Clinical trial NCT03018288
Conditions: Glioblastoma
Keywords: Malignant Gliomas Immunotherapy
Sponsor: National Cancer Institute (NCI)
Start date: 2017-09-21; Completion date: 2022-12-20
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Background:

Glioblastoma (GBM) refers to a specific kind of brain cancer called glioblastoma. The standard treatment for GBM is radiation plus temozolomide, an oral chemotherapy drug. Pembrolizumab is an immune therapy that is now used to treat other cancers. The addition of pembrolizumab to the standard treatment of radiation and temozolomide has been shown to be well tolerated. Researchers want to see if adding a vaccine made from the person's own tumor will improve the effect of the pembrolizumab. The vaccine which is developed from fresh tumor taken at the time of surgery is called heat shock protein peptide complex-96 (HSPPC-96).

Objectives:

To see if the adding of pembrolizumab and HSPPC-96 improves the standard treatment for glioblastoma.

Eligibility:

Adults at least 18 years old with glioblastoma.

Design:

Participants will be screened with typical cancer tests:

Brain scan

Medical history

Blood and urine tests

Questions about quality of life and symptoms

These tests will be repeated throughout the study.

Participants will have surgery to remove their tumor. A tissue sample from the tumor will be sent to a lab. A vaccine will be made from it.

Some participants will get pembrolizumab and vaccine. Some will get pembrolizumab and placebo. Participants will not know which they get.

Participants will get radiation for 6 weeks.

Participants will take temozolomide by mouth before each treatment.

Participants will get pembrolizumab by intravenous (IV) for 30 minutes 3 times over the radiation cycle.

Participants will keep taking the 2 drugs every few weeks for about a year. Some may take pembrolizumab for an additional year.

Most participants will get the vaccine or placebo after radiation. They will get it 5 times over 6 weeks. Some participants will continue to get the vaccine every few weeks for 1 or 2 years.

Participants will repeat the screening tests when they stop study treatment. They will also have follow-up phone calls.

Detailed description:
Background:

* Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these tumors almost always recur.
* Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to standard therapy which consists of concurrent radiation with temozolomide chemotherapy after maximal surgical resection in patients with newly diagnosed disease and salvage chemotherapy with either rechallenge with temozolomide or an alternative alkylating agent such as lomustine (CCNU) or cisplatin. To date, none of the combination strategies have demonstrated clinical benefit. Furthermore, in subjects with an unmethylated MGMT (O6-methylguanine-DNA methyltransferase) promoter temozolomide has only modest benefit and salvage therapies have not demonstrated a significant impact in this subject group underscoring the need for more research.
* Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking specific immune responses that may produce a more sustained and less toxic effect than conventional therapy. Heat-shock proteins (HSPs), which function as intracellular chaperones, can be used to deliver a variety of tumor antigens to antigen presenting cells for immune stimulation.
* Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including autologous antigenic peptides (aka vaccine). Heat shock proteins (HSP) are molecules that respond to cellular stress and counteract abnormal protein folding. They are known to modulate immune responses, especially the HSP gp-96. In a stressful environment, such as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects the tumor and leads to resistance to therapy. HSP expression is associated with cellular proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis.
* Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4)/kappa isotype designed to directly block the interaction between Programmed cell death protein 1 (PD-1) and its ligands, programmed death-ligand 1 (PD-L1) and programmed cell death-ligand 2 (PD-L2). Additionally, pembrolizumab is thought to also have activity in the peripherally circulating T-effector cells by reversing lymphocyte exhaustion. It is currently Food and Drug Administration (FDA) approved for use in patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor and non-small cell lung cancer (NSCLC) with elevated PD-L1 in the tumor. recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy. It is also FDA approved for use with advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after other treatments and with tumors that express a protein called PD-L1 and for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
* This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-1 inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are MGMT promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and will provide important data on immune-modulatory effect of this combination. This may be of particular value in patients with high peripheral PD-L1 expression, but also the value of PD-1 added to standard GBM therapy. As vaccine needs to be generated from the patient s tumor, patients will need to be identified prior to surgery.

Eligibility:

* MRI findings consistent with a suspected GBM or histologically confirmed newly diagnosed GBM that has not been treated and would benefit from further surgical resection.
* Tumor must be supratentorial.
* GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be allowed unless there is plan for second surgery to remove greater than or equal to 80% of the tumor) and patients tumors must not have O6-Methylguanine-deoxyribonucleic acid (DNA) Methyltransferase (MGMT) promoter methylation and must be isocitrate Dehydrogenase (IDH) wildtype.
* No prior treatment with radiation or chemotherapy for their GBM.
* Age greater than or equal to 18 years on day of signing informed consent

Objective:

\- The primary endpoint is to determine whether the one-year overall survival (OS) rate is improved in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and are IDH wildtype treated with radiation therapy (RT) + temozolomide (TMZ) + Pembrolizumab followed by TMZ + Pembrolizumab + HSPPC-96 vaccine or Placebo vaccine x 6 cycles (1 cycle is 9 weeks).

Design:

* This will be a randomized, double blind phase II trial of surgery, RT + TMZ + Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and are IDH wildtype.
* Subjects will be assigned to intervention based on ability to generate vaccine as follows:

  * If \>= 80 % of tumor removed, \>=7 g of tumor is resected but HSPPC-96 cannot be generated, subjects will be treated on the ancillary arm of RT+TMZ +Pembrolizumab followed by TMZ+ Pembrolizumab.
  * If\>= 80% of contrasting enhanced tumor removed (based on T1 Post contrast magnetic resonance imaging (MRI) using cross sectional measurement), \>= 7 g of tumor is resected and sufficient HSPPC-96 is generated, subjects will be included in the main cohort and will be randomized on a 1:1 basis to receive:

    * RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo

OR

\--- RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-96

-Subjects whose tumor does not meet the criteria (unmethylated MGMT promoter and IDH wildtype by pathology) and for whom \< 80 % of tumor is removed or \< 7g of tumor is resected are not eligible for further intervention. Approximately 8 potentially eligible patients are screened per month, and it is anticipated that at least 1-2 per month will be accrued per site.

