survivors.35,36  
 
3.3.2 Rationale for Dosing Schedule 
Fractionated radiotherapy will be administered according to established, standard-of-care 
guidelines utilizing intensity-modulated radiation therapy (IMRT), 3-dimensional conformal 
radiation therapy (3D-CRT) or proton beam radiation therapy at a dose of 3.5 Gy/fraction times 
10 fractions (5 days a week for 2 weeks). Daily image-guided radiation therapy (IGRT) is 
required including non-volumetric (Orthogonal or near-orthogonal 2D imaging that is integrated 
with the radiation delivery device) and volumetric (diagnostic CT, cone beam CT with MV or 
kV x-ray beam, MRI-linac or Tomotherapy technology) systems. Although a variety of dosing 
schedules of re-irradiation have been utilized for recurrent glioblastoma patients, the largest 
series have utilized a targeted cumulative dose of 35-36 Gy administered over 10-18 
fractions.19,37,38 In general, these schedules have been well tolerated with adverse events typically 
limited to mild and manageable acute events, including fatigue, alopecia and nausea, as well as 
negligible rates of serious late events such as CNS toxicity or radiation necrosis. For example, 
among 147 patients with recurrent high-grade glioma reported by Fogh et al who received a 
median of 3.5 Gy/fraction times 10 fractions over 2 weeks, all patients were able to complete the 
prescribed radiation dose without interruption and no patients demonstrated clinically significant 
acute morbidity, while no patients required hospitalization or surgery for early acute or delayed 
toxicity. In this series, only one patient was reported to have developed a serious (grade 3) late 
CNS toxicity.19 
 


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Limited prospective data exist regarding the safety of immune checkpoint therapy when 
combined with radiotherapy. Although both immune checkpoint blockade and radiotherapy can 
increase inflammatory reactions and cerebral edema with published case reports of radiation 
necrosis,39 studies to date in metastatic brain tumor patients demonstrate low rates of 
symptomatic radiation necrosis for combined modality therapy which do not appear to be 
significantly increased compared to radiation alone.40-45 In this same patient population, one 
study to date reveals a modest increase in grade 3 seizures for patients treated with combined 
modality therapy compared to those treated with radiation therapy alone.46   
 
3.4 
Study Rationale 
 
3.4.1 Rationale for Trial and Selected Population 
Inhibitors of programmed death 1 (PD-1) signaling, such as pembrolizumab, have achieved 
dramatic benefit across a spectrum of cancers, although only a subset of patients respond.47 
Preliminary results of initial clinical trials evaluating pembrolizumab for recurrent GBM 
demonstrate similar findings. Among 26 patients treated with single agent pembrolizumab, there 
was one partial response (4%), while 44% of patients remained progression-free for at least six 
months and the median OS was 14 months.48  Results of a recently reported randomized phase 
III study of nivolumab, another PD-1 blocking antibody, confirmed a low rate of therapeutic 
benefit among recurrent glioblastoma patients.49 Specifically, the ORR for patients treated with 
nivolumab was only 8%, although the durability of radiographic response was encouraging at 
11.4 months. One reason for the low rate of therapeutic benefit observed to date is that GBM is a 
“cold” tumor, characterized by a relatively low rate of mutational load and an overall low level 
of immune cell infiltrate.50-54  
 
Tumors with a higher immune cell infiltrate exhibit a higher rate of therapeutic benefit with PD-
1 blockade. Strategies to increase the number of infiltrating immune cells into the tumor 
microenvironment offer the potential to increase the rate of achieved therapeutic benefit 
associated with PD-1 blockade. In the current submission, we propose a phase 2 study to 
evaluate the impact of re-irradiation (re-RT), as a strategy to increase immune cell infiltration 
into the tumor microenvironment and thereby generate a “hot” tumor microenvironment, when 
combined with pembrolizumab for recurrent GBM patients.  
 
The rationale for adding re-irradiation in the current proposal is based on several factors. First, 
preclinical data in several solid tumor types demonstrates enhanced activity when RT is 
combined with either PD-1 blockade or dual blockade of PD-1 and CTLA-4.55   In addition, 
radiation therapy has been shown to enhance the therapeutic benefit of anti-PD-1 treatment in an 
orthotopic, immunocompetent GBM model,35 while blocking PD-L1 can reverse radiation 
resistance.56  Second, radiation therapy has been shown to induce immunogenic cell death26 
which can augment antigen-specific anti-PD-1 immune responses via cross presentation of tumor 
antigens.57 Third, re-RT alone is considered a standard of care with modest benefit observed 
among a subset of recurrent GBM patients.18,19,38 Fourth, local radiation therapy can generate 
abscopal responses at distant tumor sites among oncology patients34,58 suggesting that such 
responses beyond the targeted radiation field could provide benefit for diffusely infiltrative 
tumors such as GBM.  
 


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In addition, a highly encouraging rate of durable radiographic response has been observed 
anecdotally among recurrent GBM patients treated with PD-1 blockade and re-RT. Specifically, 
a recent retrospective series at Columbia University included 20 consecutive patients with 
recurrent high-grade glioma (18 GBM) who were treated with re-RT and anti-PD-1 therapy.59 
Most patients were heavily pre-treated including a median number of 2 (range, 1-4) prior salvage 
treatments while 55% had progressed on prior bevacizumab. Eight patients received 
pembrolizumab (2 mg/Kg q3w) and 12 patients received nivolumab (3 mg/Kg or 240 mg q2w). 
The median re-RT dose was 35 Gy (12 Gy to 35 Gy). There were 7 confirmed partial responses 
(35% ORR), including 4/9 bevacizumab naïve (44%) and 3/11 bevacizumab failure patients 
(27%).  The median duration of response was 5 months (2.2 to 10+ months), median PFS was 4 
months and median OS was 10 months. There were neither obvious cases of cerebral edema 
related to treatment nor any new unexpected adverse events. Fifteen patients (75%) had stable or 
reduced dexamethasone dosing, while five patients (25%) required a mild increase of 
corticosteroid dosing (2-4 mg).  
 
Our proposed study is therefore designed to prospectively evaluate the role of re-RT when added 
to pembrolizumab PD-1 blockade for recurrent GBM patients.  
 
3.4.2 Justification for Pembrolizumab Dose 
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor type.  
As outlined below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg 
Q3W versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and 
KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, 
KN001 Cohort F2 and KN006).  These studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5- to 7.5-fold difference in 
exposure.  The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest 
doses studied.  Subsequently, flat dose-exposure-response relationships were also observed in 
other tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor 
type.  These findings are consistent with the mechanism of action of pembrolizumab, which acts 
by interaction with immune cells, and not via direct binding to cancer cells. 
 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 


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PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor. 
 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 
 
3.4.3 Rationale for Efficacy Endpoints 
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab when administered with re-irradiation compared to historical controls among 
participants with bevacizumab-naïve (cohort A) and bevacizumab-refractory (cohort B) recurrent 
glioblastoma. Overall radiographic response (ORR) and overall survival at 12 months (cohort A) 
and overall survival at 6 months (cohort B) will be the primary endpoints, and ORR duration, as 
well as median OS and PFS (median and at 6 months) will be secondary efficacy endpoints.  
Response per modified RANO criteria1 as assessed by the investigator will be used for efficacy 
endpoints (Section 12). RANO will also be used by the local site to determine eligibility and 
make treatment decisions. 
 
3.4.4 Safety endpoints 
An important secondary objective of this study is to characterize the safety and tolerability of 
pembrolizumab when administered with re-irradiation among participants with recurrent 
glioblastoma. The safety analysis will be based on participants who experience toxicities as 
defined by CTCAE 4.0 criteria. Safety will be assessed by quantifying the toxicities and grades 
experienced by participants who have received pembrolizumab with re-irradiation, including 
serious adverse events (SAEs) and events of clinical interest (ECIs).  
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to all 
AEs, SAEs, and fatal AEs. Furthermore, specific immune-related adverse events (irAEs) will be 
collected and designated as immune-related events of clinical interest (ECIs) as described in 
Section 8.4.4.2. 
 
 
3.5 
Correlative Studies Background 
 
When available, archival tumor material will be evaluated for tumor infiltrating lymphocytes, 
PD-1 expressing lymphocytes, measurement of tumor cell PD-L1 expression and evaluation of 
an inflamed T cell gene expression profile. 
 
 


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4. PARTICIPANT SELECTION 
 
Male/female participants of at least 18 years of age with recurrent glioblastoma will be enrolled 
in this trial.  
 
Screening evaluations are detailed in Study Calendar (Section 11). All assessments are to occur 
within 14 days of start of study therapy except where otherwise noted. The participant must be 
thoroughly informed about all aspects of the study, including the study visit schedule and 
required evaluations and all regulatory requirements for informed consent. The written informed 
consent must be obtained from the participant prior to enrollment.  
 
Following registration, any additional laboratory assessments obtained prior to start of treatment 
will not be used to re-confirm eligibility. Please refer to Section 7 Dosing Delays/Dose 
Modifications for toxicity management between registration and start of study treatment. 
 
4.1 
Eligibility Criteria  
 
In order to be eligible for participation in this trial, all participants must meet the following 
criteria on screening examination:  
 
4.1.1 Have histologically confirmed World Health Organization (WHO) Grade IV 
glioblastoma. Participants will be eligible if the original histology was low-grade glioma 
and a subsequent histological diagnosis of glioblastoma is made. Other WHO grade IV 
glial neoplasms such as gliosarcoma are NOT eligible. 
 
4.1.2 Be willing and able to provide written informed consent/assent for the trial. 
 
4.1.3 Be ≥ 18 years of age on day of signing informed consent.  
 
4.1.4 Have a Karnofsky performance status (KPS) ≥ 70 (Appendix A).  
 
4.1.5 Participants must have shown unequivocal evidence for tumor progression by MRI scan.  
 
4.1.6 MRI within 14 days prior to start of study therapy. MRIs should include vascular imaging 
when possible. Corticosteroid dose must be stable or decreasing for at least 5 days prior 
to the scan. If steroids are added or the steroid dose is increased between the date of the 
screening MRI scan and the start of treatment, a new baseline MRI or CT is required.  
 
4.1.7 Measurable disease as per RANO criteria. 
 
4.1.8 Be at first or second relapse (cohort A). For cohort B, participants must have progressed 
on no more than one prior bevacizumab-containing regimen (cohort B). Participants who 
were treated with prior bevacizumab but did not progress or experienced significant 
toxicity, are not eligible. 
NOTE: Relapse is defined as progression following initial therapy (i.e., radiation ± 
chemotherapy).  
• 
If the participant had a surgical resection for relapsed disease and no antitumor 
therapy was instituted for up to 12 weeks, this is considered one relapse.  
• 
For participants who had prior therapy beyond surgery for a low-grade glioma that 
is considered standard of care for high-grade glioma (radiation therapy, 


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chemotherapy with temozolomide or nitrosoureas, etc), the surgical diagnosis of 
glioblastoma will be considered the first relapse.  
• 
Patients in screening for Cohort B may have received any # of non-bevacizumab-
containing regimens. 
 
4.1.9 Previous first line therapy with at least radiotherapy utilizing standard dosing of CNS 
radiation - for either high-grade or low-grade glial neoplasm  
 
4.1.10 From the projected start of scheduled study treatment, the following time periods must 
have elapsed:  
1. At least 3 weeks from prior surgical resection  
a. Participants having undergone recent resection of recurrent or progressive 
tumor will be eligible as long as they have recovered from the effects of 
surgery and have measurable residual disease prior to starting study therapy.  
2. At least 1 week from stereotactic biopsy  
3. At least 6 months from completion of prior radiotherapy   
a. If patients have not passed an interval of at least 6 months, they may still be 
eligible if they meet the following criteria: 
i. New area of enhancement outside the 80% isodose line of the original 
radiation field as determined by the treating investigator. 
4. At least 4 weeks (or 5 half-lives, whichever is shorter) from any investigational agent 
5. At least 4 weeks from cytotoxic therapy  
a. Exceptions:  
i. At least 23 days for temozolomide 
ii. At least 6 weeks from nitrosoureas 
b. At least 4 weeks (or 5 half-lives, whichever is shorter) for daily administered 
chemotherapeutics  
6. At least 6 weeks from antibodies 
7. At least 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor 
therapies (not including tumor treating fields or cancer vaccines); at least 1 week 
from NovoTTF (Optune) or other tumor treating fields and cancer vaccines 
8. Cohort B patients only: Day 1 of bevacizumab (or biosimilar) on-study must be at 
least 3 weeks from last dose of prior course of Avastin/bevacizumab. 
 
4.1.11 Participants must have recovered to grade 0 or 1 or pre-treatment baseline from clinically 
significant toxic effects of prior therapy (exceptions include alopecia, laboratory values 
listed per inclusion criteria, and lymphopenia, which is common after therapy with 
temozolomide).  
 
4.1.12 Demonstrate adequate organ function as defined in Table 2, all screening labs should be 
performed within 14 days of treatment initiation.  
 
Table 2. Adequate Organ Function Laboratory Values 
 
Laboratory Values System 
Laboratory Value 
Hematologic 
Absolute neutrophil count (ANC) 
≥1,500 /mcL  
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/La  


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Table 2. Adequate Organ Function Laboratory Values (cont.) 
 
Laboratory Values System 
Laboratory Value  
Renal 
Serum creatinine OR  
Measured or calculatedb creatinine 
clearance (GFR can also be used in 
place of creatinine or CrCl) 
≤1.5 X institutional upper limit of normal (ULN) OR  
≥60 mL/min for participant with creatinine levels > 1.5 
X institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X institutional ULN 
OR  
Direct bilirubin ≤ institutional ULN for participants 
with total bilirubin levels > 1.5 X institutional ULN  
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X institutional ULN OR  
≤ 5 X institutional ULN for participants with Gilberts 
syndrome 
Coagulation 
International Normalized Ratio (INR) 
or Prothrombin Time (PT)  
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5 X institutional ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is within 
therapeutic range of intended use of anticoagulants  
Pulmonary 
Resting baseline oxygen saturation by 
pulse oximetry 
≥92% at rest 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
NOTE: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies. 
 
4.1.13 Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, must have a negative urine or serum pregnancy within 72 
hours prior to registration. If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required.  
• Women in the following categories are not considered WOCBP: 
o Premenarchal 
o Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history 
interview. 
 


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o  Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without 
an alternative medical cause.  
• A high follicle stimulating hormone (FSH) level in the 
postmenopausal 
range 
may 
be 
used 
to 
confirm 
a 
postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, 
confirmation 
with 
two 
FSH 
measurements 
in 
the 
postmenopausal range is required.  
 Females on HRT and whose menopausal status is in doubt will be 
required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. 
Otherwise, they must discontinue HRT to allow confirmation of 
postmenopausal status before study enrollment. 
 
4.1.14 Women of child-bearing potential (WOCBP; see definition above), must agree to use a 
highly effective method of contraception consistently and correctly as described below 
during study treatment and for 120 days after study discontinuation.  
1. Highly Effective Contraceptive Methods That Are User Dependent a (Failure rate of < 
1% per year when used consistently and correctly.) 
a. Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
i. Oral  
ii. Intravaginal  
iii. Transdermal  
iv. Injectable 
b. Progestogen-only hormonal contraception b, c 
i. Oral  
ii. Injectable 
2. Highly Effective Methods That Have Low User Dependency (Failure rate of <1% per 
year when used consistently and correctly) 
a. Progestogen- only contraceptive implant b, c 
b. Intrauterine hormone-releasing system (IUS) b 
c. Intrauterine device (IUD) 
d. Bilateral tubal occlusion 
e. Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception should 
be used. 
f. Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 


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NOTES: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
a. Typical use failure rates are lower than perfect-use failure rates (i.e. when used 
consistently and correctly).  
b. If hormonal contraception efficacy is potentially decreased due to interaction with 
study treatment, condoms must be used in addition to the hormonal contraception 
during the treatment period and for at least during study treatment and for 120 days 
after study discontinuation after the last dose of study treatment.   
c. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit 
ovulation. 
 
4.1.15 Male participants must agree to use at least one of the following methods of 
contraception starting with the first dose of study therapy through 120 days after the last 
dose of therapy:  
1. Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
2. Use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year as described in Eligibility criterion 4.1.14 when having penile-
vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant. 
a. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during 
each episode of penile penetration. 
 
 
4.2 
Exclusion Criteria 
 
The participant must be excluded from participating in the trial if the participant:  
 
4.2.1 Has recurrent tumor greater than 6 cm in maximum diameter 
 
4.2.2 Is currently participating or plans to participate in another study of an investigational 
agent or using an investigational device.  
 
Note:  Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been at least 4 weeks (or 5 half-lives, whichever is shorter) 
from the last dose of the previous investigational agent to date of registration. 
4.2.3 Has tumor primarily localized to the brainstem or spinal cord.  
 
4.2.4 Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease. 
NOTE: Not all instances of multifocal disease will exclude a potential patient; only 
patients with multifocal sites of active disease will be excluded.  (e.g. A patient with a 
previously treated lesion that remains stable would not be excluded.) 
 
Medical History/Conditions/Concomitant Medical Illnesses:  
 
4.2.5 Has a diagnosis of immunodeficiency.  
 


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4.2.6 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator. Examples include - but are not 
limited to - unstable angina pectoris, cardiac arrhythmia or psychiatric illness/social 
situations that would limit compliance with study requirements.  
 
4.2.7 Has history of known coagulopathy that increases risk of bleeding or a history of 
clinically significant hemorrhage within 12 months of start of study drug.  
 
4.2.8 Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan other than 
those that are grade ≤ 1 and either post-operative or stable on at least 2 consecutive MRI 
scans.  
 
4.2.9 Has gastrointestinal bleeding or any other hemorrhage/bleeding event CTCAE Grade > 3 
within 6 months of start of study drug.  
 
4.2.10 Has a known additional malignancy that is progressing or requires active treatment within 
1 year of start of study drug, except for those treated with surgical therapy only (e.g. 
basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical 
cancer that has undergone potentially curative therapy).  
 
4.2.11 Has active autoimmune disease requiring systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg thyroxine, insulin, or physiologic corticosteroid replacement for 
adrenal insufficiency or pituitary/hypothalamic dysfunction, etc.) is not considered a form 
of systemic treatment.  
 
4.2.12 Has history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.  
 
4.2.13 Has an active infection requiring systemic therapy. 
 
4.2.14 Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.  
 
4.2.15 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies) and 
is receiving antiretroviral therapy. Such patients are ineligible because of the potential for 
pharmacokinetic interactions with pembrolizumab and because these participants are at 
increased risk of lethal infections.  Appropriate studies will be undertaken in participants 
receiving combination antiretroviral therapy when indicated. 
 
4.2.16 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).  
 
4.2.17 Has a history of non-healing wounds or ulcers, or bone refractures within 3 months of 
fracture.  
 


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4.2.18 Has a history of arterial thromboembolism within 12 months of start of study drug. 
 
4.2.19 Has had clinically significant cardiovascular disease within 12 months of start of study 
drug, including myocardial infarction, unstable angina, grade 2 or greater peripheral 
vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart 
failure, or arrhythmias not controlled by outpatient medication, percutaneous 
transluminal coronary angioplasty/stent.  
 
4.2.20 Has a known history of active TB (Bacillus Tuberculosis) 
 
4.2.21 Has a known hypersensitivity to any of the study therapy products and/or any of their 
excipients.  
4.2.22 Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the 
trial, starting with the screening visit through 120 days after the last dose of trial 
treatment. Pregnant women are excluded because there is an unknown but potential risk 
for adverse events affecting a developing fetus and/or the mother secondary to treatment 
with pembrolizumab. There is also an unknown but potential risk for adverse events 
affecting nursing infants secondary to treatment of the mother with pembrolizumab, thus, 
breastfeeding must be discontinued if the mother is treated with pembrolizumab.   
 
Prior Therapy: 
 
4.2.23 Has received prior interstitial brachytherapy, implanted chemotherapy, stereotactic 
radiosurgery or therapeutics delivered by local injection or convection enhanced delivery 
(this exclusion applies to any locally administered therapy, including intratumoral 
vaccines).  
 
4.2.24 Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 or with an agent 
directed to another stimulatory or co-stimulatory T-cell receptor (eg CTLA-4, OX-40, 
CD137)  
 
4.2.25 Has received prior VEGF or VEGFR inhibitor therapy such as bevacizumab, cediranib, 
aflibercept, vandetanib, XL-184, sunitinib, etc. (Cohort A only) 
 
Other Meds:  
 
4.2.26 Is receiving any form of immunosuppressive therapy (e.g. chronic systemic steroid 
therapy exceeding dosage of 10 mg daily of prednisone equivalent) within 7 days prior to 
the first dose of study drug.  
 
4.2.27 Has 
received 
systemic 
immunosuppressive 
treatments, 
aside 
from 
systemic 
corticosteroids as described in Section 4.2.28 (such as methotrexate, chloroquine, 
azathioprine, etc), within six months of start of study drug.  
 


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4.2.28 Requires treatment with high dose systemic corticosteroids defined as dexamethasone > 2 
mg/day or bioequivalent for at least 3 consecutive days within 2 weeks of start of study 
drug.  
• 
Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone 
equivalents are permitted in the absence of active autoimmune disease. 
• 
Participants are permitted to use topical, ocular, intra-articular, intranasal, and 
inhalational corticosteroids (with minimal systemic absorption).  
• 
Physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 
mg/day prednisone equivalents.  
• 
A brief course of corticosteroids for prophylaxis (eg, contrast dye allergy) or for 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) is permitted. 
 
4.2.29 Requires therapeutic anticoagulation with warfarin at baseline; patients must be off 
warfarin or warfarin-derivative anti-coagulants for at least 7 days prior to starting study 
drug; however, therapeutic or prophylactic therapy with low-molecular weight heparin is 
allowed.  
 
4.2.30 Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include - but are not limited to - the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–
Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed. 
 
4.3 
Inclusion of Women and Minorities  
 
Both men and women of all races and ethnic groups are eligible for this trial.  
 


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23 
 
5. REGISTRATION PROCEDURES  
 
All 
sites 
should 
call 
the 
Study 
Coordinator 
at 
617-582-7101 
or 
email 
to 
NeuroOnc_Coor@dfci.harvard.edu to verify slot availability.  
 
5.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant must be taken off-study 
in the CTMS (OnCore) with an appropriate date and reason entered. 
 
5.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Participant Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
5.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
DFCI Coordinating Center staff.  All sites should contact the DFCI Coordinating Center to verify 
slot availabilities.  A list of required forms can be found in Appendix E. 
 
Following registration, participants should begin protocol therapy within 7 days. Issues that 
would cause treatment delays should be discussed with the Overall PI.  If there is an issue with 
meeting this specified timeframe, please contact study’s Overall PI for documented prospective 
approval.  If a participant does not receive protocol therapy within 7 days following registration, 
and study’s Overall PI has not approved the delay, the participant must be taken off-study in the 
CTMS (OnCore) with an appropriate date and reason entered.  The DFCI Coordinating Center 
should be notified of potential delays and participants not proceeding to receive study treatment 
as scheduled as soon as possible. 
 
5.4 
Registration Process for Other Investigative Sites 
 
Please refer to Appendix E (Section 3.7) for registration details. 
 


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6. TREATMENT PLAN 
 
This is a multicenter, open-label, phase II trial of pembrolizumab with re-irradiation among 
recurrent glioblastoma patients enrolled to two parallel non-comparative treatment arms 
including patients who are bevacizumab naïve (Cohort A) and those who have progressed on one 
prior bevacizumab regimen (Cohort B). The combinatorial regimens assessed for each cohort 
have not been formally evaluated for toxicity, thus an initial safety lead-in will be performed to 
define the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of 
pembrolizumab when administered with re-irradiation (Cohort A) and when administered with 
re-irradiation and bevacizumab (Cohort B) as detailed below. Of note, the adverse event profiles 
of pembrolizumab, radiation therapy and bevacizumab are in general non-overlapping, thus the 
agents are expected to be well tolerated when co-administered. The dose of pembrolizumab 
administered during the safety lead-in will not exceed the established phase II dose of 
pembrolizumab when administered as monotherapy. The safety lead-in also incorporates a de-
escalation of pembrolizumab dosing if unexpected dose-limiting toxicity is observed and follows 
standard 3+3 phase I guidelines. No investigational or commercial agents or therapies other than 
those described below may be administered with the intent to treat the participant's malignancy.  
Reported adverse events and potential risks are described in Section 8.  Appropriate dose 
modifications are described in Section 7. 
 