Arms: arm 1: Standard treatment with experimental treatment (pembro) added. arm 2: Temozolomide+Pembrolizumab arm 3: Temozolomide+Pembrolizumab+ HSPPC96 Vaccine arm 4: Temozolomide+Pembrolizumab+ Placebo
Interventions: intervention 1: Pembrolizumab intervention 2: HSPPC-96 intervention 3: Temozolomide intervention 4: Placebo intervention 5: Surgery
Intervention descriptions: intervention 1: Pembrolizumab at 200mg will be administered on day 1 as a 30-minute intravenous (IV) infusion (prior to radiation therapy (RT) every 3 weeks during RT on days 1, 22 and 43. At one year, if participants are doing well, they may continue pembrolizumab for 12 more months alone or in conjunction with heat shock protein peptide complex -96 (HSPPC 96) or placebo vaccine if any is available. intervention 2: One week post RT, patients will receive weekly x 4 a dose of heat shock protein peptide complex -96 (HSPPC 96) 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of temozolomide (TMZ). HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Participants who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if participants are doing well, they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available. intervention 3: Temozolomide (TMZ) will be administered on day 1 of radiation therapy (before radiation therapy (RT) treatment) and continue throughout RT at the dose of 75 mg/m\^2. Post RT: The starting TMZ dose will be 150 mg/m\^2/day for cycle 1, days 1-5, with a single dose escalation to 200 mg/m\^2/day (days 29-33) and for all subsequent treatment if no treatment-related adverse events greater than Grade 2 are noted. TMZ will be given for 6 cycles. intervention 4: One week post radiation therapy (RT), participants will receive weekly x 4 a dose of heat shock protein peptide complex -96 (HSPPC 96) 0.4mL intradermal vaccine or placebo. HSPPC-96 vaccine or placebo will then be given 21 days after the day 5 dose of Temozolomide (TMZ). HSPPC-96 vaccine or placebo vaccine will be given for 6 cycles or until supply runs out. Participants who receive placebo will be matched for number of vaccine injections that were generated by their tumor tissue. At one year, if participants are doing well, they may continue pembrolizumab for 12 more months alone or in conjunction with HSPPC-96 or placebo vaccine if any is available. intervention 5: Tissue for vaccine production and neo-epitope monitoring.

Protocol documents:
Prot_SAP_003.pdf: 
1
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
Abbreviated Title: GBM Pembro HSPPC
NIH Protocol #: 17C0034 
Version Date:   06/25/2025
NCT Number:  NCT03018288
Title: A randomized, double blind phase II trial of Surgery, Radiation Therapy plus 
Temozolomide and Pembrolizumab with and without HSPPC-96 in newly diagnosed 
Glioblastoma (GBM)
Coordinating Center: BTTC Coordinating Center, Center for Cancer Research, NCI
Responsible DSMB:  NCI Data Safety Monitoring Board 
NCI Principal Investigator: 
Kevin A. Camphausen, M.D.,
Neuro Oncology Branch (NOB), CCR, NCI
10 Center Dr Room B2-3675Bethesda, MD 20892
Phone: 240-760-6205 
Email: camphauk@mail.nih.gov
Drug Name:
HSPPC-96
Pembrolizumab
Temozolomide
IND Number:
17203
17203
17203
Sponsor:
National Cancer 
Institute, Center for 
Cancer Research
National Cancer 
Institute, Center for 
Cancer Research
National Cancer 
Institute, Center for 
Cancer Research
Manufacturer:
Agenus
Merck
generic
Supplier:
Agenus
Merck
CC Pharmacy


2
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
 
LEAD PI AND STUDY CHAIR
Kevin A. Camphausen, M.D. 
Neuro-Oncology Branch
National Cancer Institute
National Institutes of Health
10 Center Drive
Bethesda, MD 20892
Email: camphauk@mail.nih.gov 
BTTC COORDINATING CENTER
National Cancer Institute
National Institutes of Health
9030 Old Georgetown Road 
Bloch Bldg. 82, Room 229
Bethesda, MD 20892
Phone: 240-760-6060
Email: nci_bttc@mail.nih.gov
       
BTTC PARTICIPATING INVESTIGATORS/SITES (ENROLLING):
The BTTC Participating Investigators/Sites listed in the NIH IRB system will enroll study 
subjects as described in the protocol.  Each site will obtain IRB Approval at their site.
A DISCLAIMER STATEMENT FOR BTTC PROTOCOLS
This is a research protocol of the Brain Tumor Trials Collaborative describing an experimental 
treatment procedure.  It is a privileged document and is not intended to be circulated or used for 
other purposes.  The Brain Tumor Trials Collaborative assumes no responsibility for its use 
outside of the constraints of this research protocol or by investigators other than those approved 
by the Consortium.


3
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
PRÉCIS 
Background:
•
Malignant gliomas are unfortunately, in most cases, a uniformly fatal tumor. Despite 
aggressive surgery, radiation treatment (RT) and chemotherapy at initial diagnosis these 
tumors almost always recur.
•
Many clinical trials in glioblastoma (GBM) have evaluated the addition of agent(s) to 
standard therapy which consists of concurrent radiation with temozolomide 
chemotherapy after maximal surgical resection in patients with newly diagnosed 
disease and salvage chemotherapy with either rechallenge with temozolomide or an 
alternative alkylating agent such as CCNU or cisplatin. To date, none of the 
combination strategies have demonstrated clinical benefit. Furthermore, in subjects 
with an unmethylated MGMT (O6-methylguanine-DNA methyltransferase) promoter 
temozolomide has only modest benefit and salvage therapies have not demonstrated a 
significant impact in this subject group underscoring the need for more research.
•
Immunotherapy offers the promise of improving outcomes for patients with GBM by 
evoking specific immune responses that may produce a more sustained and less toxic 
effect than conventional therapy.  Heat-shock proteins (HSPs), which function as 
intracellular chaperones, can be used to deliver a variety of tumor antigens to antigen 
presenting cells for immune stimulation. 
•
Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein 
glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including 
autologous antigenic peptides (aka “vaccine”). Heat shock proteins (HSP) are molecules 
that respond to cellular stress and counteract abnormal protein folding. They are known 
to modulate immune responses, especially the HSP gp-96. In a stressful environment, 
such as a tumor, HSPs are upregulated and highly expressed on tumor cells. This protects 
the tumor and leads to resistance to therapy. HSP expression is associated with cellular 
proliferation, apoptosis evasion, tissue invasion, metastasis, and angiogenesis. 
•
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2. Additionally, pembrolizumab is thought to 
also have activity in the peripherally circulating T-effector cells by reversing 
lymphocyte exhaustion. It is currently FDA approved for use in patients with 
unresectable or metastatic melanoma and disease progression following ipilimumab 
and, if BRAF V600 mutation positive, a BRAF inhibitor and NSCLC with elevated PD-
L1 in the tumor. recurrent or metastatic HNSCC with disease progression on or after 
platinum-containing chemotherapy.   It is also FDA approved for use with advanced 
(metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed after 
other treatments and with tumors that express a protein called PD-L1 and for the 
treatment of patients with recurrent or metastatic head and neck squamous cell 
carcinoma (HNSCC) with disease progression on or after platinum-containing 
chemotherapy
•
This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-
1 inhibition (pembrolizumab) in newly diagnosed GBM patients whose tumors are 
MGMT promoter unmethylated and are isocytrate dehydrogenase (IDH) wildtype; and 