6.1 
Safety Lead-In Treatment Regimen 
The safety lead-in will utilize a standard 3+3 design to determine the RP2D/MTD of 
pembrolizumab for each cohort.  Pembrolizumab will initially be administered at 200 mg (flat 
dosing) intravenously (IV) every 3 weeks, which is the RP2D established for monotherapy 
administration. The dose of pembrolizumab administered during the safety lead-in will not 
exceed 200 mg IV every 3 weeks. Bevacizumab will be administered at 15 mg/kg IV every 3 
weeks for Cohort B. The first 6 patients for each cohort will be considered as safety lead-in and 
observed in groups of 3 for DLTs for an evaluation period of 42 days (see DLT definitions in 
Section 6.1.1) as follows for each cohort:  
 
• If at Dose Level 0, ≤1 of the first 3 patients develop DLT, 3 more patients will be 
enrolled to Dose Level 0. 
• If at Dose Level 0, >1 of the first 3 patients or >1 of the first 6 patients develop DLT, 
cohort enrollment will be stopped immediately, and re-started from the beginning with 
3+3 patients enrolled at a pembrolizumab dosing interval of 4 weeks (Dose Level -1). 
• If at Dose Level -1, >1 of the first 3 patients or >1 of 6 patients develop DLT, cohort 
enrollment will be stopped immediately, and re-started from the beginning with 3+3 
patients enrolled at a pembrolizumab dosing interval of 6 weeks (Dose Level -2). 
• If at Dose level -2, >1 of the first 6 patients develops DLT, the safety lead-in will be 
discontinued. In this case, the phase II portion of this study to the two independent 
cohorts will not be conducted. 
NOTE: Patients will need to be assessed on or after their actual Day 42 on treatment for the DLT 
assessment to be considered comprehensive. 
Dose-limiting toxicities (DLT) will be determined by toxicities related to pembrolizumab during 
or beginning over the first 42 days of treatment as defined below in Section 5.1.1.  
Any necessary dose de-escalations will be made by extending the dosing interval of 
pembrolizumab as detailed below (Table 3): 


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25 
 
Table 3 Dose levels and doses to be evaluated in Safety Lead-In 
 
 Pembrolizumab (Cohorts A&B) 
Bevacizumab (Cohort B) 
Dose Level 
Dose (mg) 
Frequency 
Dose (mg/kg) 
Frequency 
Zero (0) 
200 
Every 3 weeks 
15 
Every 3 weeks 
Minus one (-1) 
200 
Every 4 weeks 
15 
Every 3 weeks 
Minus two (-2) 
200 
Every 6 weeks 
15 
Every 3 weeks 
 
6.1.1 Definition of Dose-Limiting Toxicity (DLT) 
 
A DLT is defined as any grade ≥ 3 adverse event that is at least possibly, probably or definitely 
related to pembrolizumab during the DLT period unless judged by the treating Investigator to be 
more likely related to underlying tumor, concurrent medication or co-morbid event. The DLT 
period is considered the first 42 days of study therapy; the DLT period does not necessarily need 
to include labs and other evaluations taken during cycle 3 restaging). Events that are considered 
unlikely related to pembrolizumab, but at least probably related to bevacizumab will not be 
considered a DLT.   
The following exceptions will not be classified as DLT: 
• Grade 3 Immune-related adverse events (irAEs – see definition below) that downgrade to 
Grade ≤ 2 within 5 days, or to Grade ≤ 1 or baseline within 14 days after onset of the 
event, whereby maximal supportive care, including systemic corticosteroids, is permitted. 
• Grade 3 asymptomatic endocrinopathy, managed with or without systemic corticosteroid 
therapy and/or hormone replacement therapy. 
• Grade 3 inflammatory reaction attributed to a local antitumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc). 
• Grade 2 pneumonitis, neurological event, or uveitis that downgrades to Grade ≤ 1 within 
3 days, whereby maximal supportive care is permitted. 
• Liver transaminase elevation ≤ 8 times institutional ULN. 
• Total bilirubin ≤ 5 times institutional ULN. 
• Any pre-existing lab abnormality that deteriorates to Grade 3/4, but where the increment 
of deterioration is considered not clinically significant by Investigator, overall study 
Principal Investigator and sponsor. 
DLT will also include grade 2 immune-related adverse events that occur during the DLT period 
defined above that require interruption of pembrolizumab and do not improve to grade ≤ 1 with 
appropriate supportive care and symptomatic treatment with 14 days. 
 
Immune-related adverse events (irAEs) are defined as AEs of immune nature (i.e., inflammatory) 
in the absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. 
 


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While rules for adjudicating DLTs are specified above, an AE of Grade < 3 (except if listed as 
exempt above), may also be defined as a DLT after a consultation with the Sponsor and the 
overall study Principal Investigator, based on the established safety profile of pembrolizumab. 
 
Patients who experience DLT will be discontinued from study therapy and will enter the post-
study follow-up phase of the study (see Section 6.9-6.12). 
 
Adverse events that meet DLT criteria but occur outside the DLT window will be classified as 
unacceptable AEs and study treatment will be discontinued per Section 6.8  
 
6.2 
Phase II Treatment Regimen 
 
The dose of pembrolizumab to be administered in this trial for all patients (cohort A and cohort 
B) is 200 mg (flat dosing) every three weeks intravenously because this is the FDA approved 
dosing schedule for melanoma, non-small cell lung cancer, head and neck squamous cell 
carcinoma, classical Hodgkin’s lymphoma, urothelial carcinoma and microsatellite instability-
high cancers (see pembrolizumab package insert).  Re-irradiation will be administered to patients 
on cohort A and cohort B to achieve 35 Gy over ten fractions. Patients on Cohort B who have 
previously progressed on bevacizumab will continue bevacizumab – or biosimilar - at a dose of 
15 mg/kg intravenously every three weeks. 
 
Eligible, bevacizumab-naive patients will enroll to receive pembrolizumab plus re-irradiation 
(Cohort A; n=30). Eligible patients who have progressed on one prior bevacizumab regimen will 
enroll to receive pembrolizumab plus re-irradiation plus bevacizumab (or biosimilar) 
continuation (Cohort B; n=30). The outcome of each treatment arm will be assessed separately 
relative to appropriate historical controls.  
 
Each treatment cycle for both cohorts will be 3 weeks (21 days).  
 
The therapeutic agents to be used in this trial are outlined below in Table 3.  
 
Table 3. Trial Treatment Overview 
Treatment 
Cohort Dose/ 
Potency 
Dose 
Frequency 
(& window) 
Route of 
Administration 
Treatment 
Period 
Use 
Pembrolizumab 
A & B 
200 mg 
Q3W  
(+/- 3 days) 
IV infusion 
Day 1 of 
each cycle 
Experimental 
Re-irradiation 
A & B 
35 Gy 
Daily 
External beam 
5 days/ week  
x 2 weeks 
Standard of 
care 
Bevacizumab 
(or biosimilar) 
B 
15 mg/kg 
Q3W 
(+/- 3 days) 
IV infusion 
Day 1 of 
each cycle 
Standard of 
care 
 
Trial treatment should begin as close as possible to the date on which the participant is 
registered.  See Section 5.3. 
 
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations. 


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6.3 
Allocation of accrual to two parallel non-comparative treatment arms  
 
Patients meeting eligibility criteria will be enrolled to the appropriate treatment cohort of the 
study at the time of registration in the Clinical Trials Management System (CTMS) OnCore 
directly by their Study Team (for DF/HCC patients) or by DFCI Coordinating Center Staff (for 
External Sites); see Section 5. The outcome for each treatment arm will be assessed separately 
relative to appropriate historical controls.  
 
6.3.1 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigators and participants will know the 
treatment administered. 
 
6.3.2 Stratification 
Participants on this trial will be stratified to either Cohort A or Cohort B based on previous 
treatment with bevacizumab. 
 
6.4 
Patient Evaluability and Replacement 
 
The analysis of the primary endpoint will be based on both the intent-to-treat (ITT) and the per-
protocol (PP) populations. Patients who receive at least one dose of pembrolizumab and at least 
baseline and one post-baseline disease assessment will be included in the ITT population. 
Patients who receive at least 75% of the planned study re-irradiation therapy doses for each 
cohort and at least one dose of pembrolizumab, as well as respective disease assessments, 
without major protocol violations, are considered fully evaluable and will be included in the PP 
population. 
 
6.5 
Agent Administration 
 
Trial treatment should be administered after all procedures/assessments have been completed as 
detailed on the Study Calendar (Section 11.0).  
 
Order of Administration:  
• For cohort B participants: On days when participants receive both pembrolizumab and 
bevacizumab (or biosimilar), pembrolizumab will be administered first (see section 6.4.1 
for more information).  
• For all participants: When radiation is received on the same day as another study agent, it 
does not matter whether radiation is given before or after the other study agent(s). 
 
Trial treatment may be administered up to 3 days before or after the scheduled day of each cycle 
due to administrative reasons. All study treatments are anticipated to be administered on an 
outpatient basis; however, inpatient administration is permitted. 
 
6.5.1 Pembrolizumab Administration 
The rationale for selection of doses to be used in this trial is provided in Section 3.4.2 – 
Background and Rationale.  
 
The dose amount required to prepare the pembrolizumab infusion solution will be 200 mg (flat 
dosing) for patients enrolled to both cohorts of this study. Pembrolizumab will start within 1 
week of the start of re-irradiation and will then be administered at a dose frequency of every 3 
weeks (+/-3 days), on Day 1 of each 21-day treatment cycle. Pembrolizumab will be 


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administered as a 30 minute IV infusion.  Sites should make every effort to target infusion timing 
to be as close to 30 minutes as possible.  However, given the variability of infusion pumps from 
site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 
minutes: -5 min/+10 min). 
 
For cohort B participants receiving pembrolizumab and bevacizumab (or biosimilar), 
pembrolizumab will be administered first, and bevacizumab (or biosimilar) will begin no sooner 
than 1 hour after completion of pembrolizumab for the first cycle of therapy. Thereafter 
bevacizumab (or biosimilar) may begin upon completion of pembrolizumab.  
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
Pembrolizumab will be provided to patients enrolled on this study by Merck Pharmaceuticals. 
 
6.5.2 Re-irradiation  
Fractionated radiotherapy will be administered according to established, standard-of-care 
guidelines utilizing intensity-modulated radiation therapy (IMRT), 3-dimensional conformal 
radiation therapy (3D-CRT) or proton beam radiation therapy at a dose of 3.5 Gy/fraction times 
10 fractions (5 days a week for 2 weeks). Daily image-guided radiation therapy (IGRT) is 
required including non-volumetric (orthogonal or near-orthogonal 2D imaging that is integrated 
with the radiation delivery device) and volumetric (diagnostic CT, cone beam CT with MV or 
kV X-ray beam, MRI-linac or tomotherapy technology) systems.  Please refer to Appendix H for 
Recommended Radiation Therapy Guidelines (to be provided to radiation oncologist). 
 
Participants are permitted to receive re-irradiation on study as described in this section (and 
Appendix H) at the following locations:  
a. the Radiation Oncology Department of the participating institution; 
b. an IRB-approved satellite site of the participating institution; 
c. any NRG Oncology-approved site; 
d. or at another location, with prior documented approval from the study’s Overall PI. 
 
Re-irradiation will ideally start on Day 1 of pembrolizumab/bevacizumab (or biosimilar) Cycle 
1, but can start +/- 7 days from C1D1. 
 
6.5.3 Bevacizumab (or biosimilar)* Administration 
* DFCI recently released a guideline re: the use of commercial biosimilars in clinical trials, 
which states: “for standard of care treatment using biologic products in a clinical trial that are not 
paid for by sponsor and that are billed as standard of care to patient’s insurance, the biosimilar 
products dictated by the patient’s insurance would be used.”  Therefore, on this study, sponsor 
will allow the use of a bevacizumab biosimilar.  
 
For cohort B participants receiving pembrolizumab and bevacizumab (or biosimilar), 
bevacizumab (or biosimilar) will be dosed at 15 mg/kg intravenously every 3 weeks (+/- 3 days), 
on Day 1 of each 21-day treatment cycle.  Doses of bevacizumab (or biosimilar) must be at least 
10 days apart. The baseline weight of the participant will be used to calculate the bevacizumab 
(or biosimilar) dose unless there is a ≥ 10% change during the course of the study.  Alternatively, 
institutional standard practice for weight-based dose re-calculations can be utilized for 
bevacizumab (or biosimilar) dosing, provided site gets Overall PI’s documented approval to do 
so prospectively.  The rationale for the selection of bevacizumab (or biosimilar) dosing used in 


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this study is provided in the bevacizumab package insert. Bevacizumab (or biosimilar) will begin 
with the first pembrolizumab dose. The bevacizumab (or biosimilar) infusion will begin no 
sooner than 1 hour after completion of pembrolizumab for the first cycle of therapy. Thereafter 
bevacizumab (or biosimilar) may begin upon completion of pembrolizumab whenever both 
infusions fall on the same day. Bevacizumab (or biosimilar) should be stored, prepared and 
administered in accordance with each site’s institutional standards. 
 
6.6 
Pre-Treatment Criteria 
 
6.6.1 Initiation of Pembrolizumab and Re-irradiation (Cycle 1, day 1) 
Initiation of pembrolizumab and re-irradiation (plus bevacizumab - or biosimilar - for Cohort B 
participants) will commence for patients meeting clinical and laboratory eligibility criteria 
defined in Section 4. Results of assessments performed during eligibility screening (within 14 
days of initiation of study therapy) will be sufficient to start study therapy and will not need to be 
repeated prior to Cycle 1, day 1. 
 
6.6.2 Subsequent Cycles 
PEMBROLIZUMAB: Pembrolizumab dosing will continue every 3 weeks (+/- 3 days) unless 
criteria for dose interruption (Section 7.2) or study therapy discontinuation criteria (Section 6.7) 
are met. In the event of a dose delay, dosing will be resumed when criteria to resume treatment 
(Section 7.2) are met. 
BEVACIZUMAB (OR BIOSIMILAR): For cohort B participants, bevacizumab (or biosimilar) 
will continue every 3 weeks (+/- 3 days) unless criteria for dose delay (Section 7.4) or study 
discontinuation criteria (Section 6.7) are met. In the event of a dose delay, dosing will be 
resumed when criteria to resume treatment (Section 7.4) are met. 
IN THE EVENT OF A DOSE DELAY ON COHORT B:  
In the event that both study drugs are held, dosing with either drug will resume when criteria to 
resume treatment with that drug are met (Section 7.2 for pembrolizumab and Section 7.4 for 
bevacizumab – or biosimilar).  
NOTE: In the event that only one study drug is held, treatment with that drug will not be 
provided mid-cycle; that cycle’s dose will be skipped and treatment with that drug will resume 
on Day 1 of the subsequent cycle, provided criteria to restart treatment is met at that time.  
6.7 
General Concomitant Medication and Supportive Care Guidelines 
 
Medications or vaccinations specifically prohibited in the exclusion criteria (Sections 4.2 & 
6.6.2) are not allowed during the ongoing trial except as outlined below.  If there is a clinical 
indication for one of these or other medications or vaccinations specifically prohibited during the 
trial, discontinuation from trial therapy or vaccination may be required.  The treating investigator 
should discuss any questions regarding this with the sponsor and the overall study PI or his 
designee.  The final decision on any supportive therapy or vaccination rests with the treating 
physician.  However, the decision to continue the participant on trial therapy or vaccination 
schedule requires the mutual agreement of the Investigator, Sponsor & Overall study PI or his 
designee, and the participant.  


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30 
 
6.7.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs as defined in Section 8.4.4.2. 
6.7.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy not specified in this protocol 
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology or for the treatment of 
cerebral edema or supportive post-operative management.  The use of physiologic 
replacement doses of corticosteroids for conditions such as adrenal insufficiency and 
pituitary/hypothalamic dysfunction are allowed. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor and 
the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 


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31 
 
6.7.3 General Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined in Section 6.6.4 along with the pembrolizumab dose 
modification guidelines in Section 7.2.  Where appropriate, these guidelines include the use of 
oral or IV treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses of 
steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  
For each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be related to 
pembrolizumab. 
 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Participants should be strongly 
encouraged to maintain liberal oral fluid intake. 
• Infection: Participants with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
• Immune-related adverse events: Please see Section 6.6.4 below regarding diagnosis and 
management of adverse experiences of a potential immunologic etiology.   
 
6.7.4 Supportive Care Guidelines  
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating Investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined below and in Section 7.2.  Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased.  For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care.  The treatment guidelines are intended to be applied when the Investigator 
determines the events to be related to pembrolizumab.  
 
Note: If after the evaluation, the event is determined not to be related, the Investigator does not 
need to follow the treatment guidance (as outlined below and Section 7.2).   
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. Additional guidance for organ specific immune-
related adverse events includes: 
 
6.7.4.1 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 


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o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional 
anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
6.7.4.2 Diarrhea/Colitis:  
Participants should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).  In symptomatic participants, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. 
o All participants who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion.  For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose oral 
steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
6.7.4.3 T1DM or Grade 3-4 hyperglycemia 
For Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 
hyperglycemia associated with metabolic acidosis or ketonuria.  
o Evaluate participants with serum glucose and a metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
 
6.7.4.4 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 


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33 
 
6.7.4.5 Hyperthyroidism or hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor participants 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. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as 
initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyronine, is indicated per standard of care. 
 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Replacement of appropriate hormones may be required as 
the steroid dose is tapered. 
6.7.4.6 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
6.7.4.7 Renal failure or nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
6.7.4.8 Management of Infusion Reactions:  
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. 
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 4.  Pembrolizumab Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Stop Infusion and monitor symptoms. 
Subject may be 


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34 
 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic 
medications indicated for ≤24 hrs 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject should 
be premedicated for the next scheduled dose. 
 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
administration of pembrolizumab on study. 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 
Grades 3 or 4 
 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
 
Participant is permanently discontinued from 
further administration of pembrolizumab on 
study. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.   
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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6.7.4.1 
Cerebral Edema 
Due to the immunologic nature of anti-PD-1 therapy administration, cerebral edema could 
theoretically result as a consequence of anti-PD-1 therapy administration due to immune 
infiltration of the brain. In addition, re-irradiation is expected to elicit cerebral edema.60 
Symptoms related to cerebral edema may include headache or neurologic deficit that is either 
new or worsened. Participants with any signs or symptoms of cerebral edema in the investigator's 
judgement should be treated as clinically appropriate including initiation or increased systemic 
corticosteroid dosing, treatment with an osmotic diuretic or surgical decompression. Subsequent 
pembrolizumab dosing should be immediately interrupted if significant clinical symptoms 
attributable to cerebral edema in the investigator's judgement develop. Treatment with additional 
pembrolizumab doses may only be re-initiated if clinically significant symptoms attributable to 
cerebral edema have stabilized or significantly resolved in the investigator's judgement. 
Participants who develop gr 4 cerebral edema (CTCAE v.4) attributable to pembrolizumab 
administration in the investigator's judgement should not receive further pembrolizumab doses. 
Of note, gr 4 cerebral edema (CTCAE v.4) is defined as life-threatening or requiring urgent 
intervention. For this study, urgent intervention refers to interventions such as intensive care 
(ICU) admission, intubation for hyperventilation, administration of hypertonic or hyperosmotic 
agents and surgical decompression.  
 
6.7.4.2 Other Central Nervous System (CNS) Toxicity 
Anti-PD-1 therapy can rarely cause adverse events involving the peripheral and central nervous 
system including, but not limited to: neuropathy, myasthenia gravis, aseptic meningitis, 
paraneoplastic syndromes and encephalitis.61 For suspected immune-mediated adverse reactions 
affecting the CNS, ensure adequate evaluation to confirm etiology or exclude other causes. 
Based on the severity of the CNS adverse reaction, withhold pembrolizumab and administer 
corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and consider 
continuing a gradual taper over at least 1 month. Based on limited data from clinical studies in 
patients whose CNS immune-related adverse reactions could not be controlled with 
corticosteroid use, administration of other systemic immunosuppressants can be considered. 
Resume pembrolizumab when the CNS immune-mediated adverse reaction remains at Grade 1 
or less following corticosteroid taper. Permanently discontinue pembrolizumab for any Grade ≥ 
3 CNS immune-mediated adverse reaction and for any life-threatening immune-mediated 
adverse reaction.  
 
6.7.4.3 Hypertension 
For grade ≥ 2, consider initiation of anti-hypertensive therapy per institutional guidelines. 
 
6.7.5 Diet/Activity/Other Considerations 
 
6.7.5.1 Diet 
Participants should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
6.7.5.2 Contraception 
Pembrolizumab and bevacizumab (or biosimilar) may have adverse effects on a fetus in utero.  
Refer to Section 4.1.14 for approved methods of contraception for female participants who are 
WOCP (defined in Section 4.1.13), and refer to Section 4.1.15 for approved methods of 
contraception for male participants.  


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36 
 
For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition.) 
6.7.5.3 Use in Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The 
study Investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to Merck.  If a male participant 
impregnates his female partner, the study personnel at the site must be informed immediately. 
6.7.5.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, participants who are breast-feeding are not eligible for enrollment. 
6.8 
Duration of Therapy and Criteria for Taking Participants Off Protocol Treatment 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), study treatment may 
continue up to completion of 35 pembrolizumab treatments (approximately 2 years), or until one 
of the following criteria applies: 
• 
Disease progression (see modified RANO criteria and confirmation of disease 
progression criteria in Sections 12.2 and 12.5) 
• 
Unacceptable adverse event(s) 
• 
Recurrent Grade 2 pneumonitis 
• 
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, 
in the opinion of the investigator and/or sponsor, places the participant at unnecessary 
risk from continued administration of study treatment. 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• 
The participant has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
Investigator’s decision to withdraw the subject 
• 
Participant decides to withdraw from the protocol therapy 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• 
The participant is lost to follow-up 
• 
Termination of the trial by the study’s sponsor. 
 


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Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, David A. Reardon, M.D. at 617-632-4750 or 617-632-3352, pager 43339.  
 
6.9 
Post-Therapy Adverse Events 
 
After the end of treatment, all participants will be followed for 30 days for adverse event 
monitoring and 90 days for serious adverse event reporting (or until death, whichever occurs 
first). 
 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event. 
 
6.10 
End of Treatment Evaluation and 30-day Post Last Dose Follow-Up 
 
Procedures to be conducted at both the ‘End of Treatment’ and ‘30-day Post Last Dose Follow-
up’ visits are listed in the Study Calendar (Section 11).   
 
6.11 
Active Follow-Up 
 
Participants who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up. See Study Calendar (Section 11) for visit 
frequency (and acceptable windows).  
 
6.12 
Long-term Follow-Up  
 
After documented disease progression, participants will be followed by telephone or medical 
record review for overall survival until they meet criteria for removal from study as detailed 
below. See Study Calendar (Section 11) for visit frequency (and acceptable windows).  
 
6.13 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
• Sponsor decides to terminate the study 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 


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In addition, the study team will ensure Off Treatment/Off Study information is updated in 
OnCore in accordance with DF/HCC policy REGIST-101. 
 
6.13.1 Withdrawal of Informed Consent 
Participants who request to discontinue study treatment will remain in the study and must 
continue to be followed for protocol specified follow-up procedures. The only exception to this 
is when a participant specifically withdraws consent for any further contact with him/her or 
persons previously authorized by subject to provide this information. Participants should notify 
the investigator of the decision to withdraw consent from future follow-up in writing, whenever 
possible. The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study drug only or also 
from study procedures and/or post treatment study follow-up, and entered on the appropriate 
CRF page. In the event that vital status (whether the participant is alive or dead) is being 
measured, publicly available information should be used to determine vital status only as 
appropriately directed in accordance with local law. 
 
6.13.2 Lost to Follow-Up  
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant as noted above. Lost to 
follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. If 
it is determined that the participant has died, the site will use permissible local methods to obtain 
the date and cause of death.  
 
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. If after all attempts, the 
participant remains lost to follow-up, then the last known alive date as determined by the 
investigator should be reported and documented in the participant’s medical records. 
 
6.14 
Participant Replacement Strategy 
 
Additional participants may be enrolled in a given cohort to ensure that the required number of 
evaluable participants in each cohort is achieved. A participant that discontinues the trial for 
progressive disease or a drug-related AE will not be replaced and will be counted in the 
evaluable population of participants for the respective cohort.  
 
6.15 
Beginning and End of the Trial 
 
The study begins when the first participant signs the informed consent form. The end of the 
study may be designated as the time point when all participants have discontinued the study or 
are a minimum of 6 months post initial study medication administration. If, by the end of the 
study, there remains at least 1 participant still on study treatment for at least 6 months, the 
participant(s) may enter additional treatment cycles.  
 
The participant is considered on study until such time that s/he meets any of the discontinuation 
criteria and notification is given to the Sponsor. 
 


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39 
 
6.16 
Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
1. 
Quality or quantity of data recording is inaccurate or incomplete 
2. 
Poor adherence to protocol and regulatory requirements 
3. 
Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to participants 
4. 
Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 
 
7. DOSING DELAYS/DOSE MODIFICATIONS 
Dose delays and modifications will be made as indicated below.  The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for dose delays and dose modifications. A copy of the CTCAE 
version 4.0 can be downloaded from the CTEP website 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
7.1 
Dose Selection/Modification: General Information 
 
7.1.1 
Baseline values are from screening assessments. Whenever treatment is held pending 
resolution of toxicity to grade 1 or return to baseline, this criterion may also be met if the toxicity 
resolves to within 1 grade of the baseline value for a pre-existing laboratory abnormality.  
 
7.1.2 
Participants who experience an adverse event that requires a treatment delay should 
be monitored with appropriate laboratory testing or other clinical evaluation at least weekly until 
resolution; if the adverse event does not resolve within 4 weeks, the interval for testing may be 
reduced after consultation and written approval by the Overall Principal Investigator (or his 
designee). 
 
7.1.3 
For Cohort A participants:  
7.1.3.1 In the event of a treatment delay due to a toxicity, the cycle count should be 
interrupted until the criteria to resume treatment with pembrolizumab are met. 
7.1.4 
For Cohort B participants: 
7.1.4.1 Study drugs are either held together or separately, depending on the reason for 
the hold. 
7.1.4.2 If only one study drug is held, then the cycle count continues.  If both study 
drugs are held, then cycle count should be interrupted until the criteria to 
resume treatment are met.  
NOTE: In the event that only one study drug is held, treatment with that drug will not be 
provided mid-cycle; that cycle’s dose will be skipped and treatment with that drug will 
resume on Day 1 of the subsequent cycle, provided criteria to restart treatment is met at 
that time. 
 


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40 
 
7.1.5 
If - in the best interest of the patient - the investigator wants to hold study agent(s) 
after an adverse event in a manner not outlined in Section 7, this is permissible following 
discussion and agreement with the overall Principal Investigator, Dr. David A. Reardon or 
designee. 
 
7.1.6 
For holds due to related toxicities, if the participant does not meet criteria to resume 
treatment within 12 weeks of the date of the toxicity (unless otherwise specified in the protocol), 
the participant must permanently discontinue the relevant study agent. However, if the 
participant is benefiting from the study, the investigator may contact the overall Principal 
Investigator, Dr. David A. Reardon or designee to determine if the participant can remain on 
study. 
 
7.1.7 
For all holds for reasons other than treatment-related toxicities 
1. 
Ideally, participants will be placed back on study therapy within 3 weeks of the 
scheduled interruption (a 6 week hold); 
2. 
However, the hold may be extended to 12 weeks, should the Treating 
Investigator deem it necessary to do so. 
3. 
In the event that a participant is unable to resume treatment within 12 weeks of 
the event precipitating the hold, Investigator Team must receive approval from 
the overall Principal Investigator or designee if they intend to extend the hold 
and continue to treat the participant on study.     
 
7.1.8 
A participant in Cohort B is only considered to be off-treatment if s/he has 
discontinued both pembrolizumab and bevacizumab (or biosimilar).  If the participant is 
discontinued from  pembrolizumab but continues treatment with bevacizumab - or biosimilar (or 
if the participant is discontinued from treatment with bevacizumab (or biosimilar) but continues 
pembrolizumab), s/he will continue to be monitored per the regular study schedule. 
 
7.1.9 
For other unspecified events of any grade considered unlikely to be related or not 
related to study drug, participants should maintain treatment with pembrolizumab. Interruption 
of  pembrolizumab is permitted if the investigator consults with the overall Principal Investigator 
or designee to determine that this is in the interest of the participant.    
 
7.2 
Pembrolizumab Dose Modifications 
 
There are no reductions in the pembrolizumab dose. Guidelines for pembrolizumab dose 
management due to adverse events considered at least possibly related to pembrolizumab are 
summarized in Table 5 (immune-related events) and Table 6. If adverse events occur that require 
holding pembrolizumab, the dose will remain the same once treatment resumes. Patients who 
require pembrolizumab hold or discontinuation are permitted to continue to receive study 
treatment with bevacizumab (or biosimilar) alone. 
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities despite appropriate 
replacement therapies when appropriate, and severe or life-threatening AEs as per Table 6 
below. 
 


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41 
 
NOTE: Subjects who experience a recurrence of the same severe or life-threatening event 
at the same grade or greater with re-challenge of pembrolizumab should be discontinued 
from treatment with Pembrolilzumab. 
 
Immune-related AEs associated with pembrolizumab: AEs associated with pembrolizumab 
exposure may represent an immunologic etiology. These immune-related AEs (irAEs) may occur 
shortly after the first dose or several months after the last dose of pembrolizumab treatment and 
may affect more than on body system simultaneously. Therefore, early recognition and initiation 
of treatment is critical to reduce complications.  Based on existing clinical study data, most 
irAEs were reversible and could be managed with interruptions of pembrolizumab, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or tests 
such as bronchoscopy, endoscopy, skin biopsy may be included as part of the evaluation. Based 
on the severity of irAEs, withhold or permanently discontinue pembrolizumab and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided below in Table 5.  
 


 
 
Page 42 
General irAE Instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if the 
irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the last study 
intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
Table 5. Pembrolizumab Dose Modification Guidelines for Pembro-related irAEs 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab 
Discontinue Participant’s 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
• Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation (ie, 
peritoneal signs and ileus) 
• Participants with ≥Grade 2 
diarrhea suspecting colitis should 
consider GI consultation and 
performing endoscopy to rule out 
colitis 
• Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion 
4, or 
recurrent 
G3 
Permanently discontinue 
Permanently discontinue 
AST/ALT elevation 
or Increased 
Bilirubin 
2a 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose 
Administer corticosteroids (initial 
dose of 0.5 to 1 mg/kg prednisone or 
equivalent) followed by taper 
 Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable) 
3 b -4 c 
Permanently discontinue  
Permanently discontinue 
Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4  
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure d 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable 
• 
Initiate insulin replacement 
therapy for participants with 
T1DM 
• 
Administer antihyperglycemic in 
participants with hyperglycemia 
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 


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43 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab 
Discontinue Participant’s 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Hypophysitis 
2 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
3-4 
Decision whether to withhold 
or permanently discontinue 
pembrolizumab is at the 
discretion of the Investigator / 
Treating MD. d 
Can restart when toxicity 
resolves to Grade 0-1. Therapy 
with pembrolizumab can be 
continued while endocrine 
replacement therapy is 
instituted  
Permanently discontinue, or 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
Monitor for signs and symptoms of 
thyroid disorders 
3-4 
Decision whether to withhold 
or permanently discontinue 
pembrolizumab is at the 
discretion of the Investigator / 
Treating MD. d 
Permanently discontinue, or 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Hypothyroidism 
2-4 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) 
per standard of care 
Monitor for signs and symptoms of 
thyroid disorders 
Immune system disorders - 
Other: Guillain-Barre syndrome 
- Any Grade 
Permanently discontinue 
Permanently discontinue 
 
 
Myocarditis 
1 
Toxicity resolves to Grade 0 
Toxicity does not resolve within 
12 weeks of last dose 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
2-4 
Permanently discontinue 
Permanently discontinue 
Myositis 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose 
 
 
4 
Permanently discontinue 
Permanently discontinue 
 
 


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44 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab 
Discontinue Participant’s 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neuropathy 
(peripheral motor or 
sensory) 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose 
 
 
4 
Permanently discontinue 
Permanently discontinue 
 
 
Pancreatitis 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose 
 
 
4 
Permanently discontinue 
Permanently discontinue 
 
 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
• Administer corticosteroids (initial 
dose of 1 to 2 mg/kg prednisone 
or equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
• Monitor participants for signs and 
symptoms of pneumonitis 
• Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
3-4, or 
recurrent 
G2 
Permanently discontinue 
Permanently discontinue 
Neurological 
Toxicities 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
3- 4 
Permanently discontinue 
Permanently discontinue 
Nephritis (grading 
according to 
increased creatinine 
or acute kidney 
injury) 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
Monitor changes of renal function 
3-4 
Permanently discontinue 
Permanently discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
SJS, TEN, 
or DRESS 
Hold pembrolizumab until 
suspected conditions are ruled 
out 
Permanently discontinue if 
suspected condition is confirmed 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology or exclude other causes 
Confirmed 
SJS, TEN, 
or DRESS 
Permanently discontinue 
Permanently discontinue 
All Other irAEse 
Intolerable/ 
persistent 
Gr2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 
per day within 12 weeks 
Based on severity of AE administer 
corticosteroids 
Ensure adequate evaluation to confirm 
etiology or exclude other causes 
3 (first 
occurrence) 
Decision whether to withhold 
or permanently discontinue 
pembrolizumab depends on 
event. f 
Permanently discontinue, or 
Toxicity does not resolve within 
12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg 
or less of prednisone or equivalent 


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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Pembrolizumab 
Discontinue Participant’s 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
per day within 12 weeks 
4 (or 
recurrent 
Gr3)  
Permanently discontinue 
Permanently discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with 
Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes 
mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs, or any life-threatening event. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if baseline 
abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab may 
be resumed. 
e Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
f Events that require discontinuation include - but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 


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Table 6. Pembrolizumab Dose Modification Guidelines for Other Pembro-related AEs 
Toxicity 
Hold Treatment 
For Grade 
Timing for Restarting Pembrolizumab 
Discontinue Participant’s Pembrolizumab 
 
Infusion Reaction 
2a 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-Related 
Toxicityb 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to reduce 
corticosteroid to 10 mg or less of prednisone or equivalent per day within 12 
weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs, or any life-threatening event. 
a If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the participant should be premedicated for the next scheduled dose; Refer to Infusion Treatment Guidelines for further management details. 
b Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for 
which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 


 
 
Page 47 
 
 
7.2.1 Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. For all holds for 
reasons other than treatment-related toxicities: 
1. Ideally, participants will be placed back on study therapy within 3 weeks of the scheduled 
interruption (a 6 week hold); 
2. However, the hold may be extended to 12 weeks, should the Treating Investigator deem it 
necessary to do so. 
3. In the event that a participant is unable to resume treatment within 12 weeks of the event 
precipitating the hold, Investigator Team must receive approval from the overall Principal 
Investigator or designee if they intend to extend the hold and continue to treat the participant 
on study.     
The reason for interruption should be documented in the patient's study record 
 
 
7.3 
Re-Irradiation Dose Modification/Interruption/Discontinuation 
 
There will be no dose modifications for re-irradiation dosing. Any toxicity associated or possibly 
associated with re-irradiation treatment should be managed according to standard medical 
practice. Participants who develop significant (grade ≥ 3) toxicity related to re-irradiation should 
be managed with maximal medical therapy and may be considered for dose interruption if 
inadequately responsive to maximal medical therapy. Every effort should be made to resume re-
irradiation as soon as possible.  
For any participant requiring interruption of re-irradiation for > 1 week: Sites must contact the 
Study PI to discuss whether it is in the patient’s best interest to resume re-irradiation therapy or 
whether s/he should discontinue re-irradiation.   
Re-irradiation will be discontinued for any participant who develops a grade 4 adverse event 
related to re-irradiation.  
 
7.4 
Bevacizumab (or Biosimilar) Dose Modification/ Interruption/ Discontinuation 
(Cohort B) 
There are no reductions in the bevacizumab (or biosimilar) dose. Guidelines for bevacizumab (or 
biosimilar) dose management due to adverse events considered at least possibly related to 
bevacizumab (or biosimilar) are summarized in Table 7. If adverse events occur that require 
holding bevacizumab (or biosimilar), the dose will remain the same once treatment resumes. 
Patients who require bevacizumab (or biosimilar) hold or discontinuation are permitted to 
continue to receive study treatment with pembrolizumab alone. 
Any toxicity associated or possibly associated with bevacizumab (or biosimilar) treatment should 
be managed according to standard medical practice. Bevacizumab (or biosimilar) has a terminal 
half-life of 2 to 3 weeks; therefore, its discontinuation results in slow elimination over several 
months. There is no available antidote for bevacizumab (or biosimilar).  


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Participants should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity occurs because of bevacizumab (or biosimilar) at any time during the 
study, treatment with bevacizumab (or biosimilar) should be discontinued.  
Adverse events requiring delays or permanent discontinuation of bevacizumab (or biosimilar) are 
listed in Table 7. 
 
Table 7. Bevacizumab (or biosimilar) Dose Management Due to Adverse Events (Regardless of 
Attribution) 
Event 
CTCAE v. 4 Grade 
Action to be Taken with Bevacizumab (or biosimilar) Dose 
Arterial Thromboembolic event - Any grade 
(Angina, myocardial infarction, transient ischemic attack, 
cerebrovascular accident, and any other arterial 
thromboembolic event) 
Discontinue bevacizumab (or biosimilar). 
Bowel Obstruction 
Grade 1 
Continue patient on bevacizumab (or biosimilar) for partial 
obstruction NOT requiring medical intervention. 
Grade 2 
Hold bevacizumab (or biosimilar) for partial obstruction 
requiring medical intervention.  Patient may restart upon 
complete resolution. 
Grade 3/4 
Hold bevacizumab (or biosimilar) for complete obstruction.  If 
surgery is necessary, patient may restart bevacizumab (or 
biosimilar) after full recovery from surgery, and at investigator’s 
discretion. 
Congestive Heart 
Failure (Left 
ventricular systolic 
dysfunction) 
Grade 1/2 
No bevacizumab (or biosimilar) dose modifications 
Grade 3 
Hold bevacizumab (or biosimilar) until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab (or biosimilar). 
GI Perforation 
Any Grade 
Discontinue bevacizumab (or biosimilar). 
Hemorrhage 
Grade 1 - non-CNS 
No dose modifications 
Grade ≥ 1 New CNS hemorrhage 
Discontinue bevacizumab (or biosimilar). 
Grade > 1 non-CNS hemorrhage  
Discontinue bevacizumab (or biosimilar).  
Hypertension 
Grade 1/2 
No bevacizumab (or biosimilar) dose modifications 
• 
For grade ≥ 2, consider initiation of anti-hypertensive 
therapy per institutional guidelines. 
Grade 3 
If not controlled to ≤ 159/99 mmHg with medication, discontinue 
bevacizumab (or biosimilar). 
Grade 4, including RPLS 
(confirmed by MRI) or 
hypertensive encephalopathy 
Discontinue bevacizumab (or biosimilar). 
Infusion Related 
Reaction 
Grade 1/2 
Slow bevacizumab (or biosimilar) infusion to 50% or less or 
interrupt. When symptoms have completely resolved, the 
infusion may be continued at not more than 50% of the rate prior 
to the reaction and increased in 50% increments every 30 minutes 
if well tolerated. bevacizumab (or biosimilar) infusions may be 
restarted at the full rate during the next cycle. 
Grade 3/4 
Discontinue bevacizumab (or biosimilar). 
Proteinuria 
Grade 1/2 
No bevacizumab (or biosimilar) dose modifications 
Grade 3 
Hold bevacizumab (or biosimilar) treatment until ≤ Grade 2, as 
determined by 24 hr collection ≤ 3.5 g 
Grade 4  
(nephrotic syndrome) 
Discontinue bevacizumab (or biosimilar) 
Venous Thrombosis 
Grade 1/2 
No bevacizumab (or biosimilar) dose modifications 


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Grade 3/ Asymptomatic Grade 4 
Hold bevacizumab (or biosimilar).  If the planned duration of 
full-dose 
anticoagulation 
is 
<2 weeks, 
bevacizumab 
(or 
biosimilar) should be held until the full-dose anticoagulation 
period is over.  If the planned duration of full-dose 
anticoagulation is >2 weeks, bevacizumab (or biosimilar) may be 
resumed during the period of full-dose anticoagulation if the 
following criterion is met: 
• The participant must be therapeutically anti-coagulated with 
an approved anticoagulant agent according to standard 
prescribing guidelines. 
Symptomatic Grade 4 
Discontinue bevacizumab (or biosimilar). 
Wound dehiscence requiring medical or surgical therapy 
Discontinue bevacizumab (or biosimilar) 
Other Unspecified 
Bevacizumab (or 
biosimilar)-Related 
Adverse Events 
Grade 3 
Hold bevacizumab (or biosimilar) until recovery to ≤ Grade 1 
 
Grade 4 
Discontinue bevacizumab (or biosimilar). 
 


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8. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 8.1) will determine whether the event 
requires expedited reporting in addition to routine reporting.   
 
8.1 
Anticipated Toxicities 
 
A list of the adverse events and potential risks associated with the agents administered in this 
study appear below [reported by CTCAE v. 4 System Organ Class (SOC)],  
In order for an event to be expected (known correlation to study drug) for the purposes of 
adverse event reporting on this study, the event must be included in this section (or be 
included in the informed consent document as a potential risk).  This list will also be used to 
help determine whether dose delays and modifications will be made on study. 
 
8.1.1 Adverse Events for Pembrolizumab 
NOTE: The list below serves to provide study guidance and is not all-inclusive.  Please refer to 
the current pembrolizumab Investigator Drug Brochure for a comprehensive list of adverse 
events and potential risks associated with pembrolizumab. 
• BLOOD AND LYMPHATIC SYSTEM DISORDERS *: anemia 
• CARDIAC DISORDERS: heart failure, myocarditis 
• ENDOCRINE DISORDERS: adrenal insufficiency, hyperthyroidism, hypothyroidism,  
• EYE DISORDERS *: uveitis 
• GASTROINTESTINAL DISORDERS *: abdominal pain, colitis, constipation, diarrhea, 
nausea, pancreatitis, vomiting 
• GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: edema 
limbs, fatigue, fever, infusion related reaction 
• HEPATOBILIARY DISORDERS: Hepatobiliary disorders - Other, specify: sclerosing 
cholangitis 
• IMMUNE SYSTEM DISORDERS: allergic reaction, autoimmune disorder including but 
not limited to hypophysitis, thyroiditis, type 1 diabetes mellitus, iritis, hepatitis, 
myopathy, Guillain-Barre syndrome, myasthenia gravis (MG), Rejection of solid organ 
or tissue transplants (corneal, kidney, or liver), nephritis, pemphigus, vitiligo 
• INFECTIONS AND INFESTATIONS: skin infection, urinary tract infection, upper 
respiratory infection, lung infection, hepatic infection, hepatitis viral 
• INJURY, POISONING AND PROCEDURAL COMPLICATIONS * 
• INVESTIGATIONS: activated partial thromboplastin time prolonged, alanine 
aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase 
increased, blood bilirubin increased, creatinine increased, GGT increased, INR increased, 
neutrophil count decreased, platelet count decreased, weight loss 
• METABOLISM AND NUTRITION DISORDERS: anorexia, hypoalbuminemia, 
hyponatremia 
• MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: myalgia, 
arthralgia, arthritis, myositis 
• NERVOUS SYSTEM DISORDERS *: dizziness, dysgeusia, edema cerebral**, 
headache, peripheral motor neuropathy, peripheral sensory neuropathy, seizures 
o Nervous system disorders – other, specify: Tumor inflammation** 


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• PSYCHIATRIC DISORDERS: confusion 
• RENAL AND URINARY DISORDERS *: hematuria 
• REPRODUCTIVE SYSTEM AND BREAST DISORDERS * 
• RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS *: cough, dyspnea, 
pneumonitis 
• SKIN AND SUBCUTANEOUS TISSUE DISORDERS: exfoliative dermatitis 
o All CTCAE v. 4 rashes are considered expected: bullous dermatitis, erythema 
multiforme, erythroderma, palmar-plantar erythrodysesthesia syndrome, pruritus, 
rash acneiform, rash maculo-papular, skin hyperpigmentation, skin 
hypopigmentation, skin induration, skin ulceration, Stevens-Johnson syndrome, 
toxic epidermal necrolysis (TEN) 
• VASCULAR: vasculitis 
 
* In addition, the following potential risk is considered expected within all applicable SOCs:  
• bleeding/hemorrhage  
 
**As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event (no definition for Gr1, Gr2, 
Gr3, or Gr5), please record events of ‘Edema cerebral’ deemed by Investigator to be Gr1-Gr3 or 
Gr5 as ‘Nervous system disorders, Other: Tumor inflammation’ (as Gr1-Gr3 or Gr5, 
accordingly). 
 
 
8.1.2 Adverse Events for Re-Irradiation 
Acute:  
• Expected:  
o Skin and subcutaneous tissue disorders: alopecia (radiation-induced) 
o General disorders and administration site conditions: fatigue 
o Injury, poisoning and procedural complications: dermatitis radiation 
 Injury, poisoning and procedural complications – other, specify:  
• soreness of the scalp 
o Nervous system disorders: edema cerebral** 
 Nervous system disorders – other, specify:  
• Tumor inflammation** 
• Possible:  
o Ear and labyrinth disorders: Middle ear inflammation (serous otitis media 
with short-term hearing impairment) 
o Gastrointestinal disorders: dry mouth; nausea; vomiting 
o Nervous system disorders: dysgeusia; headache; seizure 
 Nervous system disorders – other, specify:  
• Weakness 
Early Delayed: 
• Possible: 
o Nervous system disorders: lethargy 
o Exacerbation of existing neurologic deficits (defined by CTCAE 4.0) 
occurring 1-3 months after radiotherapy 
Late Delayed: 
• Possible:  
o Endocrine disorders: Endocrine disorders – other, specify:  
 endocrine dysfunction 


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o Eye disorders: cataracts 
o Nervous system disorders: cognitive disturbance; central nervous system 
necrosis 
o Psychiatric disorders: personality change 
• Possible (in appropriate anatomic context):  
o Ear and labyrinth disorders: hearing impaired 
o Eye disorders: blurred vision 
 
**As CTCAE v. 4 recognizes ‘Edema cerebral’ only as a Gr4 event (no definition for Gr1, 
Gr2, Gr3, or Gr5), please record events of ‘Edema cerebral’ deemed by Investigator to be 
Gr1-Gr3 or Gr5 as ‘Nervous system disorders, Other: Tumor inflammation’ (as Gr1-Gr3 or 
Gr5, accordingly). 
 
8.1.3 Adverse Events for Bevacizumab (or biosimilar) 
• BLOOD AND LYMPHATIC SYSTEM DISORDERS *: anemia, hemorrhage 
• CARDIAC DISORDERS: acute coronary syndrome, ventricular arrhythmia, heart failure 
• EYE DISORDERS * 
• GASTROINTESTINAL DISORDERS *: abdominal pain, colonic perforation, 
constipation, nausea, esophageal fistula 
• GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: infusion 
related reaction 
• HEPATOBILIARY DISORDERS * 
• IMMUNE SYSTEM DISORDERS: allergic reaction 
• INFECTIONS AND INFESTATIONS: skin infection 
• INJURY, POISONING AND PROCEDURAL COMPLICATIONS*: wound 
complication, wound dehiscence 
• INVESTIGATIONS: neutrophil count decreased, platelet count decreased 
• NERVOUS SYSTEM DISORDERS *: headache, intracranial hemorrhage, 
leukoencephalopathy, seizures, stroke 
• PSYCHIATRIC DISORDERS: confusion 
• RENAL AND URINARY DISORDERS *: acute kidney injury, proteinuria 
• REPRODUCTIVE SYSTEM AND BREAST DISORDERS * 
• RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS *: dyspnea, 
hoarseness 
• VASCULAR DISORDERS: hypertension, thromboembolic event  
 
* In addition, the following potential risk is considered expected within all applicable SOCs:  
• bleeding/hemorrhage  
 
Please also refer to the current bevacizumab (or biosimilar) package insert for a 
comprehensive list of adverse events and potential risks associated with bevacizumab (or 
biosimilar). 
 
8.2 
Definitions 
 
8.2.1 Adverse Event (AE) 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 


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develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study.  
 
Merck defines an adverse event as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples of 
this may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
 
Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
induce clinical signs or symptoms or require treatment or further diagnostic tests.  
 