4
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
will provide important data on immune-modulatory effect of this combination. This 
may be of particular value in patients with high peripheral PD-L1 expression, but also 
the value of PD-1 added to standard GBM therapy.  As vaccine needs to be generated 
from the patient’s tumor, patients will need to be identified prior to surgery.
Eligibility: 
•
MRI findings consistent with a suspected GBM or histologically confirmed newly 
diagnosed GBM that has not been treated and would benefit from further surgical 
resection.
•
Tumor must be supratentorial.
•
GBM diagnosis must be made by surgical excision (stereotactic biopsy will not be 
allowed unless there is plan for second surgery to remove ≥ 80 % of the tumor) and 
patients tumors must not have MGMT promoter methylation and must be IDH 
wildtype. 
•
No prior treatment with radiation or chemotherapy for their GBM.
•
Age ≥ 18 years on day of signing informed consent
Objective: 
•
The primary endpoint is to determine whether the one-year overall survival (OS) rate is 
improved in newly diagnosed GBM patients whose tumors have an unmethylated 
MGMT promoter and are IDH wildtype treated with RT + TMZ + Pembrolizumab 
followed by TMZ + Pembrolizumab + HSPPC-96 vaccine or Placebo vaccine x 6 
cycles (1 cycle is 9 weeks).
Design: 
•
This will be a randomized, double blind phase II trial of surgery, RT + TMZ + 
Pembrolizumab followed by TMZ + Pembrolizumab +/- HSPPC-96 in newly diagnosed 
GBM patients whose tumors have an unmethylated MGMT promoter and are IDH 
wildtype. 
•
Subjects will be assigned to intervention based on ability to generate vaccine as follows:
o
If ≥ 80 % of tumor removed and ≥7 g of tumor is resected but HSPPC-96 cannot 
be generated, subjects will be treated on the ancillary arm of RT+TMZ 
+Pembrolizumab followed by TMZ+ Pembrolizumab.  
o
If ≥ 80% of contrasting enhanced tumor removed (based on T1 Post contrast MRI 
using cross sectional measurement), ≥7 g of tumor is resected and sufficient 
HSPPC-96 is generated, subjects will be included in the main cohort and will be 
randomized on a 1:1 basis to receive:
▪
RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab + Placebo
OR
▪
RT+TMZ +Pembrolizumab followed by TMZ+Pembrolizumab+HSPPC-
96
•
Subjects whose tumor does not meet the criteria (unmethylated MGMT promoter and 
IDH wildtype by pathology) and for whom < 80 % of tumor is removed or < 7g of tumor 
is resected are not eligible for further intervention. Approximately 8 potentially eligible 


5
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
patients are screened per month, and it is anticipated that at least 1-2 per month will be 
accrued per site. 


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
TABLE OF CONTENTS 
PRÉCIS...........................................................................................................................................3
TABLE OF CONTENTS ................................................................................................................6
SCHEMA.......................................................................................................................................14
STATEMENT OF COMPLIANCE ..............................................................................................16
1.
INTRODUCTION..................................................................................................................17
1.1
Study Objectives..........................................................................................................17
1.1.1
Primary Objective: ..................................................................................................17
1.1.2
Secondary Objectives:.............................................................................................17
1.1.3
Exploratory Objectives:...........................................................................................17
1.2
Background and Rationale...........................................................................................18
1.2.1
Disease Background................................................................................................18
1.2.2
Intervention Background & Overview....................................................................19
1.2.3
Rationale for the Pembrolizumab dose ...................................................................20
1.2.4
Heat Shock Protein-Peptide Complex-96 (HSPPC-96) ..........................................21
1.2.5
Rationale for the Current Study ..............................................................................23
1.2.6
Rationale for the patient-reported outcomes:..........................................................24
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT........................................................25
2.1
Eligibility Criteria........................................................................................................25
2.1.1
Inclusion Criteria.....................................................................................................25
2.1.2
Exclusion Criteria....................................................................................................27
2.1.3
Recruitment Strategies ............................................................................................30
2.2
Screening Evaluation...................................................................................................30
2.2.1
Screening activities performed prior to obtaining informed consent......................30
2.2.2
Screening activities performed after a consent for screening has been signed .......30
2.3
Participant Registration and Status Update Procedures...............................................31
2.3.1
Informed Consent/Authorization.............................................................................31
2.3.2
Registration at the NCI............................................................................................31
2.3.3
Registration at Participating BTTC Sites................................................................31
2.3.4
Initiation of Therapy (Radiation Therapy, Temozolomide and Pembrolizumab)...32
2.3.5
Registration Step 3: Randomization for NCI..........................................................32
2.3.6
Registration Step 3: Randomization for Participating Sites....................................33


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2.3.7
Study Status Updates for Participating Sites...........................................................33
2.3.8
Screen Failures........................................................................................................33
2.4
Treatment Assignment and Randomization /Stratification Procedures.......................34
3
STUDY IMPLEMENTATION..............................................................................................35
3.1
Early Termmination.....................................................................................................35
3.2
Study Design................................................................................................................35
3.2.1
Blinding...................................................................................................................36
3.3
Surgery & Tissue Collection for Vaccine Administration ..........................................37
3.3.1
Surgery ....................................................................................................................37
3.3.2
Tissue Collection for Vaccine Production at NCI...................................................37
3.3.3
Tissue Collection for Vaccine Production at Participating BTTC Sites.................38
3.4
Radiation Therapy (RT)...............................................................................................38
3.5
Drug Administration....................................................................................................38
3.5.1
(RT+TMZ+Pembro)................................................................................................38
3.5.2
HSPPC-96 Vaccine or Placebo ...............................................................................38
3.6
Post RT Treatment Regimen .......................................................................................39
3.6.1
For patients not randomized (ancillary arm 2)........................................................39
3.6.2
For patients randomized to vaccine or placebo.......................................................39
3.7
Baseline Assessments (Post-Surgery And Pre-Treatment RT+TMZ+Pembro)..........40
3.8
Assessments While On Trial During And Post RT .....................................................40
3.8.1
Questionnaires.........................................................................................................41
3.9
Telehealth/Remote Visits.............................................................................................42
3.10
Dose Modifications......................................................................................................43
3.10.1
Pembrolizumab Dose Modifications.......................................................................43
3.10.2
Guidelines for Drug-Related Adverse Events due to Pembrolizumab....................50
3.10.3
Pembrolizumab Supportive Care ............................................................................50
3.10.4
Temozolomide Dose Modifications........................................................................52
3.10.5
HSPPC-96/Placebo Dose Modifications.................................................................53
3.10.6
Vaccine Injection Site Reactions.............................................................................53
3.11
Study Calendar.............................................................................................................54
3.12
Surgical Guidelines......................................................................................................57
3.13
Cost and Compensation ...............................................................................................57


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
3.13.1
Costs........................................................................................................................57
3.13.2
Compensation..........................................................................................................57
3.13.3
Reimbursement........................................................................................................57
3.14
Criteria for Removal from Protocol Therapy and Off Study Criteria .........................57
3.14.1
Criteria for Removal from Protocol Therapy..........................................................57
3.14.2
Off Study Criteria....................................................................................................58
3.14.3
Lost to Follow-up....................................................................................................58
4
CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) ..58
4.1
Acceptable Concomitant Medications.........................................................................59
4.2
Prohibited Concomitant Medications ..........................................................................59
4.3
Diet/Activity/Other Considerations.............................................................................60
4.3.1
Diet..........................................................................................................................60
4.3.2
Contraception ..........................................................................................................60
5
BIOSPECIMEN COLLECTION...........................................................................................61
5.1
Correlative Studies for Research/Pharmacokinetic Studies ........................................61
5.1.1
Collection of correlative blood time points:............................................................62
5.1.2
PD-L1 expression on tumor cells............................................................................62
5.1.3
Tissue will be interrogated by Next Generation Sequencing for tumor antigens ...62
5.1.4
Tissue Collection at NCI.........................................................................................63
5.1.5
Sample Storage, Tracking and Disposition.............................................................63
5.2
Samples for Genetic/Genomic Analysis......................................................................63
5.2.1
Scope of the analysis...............................................................................................63
5.2.2
Certificate of Confidentiality ..................................................................................64
5.2.3
Incidental Findings..................................................................................................64
6
DATA COLLECTION AND EVALUATION......................................................................64
6.1
Data Collection ............................................................................................................64
6.1.1
Exceptions to Data Collection.................................................................................65
6.1.2
Source Documentation Timeframes........................................................................65
6.1.3
Database Entry Timeframes....................................................................................66
6.1.4
Confidentiality.........................................................................................................67
6.1.5
Safety Data..............................................................................................................67
6.1.6
Data Monitoring......................................................................................................68


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
6.2
Data Sharing Plans.......................................................................................................68
6.2.1
Human Data Sharing Plan.......................................................................................68
6.2.2
Genomic Data Sharing Plan....................................................................................68
6.3
Response Criteria.........................................................................................................69
6.3.1
Definitions...............................................................................................................69
6.3.2
Disease Parameters..................................................................................................69
6.3.3
RANO Criteria for Response ..................................................................................69
6.3.4
iRANO (Exploratory)[45].......................................................................................70
6.3.5
Evaluation of Best Overall Response......................................................................71
6.3.6
Dose Limiting Toxicity...........................................................................................71
6.3.7
Progression-Free Survival.......................................................................................71
6.3.8
Overall survival.......................................................................................................71
6.3.9
Response Review ....................................................................................................71
6.4
Toxicity Criteria...........................................................................................................72
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN .....72
7.1
Definitions ...................................................................................................................72
7.2
OHSRP Office of Compliance and Training / IRB Reporting ....................................72
7.2.1
Expedited Reporting................................................................................................72
7.2.2
IRB Requirements for NCI PI Reporting at Continuing Review............................72
7.3
NCI Clinical Director Reporting .................................................................................72
7.4
NCI Guidance For Reporting Expedited Adverse Events For Multi-Center Trials ....73
7.4.1
Reporting Deviations and Unanticipated Problems for Multi-Center Trials ..........74
7.5
NIH Required Data and Safety Monitoring Plan.........................................................74
7.5.1
Data Safety Monitoring Board (DSMB).................................................................75
7.5.2
Patient-Reported Outcomes.....................................................................................75
7.6
Exploratory Objectives & Endpoints...........................................................................76
8
SPONSOR PROTOCOL/SAFETY REPORTING................................................................76
8.1
Definitions ...................................................................................................................76
8.1.1
Adverse Event .........................................................................................................76
8.1.2
Serious Adverse Event (SAE).................................................................................76
8.1.3
Life-threatening.......................................................................................................77
8.1.4
Severity....................................................................................................................77