8.2.2 Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in 
an unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of 
the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home; blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same timeframe as 
SAEs to meet certain local requirements. Therefore, the following events are considered 
serious by Merck for collection purposes: 


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• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose. 
Events not considered to be serious adverse events in this trial are  
• Lymphopenia (grades 2-4) 
• Progression of the cancer under study 
• A visit to the emergency room or another hospital department that does not result in a 
hospitalization of > 24 hours (unless considered an important medical or life-threatening 
event) 
• And hospitalization for any of the following: 
o 
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition, or for elective procedures 
o 
seizure, if felt related to patient’s underlying disease  
o 
routine health assessment for baseline/trending of health status (eg, routine 
colonoscopy) 
o 
elective or pre-planned treatment for a pre-existing condition that did not worsen 
o 
scheduled debulking surgery  
o 
treatment of patient’s underlying disease (e.g. admission after patient is removed 
from active study treatment for craniotomy) 
o 
emergency outpatient treatment for an event not fulfilling the serious criteria 
outlined above and not resulting in inpatient admission 
o 
respite care not associated with an adverse event attributed to the study drug 
o 
another life circumstance that carries no bearing on health status and requires no 
medical/surgical intervention (eg, lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason). 
 
8.3 
Evaluating Adverse Events 
 
All adverse events will be evaluated and assessed by a qualified Investigator (physician, when 
necessary per local institutional policy) for determinations of: 
1. Gradea, per NCI Common Terminology for Adverse Events (CTCAE), version 4.0 
Any adverse event which changes CTCAE grade over the course of a given episode will have 
each change of grade recorded on the adverse event case report forms/worksheets. 
2. Seriousnessa as defined in Section 8.2.2, regardless of CTCAE grade  
3. Attributiona to each of the aspects of study treatment: Pembrolizumab, Re-Irradiation (when 
applicable), and bevacizumab (or biosimilar, when applicableb.  Attribution of AEs must be 
classified based on the following definitions: 
• Definite – The AE is clearly related to the study agent/treatment. 
• Probable – The AE is likely related to the study agent/treatment. 
• Possible – The AE may be related to the study agent/treatment. 
• Unlikely – The AE is doubtfully related to the study agent/treatment. 
• Unrelated – The AE is clearly NOT related to the study agent/treatment. 
4. Expectednessa with each of the aspects of study treatment: Pembrolizumab, Re-Irradiation 
(when applicable), and bevacizumab (or biosimilar), when applicable.  Adverse events can be 
'Expected' or 'Unexpected.'    


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For the purposes of this study: 
An adverse event 
is considered … 
When it … 
Or when it … 
Expected 
Appears in section 8.1 of the protocol 
(taken from the current Investigator’s 
Brochure or package insert) 
Is included in the informed 
consent 
document 
as 
a 
potential risk 
Unexpected 
Varies in nature, intensity, or frequency 
from information provided in the current 
protocol or IB / package insert  
Is 
NOT 
included in 
the 
informed consent document as 
a potential risk 
5. Durationa of event (start and stop dates) 
6. Action Takena:  
• Were any concomitant meds introduced as a result of the event? 
• Dechallengec: 
Was 
any 
study 
drug/treatment 
discontinued, 
held, 
or 
dose/exposure/frequency reduced? 
If yes, did the AE 
resolve or improve? 
If yes … Then this is a positive dechallenge 
If no … 
Then this is a negative dechallenge 
• Rechallenge d, e: Was the subject re-exposed to the study drug/treatment? 
If yes, did the AE 
recur or worsen? 
If yes … Then this is a positive rechallenge 
If no … 
Then this is a negative rechallenge 
 
7. Whether event meets definition of an Event of Clinical Interest (ECI); see section 8.4.4.2 of 
the protocol for definition.  
NOTE: For events that are secondary to an event deemed expected with a study agent/modality (e.g. 
rectal pain as a result of diarrhea), please record as “possibly related to” and “expected with” the 
agent/modality. 
Footnotes for Evaluating Adverse Events 
a. 
These assessments should be recorded by the Investigator in real time if feasible, and maintained in either the 
patient’s research chart or medical record for review by sponsor team upon trial monitoring. 
b. For Cohort B (in which multiple agents are administered as part of a combination regimen), the investigator 
may attribute each adverse event causality to the combination regimen or to a single agent of the combination.  
In general, causality attribution should be assigned to the combination regimen (i.e., to all agents in the 
regimen). However, causality attribution may be assigned to a single agent if in the investigator’s opinion, there 
is sufficient data to support full attribution of the adverse experience to the single agent. 
c. 
This criterion is not applicable if: (1) the AE resulted in death or permanent disability; or (2) the AE 
resolved/improved despite continuation of study drugs 
d. This criterion is not applicable if the initial AE resulted in death or permanent disability 
e. 
If a rechallenge is planned for an AE which was serious and which may have been caused by study 
drug/treatment, or if reexposure to the drug/treatment poses additional potential significant risk to the 
subject, then the rechallenge MUST BE APPROVED IN ADVANCE by the Overall PI, as per dose 
modification guidelines in the protocol. 
 
8.3.1 Evaluating Adverse Events for Merck 
See Table 8 below for Merck clarifications re: Evaluating Adverse Events.  
 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


 
 
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Table 8. Merck Clarifications re: Evaluating Adverse Events 
 
A qualified investigator (physician, when necessary per local institutional policy), will evaluate all adverse events as to: 
 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid 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 or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
Merck Product  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator 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 the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 


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57 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT 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 the Merck product 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an 
associated AE.) 


 
 
Page 58 
8.4 
Procedures for AE and SAE Recording and Reporting 
 
8.4.1 Assessing and Recording Adverse Events 
Adverse events may occur during the course of the use of pembrolizumab in this clinical trial or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened participants during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed but 
before treatment allocation/randomization must be reported by the investigator if the event 
causes the participant to be excluded from the study, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, or a 
procedure.  
• All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator.  
• All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following cessation of 
study treatment if the participant initiates new anticancer therapy, whichever is earlier 
must be reported by the investigator.  
• All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer 
therapy  must be reported by the investigator.  
• Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately by the investigator if the 
event is considered to be drug-related. 
 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers the event to 
be reasonably related to the study treatment or study participation, the investigator must 
promptly notify Merck. 
 
8.4.2 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater (≥5 times the indicated dose).  No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, pembrolizumab should be discontinued 
and the participant should be observed closely for signs of toxicity.  Appropriate supportive 
treatment should be provided if clinically indicated. 
 


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If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of pembrolizumab meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported by the investigator: 
• Emailed within 24 hours to the Overall PI / Study Sponsor, Dr. David Reardon, and the 
DFCI Neuro Oncology Coordinating Center central SAE email at the following address: 
NeuroOnc_SAE@dfci.harvard.edu. 
• and faxed within 2 working days to Merck Global Safety (Attn: Worldwide Product 
Safety); FAX 215-661-6229. 
 
8.4.3 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if they cause 
the participant to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo treatment 
or a procedure.   
Pregnancies and infant exposures during breastfeeding that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 days 
following cessation of treatment if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Such events (pregnancy and infant exposure during breast feeding) must be reported by the 
investigator: 
• Emailed within 24 hours to the Overall PI / Study Sponsor, Dr. David Reardon, and the 
DFCI Neuro Oncology Coordinating Center central SAE email at the following address: 
NeuroOnc_SAE@dfci.harvard.edu. 
• and faxed within 2 working days to Merck Global Safety (Attn: Worldwide Product 
Safety); FAX 215-661-6229. 
 


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60 
 
8.4.4 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
8.4.4.1 Serious Adverse Events 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause that occurs to any participant must be reported within 24 hours 
to the Sponsor and within 2 working days to Merck Global Safety if it causes the participant to 
be excluded from the trial, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time-period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause whether or not related to the Merck product, 
must be reported within 24 hrs to the Sponsor & within 2 working days to Merck Global Safety. 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) 
regardless of study phase or attribution. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at any 
time following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time-period specified in the previous paragraph 
also must be reported immediately to Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
 
8.4.4.2 Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
For the time-period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant must be 
reported within 2 working days to Merck Global Safety if it causes the participant to be excluded 


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61 
 
from the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
For the time-period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported 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 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, 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.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
 
8.4.5 Participant Deaths 
A death on study requires both routine and expedited reporting regardless of causality, unless as 
noted below.  Attribution to treatment or other cause must be provided. 
 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, malignant 
and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under the system 
organ class (SOC) of the same name.  Evidence that the death was a manifestation of underlying 
disease (e.g., radiological changes suggesting tumor growth or progression: clinical deterioration 
associated with a disease process) should be submitted.  
 
If the participant is in long term follow up, report the death at the time of continuing review. 
 
8.4.6 Expedited Adverse Event Reporting Guidelines 
Adverse event reporting instructions for each site are detailed in Table 9 below.  
 
8.4.6.1 Expedited AE Reporting Requirements (By Site to Overall PI and Merck)  
The study must be conducted in compliance with local safety reporting requirements, and 
reporting requirements of the principal investigator.  
 
Each adverse event will be assessed to determine if it meets the criteria for reporting. Adverse 
event reporting is to occur according to the site’s specific IRB guidelines, and as outlined in this 
Section. Any serious adverse event occurring after the participant has initiated study treatment 
and until 90 days after the participant has stopped the study drug or the start of new anti-cancer 
treatment (whichever comes first) must be reported.  Serious adverse events must be followed 
until resolution. 


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62 
 
Investigators must report to the Overall PI and Merck any serious adverse event (SAE) that 
occurs after a subject’s consent, during treatment, or within 90 days of the last dose of treatment 
(or until the start of new anti-cancer treatment, whichever comes first) via the appropriate 
applicable reporting form (MedWatch 3500A and/or local institutional IRB submission form).  
 
Use the DF/HCC protocol number (18-277) and the protocol-specific participant ID assigned 
during trial registration on all reports. 
 
It is the responsibility of each participating investigator to report adverse events to the Overall 
PI, Merck, DF/HCC IRB, and/or others as described below.  Adverse event reporting by each 
site is detailed in Table 9.  The Overall PI or representative Coordinating Center personnel will 
ensure the report is forwarded to the proper parties, as appropriate. 
 
For multi-institution studies where a DF/HCC investigator is serving as the Overall Principal 
Investigator, each participating institution must abide by the reporting requirements set by the 
DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with a 
possible, probable or definite attribution, unexpected grade 4 toxicities, and grade 5 (death) 
regardless of study phase or attribution. 
 
Submissions of Follow-Up Information:  
Whenever feasible, the participating investigator should provide follow-up information on the 
serious adverse event within the following 24-48 hours.  Follow-up information should 
describe whether the event has resolved or continues, if and how the event was treated, and 
whether the participant will continue or discontinue study participation. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately evaluate 
the SAE report (e.g., hospital discharge summary, consultant report, or autopsy report).  
 
8.4.6.2 IRB Reporting 
Investigative sites within DF/HCC and DF/PCC will submit Reportable AEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
External participating sites will Submit Reportable AEs that occur (including up to within 90 
days of the last administration of study therapy) to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. A copy of the submitted institutional 
SAE form should be forwarded to the Overall PI within the timeframes detailed in Table 9.  The 
Overall PI or representative will submit AE reports from external institutions to the DFCI OHRS 
according to DFCI IRB policies and procedures in reporting adverse events.  
 
8.4.6.3 Expedited Reporting to Hospital Risk Management 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 


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63 
 
Confidential 
 
Table 9. Reporting to Study’s Overall PI & DFCI Coordinating Center, Merck, and IRB 
Adverse Event Characteristics 
Notification Requirement 
Serious- 
ness 
Toxicity  
Details 
Known 
correlation 
Attribution to 
study drug(s) 
D. Reardon, MD  
(Overall PI and IND-holder)  
& DFCI Coordinating Center 
Via Email b, with Safety 
Reporting Coversheet c & 
MedWatch 3500A d 
Merck Global Safety 
Via Faxc, with Safety 
Reporting 
Coversheet c and 
MedWatch 3500A d 
IRB Submissions 
Serious 
Any 
(incl any Grade 5) 
Any 
(Expected or 
Unexpected) 
 
Any 
 
 
Within 2 working days from notification a 
All Local IRBs 
(including IRB Submission for DF/HCC Sites) 
To be submitted to local IRB by Site 
Investigator Team if event meets local IRB 
submission requirements. 
To be submitted within IRB established 
reporting timelines. 
For DF/HCC sites, please ensure that Dr. 
Reardon (or representative) prospectively 
approves all submissions. 
DF/HCC IRB 
DFCI Coordinating Center will be 
responsible for submitting events from 
non-DF/HCC sites to DF/HCC IRB per 
DF/HCC reporting requirements.   
Non-
Serious 
Events of Clinical Interest 
(ECIs)e 
Non-
Serious 
 
Grade 4 
Unexpected 
 
Any 
 
Within 5 calendar days from notificationa 
Grade 2 or 3; moderate or 
severe 
Possible, 
probable, 
definite 
Any 
Overdose                   
(as defined in Section 8.4.2) 
N/A 
 
N/A 
 
 
Within 2 working days from notification a 
N/A 
Pregnancy or Lactation    
(as defined in Section 8.4.3) 
a. In the event that the participating investigator does not become aware of the serious adverse event immediately (e.g., participant sought treatment elsewhere), the 
participating investigator is to report the event within 24 hrs (serious events) or 5 calendar days (non-serious events) after learning of it and document the time of his or her 
first awareness of the adverse event. 
b. Email the Medwatch 3500A form, facsimile coversheet, and the IRB SAE report to the DFCI Coordinating Site with the subject title as “18-277: Pembro + Re-RT SAE” to 
NeuroOnc_SAE@dfci.harvard.edu.  All SAE reports received at this account are forwarded immediately to Dr. David Reardon (the study’s Overall Principal Investigator and 
sponsor/IND-holder), and to Coordinating Center personnel. 
c. 
Safety Reporting Coversheet is found in Appendix B.  Coversheet contains all applicable destinations: emails and FAX numbers. 
d. Medwatch 3500A downloadable form at  http://www.fda.gov/medwatch/getforms.htm 
e. See Section 8.4.4.2 of the protocol for definition of Events of Clinical Interest (ECIs). 
 


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64 
 
8.4.7 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
AEs reported through expedited processes (e.g., reported to the Sponsor, IRB, etc.) must 
also be reported in routine study data submissions (eDC). 
 
8.4.8 Adverse Event Reporting by Study’s Sponsor and Overall PI 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
Dr. Reardon (the study’s Sponsor and Overall Principal Investigator) or a designee will: 
• Submit to DF/HCC IRB any AE reports received from external institutions according to 
DFCI IRB policies and procedures in reporting adverse events. 
• Circulate to all participating sites  
o All reportable adverse events received on study that are considered serious, 
unexpected, and at least possibly associated with study therapy.  A cover letter 
will indicate the protocol title, the IND#, and whether the FDA and/or DF/HCC 
IRB were informed. 
o All IND safety reports received on study that have not occurred directly on this 
protocol. A letter will accompany the report indicating whether a consent form 
change or protocol change is required or other actions including a statement re: 
whether the report has been or will be submitted to DF/HCC IRB for review. 
• NOTE: AEs will not be submitted to FDA for this study, as the trial was determined to be 
IND-exempt.   
o All communications with the FDA regarding this trial would be made by the 
Overall PI, as study sponsor (or an appropriate designee). 
 


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65 
9. AGENT INFORMATION 
9.1 
Investigational Product:  Pembrolizumab 
 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro 
data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.  
Pembrolizumab has an acceptable preclinical safety profile and is being advanced for clinical 
development as an IV immunotherapy for advanced malignancies. 
 
Additional detailed information on pembrolizumab is available in the Investigator’s Brochure. 
 
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. 
 
9.1.1 Description 
Pembrolizumab is a humanized anti-PD-1 mAb of the IgG4/kappa isotype with a stabilizing 
S228P sequence alteration in the fragment crystallizable (Fc) region.  Pembrolizumab binds to 
human PD-1 and blocks the interaction between PD-1 and its ligands. The theoretical molecular 
weight of the polypeptide is 146,288 Da and its theoretical pI is 7.5.  Pembrolizumab exhibits 
linear pharmacokinetics at dose levels of clinical relevance (1-10 mg/kg). It exhibits low 
clearance and limited volume of distribution that is typical for therapeutic antibodies. Mean 
estimated t1/2 values are 14.1-21.6 days. Additional information on pembrolizumab 
nomenclature is detailed in the following table: 
 
Table 10. Pembrolizumab Nomenclature Details 
 
Code Name 
Pembrolizumab (anti-PD-1) 
Other Code Name 
SCH 900475 (anti-PD-1) 
Chemical Name 
Humanized X PD-1 mAb (H409A11) IgG4 
CAS Number 
1374853-91-4 
CAS Name 
Anti-(human protein PDCD1 (programmed cell death 1)) immunoglobulin 
G4 (human-Mus musculus monoclonal heavy chain) disulfide with 
human-Mus musculus monoclonal light chain, dimer 
Generic Name 
Not available 
Commercial Name 
Pembrolizumab 
 
9.1.2 Form 
Pembrolizumab is supplied as a clear to opalescent solution that is essentially free of extraneous 
particles and may contain proteinaceous particulates. One dosage form of pembrolizumab will be 
provided by Merck in Type I glass vials intended for single use only as summarized in the Table 
11 below. 
 
The pembrolizumab to be supplied for this trial is commercial material which 
is manufactured in an FDA approved manufacturing facility and controlled in 
accordance with the KEYTRUDA BLA 125514. 
 


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66 
Table 11. Pembrolizumab Study Supply Information 
Product Name 
& Potency 
Dosage 
Form 
Source/Additional Information 
 Pembrolizumab  
 100 mg / 4 mL 
Solution 
for 
Infusion 
Provided centrally by Merck. 
• Liquid DP (manufactured using the fully formulated DS with 
L-histidine as a buffering agent, polysorbate 80 as a 
surfactant, and sucrose as a stabilizer/tonicity modifier) 
• Sterile, non-pyrogenic, aqueous, preservative-free solution.    
• Contains an excess fill of 6.25 mg (equivalent to 0.25 mL 
solution) to ensure the recovery of label claim of 100 mg  
pembrolizumab per vial (equivalent to 4.0 mL of solution). 
 
9.1.3 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
Vials will be provided in an open label fashion for subject dosing. 
 
9.1.4 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, 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. 
 
9.1.5 Storage, Handling and Preparation Requirements 
Pembrolizumab is stored under refrigerated conditions (2° to 8°C), as specified in the Pharmacy 
Manual for pembrolizumab as provided by Merck. 
 
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. 
 
9.1.6 Administration 
Pembrolizumab will be administered as a 30 minute IV infusion using an infusion pump 
(treatment cycle intervals may be increased due to toxicity as described in Section 6.2).  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). Attach the infusion 
line to the pump and prime the line, either with normal saline (at least 25 mL) or with infusion 
solution as per local SOP, before starting the infusion. Maximum infusion rate should not exceed 
6.7 ml/min through a peripheral or indwelling catheter. Use 30 mL normal saline to flush the 
infusion line at the end of the infusion if institutional guidelines allow.  
 


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67 
Unused infusion solution should not be used for another infusion of the same participant or 
different participant. 
 
DO NOT administer the product as an intravenous push or bolus. 
 
DO NOT combine, dilute or administer it as an infusion with other medicinal products. 
 
A central line is not required for Pembrolizumab administration, but may be used if available.  
 
The following infusion set materials are compatible with Pembrolizumab 
• PVC infusion set that is plasticized using Di-2-ethylhexyl Terephthalate DEHP 
• PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
• Polyehtylene lined PVC infusion set 
• Polyrethane 
• Plybutadiene 
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone 
(PES) or polysulfone must be used during administration to remove any adventitious particles. If 
the infusion set does not contain a 0.2 to 5 µm in-line filter, it is recommended to use a 0.2 to 5 
µm add-on filter which may contain an extension line (the materials of the extension line and 
filter should be as mentioned above). 
 
9.1.7 Ordering 
Investigative sites will order and acquire Pembrolizumab directly from Merck per Section 4.0 of 
Appendix E (Data and Safety Monitoring Plan).  
 
9.1.8 Accountability 
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.  The investigator, or a responsible party designated by 
the investigator, should maintain a careful record of the inventory and disposition of the agent 
using the NCI Drug Accountability Record Form (DARF) or another comparable drug 
accountability form.  (See the NCI Investigator’s Handbook for Procedures for Drug 
Accountability and Storage.) 
 
9.1.9 Destruction and Return 
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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68 
9.2 
Bevacizumab* 
 
* DFCI recently released a guideline re: the use of commercial biosimilars in clinical trials, 
which states: “for standard of care treatment using biologic products in a clinical trial that are not 
paid for by sponsor and that are billed as standard of care to patient’s insurance, the biosimilar 
products dictated by the patient’s insurance would be used.”  Therefore, on this study, sponsor 
will allow the use of a bevacizumab biosimilar.  
 
Bevacizumab (NSC # 704865) is a humanized IgG1 monoclonal antibody (MAb) that binds all 
biologically active isoforms of human VEGF (or VEGF-A) with high affinity (kd = 1.1 nM). The 
antibody consists of a human IgG1 framework and the antigen-binding complementarity-
determining regions from the murine anti-VEGF MAb A.4.6.1.16-18. Bevacizumab is 
commercially available and FDA approved for participants with recurrent glioblastoma. For 
further details and molecule characterization, see the bevacizumab FDA labeling information 
available at: 
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails 
The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total 
serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab 
and bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of 
491 participants who received 1 to 20 mg/kg of bevacizumab weekly, every 2 weeks, or every 3 
weeks, the estimated half-life of bevacizumab was approximately 20 days (range 11−50 days). 
The predicted time to reach steady state was 100 days. The accumulation ratio following a dose 
of 10 mg/kg of bevacizumab every 2 weeks was 2.8. 
The clearance of bevacizumab varied by body weight, gender, and tumor burden. After 
correcting for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 
L/day) and a larger Vc (3.25 L vs. 2.66 L) than females. Participants with higher tumor burden 
(at or above median value of tumor surface area) had a higher bevacizumab clearance (0.249 
L/day vs. 0.199 L/day) than participants with tumor burdens below the median. 
 
9.2.1 Form 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate 
for solution for intravenous (IV) infusion. Vials contain bevacizumab with phosphate, trehalose, 
polysorbate 20, and sterile water for injection (SWFI), USP. Vials contain no preservative and 
are suitable for single use only.  
This agent is commercially obtained and is manufactured by Genentech. 
 
9.2.2 Storage and Stability 
According to guidelines specified in the package insert. 
 
9.2.3 Preparation  
According to guidelines specified in the package insert. 
 
9.2.4 Administration   
Bevacizumab is to be administered according to institutional standards and guidelines specified 
in the package insert. 


DF/HCC Protocol #: 18-277 
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69 
The dose of bevacizumab is 15 mg/kg IV on Day 1 of each three-week cycle. A window of +/- 3 
days for bevacizumab dosing is acceptable, but bevacizumab doses must always be at least 10 
days apart.  
There are no reductions in the bevacizumab dose. Guidelines for bevacizumab dose 
management due to adverse events considered at least possibly related to bevacizumab are 
summarized in Table 7. If adverse events occur that require holding bevacizumab, the dose will 
remain the same once treatment resumes. Patients who require bevacizumab hold or 
discontinuation are permitted to continue to receive study therapy with Pembrolizumab. 
 
9.2.5 Accountability 
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of bevacizumab which are to include start time of infusion, stop time of 
infusion, total volume.  
 
 
10. BIOMARKER STUDIES 
 
The precise mechanism by which Pembrolizumab exerts anti-tumor activity is not clear but it is 
likely related to modulation of the immune system to generate anti-tumor immune responses that 
are capable of eliminating existing tumors and generating immune memory responses to prevent 
future relapse. The effect of PD-1 blockade on effector T cells and regulatory T cells is a critical 
component of anti-tumor activity. Archival tumor expression of PD-L1 will be evaluated. 
Archival tumor will be collected on all patients when available, and submission of archival 
tumor material will not be required prior to initiation of study therapy. In addition, if a biopsy or 
surgical resection is performed at the time of potential progression, a tumor sample (block or 
slides) should also be submitted if sufficient tumor material is available. 
 