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Abbreviated Title: GBM Pembro HSPPC
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8.1.6
Events Of Clinical Interest (ECI) For This Trial Include: ......................................78
8.1.7
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor....................................................................................................................78
8.2
Assessment of Safety Events.......................................................................................79
8.3
Reporting of Serious Adverse Events..........................................................................79
8.4
Safety Reporting Criteria to The Pharmaceutical Collaborators .................................79
8.4.1
To be Sent by OSROSafety.....................................................................................79
8.4.2
To be Sent by BTTC study team.............................................................................80
8.4.3
Events of Clinical Interest.......................................................................................81
8.4.4
Reporting Serious Adverse Events to Merck and Agenus......................................82
8.5
Reporting Pregnancy ...................................................................................................82
8.5.1
Maternal exposure..................................................................................................82
8.5.2
Paternal exposure ....................................................................................................83
8.6
Regulatory Reporting for Studies Conducted Under CCR Sponsored IND................83
9
CLINICAL MONITORING ..................................................................................................83
10
STATISTICAL CONSIDERATIONS...................................................................................84
10.1
Sample Size and Accrual.............................................................................................85
10.2
Data Analyses Plans.....................................................................................................86
10.3
Secondary Objectives & Endpoints.............................................................................86
11
COLLABORATIVE AGREEMENTS ..................................................................................86
11.1
Agreement Type ..........................................................................................................86
11.2
Multi-Institutional Guidelines .....................................................................................86
11.2.1
Participating Institution Site Initiation....................................................................86
11.2.2
IRB Approvals.........................................................................................................87
12
HUMAN SUBJECTS PROTECTIONS ................................................................................87
12.1
Rationale For Subject Selection...................................................................................87
12.2
Participation of Children..............................................................................................87
12.3
Participation of Subjects Unable to Give Consent (NCI)............................................87
12.4
Participation of Adults Unable to Give Consent (BTTC) ...........................................88
12.5
Evaluation of Benefits and Risks/Discomforts............................................................88
12.5.1
Risks........................................................................................................................88
12.5.2
Benefits....................................................................................................................89


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12.6
Consent Process and Documentation...........................................................................89
12.6.1
Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation ............................................................................................................90
12.6.2
Request for Waiver of Consent for Screening Activities........................................90
12.6.3
Reconsent via phone at BTTC Sites (outside of NCI) ............................................90
13
REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................................91
13.1
Study Discontinuation and Closure .............................................................................91
13.2
Quality Assurance and Quality Control.......................................................................91
13.3
Conflict of Interest Policy............................................................................................91
13.4
Confidentiality and Privacy .........................................................................................92
14
PHARMACEUTICAL INFORMATION..............................................................................93
14.1
Pembrolizumab/Keytruda ®........................................................................................93
14.1.1
Chemical Name.......................................................................................................93
14.1.2
CAS Name and Number..........................................................................................93
14.1.3
Molecular Formula: C6534H10004N1716O2036S46 (peptide) .........................................93
14.1.4
Molecular Weight: 149 kDa....................................................................................93
14.1.5
Appearance..............................................................................................................93
14.1.6
Storage and Stability ...............................................................................................93
14.1.7
Supplier ...................................................................................................................93
14.1.8
Mechanism of Action..............................................................................................93
14.1.9
Administration for this study...................................................................................93
14.1.10 Preparation ..............................................................................................................94
14.1.11 Preparation for Intravenous Infusion.......................................................................94
14.1.12 Incompatibilities......................................................................................................94
14.1.13 Side Effects .............................................................................................................95
14.2
Temozolomide .............................................................................................................97
14.2.1
Chemical Name.......................................................................................................97
14.2.2
Molecular Formula: C6H6N6O2...............................................................................97
14.2.3
Molecular Weight: 194.15.......................................................................................97
14.2.4
Appearance..............................................................................................................97
14.2.5
Supply: Commercially Available............................................................................97
14.2.6
Pill Diary .................................................................................................................97


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14.2.7
Storage and Stability ...............................................................................................98
14.2.8
Metabolism and Elimination...................................................................................98
14.2.9
Mechanism of Action..............................................................................................98
14.2.10 Special Populations .................................................................................................98
14.2.11 Drug-Drug Interactions ...........................................................................................99
14.2.12 Adverse Events:.......................................................................................................99
14.2.13 Special Handling and Precautions...........................................................................99
14.2.14 Contraindications ....................................................................................................99
14.2.15 Pregnancy Category D ............................................................................................99
14.2.16 Fertility..................................................................................................................100
14.3
Heat Shock Protein-Peptide Complex-96 Vaccine (HSPPC-96)...............................100
14.3.1
Molecular Formula................................................................................................100
14.3.2
Peptide Component ...............................................................................................100
14.3.3
Appearance............................................................................................................101
14.3.4
Availability............................................................................................................101
14.3.5
HSPPC-96 Vaccine Label.....................................................................................101
14.3.6
Storage and Stability .............................................................................................101
14.3.7
Preparation ............................................................................................................101
14.3.8
Administration.......................................................................................................101
14.3.9
Toxicities...............................................................................................................102
14.4
Placebo.......................................................................................................................102
14.4.1
Supply ...................................................................................................................102
14.4.2
Product Description...............................................................................................102
14.4.3
Placebo Label........................................................................................................102
14.4.4
Storage...................................................................................................................102
14.4.5
Administration.......................................................................................................102
14.4.6
Dose.......................................................................................................................102
14.5
Ordering Study Agent................................................................................................103
14.5.1
Heat Shock Protein-Peptide Complex-96 .............................................................103
14.5.2
Pembrolizumab......................................................................................................103
14.5.3
Temozolomide.......................................................................................................103
14.5.4
Agent Storage and Accountability: .......................................................................103


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14.5.5
BTTC Procedures for Agent Accountability and Storage.....................................104
14.5.6
Verification of Compliance...................................................................................105
14.6
Returning or destroying unused and/or defective agent: ...........................................105
14.6.1
Pembrolizumab Return Procedure ........................................................................105
14.6.2
HSPPC-96 or Placebo Return Procedure ..............................................................105
15
REFERENCES.....................................................................................................................106
16
APPENDICES......................................................................................................................109
16.1
Performance Status Criteria.......................................................................................109
16.2
Tumor Tissue Submission for Vaccine Manufacture ................................................110
16.3
Vaccine Tissue Procurement And Shipping Instructions ..........................................111
16.4
Tumor Procurement Form .........................................................................................116
16.5
LabConnect Manual for Whole Blood PBMC Processing and Shipping..................117
16.6
HSPPC-96 Vaccine or Placebo Return Instructions..................................................118
16.7
HSPPC-96 Intradermal Injection Instructions...........................................................119
16.8
Infusion Reaction Treatment Guidelines...................................................................122
16.9
MD Anderson Symptom Inventory (MDASI-BT) ....................................................124
16.10
CCR Reportable Event Form (REF)..........................................................................125
16.11
Unblinding Request Memo........................................................................................128
16.12
Unblinding Notification Memo .................................................................................130
16.13
Study Phases and Correlative Blood Draws ..............................................................131
16.14
Pill Diary....................................................................................................................132
16.15
Investigator Agreement .............................................................................................134


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SCHEMA
Patient comes off study if tumor 
type and both resection criteria 
not met
 MRI findings consistent with a suspected GBM or a histologically confirmed newly diagnosed GBM that 
has not been treated and would benefit from further surgical resection
Arm 2: TMZ+ 
Pembrolizumab up to 6 
cycles   
Surgery
-tissue for vaccine 
production and neo-
epitope monitoring
RT + TMZ + Pembrolizumab
Arm 4: TMZ + 
Pembrolizumab + placebo for 
a minimum of 6 cycles (or 
until number of cycles 
matches vaccine doses made)
Randomization
Once off treatment, continue follow-up every 8-16 weeks.
After 6 cycles post-RT, subjects may continue on Pembrolizumab + vaccine 
or placebo (until depletion of vaccine or placebo). Subjects maybe continue 
on Pembrolizumab for up to 12 months if benefiting from treatment.
After 6 cycles post-RT, 
subjects may continue on 
Pembrolizumab for another 
12 months if benefiting from 
treatment.
Arm 1: unmethylated MGMT promoter and IDH 
wildtype by pathology ≥ 80 % contrast enhanced tumor 
resected and ≥7 grams of tissue collected
Arm 3: TMZ + 
Pembrolizumab + HSPPC-96 
for a minimum of 6 cycles (or 
until vaccine depletion for 
HSPPC-96). 
Sufficient vaccine made (minimum of four)
NO
YES


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CR: complete response; PD: Progressive Disease; GBM: glioblastoma multiforme; PR: partial response; RT: 
radiation therapy; SD: stable disease; TMZ: temozolomide.
CR/PR/SD: continue treatment until PD or 2 years.


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STATEMENT OF COMPLIANCE
The trial will be carried out in accordance with International Council for Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training.
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form.


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1. INTRODUCTION
1.1
STUDY OBJECTIVES
1.1.1
Primary Objective: 
o
To determine whether the one-year overall survival rate (OS) is improved in newly 
diagnosed GBM patients whose tumors have an unmethylated MGMT promoter and are 
IDH wildtype treated with RT + Temozolomide (TMZ) + Pembrolizumab followed by 
Pembrolizumab + TMZ and either HSPPC-96 x 6 cycles (1 cycle is 9 weeks) or placebo 
vaccine.
Nota Bene: Those patients whose tumor does not meet the criteria (unmethylated MGMT 
promoter and IDH wildtype by pathology) and with < 80% of contrast enhanced tumor 
removed or < 7g of tumor resected are ineligible.  
1.1.2
Secondary Objectives:
o
To determine the following 
o
Progression Free Survival-6 (PFS-6) (percentage of patients alive and progression-
free at 6 months post registration).
o
Overall Survival (OS). 
o
Overall Survival (OS) OS-6 and 24 (percentage of patients alive at 6 and 24 months 
respectively). 
o
Response will be determined by Table 2 below using RANO as main criteria. If a lesion 
is 25% larger but there remains a question as to disease progression or 
pseudoprogression due to treatment, the patient can remain on treatment until this can be 
defined, if true progression occurred earlier, the earlier date will be used.
o
Safety of Pembrolizumab +/- HSPPC-96 in GBM. 
o
To evaluate the occurrence of symptoms and correlate to disease progression and 
tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT).  This will include:
•
To longitudinally evaluate patient reported outcome measures using self-reported 
symptom severity and interference with daily activities using the MDASI-BT 
questionnaire.
•
To measure symptom burden over the course of therapy to evaluate differences 
between patients individual symptom severity, overall mean symptom severity, and 
difference in scores on the interference items between responders and non-
responders.
•
To describe the variability of symptom severity longitudinally over the treatment 
course and follow-up period.
1.1.3
Exploratory Objectives:
o
To determine if there is a correlation with clinical outcome of PDL1 expression and T-
Cell infiltrate in pathology from first, and if applicable, second surgical specimens 
with outcome.


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o
To assess tumor tissue for neo-antigens.
o
To collect peripheral monocytes for PD-L1 levels to confirm that low level 
expression leads to better outcome and if higher levels that are treated with 
Pembrolizumab might improve outcome.
o
Assess changes in peripheral T-Cell activation and tryptophan metabolites.
o
Evaluate response using iRANO criteria.
o
Agenus will isolate additional heat shock protein (HSP)-peptide complexes from 
“waste streams” generated during the manufacture of HSPPC-96 (Prophage) from 
GBM tumor tissue.  From these HSP-peptide complexes, Agenus may generate a 
novel “multi-chaperone” vaccine that Agenus will evaluate in preclinical studies. 
1.2
BACKGROUND AND RATIONALE
1.2.1
Disease Background
Malignant gliomas, particularly GBM are nearly always fatal. Despite aggressive surgery, 
radiation treatment (RT) and chemotherapy at initial diagnosis these tumors almost always 
recur. There have been many studies in patients with newly diagnosed GBM, either altering the 
dosing schedule of the temozolomide (RTOG 0525) [1] or adding anti-angiogenic agents to the 
standard treatment regimen.  None have proven to prolong survival and the latter treatments 
targeting neovascularization were particularly disappointing given that angiogenesis is a cardinal 
feature of GBM. [2] [3]
Many clinical trials in GBM have evaluated the addition of agent(s) to standard therapy which 
consists of concurrent radiation with temozolomide chemotherapy after maximal surgical 
resection in patients with newly diagnosed disease and salvage chemotherapy with either 
rechallenge with temozolomide or an alternative alkylating agent such as CCNU or cisplatin. 
To date, none of the combination strategies have demonstrated clinical benefit. Furthermore, 
in subjects with an unmethylated MGMT (O6-methylguanine-DNA methyltransferase) 
promoter temozolomide has only modest benefit and salvage therapies have not demonstrated 
a significant impact in this subject group underscoring the need for more research.
Novel approaches being evaluated in GBM treatment include immunologic therapies, such as 
therapeutic vaccines that are either derived from the subject’s own tumor (HSPPC-96) or have 
been designed to target specific epitopes on tumor cells (CDX-110, ICT-107). Preliminary 
results were promising from Phase 2 trials of CDX-110 (rindopeptimet), ICT 107, HSPPC-96, 
and others. [4-6]. However, a randomized Phase 3 trial evaluating the CDX-110 did not 
demonstrate efficacy [7].
There are several agents currently under investigation that target the local immune response in 
solid tumors, particularly in melanoma, such as ipilimumab (blockade of cytotoxic T 
lymphocyte–associated protein 4 [CTLA-4]) and programmed cell death protein 1 (PD-1; PD-L1 
blockade). Such agents are either FDA approved or being evaluated in various solid tumors with 
the most activity seen in [8].
There are many immunologic approaches to treatment of GBM. Gliomas can upregulate B7-H1 
expression in circulating monocytes and tumor-infiltrative macrophages through modulation of 