10.1 
Archival Tumor PD-L1 Expression 
 
If available, a minimum of 1 formalin-fixed paraffin-embedded (FFPE) archival tumor tissue 
block (preferred) or a minimum of 10 FFPE unstained sections from most recent pre-registration 
biopsy/surgery are to be submitted within 60 days of registration for tumor PD-L1 expression. 
 
Guidelines for submission of archival tumor tissue: 
• A memorandum indicating the study, the date of submission, name of study site 
submitting the tissue, and a list of contents.  The DFCI Coordinating Center will supply a 
template memorandum to sites at the time of the SIV or upon request.  
• A copy of the pathology and surgical report for the sample being submitted should be 
included in the shipment.  
• Slides should be shipped in a plastic slide holder/slide box.  Place a small wad of padding 
in top of the container in order to avoid slides breaking during shipping and handling 
process.  
• An email is to be sent before or at the time of each shipment to the Coordinating Center 
(NeuroOnc_Coor@dfci.harvard.edu) indicating what is being shipped and when.   
• Please note that the submitting institution is responsible for the costs of shipping and 
handling.  


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70 
• Ship samples to: 
Dana-Farber Cancer Institute 
450 Brookline Ave, LG-GC12D 
Attn: DFCI Center for Neuro-Oncology Coordinating Center (Central Sub - 
study #18-277)  
Boston, MA  02215  
 
ph: 617-632-5394 
 
Please find a sample requisition / shipment form for completion in Appendix C. 
 
NOTE: Archival tumor samples will be shipped by Investigator Teams to the DFCI Coordinating 
Center, and subsequently batch shipped to a central lab determined by Merck for determination 
of PD-L1 expression at the end of the study.  
 
10.2 
Archival Tumor Immune Gene Expression Signature 
 
If available, an additional formalin-fixed paraffin-embedded (FFPE) archival tumor tissue block 
- or 5-10 FFPE unstained sections from most recent pre-registration biopsy/surgery – will also be 
submitted within 60 days of registration for targeted gene expression profiling via a Nanostring 
assay. 
 
Guidelines for submission of archival tumor tissue: 
• A memorandum indicating the study, the date of submission, name of study site 
submitting the tissue, and a list of contents.  The DFCI Coordinating Center will supply a 
template memorandum to sites at the time of the SIV or upon request.  
• A copy of the pathology and surgical report for the sample being submitted should be 
included in the shipment.  
• Slides should be shipped in a plastic slide holder/slide box.  Place a small wad of padding 
in top of the container in order to avoid slides breaking during shipping and handling 
process.  
• An email is to be sent before or at the time of each shipment to the Coordinating Center 
(NeuroOnc_Coor@dfci.harvard.edu) indicating what is being shipped and when.   
• Please note that the submitting institution is responsible for the costs of shipping and 
handling.  
 
Ship samples to: 
Dana-Farber Cancer Institute 
450 Brookline Ave, LG-GC12D 
Attn: DFCI Center for Neuro-Oncology Coordinating Center (Central Sub - 
study #18-277)  
Boston, MA  02215  
 
ph: 617-632-5394 
 
Please find a sample requisition / shipment form for completion in Appendix C. 
 
NOTE: Archival tumor samples will be shipped by Investigator Teams to the DFCI Coordinating 
Center, and subsequently batch shipped to a central lab determined by Dr. Reardon for targeted 
gene expression profiling via a Nanostring assay at the end of the study.  


DF/HCC Protocol #: 18-277 
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71 
11. STUDY CALENDAR  (Protocol Table 12) 
 
Baseline evaluations are to be conducted within 14 days of start of protocol therapy unless 
indicated otherwise.  Pre-treatment baseline brain MRI must be done < 14 days prior to the start 
of therapy.  Cycles are 3 weeks (21 days).  Study assessments must be performed and reviewed 
prior to administration of any study agent at any treatment visit. Study assessments and agents 
should be administered within +/-3 days of the protocol-specified date, unless otherwise noted. 
 
Assessments 
Screen-
ing a 
Pembro/Bev Treatment 
Cycles 
End of 
 Tx c, gg 
30-Day 
Post Last 
Dose d, gg 
Follow-Up 
 
 
Cycle 1 
D1b 
D1b of Subsequent 
Cycles  
Active e 
Long 
Term f 
Informed consent g 
X 
  
  
  
  
  
  
Background information/history 
h 
X 
  
  
  
  
  
  
Inclusion/exclusion criteria i 
X 
  
  
  
  
  
  
Vital signs j, gg 
X 
X 
X 
X 
  
  
  
Resting O2 sat by pulse oximetry 
X 
 
 
 
 
 
 
Physical Exam k 
X 
Xk 
X 
X 
  
  
  
Neurologic Exam l 
X 
X 
X 
X 
  
  
  
Karnofsky Performance Status m 
X 
X 
X 
X 
X 
  
  
Concomitant medications n 
X 
Xn 
 
 
Adverse event assessment o 
  
Xo 
Pregnancy Test – Urine or 
Serum β-HCG p 
X 
X 
X 
X 
  
  
  
Coagulation q 
X 
  
  
  
  
  
  
Hematology r 
X 
X 
X 
X 
  
  
  
Serum Chemistry s, gg 
X 
X 
X 
X 
  
  
  
Urinalysis t, gg 
X 
X 
X 
  
  
  
  
T3, FT4, TSH u 
X 
X 
X 
X 
  
  
  
EORTC QLQ-C30 v 
  
X 
X 
X 
  
  
  
Imaging – CT or MRI w 
X 
X 
X 
X 
  
X 
 
 Response Assessment x 
  
X 
X 
X 
  
X 
 
 NANO Scale y 
X 
X 
X 
X 
  
X 
 
Pembrolizumab z 
 
X 
X 
  
  
  
 
Re-Irradiation aa 
 
X aa 
 
  
  
  
  
Bevacizumab (or biosimilar) 
bb
 
X 
X 
  
  
  
 
Submission of archival tissue cc 
 
X 
X 
 
 
 
 
Submission of tumor sample  
at the time of progression or 
suspected progression dd  
 
 
 
 
 
 
 
Post-end-of-treatment  
oncology therapies ee 
 
 
 
 
X 
X 
X 
Survival ff 
 
 
 
 
X 
X 
X 


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72 
 
Footnotes: 
a. 
All screening procedures to be performed within 14 days of start of study treatment, except informed consent 
may occur up to 28 days prior to registration. 
b. Day 1 Assessments: 
a. 
For C1D1 - and Day 1 of Re-Irradiation - Assessments ONLY: Screening assessments may serve as 
day 1 assessments (exceptions below): 
i. Pregnancy Test: In the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study treatment, another pregnancy test - urine or serum - must be 
performed and confirmed negative before subject may receive Day 1 dose 
ii. In the event that there are any indications that the participant’s condition is deteriorating, 
laboratory evaluations should be repeated within 48 hours prior to initiation.   
b. For all subsequent Day 1 assessments: Required assessments will be performed and reviewed prior to 
study agent administration (+/-3 days of scheduled cycle day 1). 
i. Pembrolizumab and bevacizumab (or biosimilar) to be administered +/-3 days from Day 1 of 
each cycle.   
c. 
End of Tx: End of treatment assessments to be performed within 7 days after last day drug administration or 
within 7 days after decision to end treatment.  Assessments may continue for ongoing reportable adverse events.  
d. 30-Day Post Drug: A contact/visit is to be performed at 30 days (+7 days) after the last study drug is given.  
This may be performed via documented phone conversation with a study nurse or clinician or a clinic visit.  All 
participants will be followed until resolution or stabilization of any serious or reportable adverse events 
occurring during treatment or starting within 30 days of last study drug.  
e. 
Active Follow Up:  For participants who discontinue study treatment for reasons other than disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging at a schedule 
developed by the treating investigator until: (1) documented disease progression, (2) death or (3) the end of the 
study, whichever occurs first. 
f. 
Long Term Follow Up: Participants will be followed every 3 months (+/- 1 month) via contact or medical 
record review until death for post-treatment therapies, reason for stopping those therapies, and survival.   
g. Informed Consent: Must be obtained by MD attending.  No study specific screening procedures may occur until 
after the informed consent process is complete. Informed Consent may be obtained within 28 days of 
registration. 
h. Background information/history: To include review of treatment history for GBM, any ongoing medical 
conditions and medical history pertaining to eligibility on study and involvement during study.   
i. 
Inclusion/exclusion criteria: Source documentation providing investigator’s confirmation that the participant 
had met all eligibility criteria must be available prior to registration.  
j. 
Vital signs: Weight, heart rate, blood pressure, & respiration rate. Vital signs must be performed prior to 
administration of treatment on treatment days. Temperature is required at screening and should be obtained as 
clinically indicated thereafter. Height required only at screening and may be obtained within 1 year of 
registration.  
k. Physical Exams: Complete Physical Exam will be completed by the investigator or qualified designee at 
screening, C1D1, weekly while receiving RT (during Cycle 1), and at the start of all subsequent cycles.  
l. 
Neurologic Exam: To be completed by the investigator or qualified designee at screening, C1D1 and start of all 
subsequent cycles. 
m. Performance Status: See Appendix A for KPS scale. 
n. Concomitant medications: Concomitant medications and reason for administration should be documented in the 
case history from within 28 days before starting study treatment up to the 30-Day Post Drug Visit.  
Concomitant medications administered after 30 days after the last dose of trial treatment should be recorded for 
SAEs and ECIs. 
o. Adverse event assessment: Adverse events experienced by participants will be collected and recorded 
registration to the 30-Day Post Last Dose Visit (+ 7 days depending on when 30-Day Post Last Dose 
visit/contact occurs) and all SAEs (related and unrelated to trial treatment) / ECIs up to 90 days after the last 
dose of trial treatment or the start of new anti-cancer treatment, whichever comes first.  Afterwards, report only 
SAEs and ECIs that are considered related to trial treatment.   
a. 
NOTE: Adverse events may also occur in screened subjects during pre-dose period as a result of a 
protocol-specific intervention, including washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure. 
p. Pregnancy Test:  For women of child bearing potential, a pregnancy test must be performed.  If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required.   
q. Coagulation:   PT, PT/INR, aPTT required at screening only and then as clinically indicated.  
r. 
Hematology:  erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus differential (neutrophils, 


DF/HCC Protocol #: 18-277 
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73 
lymphocytes, monocytes, eosinophils, basophils). 
s. 
Serum Chemistry: albumin, alkaline phosphatase (ALP), bicarbonate/HCO3 or CO2 (if considered standard of 
care in your region), BUN, calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, 
phosphorus, potassium, SGOT (AST), SGPT (ALT), sodium, total protein, total bilirubin (direct bilirubin, if 
total bilirubin is elevated above the upper limit of normal), uric acid. 
t. 
Urinalysis: blood, glucose, protein, specific gravity.  Microscopic exam if abnormal results are noted.  If 
dipstick protein is ≥ 2+, then a urine protein creatinine ratio should be obtained.   
u. T3, FT4, & TSH: total triiodothyronine (T3), free tyroxine (T4), and thyroid stimulating hormone (TSH).  T3, 
FT4, & TSH must be drawn prior to pembrolizumab administration; if results are not available for review prior 
to pembrolizumab administration, study treatment may proceed.  Results should be reviewed when they become 
available.   
v. In most cases, EORTC QLQ-C30 Assessments to be self-administered by patients; when necessary, they may 
be administered by a qualified Study Team member; see Appendix G for copies of the QOLs.  NOTES:  
a. 
Scores do NOT need to be documented and reviewed prior to patient receiving study therapy. 
b. If the QLQ is administered as an interview, the patient’s responses will be recorded verbatim and the 
interviewer should not influence the patient’s answers. 
w. Imaging: gadolinium-enhanced contrast and non-contrast MRI.  CT alternative, if MRI contraindicated.  Initial 
imaging should be performed within 14 days prior to start of study therapy.  On-study imaging should be 
performed every 6 weeks, on Day 1 of Cycle 3 and every odd cycle for the first year, and then every 9 weeks 
(Day 1 of every 3rd cycle) thereafter.  Scans should be performed within 7 days prior to the cycle start (and 
ideally within 3 days prior).  Adjustments to this -7 day window are allowable per the treating physician’s 
discretion; however, restaging scans MUST BE performed and reviewed before the subsequent cycle’s dose 
may be initiated.   
a. 
NOTE: The same imaging technique should be used for a participant throughout the trial, whenever 
feasible. Local reading (investigator assessment) will be used to determine eligibility and for 
participant management.    
b. NOTE: In the event that a study patient has a treatment-delay, the imaging interval will be maintained 
at every 6 weeks (every 9 weeks after 1 year on treatment) rather than adjusted to align with updated 
timing of odd cycle restaging. 
x. Response Assessment – Per modified RANO criteria (section 11);  
y. NANO scale (Section 12.6) will be completed by delegated study physician or mid-level prior to Cycle 1 Day 1 
dose, and then with each MRI (but must be completed before MRI scan results are reviewed with the subject) 
using the scorecard provided in Appendix D. 
z. 
See Sections 6.5.1 & 9.1 for pembrolizumab details.  Pembrolizumab to be administered +/-3 days from Day 1 
of each cycle (aside from C1D1). 
aa. Re-irradiation will ideally start on Day 1 of pembrolizumab/bevacizumab (or biosimilar) Cycle 1, but can start 
+/- 7 days from C1D1.  See Section 6.5.2 for re-irradiation details.  
bb. See Section 6.5.3 & 9.2 for bevacizumab (or biosimilar) details.  Bevacizumab (or biosimilar) to be 
administered +/-3 days from Day 1of each cycle (aside from C1D1), and bevacizumab (or biosimilar) doses 
must always be at least 10 days apart 
cc. Submission of archival tissue: Available tissue from most recent pre-registration biopsy/surgery to be submitted 
within 60 days of registration, if feasible.  Please see section 10 for details. 
dd. Submission of tumor sample at the time of progression or suspected progression: submission of available tissue 
from tumor sample at the time of progression or suspected progression (per section 10) within 60 days of 
resection, biopsy, if feasible.  This is an optional submission. 
ee. Post-end-of-treatment oncology therapies: Start/stop dates, names of treatment regimens and reason for 
stopping should be collected.  
ff. Survival: Date of death and reason should be collected for overall survival purposes, when applicable. 
gg. Although an explanation must be documented and filed in patient’s research chart, the following scenarios will 
not be considered protocol violations if the circumstances are beyond the study team’s ability to control: 
• Patient is unable to be weighed by standard methods in clinic, and weight is not needed at that visit for bev 
dose calculation. 
• Missed EOT or 30-day-follow-up labs or assessments if decision to come off active study treatment is 
made when patient is not on site  
• Urinalysis is not performed at a given timepoint because patient is PHYSICALLY UNABLE to provide a 
sample 
• Blood sample is collected but hemolyzes prior to analysis 


DF/HCC Protocol #: 18-277 
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74 
 
 
12. MEASUREMENT OF EFFECT 
 
Tumor response will be assessed by MRI (or CT, if MRI contraindicated) every 6 weeks, on Day 1 
of Cycle 3 and every odd cycle for the first year, and then every 9 weeks (Day 1 of every 3rd cycle) 
thereafter.  Scans should be performed within 7 days prior to the cycle start (and ideally within 3 
days prior).  Adjustments to this -7 day window are allowable per the treating physician’s 
discretion; however, restaging scans MUST BE performed and reviewed before the subsequent 
cycle’s dose may be initiated.  Modified RANO criteria1  will be utilized as outlined below. 
Clinicians may repeat response assessment more frequently as clinically indicated. 
NOTE: In the event that a study patient has a treatment-delay, the imaging interval will be 
maintained at every 6 weeks (every 9 weeks after 1 year on treatment) rather than adjusted to 
align with updated timing of odd cycle restaging. 
Local radiologic assessment of tumor measurements will be used during the study for clinical 
management and investigator-assessed disease progression. Cases of suspected radiologic disease 
progression will be confirmed by an MRI (or CT, as applicable) performed approximately 12 weeks 
after the initial radiological assessment of progression, as described below. 
 
12.1 
Anti-Tumor Effect Definitions 
 
12.1.1 Evaluable for toxicity: All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
12.1.2 Evaluable for objective response: Only those participants who have measurable disease 
present at baseline (obtained within 14 days of cycle 1, day 1) scan and have received at 
least one dose of therapy will be considered evaluable for response. These participants will 
have their response classified according to the definitions stated below. (Note: Participants 
who exhibit objective disease progression or die prior to the end of cycle 1 will also be 
considered evaluable.) 
12.1.3 Measurable disease: Bi-dimensionally, contrast-enhancing, measurable lesions with clearly 
defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 
axial slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a 
cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are too 
many measurable lesions to measure at each evaluation, the investigator must choose the 
largest two to be followed before a participant is entered on study.  The remaining lesions 
will be considered non-measurable for the purpose of objective response determination.  
Unless progression is observed, objective response can only be determined when all 
measurable and non-measurable lesions are assessed. 
12.1.4 Non-measurable evaluable disease: Unidimensionally measurable lesions, masses with 
margins not clearly defined, lesions with maximal diameter < 1cm.  
 
12.2 
Response/Progression Categories 
 
Investigator-assessed tumor response will be based upon RANO/iRANO criteria. Radiologic 
response will be assessed by comparing the pretreatment baseline and on-treatment MRI scans. 
Radiologic progression will be determined by using the smallest tumor measurement at either the 
pretreatment baseline or after initiation of study medication. Table 13 describes the radiologic and 
clinical criteria that will be used for determining tumor response. 


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75 
 
Table 13 Criteria for Response Assessment Incorporating MRI and Clinical Factors 
Response 
Criteria 
Complete 
Response 
Requires all of the following:  
• Complete disappearance of all enhancing measurable and non-measurable 
disease sustained for at least 4 weeks;  
o In the absence of a confirming scan 4 weeks later, this scan will be 
considered only stable disease. 
• No new lesions;  
• Stable or improved non-enhancing (T2/FLAIR) lesions;  
• Patients must be off corticosteroids (or on physiologic replacement doses only);  
• And stable or improved clinically.  
o Any clinical signs/symptoms must have been present at baseline and noted 
as disease-related 
Notes:  
- 
All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
- 
Patients with non-measurable disease only cannot have a complete response; 
the best response possible is stable disease. 
Partial 
Response 
Requires all of the following:  
• ≥ 50% decrease compared with baseline in the sum of products of perpendicular 
diameters of all measurable enhancing lesions sustained for at least 4 weeks;  
o In the absence of a confirming scan 4 weeks later, this scan will be 
considered only stable disease. 
• No progression of non-measurable disease;  
• No new lesions;  
• Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose 
of corticosteroids compared with baseline scan;  
• The corticosteroid dose at the time of the scan evaluation should be no greater 
than the dose at time of baseline scan;  
• And stable or improved clinically.  
o Any clinical signs/symptoms must have been present at baseline and noted 
as disease-related 
Notes:  
- 
All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
- 
Patients with non-measurable disease only cannot have a complete response; 
the best response possible is stable disease. 
Progressive 
Disease 
Defined by any of the following:  
• ≥ 25% increase in sum of the products of perpendicular diameters of enhancing 
lesions compared with the smallest tumor measurement [obtained either at 
baseline (if no decrease) or best response], on stable or increasing doses of 
corticosteroids*;  
• Any new enhancing measurable lesion;  
• Clear clinical deterioration not attributable to other causes apart from the tumor 
(eg, seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or changes in corticosteroid dose; 
o The definition of clinical deterioration is left to the discretion of the 


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76 
investigator, but it is recommended that a decline in the Karnofsky 
Performance Score (KPS) from 100 or 90 to 70 or less, a decline in KPS 
of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 
or less, for at least 7 days, be considered neurologic deterioration, unless 
attributable to co-morbid events or changes in corticosteroid dose. 
• Cohort B: Significant increase in T2/FLAIR non-enhancing lesions on stable or 
increasing doses of corticosteroids compared with baseline scan or best 
response after initiation of therapy* not felt to be caused by co-morbid events 
(eg, radiation therapy, tumor flare from inflammation due to immunotherapy, 
demyelination, ischemic injury, infection, seizures, postoperative changes, or 
other treatment effects);  
• Clear progression of non-measurable disease;  
• Or failure to return for evaluation as a result of death or deteriorating condition.  
Notes:  
- 
Confirmation of radiographic progression should be performed on follow-up 
imaging for participants who are not developing significant neurologic decline 
felt to be attributable to underlying tumor growth as detailed in Section 12.4. 
Stable 
Disease 
Requires all of the following:  
• Does not qualify for complete response, partial response, or progression;  
• Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared with baseline scan.  
• And stable clinically.  
Notes:  
- 
All measurable and non-measurable lesions must be assessed using the same 
techniques as baseline. 
- 
 
Unknown 
response 
status 
Progressive disease has not been documented and one or more measurable or non-
measurable lesions have not been assessed. 
* Stable doses of corticosteroids include subjects not on corticosteroids  
Abbreviations: MRI, magnetic resonance imaging; FLAIR, fluid-attenuated inversion recovery 
 
For purposes of this study, the minimum time from baseline for determination of SD will be 4 
weeks. 
 
The modified RANO Response Criteria to be used in this study are summarized in Table 14: 


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77 
Table 14. Summary of the RANO Response Criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease- 
<25% increase 
≥25% increase* 
T2/FLAIR 
Stable or 
decrease 
Stable or 
decrease 
NA 
NA 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or 
decrease 
Stable or decrease 
Stable or 
increasing 
Clinical Status 
Stable or 
increase 
Stable or 
increase 
Stable or increase 
Decrease* 
Requirement for 
Response  
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; NA= 
not applicable 
#:    Progression occurs when any of the criteria with * is present 
Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration 
 
Of note, patients who require increased corticosteroids within two weeks of MRI assessment 
(relative to the dose taken at the time of the prior assessment) cannot be classified as CR, PR or SD 
and should be classified as non-evaluable at that time point. Conversely, patients who decrease 
corticosteroids within two weeks of MRI assessment (relative to the dose taken at the time of the 
prior assessment) cannot be classified as PD and should be classified as non-evaluable. 
 
12.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or digital 
measurement tool. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 14 days before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
 
12.4 
Evaluation of Best Response 
 
The best overall response is the best response recorded from the start of the treatment until disease 
progression (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started). If a response recorded at one scheduled MRI does not persist at the next 
regular scheduled MRI, the response will still be recorded based on the prior scan, but will be 
designated as a non-sustained response. If the response is sustained, i.e. still present on the 
subsequent MRI at least four weeks later, it will be recorded as a sustained response, lasting until 
the time of tumor progression. Participants without measurable disease may only achieve SD or PD 
as their best “response.” 
 


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78 
12.5 
Study Continuation Beyond Initial Progressive Disease 
 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses which may manifest as initial worsening of 
enhancement and edema on MRI or CT scans (i.e. pseudoprogression). In addition, the response 
patterns seen with immunotherapeutics may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. For these reasons, the immune-related response 
criteria (irRC) have endorsed continuation of study therapy beyond initial radiographic evidence of 
progression for clinically stable patients undergoing immune based therapies.62 
 
A major advance of the RANO criteria1 to assess response in neuro-oncology over the previously 
used Macdonald criteria63 includes recognition of the prevalence of pseudoprogression during the 
first three months following completion of radiation and daily temozolomide.64,65 Specifically, 
RANO permits patients with such progressive MRI findings to continue temozolomide therapy for 
up to three months in order to avoid inaccurately classifying such patients as progressive.  
Furthermore, RANO permits patients with progressive radiographic findings at any time to continue 
current therapy pending follow-up imaging if the etiology of progressive imaging findings is 
unclear. Standard RANO may not provide an accurate response assessment of immunotherapeutic 
agents such as pembrolizumab. 
 
Therefore, the following adaptations of the RANO criteria, as reflected in the Immunologic 
Response Assessment in Neuro-Oncology (iRANO) criteria66 will be used to assess response for 
patients treated on this study (Table 15): 
• Potential Pseudoprogression: If radiologic imaging shows initial PD, participants who are 
not experiencing significant clinical decline, may be allowed to continue study treatment for 
up to three months. Patients who have radiographic evidence of further progression after up 
to three months, or who decline significantly at any time, will be classified as progressive 
with the date of disease progression back-dated to the first date that the participant met 
criteria for progression and such participants will be discontinued from study therapy. 
Although the kinetics of pseudoprogression due to immune checkpoint blockade among 
glioblastoma patients is currently unknown, three months is a reasonable estimate based on: 
1) the peak time for XRT/daily temozolomide-related pseudoprogression is usually within 
three months of completion for glioblastoma patients64,65 and; 2) three months is also the 
most common timeframe for pseudoprogression observed among patients with advanced 
melanoma or other solid tumors treated with PD-1/PD-L1immune checkpoint blockade to 
date.67-69  
 
Among patients on this study with initial radiographic PD, tumor assessment should be 
repeated regularly in order to confirm PD with the option of continuing treatment as 
described below while awaiting radiologic confirmation of progression. If repeat imaging 
shows a stabilization or reduction in the tumor burden compared to the initial scan 
demonstrating PD, treatment may be continued / resumed. If repeat imaging after up to three 
months confirms progressive disease, then the date of disease progression will be the first 
date the participant met criteria for progression and participants will be discontinued from 
study therapy. Participants who have confirmed disease progression will discontinue study 
medication and enter the follow up/survival phase of the study. In determining whether or 
not the tumor burden has increased or decreased, investigators should consider all target 
lesions as well as non-target lesions. 
 


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In participants who have initial evidence of radiographic PD, it is at the discretion of the treating 
physician whether to continue a participant on study treatment for up to three months pending 
confirmation of PD on follow-up imaging. This clinical judgment decision should be based on the 
participant’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data. Participants may receive study treatment while waiting for confirmation of PD if 
they are not experiencing significant clinical decline and if: 
• The participant is believed to demonstrate clinical benefit from the study regimen as 
determined by the treating physician;  
• The participant is adequately tolerating study therapy. 
 
When feasible, study therapy should not be discontinued until radiographic progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some participants can have a transient tumor flare in the first few 
months after the start of immunotherapy, but with subsequent disease response.62 Participants that 
are exhibiting significant neurologic decline are not required to have repeat imaging for 
confirmation of progressive disease. 
 
Table 15. Imaging and Treatment After 1st Radiologic Evidence of Progression 
 
1st radiologic evidence of PD 
 
Imaging 
Treatment 
No Significant 
Neurologic Decline 
Repeat imaging for up to 3 months to 
confirm PD 
May continue study treatment at the 
Investigator’s discretion for up to 3 months 
while awaiting confirmatory scans 
Significant 
Neurologic Decline 
Repeat imaging >6 weeks later to 
confirm PD if possible 
Discontinue treatment 
 
Repeat scan after 3 months  
 
Repeat scan confirms PD 
 
Imaging 
Treatment 
No Significant 
Neurologic Decline 
No additional imaging required; date 
of tumor progression back-dated to 
date of initial radiographic PD 
Discontinue treatment 
Significant 
Neurologic Decline 
No additional imaging required; date 
of tumor progression back-dated to 
date of initial radiographic PD 
Discontinue treatment 
 
Repeat scan shows SD, PR or CR  
 
Imaging 
Treatment 
No Significant 
Neurologic Decline 
Continue regularly scheduled imaging 
assessments every 6 weeks 
Continue study treatment at the 
Investigator’s discretion 
Significant 
Neurologic Decline 
Continue regularly scheduled imaging 
assessments every 6 weeks 
May restart study treatment if condition has 
improved and/or clinically stable per 
Investigator’s discretion 
 


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Figure 2 iRANO Algorithm for Treatment Decision Making for Radiographic Progression 
 
 
 
Participants with progressive radiographic findings are encouraged to undergo surgical intervention 
in order to delineate pseudoprogression due to inflammation associated with PD-1 blockade from 
true tumor progression. Participants with histopathologic findings of significant immune infiltrate 
and evolving gliosis will be allowed to continue study therapy. In contrast, those with clear 
evidence of progressive tumor by histopathologic evaluation will be defined as progressive and 
discontinued from study therapy. For such patients, the date of tumor progression will be the first 
date the participant met radiographic criteria for PD. 
 
12.6 
Central Radiology Review 
 
For this trial where the objective response rate is the primary co-endpoint, all responses determined 
by the investigator assessment will be reviewed by an expert(s) independent of the study at its 
completion.  This independent review of neuroimaging (MRI or CT) - to include simultaneous 
review of the participants’ files including corticosteroids usage and neurological status - will be 
performed centrally by an objective Investigator to be determined by Overall PI.   
 
All films of all views from pre-registration and subsequent scans must be submitted for central 
review when requested from the DFCI Coordinating Center on behalf of the Overall PI. CDs are 
preferred. 
 
A copy of the local treating investigator’s tumor measurements and response assessment must be 
submitted with the films. A copy of all scan reports must be attached for inclusion in the 
submission.  


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NOTE: Information re: participants’ steroids usage and neurological status will be gathered from 
the study’s database, but the review itself may result in queries / requests for confirmatory source 
from the site.   
 
Once the Central Review is complete the Reviewing Physician will document the review results. 
Once the Central Review is complete, the central review results can be made available to the local 
PI. 
  
When requested from the DFCI Coordinating Center, please send a copy of all scans (and any 
corresponding paperwork) to: 
 
David A. Reardon, MD 
c/o Christine McCluskey 
Center for Neuro-Oncology 
Dana-Farber Cancer Institute 
450 Brookline Ave, LG1B12F  
Boston, MA  02215  
ph: 617-632-5394 
fax: 617-394-2683  
NeuroOnc_Coord@dfci.harvard.edu   
 
A memo must be submitted to the DFCI Coordinating Center each time submissions are made 
including DFCI study number, participant identifiers and details of what is being submitted.  
 
The submitting institution is responsible for the costs of shipping and handling. 
 
12.7 
Neurologic Assessment in Neuro-Oncology (NANO) Scale 
 
The Neurologic Assessment in Neuro-Oncology (NANO) scale (Appendix D) was developed by an 
international, multidisciplinary committee of neuro-oncology experts to objectively assess 
neurologic function of neuro-oncology patients.70 In this trial, the NANO scale will be assessed by 
the investigator or designated study physician or mid-level at baseline (prior to ignition of study 
treatment) as well as at each clinic visit that includes an MRI evaluation as a method to characterize 
relevant changes in neurologic function. Of note, the NANO scale will not be used in this study to 
define clinical progression because the scale has not been adequately validated to date. 
 
13. DATA REPORTING / REGULATORY REQUIREMENTS 
 
13.1 
Data Reporting 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the data for 
this study. 
 
13.1.1 Responsibility for Data Submission 
All investigative sites are responsible for submitting data and/or data forms to the ODQ according 
to the schedule set by the ODQ as noted in Table 16 below. 
 


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Table 16. Study Data Submission Table 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to study registration 
On Study Form 
Within 30 days of registration 
Baseline Assessment Form 
Within 30 days of registration 
Treatment Form 
Within 30 days of treatment administration 
Adverse Event Report Form 
Within 30 days of AE assessment/notification 
Response Assessment Form 
Within 30 days of the response assessment 
Off Treatment/Off Study Form Within 30 days of completing treatment or 
being taken off study for any reason 
Follow up/Survival Form 
Within 30 days of the protocol defined follow 
up visit date or call 
 
13.1.2 Data Safety Monitoring 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with experience 
in oncology and who have no direct relationship with the study. Information that raises any 
questions about participant safety will be addressed with the Overall PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; all grade 2 or higher unexpected adverse events that have been reported; 
summary of all deaths occurring with 30 days of intervention for Phase I or II protocols; for gene 
therapy protocols, summary of all deaths while being treated and during active follow-up; any 
response information; audit results, and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request.  
 
13.1.3 Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan (Appendix E), which includes the specific responsibilities of the Overall PI, 
Coordinating Center, and Participating Institutions and the procedures for auditing. 
• The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters or 
Safety Reports to all participating institutions for submission to their individual IRBs for 
action as required. 
• Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse 
event reporting at each site. 
• Except in very unusual circumstances, each participating institution will order the study 
agent(s) directly from supplier.  A participating site may order the agent(s) only after the 
initial IRB approval for the site has been forwarded to the Coordinating Center. 
 


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14. STATISTICAL ANALYSIS PLAN 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after the study 
has begun, changes are made to primary and/or key secondary hypotheses, or the statistical methods 
related to those hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). 
Changes to exploratory or other non-confirmatory analyses made after the protocol has been 
finalized, along with an explanation as to when and why they occurred, will be listed in the Clinical 
Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the 
CSR. No separate Statistical Analysis Plan (SAP) for the primary, secondary and exploratory 
endpoints will be issued for this study. 
 
14.1 
Statistical Analysis Plan Summary 
 
This section contains a summary of the statistical analyses for this trial. This trial includes 
allocation of accrual to two experimental treatment arms including patients who are bevacizumab 
naïve (Cohort A) and those who have progressed on one prior bevacizumab regimen (Cohort B). 
The outcome of each treatment arm will be assessed separately relative to appropriate historical 
controls. Enrollment will continue until target accrual for each arm is achieved. The two 
experimental arms will not be compared to each other and are independently designed as phase II 
studies for preliminary assessment of efficacy in comparison to historical control rates. Both arms 
have independent decision rules. Full detail is in the Statistical Analysis Plan (SAP) (Section 14.2). 
 
14.1.1 Efficacy Analysis 
The primary and key secondary endpoints, primary analysis population, and statistical methods that 
will be employed for the efficacy analyses are discussed in detail in the following sections.  
 
The primary hypothesis of efficacy will be evaluated independently in each cohort. 
 
14.1.2 Safety Analyses 
Adverse events will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. All patients who receive any amount of Pembrolizumab will be evaluable for 
toxicity. The All-Patients-as-Treated population will be employed for safety analyses. Immune 
related adverse experiences are prespecified as Events of Clinical Interest (Section 8.4.4.2).  
 
14.2 
Statistical Analysis Plan 
 
14.2.1 Responsibility for Analyses/In-House Blinding 
The statistical analysis of the data obtained from this study will be the responsibility of the 
biostatistics department of the Dana-Farber/Harvard Comprehensive Cancer Center. 
 
This trial is being conducted as an open-label study, i.e., participants, investigators, and sponsor 
personnel will be aware of participant treatment assignments after each participant is enrolled and 
treatment is assigned. 
 
14.2.2 Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 2 (2.2 – 2.4). 
 


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14.2.3 Power and Sample Size 
Participants will enroll to one of two treatment arms in order to estimate the anti-tumor activity as 
well as safety of pembrolizumab plus re-irradiation among bevacizumab-naive (Cohort A) as well 
as bevacizumab-refractory (Cohort B) patients. Up to 35 participants will accrue to each cohort, 
with the goal of treating 30 eligible patients. Statistical success will be evaluated separately for each 
cohort relative to historical controls as described below.  
The primary objective of cohort A is to evaluate the efficacy of pembrolizumab plus re-RT in 
bevacizumab naïve patients through the frequency of participants with objective tumor responses 
and the frequency of participants who survive for at least 12 months (OS12). The null hypothesis 
relating to uninteresting levels of activity was determined from historical data. Fogh et al. reported 
on 147 patients treated with re-RT for recurrent high-grade astrocytoma and found an objective 
response rate (ORR) of < 10% and median survival of 11 months.19  The null hypothesis is 
specified for each endpoint independently.   the null probability of a participant experiencing a 
tumor response – ORR – is set at ≤ 10% and the null probability of a patient being alive at 12 
months – OS12 is set at ≤ 45%. Clinically significant differences constitute an increase in ORR to 
30% and/or an increase in OS12 to 70%. For the ORR endpoint, enrollment of 30 participants will 
provide 84% power at 0.026 significance level to reject the null in favor of the alternative. For the 
OS12 endpoint, 30 patients will provide 84% power at 0.03 significance level to reject the null in 
favor of the alternative. If ≥7 Cohort A participants have responses and/or ≥19 Cohort A 
participants are alive at 12 months, this regimen will be deemed worthy of further study. 
  
The primary objective of cohort B is to evaluate the efficacy of continuation of bevacizumab and 
addition of pembrolizumab plus re-RT in bevacizumab resistant participants through the frequency 
of participants with objective tumor responses and the frequency of participants who survived for at 
least 6 months (OS6). The null hypothesis relating to uninteresting levels of activity was 
determined from historical data. Reardon et al. reported on 33 GBM patients treated with 
continuation of bevacizumab and addition of metronomic chemotherapy post bevacizumab 
progression and found no objective responses and median survival of 4 months.6  The CABARET 
study which compared continuing bevacizumab to cessation of therapy following disease 
progression on bevacizumab also showed no objective responses and median survival of 3.4 
months. 
 
The null hypothesis is specified for each endpoint independently. The null probability of a 
participant experiencing a tumor response – ORR – is set at ≤ 4% and the null probability of a 
participant being alive at 6 months – OS6 – is set at ≤ 25%. Clinically significant differences 
constitute an increase in ORR to 20% and/or an increase in OS6 to 50%. For the ORR endpoint, 
enrollment of 30 participants will provide 87% power at 0.03 significance level to reject the null in 
favor of the alternative. For the OS6 endpoint, 30 patients will provide 89% power at 0.0507 
significance level to reject the null in favor of the alternative.  If ≥4 Cohort B participants have a 
response and/or ≥12 Cohort B participants are alive at 6 months, this regimen will be deemed 
worthy of further study. 
 
14.2.4 Analysis Endpoints 
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below, followed by the descriptions of the derivations of selected endpoints. 
 


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14.2.4.1 Efficacy Endpoints 
Efficacy endpoints that will be evaluated for are listed below, followed by the descriptions of the 
derivations of selected endpoints. 
 
Objective response rate, defined as the proportion of participants in the analysis population who 
achieve a complete response (CR) or partial response (PR) using RANO criteria1 is a primary 
endpoint for each cohort. Overall survival at 12 months, defined as the proportion of participants in 
the analysis population who are alive for at least 12 months following initiation of study therapy is 
also a primary efficacy endpoint for cohort A. Overall survival at 6 months, defined as the 
proportion of participants in the analysis population who are alive for at least 6 months following 
initiation of study therapy is also a primary efficacy endpoint for cohort B. Response for the 
primary analysis will be determined by the investigator assessment, and a confirmation assessment 
is required per RANO.1  All patients in Cohort A will be followed for a minimum of 12 months and 
all patients in Cohort B will be followed for a minimum of 6 months. 
 
For this trial where the objective response rate is the primary co-endpoint, all responses determined 
by the investigator assessment will be reviewed by an expert(s) independent of the study at its 
completion.  Simultaneous review of the participants’ files including corticosteroids usage and 
neurological status in conjunction with radiological images is the best approach.  
 
Secondary efficacy endpoints include: (1) PFS-6 defined as the proportion of participants in the 
analysis population who remain progression-free for at least six months following initiation of 
study therapy.; (2) progression-free survival (PFS), defined as the time from allocation to the first 
documented disease progression according to RANO or death due to any cause, whichever occurs 
first; (3) overall survival (OS), and (4) duration of response. 
 
Additional supportive analyses duration of response will be conducted using RANO criteria, in 
which a confirmation assessment of disease response must be obtained at least 4 weeks after the 
initial disease assessment response. 
 
14.2.4.2 Safety Endpoints 
Safety & Tolerability of the therapy used in each cohort = a secondary objective of this study. The 
primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by participants who have received 
Pembrolizumab, including serious adverse events (SAEs), other Reportable Adverse Events, and 
events of clinical interest (ECIs – Section 8.4.4.2). Immune related adverse experiences (irAEs, as 
defined in Section 7.2) are prespecified as events of interest. Other safety endpoints include 
laboratory safety assessments, KPS status, vital signs and physical examinations. 
 
14.2.4.3 Exploratory Endpoints 
• 
Objective: To evaluate whether archival tumor expression of PD-L1, tumor infiltrating lymphocytes 
features, or T cell inflamed gene expression profile are associated with outcome.  
• 
Objective: To evaluate Neurologic Assessment in Neuro-Oncology (NANO) in each cohort 
• 
Objective: To evaluate the change of Patient Reported Outcome scores from baseline to post-baseline 
time-points using the EORTC QLQ-C30. 
• 
Objective: To estimate ORR per iRANO 
 


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14.2.5 Analysis Population 
14.2.5.1 Efficacy Analysis Populations 
The Full Analysis Set (FAS) population will serve as the primary population for the analysis of 
efficacy data in this study. The FAS population consists of all participants within each cohort who 
have received at least one dose of study pembrolizumab treatment and have completed at least 75% 
of the planned re-irradiation therapy. 
 
Two supportive analyses of the primary and selected secondary efficacy endpoints will be 
conducted. The first supportive analysis will be conducted in the FAS-2 population, defined as all 
participants who meet the FAS population definition and have a post baseline scan OR discontinue 
the trial due to progressive disease/drug related AE. The second analysis will be conducted using 
the intention to treat (ITT) population, defined as all registered participants. 
 
Participants will be included in the cohort to which they are allocated for the analysis of efficacy 
data.  
 
14.2.5.2 Safety Analysis Populations 
The All Patients as Treated (APaT) population will be used for the analysis of safety data in this 
study. The APaT population consists of all allocated participants who received at least one dose of 
study pembrolizumab treatment. 
 
At least one laboratory or vital sign measurement obtained after at least one dose of study 
pembrolizumab treatment is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. 
 
Details on the approach to handling missing data for safety analyses are provided in Section 
14.2.6 Statistical Methods. 
 
14.2.6 Statistical Methods 
Nominal p –values may be computed for efficacy analyses as a measure of strength of association 
between the endpoint and the treatment effect rather than formal tests of hypotheses. Unless 
otherwise stated, all statistical tests will be conducted at the α=0.05 (2-sided) level. All estimated 
rates will be reported with corresponding 95% CI. 
 
14.2.6.1 Statistical Methods for Efficacy Analyses 
Efficacy will be evaluated separately in each cohort. Primarily, rates comparison will be conducted 
using exact methods. In addition, OS andPFS endpoints will be calculated using the Kaplan-Meier 
(KM) method and curves and median estimates with corresponding 95% CI will be provided as 
appropriate. Participants without efficacy evaluation data or without survival data will be censored 
at Day 1. The final efficacy analysis will be conducted whenever all patients achieved the required 
follow-up time in their respective cohort. This analysis is expected to take place at study closure: 
around 2 years after first patient has been consented. 
 
14.2.6.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Safety summaries will be reported for 
both cohorts. 


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Immune related adverse experiences (irAEs, as defined in Section 7.2) are prespecified as events of 
interest. These events will be summarized in separate tables from other AEs by toxicity grade and 
will include the counts, percentage, and 95% CI. Any AE of unknown etiology associated with 
pembrolizumab exposure will be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (irECI). Other ECIs listed in Section 8.4.4.2 will also 
be summarized in the same manner as irAEs. 
 
Adverse experiences (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory, and vital sign parameters that are not pre-specified as events of interest will be 
summarized with descriptive statistics (counts, percentage, mean, standard deviation, etc.). 
 
Continuous measures such as changes from baseline in laboratory, and vital signs parameters that 
are not pre-specified as events of interest will be summarized using descriptive statistics (mean, 
standard deviation, etc.) for baseline, on-treatment, and change from baseline values. 
 
14.2.7 Summary of Baseline Characteristics, Demographics, and Immunocorrelative 
Analyses 
14.2.7.1 Demographic and Baseline Characteristics 
Baseline characteristics will be assessed using tables and/or graphs for each cohort separately. No 
statistical hypothesis tests will be performed on these characteristics. The number and percentage of 
participants screened, allocated to treatment arm, the primary reasons for screening failure, and the 
primary reason for discontinuation will be displayed. Demographic variables (e.g., age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies will 
be summarized by treatment either by descriptive statistics or categorical tables. 
 
 
14.2.8 Interim Analyses 
14.2.8.1 Monitoring of Efficacy (Stopping Rule for Unexpected Efficacy)  
Given that re-irradiation is considered standard treatment for patients with glioblastoma, and all 
participants will be treated with re-irradiation, there is no planned interim analysis for unexpected 
efficacy. 
 
14.2.8.2 Monitoring of Toxicity (Stopping Rule for Unexpected Toxicity) 
The primary focus of toxicity monitoring will be the toxicity profile of participants treated with 
pembrolizumab. For study purposes, the occurrence of toxicity attributable to pembrolizumab that 
requires discontinuation of pembrolizumab therapy as defined in Section 7.2 is defined as 
unacceptable. Unacceptable toxicity rates of 20% or less are considered desirable. Sequential 
boundaries will be used to monitor the unacceptable toxicity rate for each cohort. Accrual to that 
cohort will be halted if excessive numbers of unacceptable toxicities are seen at any time during the 
course of study therapy for a given participant; that is, if the number of toxicities is equal to or 
exceeds bn out of n patients with full follow-up (see below table). This is a Pocock-type stopping 
boundary that yields the probability of crossing the boundary at most 0.05 when the rate of 
unacceptable toxicity is equal to 0.2.  
 


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Table 17. Stopping Rule for Unacceptable Toxicity 
Participants, n 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Boundary, bn 
- 
- 
3 
4 
4 
4 
5 
5 
6 
6 
6 
7 
7 
7 
8 
8 
8 
 
Participants, n 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
Boundary, bn 
8 
9 
9 
9 
10 
10 
10 
11 
11 
11 
11 
12 
12 
 
14.2.9 Compliance (Medication Adherence) 
A day within the study will be considered an ‘On-Therapy’ day if the participant receives the study 
medication infusion. The ‘Number of Days Should be on Therapy’ is the total number of days from 
the first day of study medication to the date of the last dose of study medication. For each 
participant, compliance rate will then be calculated using the following formula: 
 
Compliance Rate = (Actual number of therapy days/planned number of therapy days) x 100 
 
Summary statistics will be provided on percent compliance by treatment group for the FAS 
population. 
 
14.2.10 
Extent of Exposure 
Extent of Exposure for a participant is defined as number of cycles in which the participant receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for APaT 
population. 
 
14.2.11 
Accrual Targets 
 
Table 18.  Accrual Targets by Gender, ethnic category and racial category. 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
2 
+ 
3 
= 
5 
Not Hispanic or Latino 
23 
+ 
32 
= 
55 
Ethnic Category: Total of all participants 
25 
+ 
35 
= 
60 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
2 
= 
3 
Native Hawaiian or other Pacific Islander 
0 
+ 
0 
= 
0 
White 
23 
+ 
32 
= 
55 
Racial Category: Total of all participants 
25 
+ 
35 
= 
60 
 
 
 
 
 
 


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15. PUBLICATION PLAN 
 
This trial is intended for publication, even if terminated prematurely. Publication may include any 
or all of the following: posting of a synopsis online, abstract and/or presentation at a scientific 
conference, or publication of a full manuscript. The Sponsor will work with the authors to submit a 
manuscript describing trial results within 12 months after the last data become available, which may 
take up to several months after the last participant visit in some cases. Sponsor will post a synopsis 
of trial results for approved products on www.clinicaltrials.gov by 12 months after the last 
participant's last visit for the primary outcome, 12 months after the decision to discontinue 
development, or product marketing (dispensed, administered, delivered or promoted), whichever is 
later. 
 
These timelines may be extended for products that are not yet marketed, if additional time is needed 
for analysis, to protect intellectual property, or to comply with confidentiality agreements with 
other parties. Authors of the primary results manuscript will be provided the complete results from 
the Clinical Study Report, participant to the confidentiality agreement. When a manuscript is 
submitted to a biomedical journal, the Sponsor's policy is to also include the protocol and statistical 
analysis plan to facilitate the peer and editorial review of the manuscript. If the manuscript is 
subsequently accepted for publication, the Sponsor will allow the journal, if it so desires, to post on 
its website the key sections of the protocol that are relevant to evaluating the trial, specifically those 
sections describing the trial objectives and hypotheses, the participant inclusion and exclusion 
criteria, the trial design and procedures, the efficacy and safety measures, the statistical analysis 
plan, and any amendments relating to those sections. The Sponsor reserves the right to redact 
proprietary information. 
 
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of the 
results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an investigator 
and his/her colleagues may publish their data independently. In most cases, publication of 
individual trial site data does not add value to complete multicenter results, due to statistical 
concerns. In rare cases, publication of single trial site data prior to the main paper may be of value. 
Limitations of single trial site observations in a multicenter trial should always be described in such 
a manuscript. 
 
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3. Significant contributions to trial execution may also be 
taken into account to determine authorship, provided that contributions have also been made to all 
three of the preceding authorship criteria. Although publication planning may begin before 
conducting the trial, final decisions on authorship and the order of authors’ names will be made 
based on participation and actual contributions to the trial and writing, as discussed above. The first 
author is responsible for defending the integrity of the data, method(s) of data analysis and the 
scientific content of the manuscript. 
 