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autocrine/paracrine interleukin 10 (IL-10) signaling, resulting in an immunosuppressive 
phenotype.[9] Glioma-associated cancer-initiating cells have been shown to express the 
costimulatory inhibitory molecule B7-H1, [10] which is a key factor in mediating immune 
resistance in glioma[11] and can induce T-cell apoptosis. [12].
Direct cell-to-cell contact experiments have shown that the glioma-associated cancer-initiating 
cells induced T-cell apoptosis in the setting of B7-H1 expression.  [10] found that cancer-
initiating cells markedly inhibited T-cell proliferation and activation, induced regulatory T 
cells, and triggered T-cell apoptosis that was mediated by B7-H1 and soluble galectin-3. Loss 
of tumor suppressor phosphotase and tensin homolog (PTEN) function increases B7-H1 
expression and immunoresistance in glioma. [11] It also been shown that glioma-associated 
cancer-initiating cells induce immunosuppression, thereby allowing tumor cells to evade 
immunosurveillance. 
Yao et al. [13] found that B7-H1 was correlated with the malignancy grade of human astrocytic 
tumors, but preferentially in the non-dividing tumor cells. It was also upregulated at the 
growing edge of the tumors and had a negative correlation with tumor-infiltrating CD8 T cells. 
Tumor-infiltrating lymphocytes and PD-L1 expression are seen in the majority of GBM 
samples. [14, 15] Data show that lymphopenia induced by temozolomide (TMZ) can actually 
potentiate cancer immunotherapy, which may be due in part to cell death, which releases 
cellular contents that increase the immunoreactivity of the tumor environment. [16]  
1.2.2
Intervention Background & Overview
1.2.2.1
Programmed Cell Death Protein 1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.[17] Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies. [12] [18] [19, 20] [21]. In particular, the presence of CD8+ T-cells and 
the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with 
improved prognosis and long-term survival in many solid tumors.
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 Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2). [22, 23] The structure of murine PD-1 
has been resolved. [24] PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a 
cytoplasmic tail which is 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 (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following 
T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif 
within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade   [23, 25-27].  The 


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mechanism by which PD-1 down modulates T-cell responses is similar to, but distinct from that 
of CTLA-4 as both molecules regulate an overlapping set of signaling proteins[25] [26]. PD-1 
was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T- 
cells, B-cells, T regs and Natural Killer cells. [28]  [29]  Expression has also been shown during 
thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages 
and dendritic cells. [30]  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed 
or can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors. [30] [31] [32, 33]  Both ligands are type I transmembrane receptors containing 
both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic 
regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell 
activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various 
non- hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid 
organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues. [34]  
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor- 
specific T-cell expansion in subjects with melanoma. [35] This suggests that the PD- 1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an attractive 
target for therapeutic intervention.
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. It is currently FDA approved for 
use in patients with unresectable or metastatic melanoma and disease progression following 
ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  It is also FDA approved 
for advanced (metastatic) non-small cell lung cancer (NSCLC) whose disease has progressed 
after other treatments and with tumors that express a protein called PD-L1 and for the treatment 
of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with 
disease progression on or after platinum-containing chemotherapy.
1.2.3
Rationale for the Pembrolizumab dose
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation 
results indicating that 200 mg will provide exposures that are reasonably consistent with those 
obtained with 2 mg/kg dose and importantly will maintain individual patient exposures within 
the exposure range established in melanoma as associated with maximal clinical response. A 
population PK model, which characterized the influence of bodyweight and other patient 
covariates on exposure, has been developed using available data from 476 subjects from 
PN001.  The distribution of exposures from the 200 mg fixed dose are predicted to 
considerably overlap those obtained with the 2 mg/kg dose, with some tendency for individual 
values to range slightly higher with the 200 mg fixed dose.  The slight increase in PK 
variability predicted for the fixed dose relative to weight-based dosing is not expected to be 
clinically important given that the range of individual exposures is well contained within the 
range of exposures shown in the melanoma studies of 2 and 10 mg/kg to provide similar 
efficacy and safety. The population PK evaluation revealed that there was no significant 
impact of tumor burden on exposure. In addition, exposure was similar between the NSCLC 


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and melanoma indications. Therefore, there are no anticipated changes in exposure between 
different tumor types and indication settings.
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a given 
dose among tumor types. Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to Pembrolizumab to a clinically 
meaningful extent. Taken together, these data support the use of lower doses (with similar 
exposure to 2 mg/kg Q3W) in all solid tumor indications. 2 mg/kg Q3W is being evaluated in 
NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data supporting the dose 
selection.
This trial will use Pembrolizumab 200 mg every three weeks to fit with treatment schedules 
currently used.
1.2.4
Heat Shock Protein-Peptide Complex-96 (HSPPC-96)
Immunotherapy offers the promise of improving outcomes for patients with GBM by evoking 
specific immune responses that may produce a more sustained and less toxic effect than 
conventional therapy.  Heat-shock proteins (HSPs), which function as intracellular chaperones, 
can be used to deliver a variety of tumor antigens to antigen presenting cells for immune 
stimulation. 
Heat Shock Protein-Peptide Complex-96 (HSPPC-96) consists of the heat shock protein 
glycoprotein-96 (HSP gp-96) and a wide array of chaperoned proteins, including autologous 
antigenic peptides. Heat shock proteins (HSP) are molecules that respond to cellular stress and 
counteract abnormal protein folding. They are known to modulate immune responses, especially 
the HSP gp-96. In a stressful environment, such as a tumor, HSPs are upregulated and highly 
expressed on tumor cells. This protects the tumor and leads to resistance to therapy. HSP 
expression is associated with cellular proliferation, apoptosis evasion, tissue invasion, metastasis, 
and angiogenesis. 
HSPPC-96 immunization works mechanistically by interacting with antigen presenting cells 
(APCs) via specific receptors, including CD91. [36, 37] highly specific nature of the interaction 
between HSPPC-96 and APCs is a significant advantage over other cancer vaccine approaches; 
and has been shown to facilitate robust CD4+ and CD8+ T-cell immune responses. There are 
multiple mechanisms by which the vaccine works. The first is the following: The autologous 
antigens in the vaccine are bound to the chaperone proteins (HSP) with noncovalent bonds. 
Macrophages and other transfer the antigens from HSP to antigen presenting cells (e.g., DCs) 
bind and take up the HSP-antigen complexes, via receptor- mediated endocytosis (with receptors 
such as CD91). The antigens are then expressed via MHC class I and II on antigen presenting 
cells (APCs), interacting with naïve T cells, which are activated into specific CD8 T and CD4 T 
cells.  Another mechanism of the vaccine is an innate immunity pathway cells.
HSPPC-96 Ag is internalized into the APC, which activates the APC. This leads to the 
following: 