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited to 
meet publication timelines. 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
90 
 
16. REFERENCES 
 
1. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-
grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 
2010;28:1963-72. 
2. 
Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and 
Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol 
2015;17 Suppl 4:iv1-iv62. 
3. 
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant 
temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. 
4. 
Weller M, Cloughesy T, Perry JR, Wick W. Standards of care for treatment of recurrent 
glioblastoma--are we there yet? Neuro-oncology 2013;15:4-27. 
5. 
Wick W, Brandes AA, Gorlia T, et al. EORTC 26101 phase III trial exploring the 
combination of bevacizumab and lomustine in patients with first progression of a 
glioblastoma.  2016 American Society of Clinical Oncology; 2016; Chicago, ILL: ASCO. 
6. 
Reardon DA, Desjardins A, Peters K, et al. Phase II study of metronomic chemotherapy with 
bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. J 
Neurooncol 2011;103:371-9. 
7. 
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28:4531-8. 
8. 
Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-
myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23:2346-57. 
9. 
Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous CD4+ 
T cells against NY-ESO-1. N Engl J Med 2008;358:2698-703. 
10. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 
2005;23:515-48. 
11. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B 
cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 2001;98:13866-71. 
12. Zhang X, Schwartz JC, Guo X, et al. Structural and functional analysis of the costimulatory 
receptor programmed death-1. Immunity 2004;20:337-47. 
13. Chemnitz JM, Lanfranco AR, Braunstein I, Riley JL. B and T lymphocyte attenuator-
mediated signal transduction provides a potent inhibitory signal to primary human CD4 T 
cells that can be initiated by multiple phosphotyrosine motifs. J Immunol 2006;176:6603-14. 
14. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell 
activation by distinct mechanisms. Molecular & Cellular Biology 2005;25:9543-53. 
15. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
16. Berghoff AS, Kiesel B, Widhalm G, et al. Programmed death ligand 1 expression and tumor-
infiltrating lymphocytes in glioblastoma. Neuro Oncol 2015;17:1064-75. 
17. Nduom EK, Wei J, Yaghi NK, et al. PD-L1 expression and prognostic impact in glioblastoma. 
Neuro Oncol 2016;18:195-205. 
18. Combs SE, Thilmann C, Edler L, Debus J, Schulz-Ertner D. Efficacy of fractionated 
stereotactic reirradiation in recurrent gliomas: long-term results in 172 patients treated in a 
single institution. J Clin Oncol 2005;23:8863-9. 
19. Fogh SE, Andrews DW, Glass J, et al. Hypofractionated stereotactic radiation therapy: an 
effective therapy for recurrent high-grade gliomas. J Clin Oncol 2010;28:3048-53. 
20. Minniti G, Armosini V, Salvati M, et al. Fractionated stereotactic reirradiation and concurrent 


DF/HCC Protocol #: 18-277 
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91 
temozolomide in patients with recurrent glioblastoma. J Neurooncol 2011;103:683-91. 
21. Patel M, Siddiqui F, Jin JY, et al. Salvage reirradiation for recurrent glioblastoma with 
radiosurgery: radiographic response and improved survival. J Neurooncol 2009;92:185-91. 
22. Torcuator RG, Thind R, Patel M, et al. The role of salvage reirradiation for malignant gliomas 
that progress on bevacizumab. J Neurooncol 2010;97:401-7. 
23. Magnuson W, Ian Robins H, Mohindra P, Howard S. Large volume reirradiation as salvage 
therapy for glioblastoma after progression on bevacizumab. J Neurooncol 2014;117:133-9. 
24. Gutin PH, Iwamoto FM, Beal K, et al. Safety and efficacy of bevacizumab with 
hypofractionated stereotactic irradiation for recurrent malignant gliomas. Int J Radiat Oncol 
Biol Phys 2009;75:156-63. 
25. Formenti SC, Demaria S. Combining radiotherapy and cancer immunotherapy: a paradigm 
shift. J Natl Cancer Inst 2013;105:256-65. 
26. Golden EB, Pellicciotta I, Demaria S, Barcellos-Hoff MH, Formenti SC. The convergence of 
radiation and immunogenic cell death signaling pathways. Front Oncol 2012;2:88. 
27. Apetoh L, Ghiringhelli F, Tesniere A, et al. Toll-like receptor 4-dependent contribution of the 
immune system to anticancer chemotherapy and radiotherapy. Nature medicine 
2007;13:1050-9. 
28. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM. Radiation-induced 
IFN-gamma production within the tumor microenvironment influences antitumor immunity. J 
Immunol 2008;180:3132-9. 
29. Ifeadi V, Garnett-Benson C. Sub-lethal irradiation of human colorectal tumor cells imparts 
enhanced and sustained susceptibility to multiple death receptor signaling pathways. PLoS 
One 2012;7:e31762. 
30. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, 
enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp 
Med 2006;203:1259-71. 
31. Vereecque R, Saudemont A, Wickham TJ, et al. Gamma-irradiation enhances transgene 
expression in leukemic cells. Gene Ther 2003;10:227-33. 
32. Baluna RG, Eng TY, Thomas CR. Adhesion molecules in radiotherapy. Radiat Res 
2006;166:819-31. 
33. Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate 
immune system ligands of the NKG2D receptor. Nature 2005;436:1186-90. 
34. Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in 
a patient with melanoma. The New England journal of medicine 2012;366:925-31. 
35. Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-
term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys 2013;86:343-9. 
36. Belcaid Z, Phallen JA, Zeng J, et al. Focal radiation therapy combined with 4-1BB activation 
and CTLA-4 blockade yields long-term survival and a protective antigen-specific memory 
response in a murine glioma model. PLoS One 2014;9:e101764. 
37. Combs SE, Gutwein S, Thilmann C, Debus J, Schulz-Ertner D. Reirradiation of recurrent 
WHO grade III astrocytomas using fractionated stereotactic radiotherapy (FSRT). 
Strahlenther Onkol 2005;181:768-73. 
38. Wick W, Fricke H, Junge K, et al. A phase II, randomized, study of weekly 
APG101+reirradiation versus reirradiation in progressive glioblastoma. Clin Cancer Res 
2014;20:6304-13. 
39. Du Four S, Hong A, Chan M, et al. Symptomatic Histologically Proven Necrosis of Brain 
following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients. 
Case Rep Oncol Med 2014;2014:417913. 
40. Silk AW, Bassetti MF, West BT, Tsien CI, Lao CD. Ipilimumab and radiation therapy for 


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Protocol Version Date: 26-Jul-2021 
92 
melanoma brain metastases. Cancer Med 2013;2:899-906. 
41. Mathew M, Tam M, Ott PA, et al. Ipilimumab in melanoma with limited brain metastases 
treated with stereotactic radiosurgery. Melanoma Res 2013;23:191-5. 
42. Patel KR, Shoukat S, Oliver DE, et al. Ipilimumab and Stereotactic Radiosurgery Versus 
Stereotactic Radiosurgery Alone for Newly Diagnosed Melanoma Brain Metastases. Am J 
Clin Oncol 2015. 
43. Kotecha R, Miller JA, Venur VA, et al. Melanoma brain metastasis: the impact of stereotactic 
radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on 
treatment outcome. J Neurosurg 2017:1-10. 
44. Fang P, Jiang W, Allen P, et al. Radiation necrosis with stereotactic radiosurgery combined 
with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic 
melanoma. J Neurooncol 2017;133:595-602. 
45. Liniker E, Menzies AM, Kong BY, et al. Activity and safety of radiotherapy with anti-PD-1 
drug therapy in patients with metastatic melanoma. Oncoimmunology 2016;5:e1214788. 
46. Kiess AP, Wolchok JD, Barker CA, et al. Stereotactic radiosurgery for melanoma brain 
metastases in patients receiving ipilimumab: safety profile and efficacy of combined 
treatment. Int J Radiat Oncol Biol Phys 2015;92:368-75. 
47. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin 
Invest 2015;125:3384-91. 
48. Reardon DA, De Groot JF, Colman H, et al. Safety of Pembrolizumab in combination with 
bevacizumab in recurrent glioblastoma (rGBM).  2016 American Society of Clinical 
Oncology Annual Meeting; 2016; Chicago: ASCO. 
49. Reardon DA, Omuro A, Brandes AA, et al. Randomized phase 3 study evaluating the efficacy 
and safety of nivolumab vs bevacizumab in patients with recurrent glioblastoma: Checkmate 
143.  5th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies 
(WFNOS); 2017; Zurich, Switzerland: Oxford University Press. 
50. Yang I, Tihan T, Han SJ, et al. CD8+ T-cell infiltrate in newly diagnosed glioblastoma is 
associated with long-term survival. J Clin Neurosci 2010;17:1381-5. 
51. Rutledge WC, Kong J, Gao J, et al. Tumor-infiltrating lymphocytes in glioblastoma are 
associated with specific genomic alterations and related to transcriptional class. Clin Cancer 
Res 2013;19:4951-60. 
52. Sayour EJ, McLendon P, McLendon R, et al. Increased proportion of FoxP3+ regulatory T 
cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced 
survival in patients with glioblastoma. Cancer Immunol Immunother 2015;64:419-27. 
53. Rajasagi M, Shukla SA, Fritsch EF, et al. Systematic identification of personal tumor-specific 
neoantigens in chronic lymphocytic leukemia. Blood 2014;124:453-62. 
54. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search 
for new cancer-associated genes. Nature 2013;499:214-8. 
55. Twyman-Saint Victor C, Rech AJ, Maity A, et al. Radiation and dual checkpoint blockade 
activate non-redundant immune mechanisms in cancer. Nature 2015;520:373-7. 
56. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated 
radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 2014;74:5458-68. 
57. Sharabi AB, Nirschl CJ, Kochel CM, et al. Stereotactic Radiation Therapy Augments 
Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of 
Tumor Antigen. Cancer Immunol Res 2015;3:345-55. 
58. Golden EB, Chhabra A, Chachoua A, et al. Local radiotherapy and granulocyte-macrophage 
colony-stimulating factor to generate abscopal responses in patients with metastatic solid 
tumours: a proof-of-principle trial. Lancet Oncol 2015;16:795-803. 
59. Iwamoto FM, Donovan L, Schaff LR, Wang TJC, Lassman AB. Synergistic effect of 


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Protocol Version Date: 26-Jul-2021 
93 
reirradiation and PD-1 inhibitors in recurrent high-grade gliomas.  2017 American Society for 
Clinical Oncology-Society for Immunotherapy of Cancer Clinical Immuno-Oncology 
Symposium; 2017: Journal of Clinical Oncology. 
60. Qin L, Li X, Stroiney A, et al. Advanced MRI assessment to predict benefit of anti-
programmed cell death 1 protein immunotherapy response in patients with recurrent 
glioblastoma. Neuroradiology 2017;59:135-45. 
61. Fellner A, Makranz C, Lotem M, et al. Neurologic complications of immune checkpoint 
inhibitors. J Neurooncol 2018;137:601-9. 
62. Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2009;15:7412-20. 
63. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for phase II 
studies of supratentorial malignant glioma. Journal of Clinical Oncology 1990;8:1277-80. 
64. Brandes AA, Tosoni A, Spagnolli F, et al. Disease progression or pseudoprogression after 
concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro Oncol 
2008;10:361-7. 
65. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, 
and management of pseudoprogression in malignant gliomas. Lancet Oncol 2008;9:453-61. 
66. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-oncology: 
a report of the RANO working group. Lancet Oncol 2015;16:e534-42. 
67. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-
1) in melanoma. N Engl J Med 2013;369:134-44. 
68. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer. The New England journal of medicine 2012;366:2455-65. 
69. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. The New England journal of medicine 2012;366:2443-54. 
70. Nayak L, DeAngelis LM, Wen PY, et al. The Neurologic Assessment in Neuro-Oncology 
(NANO) Scalle: A Tool To Assess Neurologic Function for Integration in the Radiologic 
Assessment in Neuro-Oncology (RANO) Criteria. In: Yung WK, editor. 4th Quadrennial 
Meeting of the World Federation of Neuro-Oncology/18th Annual Meeting of the Society for 
Neuro-Oncology; 2013; San Francisco, CA: Oxford Press. 


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94 
APPENDIX A PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
 
 


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95 
APPENDIX B: STUDY SAFETY REPORTING COVERSHEET 
Study Safety Reporting Coversheet – All Cohorts  
DF/HCC Protocol No. 18-277                      Merck & Co., Inc. Protocol No. 3475-787 
Date:____________________     Number of pages including cover sheet:______ 
 
To (check off recipient of this submission): 
    David Reardon, MD, MD (Overall PI)  @ Dana Farber Cancer Institute:  
NeuroOnc_SAE@dfci.harvard.edu 
Please e-mail coversheet and MedWatch with the words ”18-277: Pembrolizumab + re-RT SAE” in the subject line 
    Merck Global Safety,  Attention: Worldwide Product Safety; Fax #: 215-661-6229                                        
From: 
Phone No: 
Study Site:  
Fax No.: 
Participant # and Initials: 
Participant Cohort: 
Type of Report:      Initial      Follow-up 
Was Patient Hospitalized?      Yes      No 
Date Event 1st Met Reporting Criteria (as defined in protocol): 
Date Investigator Team Made Aware of Event: 
 
 
(Please use another sheet if more than 2 events being reported at this time) 
Event #1 Description (CTCAE v. 4 term): 
Event #2 (if applicable) Description (CTCAE v. 4 term): 
 
Meets Protocol Definition of Serious AE?    
   Serious       Non-serious 
Meets Protocol Definition of Serious AE?    
   Serious       Non-serious 
Toxicity Grade:      G1/mild    G2/moderate                       
 G3/severe    G4/life threatening    G5 
Toxicity Grade:      G1/mild    G2/moderate                       
 G3/severe    G4/life threatening    G5 
Historical/Known Correlation to Pembrolizumab:      Expected   
Unexpected  N/A (only if unrelated) 
Historical/Known Correlation to Pembrolizumab:      Expected   
Unexpected  N/A (only if unrelated) 
Attribution to Pembrolizumab:     Unrelated    Unlikely          
 Possible     Probable     Definite 
Attribution to Pembrolizumab:     Unrelated    Unlikely          
 Possible     Probable     Definite 
Historical/Known Correlation to bevacizumab (or biosimilar):      
Expected   Unexpected  N/A (only if unrelated or pt is 
NOT on Coh B) 
Historical/Known Correlation to bevacizumab (or biosimilar):      
Expected   Unexpected  N/A (only if unrelated or pt is 
NOT on Coh B) 
Attribution to bevacizumab (or biosimilar):     Unrelated    
 Unlikely             Possible     Probable     Definite 
N/A (pt is NOT on Coh B) 
Attribution to bevacizumab (or biosimilar):     Unrelated   
  Unlikely               Possible     Probable     Definite 
N/A (pt is NOT on Coh B) 
Historical/Known Correlation to RT:      Expected   
Unexpected  N/A (only if unrelated) 
Historical/Known Correlation to RT:      Expected   
Unexpected  N/A (only if unrelated) 
Attribution to RT:     Unrelated    Unlikely       Possible    
 Probable     Definite     N/A  
Attribution to RT:     Unrelated    Unlikely     Possible    
 Probable     Definite    N/A  
Reporting Investigator: 
 
 
 
Signature of Investigator:_____________________________Date:______________ 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
96 
 
 
 
 
APPENDIX C:  PEMBRO + RE-RT TISSUE REQUISITION/SUBMISSION FORM 
 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
97 
 
page ____ of  ____ 
DF/HCC #18-277 (Pembrolizumab + Re-RT for Recurrent GBM) Tissue Requisition / Submission Form: 
For shipment to: David A. Reardon (c/o Christine McCluskey) at DFCI’s Center for Neuro-Oncology 
 
Participan
t ID # 
e.g. 
“00001” 
Particip
ant 
Initials 
 e.g. 
“ABC” 
or “D-F” 
Study 
Cohort 
A (= no 
bev) 
or  
B (= bev)  
Site  
DFCI,  
MGH, 
DUKE, or 
Columbia 
Tissue Type  
Unstained 
Slides, Blocks, 
FFPE Scrolls, 
etc.  
Submission Type 
Archival tumor from 
most recent pre-reg 
biopsy/surgery  
Or  
Tissue from time of 
progression or 
suspected progression 
Date of 
Procedure 
e.g. 
“01/02/2017” 
Accession 
# 
Block or 
Section # 
(if known) 
# of 
specimens 
(slides, etc.)  
included in 
this 
shipment 
Copy of 
corresponding 
surgical and/or 
path report 
included with 
this 
submission?  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name, Signature, and phone # of person responsible for this shipment of tissue: 
Name: __________________  Signature: ____________________  Date: _________ Phone #: ____________ 
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
- 
For DFCI NOC Coordinating Center Completion: 
The above materials were received by ______________________ (print name) on ______________ (date) at _____________ (time) 
Please confirm whether above inventory = accurate, and make note of any discrepancies, issues with samples, etc.: 
______________________________________________________________________________________________________________ 
______________________________________________________________________________________________________________ 
________________________________________ (signature) 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
98 
 
APPENDIX D   NEUROLOGIC ASSESSMENT IN NEURO-ONCOLOGY (NANO) 
SCALE 
 
Scoring assessment is based on direct observation and testing performed during clinical 
evaluation and is not based on historical information or reported symptoms. Please check 1 
answer per domain. Please check “Not assessed” if testing for that domain is not done. 
Please check “Not evaluable” if a given domain cannot be scored accurately due to pre-
existing conditions, co-morbid events and/or concurrent medications. 
Participant ID #, Initials, and Study Site:   ______________________________________ 
Date Assessment Performed (day/month/year):   ______________________________________ 
Study time point (i.e. cycle 1, day 1, etc):  ___________________________________________ 
Assessment performed by (please print name):  _______________________________________ 
 
Domains                                                                             
Key Considerations 
Gait 
0 
   Normal 
1 
   Abnormal but walks without assistance 
2 
   Abnormal and requires assistance  
(companion, cane, walker, etc.) 
3 
   Unable to walk 
   
   Not assessed 
   
   Not evaluable 
 
Strength 
0 
   Normal 
1 
   Movement present but decreased 
 against resistance 
2 
   Movement present but none against resistance 
3 
   No movement 
   
   Not assessed 
   
   Not evaluable 
 
Ataxia (upper extremity) 
0 
   Able to finger to nose touch without difficulty 
1 
   Able to finger to nose touch but difficult 
2 
   Unable to finger to nose touch 
   
   Not assessed 
   
   Not evaluable 
 
Sensation 
0 
   Normal 
1 
   Decreased but aware of sensory modality 
2 
   Unaware of sensory modality 
   
   Not assessed 
   
   Not evaluable 
 
 
• 
Walking is ideally assessed by at least 10 steps 
• 
Test each limb separately 
• 
Recommend assess proximal (above knee or 
elbow) and distal (below knee or elbow) major 
muscle groups 
• 
Score should reflect worst performing area 
• 
Patients with baseline level 3 function in one major 
muscle group/limb can be scored based on 
assessment of other major muscle groups/limb 
• 
Non-evaluable if strength is compromised  
• 
Trunk/lower extremities assessed by gait domain  
• 
Particularly important for patients with brainstem 
and cerebellar tumors  
• 
Score based on best response of at least 3 
attempts 
• 
Recommend 
evaluating 
major 
body 
areas 
separately (face, limbs and trunk)  
• 
Score should reflect worst performing area 
• 
Sensory modality includes but not limited to light 
touch, pinprick, temperature and proprioception 
• 
Patients with baseline level 2 function in one major 
body area can be scored based on assessment of 
other major body areas 


DF/HCC Protocol #: 18-277 
Protocol Version Date: 26-Jul-2021 
99 
NANO SCALE (pg 2 of 2) 
Participant ID #, Initials, and Study Site:   ______________________________________ 
Date Assessment Performed (day/month/year):   ______________________________________ 
 
Visual Fields 
0 
   Normal 
1 
   Inconsistent or equivocal partial 
           hemianopsia (≥quadrantanopsia) 
2 
   Consistent or unequivocal partial  
           hemianopsia (≥quadrantanopsia) 
3 
   Complete hemianopsia 
   
   Not assessed 
   
   Not evaluable 
 
Facial Strength 
0 
   Normal 
1 
   Mild/moderate weakness 
2 
   Severe facial weakness 
   
   Not assessed 
   
   Not evaluable 
 
Language 
0 
   Normal 
1 
   Abnormal but easily conveys meaning  
to examiner 
2 
   Abnormal and difficulty conveying  
meaning to examiner 
3 
   Abnormal.  If verbal, unable to convey  
          meaning to examiner. OR non-verbal  
          (mute/global aphasia) 
   
   Not assessed 
   
   Not evaluable 
 
Level of Consciousness 
0 
   Normal 
1 
   Drowsy (easily arousable) 
2 
   Somnolent (difficult to arouse) 
3 
   Unarousable/coma  
   
   Not assessed 
   
   Not evaluable 
 
Behavior 
0 
   Normal 
1 
   Mild/moderate alteration 
2 
   Severe alteration 
   
   Not assessed 
   
   Not evaluable 
• 
Patients who require corrective lenses should be 
evaluated while wearing corrective lenses  
• 
Each eye should be evaluated and score should 
reflect the worst performing eye  
• 
Particularly important for brainstem tumors 
• 
Weakness 
includes 
nasolabial 
fold 
flattening, 
asymmetric smile and difficulty elevating eyebrows 
• 
Assess based on spoken speech. Non-verbal cues or 
writing should not be included. 
• 
Level 1: Includes word finding difficulty; few 
paraphasic errors/neologisms/word substitutions;  
but able to form sentences (full/broken) 
• 
Level 2: Includes inability to form sentences (<4 
words per phrase/sentence); limited word output; 
fluent but “empty” speech. 
• 
None  
• 
Particularly important for frontal lobe tumors 
• 
Alteration includes but is not limited to apathy, 
disinhibition and confusion 
• 
Consider subclinical seizures for significant alteration 


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APPENDIX E  
DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN 
 
 
 
 
 
 
 
 
DFCI IRB Protocol #: 18-277 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX E 
Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety 
Monitoring Plan 
 
TABLE OF CONTENTS 
1.0 
INTRODUCTION ...........................................................................................................102 
1.1 
Purpose .................................................................................................................102 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ................................102 
2.0 
GENERAL ROLES AND RESPONSIBILITIES ...........................................................103 
2.1 
DF/HCC Sponsor .................................................................................................103 
2.2 
Coordinating Center .............................................................................................104 
2.3 
Participating Institution ........................................................................................104 
3.0 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS............................105 
3.1 
Protocol Distribution ............................................................................................105 
3.2 
Protocol Revisions and Closures .........................................................................105 
3.3 
Informed Consent Requirements .........................................................................106 
3.4 
IRB Documentation .............................................................................................106 
3.5 
IRB Re-Approval .................................................................................................106 
3.6 
Participant Confidentiality and Authorization Statement ....................................107 
3.7 
DF/HCC Multi-Center Protocol Registration Policy ...........................................107 
3.8 
DF/HCC Protocol Case Number ..........................................................................109 
3.9 
Protocol Deviations, Exceptions and Violations .................................................110 
3.10 
Safety Assessments and Toxicity Monitoring .....................................................111 
3.11 
Data Management ................................................................................................112 
4.0 
REQUISITIONING INVESTIGATIONAL DRUG........................................................112 
5.0 
MONITORING: QUALITY CONTROL ........................................................................112 
5.1 
Ongoing Monitoring of Protocol Compliance .....................................................112 
5.2 
Monitoring Reports ..............................................................................................114 
5.3 
Accrual Monitoring ..............................................................................................114 
6.0 
AUDITING: QUALITY ASSURANCE .........................................................................115 
6.1 
DF/HCC Internal Audits ......................................................................................115 
6.2 
Audit Notification ................................................................................................115 
6.3 
Audit Reports .......................................................................................................115 
6.4 
Participating Institution Performance ..................................................................115 
 
 
 
 
 
 
 
 


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1.0 INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial.  
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham 
and Women’s Hospital (BWH)) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration 
(FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically 
the home of the DF/HCC Sponsor. The Lead Institution also typically serves as the 
Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within 
DF/HCC, this person is the Overall Principal Investigator who takes responsibility for 
initiation, management and conduct of the protocol at all research locations. In applicable 
protocols, the DF/HCC Sponsor will serve as the single liaison with any regulatory 
agencies (i.e. FDA, etc.). The DF/HCC Sponsor has ultimate authority over the protocol 
and is responsible for the conduct of the study at DF/HCC and all Participating 
Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Overall Principal Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
 


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Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 
Sponsor in order that s/he may fulfill the responsibilities outlined in the protocol document 
and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP Multi-Center 
Guidelines). In general, the Lead Institution is the Coordinating Center for the DF/HCC 
Multi-Center Protocol.   
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within 
DF/HCC responsible for providing a comprehensive data management platform for 
managing clinical trial data. 
 
 
2.0 GENERAL ROLES AND RESPONSIBILITIES 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, David Reardon, MD, will accept responsibility for all aspects of 
conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
• Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives 
adequate protocol training (and/or a Site Initiation Visit prior to enrolling 
participants) and throughout trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
• Review data and maintain timely submission of data for study analysis.  
• Act as the single liaison with FDA (investigator-held IND trials), as applicable. 
• Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 


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• Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS). 
• Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review and submission to the DFCI IRB, as 
necessary.  
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
• Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 


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The general responsibilities for each Participating Institution may include but are not 
limited to: 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB of record. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents 
as requested. 
• Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research 
related activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional 
requirements and to the DF/HCC Sponsor/Coordinating Center in accordance with 
DF/HCC requirements.  
• Submit protocol deviations and violations to local IRB per institutional 
requirements and to the DF/HCC Sponsor/Coordinating Center in accordance with 
DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA 
standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
 
3.0 DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
• Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
• Revisions for life-threatening causes: Participating Institutions will receive 


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immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
• Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 
Coordinating Center will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for 
Investigator-Sponsored Multi-Center Trials.  This document will be provided separately to 
each Participating Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that for all interventional drug, biologic, or device research, only attending physicians 
obtain initial informed consent and any re-consent that requires a full revised consent 
form. 
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
• Initial approval letter of the Participating Institution's IRB  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB  
• Participating Institution’s IRB approval for all amendments 
• Annual approval letters by the Participating Institution’s IRB  
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 


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3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPAA). Any 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials.  However, because of the nature of these trials, certain protected health 
information must be collected.  DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant-specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned DF/HCC protocol case 
number (as described below) be used for all participant specific documents. Participant 
initials may be included or retained for cross verification of identification. 
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
Eligible participants will be entered on study centrally at the DFCI Coordinating Center 
(by a Coordinating Center specialist, if participant is at a non-DF/HCC site). Registration 
must occur prior to the initiation of therapy. Any participant not registered to the 
protocol before treatment begins will be considered ineligible and registration will be 
denied.  
A qualified member of the study team will confirm eligibility criteria and complete 
the protocol-specific eligibility checklist.  
Issues that would cause treatment delays should be discussed with the Principal 
Investigator. If a participant does not receive protocol therapy following registration, the 
participant’s protocol status must be changed.  A Coordinating Center specialist should be 
notified of cancellations - or any status changes - as soon as possible.  


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In order to register a participant onto study, the following must be done: 
• Obtain written informed consent from the participant prior to the performance of any 
study related procedures or assessments. 
• Complete the protocol-specific eligibility checklist using the eligibility assessment 
documented in the participant’s medical/research record.  
o 
To be eligible for registration to the study, the participant must meet each 
inclusion and exclusion criteria listed on the eligibility checklist. 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for the 
treatment study. Registration to both treatment and ancillary studies will not be completed 
if eligibility requirements are not met for all studies. 
 
3.7.1 Participant Registration and Randomization at a non-DF/HCC Site 
 
To register a participant at any non-DF/HCC site, the subsequent procedure is to be 
followed: 
 
1. The participating site’s data manager/coordinator/research nurse should contact a 
DFCI Neuro-Oncology Coordinating Center team member via telephone or email to: 
• Notify regarding the pending registration 
• Confirm the methods of sending documents and communication for 
registration 
• Communicate desired timeline of the registration (i.e. the next day, etc.).  
 
Multi-Center DFCI Neuro-Oncology Designee contact information: 
 E-mail:  NeuroOnc_Coor@dfci.harvard.edu   
Phone:  617-582-7101 
   
2. The data manager/coordinator/research nurse should then send the following 
documents to the Coordinating Center specialist: 
• Completed DF/HCC study specific Eligibility Screening Worksheet 
• Copy of protocol required test results (e.g. coagulation studies, hematology 
panel, serum pregnancy test, serum chemistry panel, urinalysis -- all as 
applicable per protocol) 
• Copy of the pathology and surgical reports 
• List of current concomitant medications (obtained within the protocol-
specified screening window) including sign/date by RN/other clinician and 
documentation of when reviewed/confirmed with patient  
• Copy of signed informed consent form 
• Copy of signed HIPAA authorization form (if separate from the informed 
consent document) 
• Copy of clinic note(s) and other medical records that document consenting 
process, screening and eligibility, if available*** 
 
Documents will be transmitted via one of the following methods: 
• 
Scanned and emailed to: NeuroOnc_Coor@dfci.harvard.edu or direct 
email of Coordinating Center specialist 
• 
Faxed to: 617-394-2683 


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109 
*** The Coordinating Center Specialists would like to review and monitor participant 
eligibility, informed consent, screening and baseline assessments on all participants.  
Providing a complete set of source documents prior to registration may delay 
registration.  Participating Institutions will work with the Coordinating Center 
Specialists to determine what documents may feasibly be available for review prior to 
enrollment, and these documents are to be provided for pre-enrollment review.  A 
complete set of documents will be provided to the Coordinating Center after registration; 
the timeline will be determined by the Coordinating Center Specialist based on the study 
team’s experience with the trial and prior monitoring findings.  If there are persistent 
issues with eligibility at a site or with a study overall, the Coordinating Center may 
require that all source documentation relevant to participant eligibility be provided prior 
to proceeding with participant registration.  
3. After having received all transferred documentation, the Designee (Coordinating 
Center specialist) will review the documents to verify eligibility, and notify the 
participating site of the result. 
4. To complete the registration process, the Designee (Multi-Center Coordinating Center 
specialist) will follow DF/HCC Standard Operating Procedure for Human Participant 
Research Titled Participant Protocol Registration (SOP #: REGIST-101) and register 
the participant centrally on the protocol, and subsequently inform the participating 
site of the successful registration via Fax or email, to include: 
• 
Participant case number 
• 
Applicable Dose Treatment level and treatment arm assignment 
5. The Designee (Multi-Center Coordinating Center specialist) will follow-up to confirm 
registration. 
 
Treatment may not begin without confirmation from the Coordinating Center 
that the participant has been registered.  
 
3.7.2 Initiation of Therapy 
 
Participants must be centrally registered with the Multi-Center Coordinating Center and 
the DF/HCC CTMS before the initiation of treatment or other protocol-specific 
interventions.  Treatment and other protocol-specific interventions may not be initiated 
until the Participating Institution receives confirmation of the participant’s registration 
from the Coordinating Center. Therapy must be initiated per protocol guidelines.  The 
DF/HCC Sponsor and DFCI IRB must be notified of any violations to this policy. 
 
3.7.3 Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, DFCI Multi-Center Coordinating Center requires the following 
identifiers for all participants: initials, date of birth, gender, race and ethnicity.  Once 
eligibility has been established and the participant successfully registered, the participant 
is assigned a unique protocol case number. Participating Institutions should submit all de-


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identified subsequent communication and documents to the Coordinating Center, using 
this case number to identify the participant.  
 
3.9 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and Overall PI and will follow their 
institutional policy for reporting to their local IRB. 
 
 
3.9.1 Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the 
IRB prior to its initiation or implementation.  
 
 
3.9.2  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 
 


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Protocol violations occurring at a Participating Institution will be submitted to that site’s 
own IRB per the IRB’s reporting policy.  Whether or not a violation needs to be reported 
to the local IRB, notification to the Coordinating Center of any violation should occur in a 
timely manner.  If a report is made to the Participating Institution’s IRB, the report and 
determination should also be forwarded to the Coordinating Center in a timely manner.  
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
3.10 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy 
will be evaluated for safety.   The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.10.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor, Overall PI, and 
the Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures. 
 
3.10.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions.  Participating Institutions will 
review and submit to their IRB according to their institutional policies and procedures. 
 
 
 
 


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3.11 Data Management 
 
DF/HCC CTRIO develops case report forms (eCRFs) for use with the protocol.  These 
forms are designed to collect data for the study. DF/HCC CTRIO provides a web based 
training for all eCRF users. 
   
3.11.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC Office of Data Quality, 
Coordinating Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
 
4.0 REQUISITIONING INVESTIGATIONAL DRUG 
 
The ordering of Pembrolizumab for this trial is described below: 
Pembrolizumab (Investigational: for all patients): Participating Institutions will order their 
own supply of Pembrolizumab directly from Merck using the Drug Supply Request Form 
(Appendix G to this protocol).  Please allow for 3 weeks for drug to arrive after the order is 
submitted.  The Participating Institution will ensure that the pharmacy will be able to 
receive and store the agent according to state and federal guidelines. The local IRB should 
be kept informed of who will supply the agent (i.e., Merck pharmaceuticals Inc.) so that 
any regulatory responsibilities can be met in a timely fashion.   
 
5.0 MONITORING: QUALITY CONTROL 
 
Monitoring and oversight of a clinical trial are federally mandated for all IND held trials. 
This quality control process for a clinical trial requires verification of protocol 
compliance and data accuracy and the protection of the rights and welfare of participants. 
The Coordinating Center, with the aid of the ODQ, provides quality control oversight for 
the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 
The Participating Institutions may be required to submit participant source documents to 
the Coordinating Center for monitoring.   Participating Institutions may also be subject to 
on-site monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 


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protocol begins, continue during protocol performance and through study completion. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants , informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management.  
 
Remote monitoring of participant eligibility, the initial informed consent process, and 
screening evaluation completion will occur via a two-stage process. 
• Prior to registering each participant, a Coordinating Center Specialist will review 
the source documentation provided in the enrollment packet to confirm, (a) that 
based on all objective measurements (lab tests; pathology report) that the 
prospective participant is eligible, (b) that the objective measurements were 
performed per protocol within the appropriate protocol-defined windows, (c) that 
the prospective participant does not have concomitant medication that precludes 
eligibility, and, if documentation is provided, (d) that the consenting process was 
adequate/adequately documented, (e) that the participant met criteria for eligibility.  
Furthermore, using the Eligibility Screening Worksheet, the Specialist will verify 
that the investigator has indicated that s/he has reviewed and confirmed as 
“eligible” the prospective participant 
• A Coordinating Center Specialist will review the second set of participant-specific 
source documents provided by study teams to confirm that (a) all screening and 
baseline assessments were completed per protocol, including AE assessment, and 
documented appropriately, (b) that all eligibility criteria were met and appropriately 
documented, and, if not previously reviewed, (c) that the consenting process was 
adequate/adequately documented.  The timeline for this review will be based on the 
experience with the study team, and the study team’s experience with the protocol.       
Interim monitoring visits will occur on the following schedule: 
• Once a site has registered a participant, up until all participants (and planned 
participants) have discontinued taking study agent (may be in follow-up), interim 
monitoring visits will occur at least twice per year (either on-site or virtula).  The 
first interim monitoring visit will occur approximately two months after the 
registration of the site’s first participant.  
• Once a site is closed to accrual and all participants have discontinued study agent, 
interim monitoring visits will occur virtually, and on-site as needed.   
 
On-Site Monitoring: On-site monitoring will occur on a regular basis. Participating 
Institutions will be required to provide access to participants’ complete medical record 
and source documents for source documentation verification during the on-site visit. In 
addition, upon request from a monitor or auditor, Participating Institutions should provide 
access to regulatory documents, pharmacy records, local policies related to the conduct of 
research, and any other trial-related documentation maintained by the participating site. If 
there are concerns for protocol compliance, issues that impact participant safety or the 
integrity of the study are found, or trends identified based on areas of need, additional 
monitoring visits may be scheduled.  
 


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Virtual Monitoring: The Coordinating Center will reasonably request source 
documentation from participating Institutions as needed to complete monitoring 
activities. Participating Institutions will be asked to forward copies of participants’ 
medical record and source documents to the Coordinating Center to aid in source 
documentation verification. 
 
Regular all-sites teleconferences will be hosted on a monthly basis by the Coordinating 
Center (unless otherwise specified by the Overall PI). During the teleconferences, sites 
should convey the following information: 
• Updates on participants: holds, dose reductions, significant events, how participant 
is doing, date of progression and date of death when available and if not already 
communicated to the Coordinating Center 
• Protocol status: which version is being used, and the status of any amendments 
• Any Reportable Adverse Events or Deviations/violations that have yet to be 
communicated to the Coordinating Center (informing the sponsor should not wait 
for the call, and the call does not supplant communicating the events via the 
regular email methods of communication). 
• Review of prospective participants 
If sites are not able to have a representative participant, they should email this 
information to the Coordinating Center.  
 
During the teleconferences, the Coordinating Center may discuss any or all of the 
following information: 
• Accrual/enrollment updates 
• Pending amendments 
• Safety reports circulated or to be circulated 
• ODQ-generated numbers and percentage of missing of missing forms, number of 
open queries with date of oldest open query, and, for participants on treatment, the 
date of their last study agent form 
• Review of new deviations, violations 
• Review of recently received expedited adverse events  
 
5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at Participating Institutions 
that are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and 
local regulations.  
 
5.3 
Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
Accrual expectations for Participating Institutions: As this is a Phase II trial, Study 
Sponsor is requesting that each participating site accrue at least 3 patients annually. 
 


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6.0 AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 
analyzed, and accurately reported per the protocol, applicable Policies, and the Code of 
Federal Regulations (CFR). 
 
6.1 DF/HCC Internal Audits 
  
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.  
 
6.2 Audit Notification 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
external audits or inspections (e.g., FDA, EMA, NCI) that involve this protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective action 
plans (if applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 
6.3 Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
 
The DF/HCC Sponsor and the IRB of record are charged with considering the totality of 
an institution’s performance in considering institutional participation in the DF/HCC 
Multi-Center protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 


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APPENDIX F   
MERCK DRUG SUPPLY REQUEST FORM: PEMBROLIZUMAB  
 
 


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APPENDIX G   
Quality of Life (QoL) Assessment: EORTC QLQ-C30  
 
* NOTE: Sometimes, these questions may be read to you by someone from your Study Treatment Team. 
Pt ID #, Initials, and Study Site:   _______________________________________ 
Date Assessment Performed (day/month/year):   _____/_____/_________ 
Study timepoint (i.e. cycle 1, day 1, etc):  __________________________ 
 
 
 


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EORTC QLQ-C30 (pg 2 of 2) 
 
Pt ID #, Initials, and Study Site:   _______________________________________ 
Date Assessment Performed (day/month/year):   _____/_____/_________ 
Study timepoint (i.e. cycle 1, day 1, etc): _________________________ 
 
 
 
 Please initial _____ & date _____/____/______ when assessment is complete 
 Who completed this form?  □ Self     □ Other, specify: _______________________   
 


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APPENDIX H   
Radiation Therapy Guidelines (To be provided to Radiation Oncologist) 
  
 
You are receiving the below guidelines because you will be treating ______________________, 
a patient enrolled on a clinical trial.  Please ensure they are followed as closely as possible.  If 
there are any significant deviations from the below guidelines, please contact the patient’s 
protocol treatment team as soon as possible (prospectively, whenever possible).   
 
Should you have any concerns or questions, please contact: ____________________  
at _______________________ (email) or _______________________ (phone). 
 
Thank you so much for being such a significant part of our patient’s quality care. 
 
 
 
Patient will be administered fractionated radiotherapy according to established, standard-of-care 
guidelines utilizing intensity-modulated radiation therapy (IMRT), 3-dimensional conformal 
radiation therapy (3D-CRT) or proton beam radiation therapy at a dose of 3.5 Gy/fraction times 
10 fractions (5 days a week for 2 weeks).  Daily image-guided radiation therapy (IGRT) is 
required including non-volumetric (orthogonal or near-orthogonal 2D imaging that is integrated 
with the radiation delivery device) and volumetric (diagnostic CT, cone beam CT with MV or 
kV X-ray beam, MRI-linac or tomotherapy technology) systems. 
 
 
1.0 Dose Specifications 
Photons: Treatment shall consist of 35 Gy delivered in 10 fractions. Target coverage and 
homogeneity limits and deviations are listed in Table I-1 based on guidance from the ongoing 
randomized, national, phase II RTOG 1205 (NCT01730950). 
 
Protons – Absorbed dose: Doses are expressed in units of RBE-weighted absorbed dose, DRBE. 
For protons, the RBE is taken to be 1.1. DRBE = 1.1 x D, where D represents the absorbed dose 
in Gy. Treatment shall consist of 35 Gy(RBE) delivered in 10 fractions. Target coverage and 
homogeneity limits and deviations are listed in Table I-1. 
 


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Table I-1. Radiation Therapy Target Coverage and Dose Limits 
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation 
Unacceptable 
Volume of PTV 
covered 
by the prescription 
dose 
photons 35 Gy – 
protons 35 Gy(RBE) 
Greater than or equal 
to 95% of the PTV 
should receive greater 
than or equal to 
photons 35 Gy – 
protons 35 Gy(RBE) 
Greater than or equal 
to 90% of the PTV 
receiving greater than 
or equal to photons 35 
Gy – protons 35 
Gy(RBE) 
Less than 90% of the 
PTV receiving greater 
than or equal to photons 
35 Gy – protons 35 
Gy(RBE) 
Minimum dose to the 
PTV (0.03 cc) 
Greater than or equal 
to 29.75 Gy (85% of 
the prescription dose) 
– protons 29.75 
Gy(RBE) 
prescription dose) – 
protons 28 Gy(RBE); 
Minimum doses of less 
than 28 Gy are 
acceptable if they 
occur due to OAR/PTV 
overlap greater than or equal 
to 28 Gy (80% of the 
Less than 28 Gy (80% 
of the prescription dose) 
–protons 28 Gy(RBE); 
Minimum doses of less 
than 28 Gy are 
unacceptable unless they 
occur in regions of 
OAR/PTV overlap 
Maximum dose to 
the 
PTV (0.03 cc) 
Less than or equal to 
42 Gy (120% Rx 
Dose) – protons 42 
Gy(RBE) 
Less than or equal to 
45.50 Gy (130% Rx 
Dose) – protons 45.50 
Gy(RBE) 
Greater than 45.50 Gy 
(130% Rx Dose) – 
protons 45.50 Gy(RBE) 
 
2.0 Technical Factors [Equipment, energies] 
The 10 treatment fractions of 3.5 Gy each will be delivered on consecutive treatment days 
(typically 5 fractions per week). Any FDA cleared external beam radiation delivery system may 
be used (including conventional linear accelerators, Cyberknife systems, tomotherapy, proton 
therapy, etc.). Imaging for treatment planning will be obtained with the patient in the same 
position and immobilization device as for treatment. All patients will be positioned via a 
combination of rigid immobilization and daily image guidance to ensure positioning accuracy of 
3 mm or better, and of a magnitude that justifies the PTV margin applied (the participating 
institutions must document the immobilization and localization methods applied). 
 
3.0 Localization, Simulation, and Immobilization  
An MRI and/or CT scanning obtained with the patient immobilized in the treatment position is 
required for treatment planning with slice thickness no greater than 3mm. Immobilization must 
be rigid (e.g. thermoplastic masks). For daily treatment, localization will include the steps of a) 
immobilization with the same device used for simulation, and b) daily image guidance (IGRT) 
using at a minimum non-volumetric (i.e. orthogonal pairs of radiographs aligned to DRRs as a 
computer-assisted process) or volumetric (i.e. cone beam CT with MV or kV x-ray beams or 
MRI Linac systems.  
 
4.0 Treatment Planning/Target Volumes  
A GTV will be defined as the residual, enhancing tumor (and non-enhancing tumor for Cohort B 
participants) with or without the most recent post-operative cavity on the most recent MRI 
images. The post-operative resection cavity will be outlined if no residual enhancing tumor is 
noted. A CTV expansion of no more than 5 mm is optional for lesions measuring less than 3.5 
cm in maximum diameter or if this is a new lesion, but must be reported when used. Otherwise, 


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no additional CTV expansion will be added. A PTV expansion that is justified based on image 
guidance and immobilization will be applied. Regardless of immobilization and localization 
methods, the PTV expansion should be no smaller than 3 mm.  If protons are used, an adjustment 
must be made within the treatment planning process to take into account of range uncertainties 
along the beam direction, following the established practice at the specific proton facility, which 
should be based on the recommendations contained in ICRU 78, paragraph 5.1.4.4. 
 
Treatment planning using multiple, non-coplanar beams or arc-based therapy is advised. IMRT 
based planning is allowed. In any case, the objective of treatment planning is to ensure sufficient 
dose conformity that the normal tissue constraints are met. 
 
5.0 Critical Structures 
Normal tissues to be contoured will include the brain, brainstem, optic nerves and chiasm.  
Planning risk volume (PRV) expansions (minimum of 3 mm) should be utilized for optic nerves 
and chiasm. Special consideration should be given to avoid doses greater than the prescription 
dose within the scalp as well as limiting the exit dose through the oral cavity and mucosa. The 
treatment parameters should be modified to optimize the conformity of the prescription isodose 
volume to the target volume while minimizing dose to critical structures. There are two scenarios 
for normal tissues limits: (1) previous radiation to the local area including critical organs at risk 
and (2) no previous radiation to the local area or organs at risk. The limits for both scenarios are 
given in Table I-2, based on guidance from the ongoing randomized, national, phase II RTOG 
1205 (NCT01730950). 
 
Table I-2. Normal Tissue Dose Limits 
Dose Metric 
Per Protocol 
Variation Acceptable 
Deviation Unacceptable 
Scenario (1): Previous radiation to the local area including critical organs at risk 
Maximum Dose 
to PRV for Optic 
Nerves and 
Chiasm (0.03 cc) 
Less than or equal to 20 
Gy photons – 20 Gy 
(RBE) protons 
Greater than 20 Gy but less than 
or equal to 25 Gy photons – 25 
Gy (RBE) protons 
Greater than 25 Gy photons 
– 25 Gy (RBE) protons 
Maximum Dose 
to Brainstem 
(0.03 cc) 
Less than or equal to 24 
Gy photons – 24 Gy 
(RBE) protons 
Greater than 24 Gy but less than 
or equal to 30 Gy photons – 30 
Gy (RBE) protons 
Greater than 30 Gy 
photons – 30 Gy (RBE) 
protons 
Scenario (2): No previous radiation to the local area or critical organs at risk 
Maximum Dose 
to PRV for Optic 
Nerves and 
Chiasm (0.03 cc) 
Less than or equal to 35 
Gy (the prescription 
dose) photons – 35 Gy 
(RBE) protons 
Greater than 35 Gy but less than 
or equal to 36.75 Gy (105 % of 
the prescription dose) photons – 
36.75 Gy (RBE) protons 
Greater than 36.75 Gy 
(105% of the prescription 
dose) photons – 36.75 Gy 
(RBE) protons 
Maximum Dose 
to Brainstem 
(0.03 cc) 
Less than or equal to 35 
Gy (the prescription 
dose) photons – 35 Gy 
(RBE) protons 
Greater than 35 Gy but less than 
or equal to 36.75 Gy (105 % of 
the prescription dose) photons – 
36.75 Gy (RBE) protons 
Greater than 36.75 Gy 
(105% of the prescription 
dose) photons – 36.75 Gy 
(RBE) protons 
 


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6.0 Standard Structure Names 
Standard structure names and dose references are summarized in Table I-3. 
 
Table I-3. Standard structure names and reference doses. 
Standard Name 
Description 
Reference 
Dose (Gy) 
Validation 
Profile 
GTV_3500 
Residual enhancing tumor or 
post-operative resection cavity 
35 
Required 
CTV_3500 
An Optional CTV expansion 
of no more than 5 mm. 
35 
Required 
PTV_3500 
planning target volume; an additional 
margin of 3 to 5 mm 
35 
Required 
Brain 
Outline of the brain 
 
Required 
OpticChiasm 
 Optic Chiasm 
 
Required 
OpticChiasm_PRV 
Optic Chiasm planning risk volume 
 
Required 
BrainStem 
Brain stem 
 
Required 
BrainStem_PRV 
Brain stem planning risk volume 
 
Required 
OpticNerve_L 
Left optic nerve 
 
Required 
OptNrv_L_PRV 
Left optic nerve planning risk volume 
 
Required 
OpticNerve_R 
Right optic nerve 
 
Required 
OptNrv_R_PRV 
Right optic nerve planning risk volume 
 
Required