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o
Activated APCs express co-stimulatory molecules (CD80, CD86, and CD40) and express 
MHC class II, which interacts with T cells and produces tumor specific CD4 cells. 
o
Activated APCs cause cytokine release (IL-1b, IL-12, IL-6, TNF-alph, GMCSF, chemokines, 
and nitric oxide). IL-12 stimulates NK cells, which enhance the antitumor activity of T cells. 
o
The interaction between HSP-antigen and APCs causes dendritic cell maturation, which 
stimulates NK cells. 
A final mechanism of the vaccine is that exposure to Gp96 leads to translocation of NFkB into 
the APC nucleus, which then regulates cancer cell growth, progression, and apoptosis. 
The advantage of the HSPPC-96 vaccine over others is the following: 
o
Multifactorial mechanism: as described above, the vaccine works by multiple pathways to 
exert its effect, rather than 1 pathway. 
o
The vaccine is individualized and does not require identification of immunogenic antigens 
required by other vaccines. 
o
Multiple antigens are used, which decreases the chance of immune evasion that occurs with a 
single antigen vaccine. 
Clinical grade HSPPC-96 can be easily purified from solid tumor and has been safely tested in 
hundreds of patients with newly diagnosed and recurrent melanoma and renal cell cancer. The 
toxicity encountered in renal cell carcinoma in prior trials is the following: injection site 
erythema (50%), injection site induration (48%), back pain (12%), headache (12%), fatigue 
(10%), nasopharyngitis (9%), incision site complication (9%), arthralgia (9%), hypertension 
(9%), urinary tract infection (8%), nausea (7%), diarrhea (6%), asthenia (6%), influenza (6%), 
constipation (5%), pyrexia (5%), and dizziness (5%). In melanoma, toxicity seen was pyrexia 
(8%), fatigue (6%), and nausea (5%). Between the trials there were 3 serious adverse events, 2 
were thyroid dysfunction, and 1 was cellulitis. [38] [39] [11]
The rate of successful HSPPC-96 vaccine manufacture is anticipated to be 80% or greater based 
on prior clinical trials. A prior phase 2 study of new diagnosed glioblastoma, vaccine was 
successfully manufactured in 84% (63/77) of attempted cases. The majority of manufacture 
failures were caused by insufficient number of vials available, below the required 4, for clinical 
use (9 cases).
A single center single arm Phase I clinical trial and a multicenter single arm Phase II clinical trial 
for recurrent GBM patients treated with HSPPC-96 have been completed. Collectively these 
studies have shown that: 1) HSPPC-96 vaccine made from recurrent GBM tumor is safe and well 
tolerated, 2) HSPPC-96 vaccine extends survival in recurrent GBM patients over historical 
controls and 3) HSPPC-96 is immunogenic in recurrent GBM patients, inducing both an 
immunologic response locally and peripherally and via innate and adaptive immune mechanisms 
[39] and confers clinical efficacy in patients with newly diagnosed and recurrent GBM.  
Importantly, in patients with newly diagnosed GBM, HSPPC-96 vaccine in combination with 
standard of care temozolomide extended response. Specifically, in the phase I trial, testing was 
performed pre- and post-vaccine on all patients. Eleven of 12 patients were shown to have a 
significant immune response, which was measured by testing peripheral blood lymphocytes 
(PBLs). PBLs were tested for phenotype, reactivity to vaccine, IFN gamma production, and 


23
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proliferation. Vaccine was well tolerated with no serious adverse events and the only toxicity 
noted was injection site erythema or induration. The median progression survival in responders 
was 47 weeks, compared to 16 weeks in the non-responder. In the phase II trial, 33 patients were 
treated. Again, there were no serious adverse events attributed to vaccine. Toxicities reported 
were injection site reaction in 12 patients, and fatigue in 9 patients. Eleven patients were still 
alive at time of analysis, with median survival of 333 days for the evaluable population. Also, all 
patients studied showed immune response, based on CD8 IFN gamma production [9]. 
In a separate single arm phase II trial of newly diagnosed GBM patients who were treated with 
RT + TMZ + HSPPC-96, median PFS and overall survival were two to three times longer than 
expected based on historical controls (median PFS was 18 v 6-9 mos and median OS was 24 v 
14-16 mos) of 24 months.  Importantly, patients with low PDL1 expression on peripheral 
monocytes had longer survival than those with high PD-L1 expression, suggesting that an 
optimal group for HSPPC-96 use with a checkpoint inhibitor would be in the high PD-L1 
expressing patients.
Importantly, in data presented at ASCO 2015, in patients with less elevated PD-L1 expression on 
peripheral monocytes, treatment with HSPPC-96 was associated with an unexpected and 
impressively longer survival than those with high more elevated PD-L1 on circulating monocytes 
(mPFS of 27 v 6-9 mos and mOS 47 v 14-16; [38] ).  
Figure 1: Overall Survival by Monocyte PD-L1
1.2.5
Rationale for the Current Study
The preclinical data about the immunologic aspects of gliomas and the data using vaccines, 
suggest that there is a strong rationale to evaluate these agents in GBM. While the blood brain 


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barrier (BBB) is often an issue for drug penetration, this would be less of an issue for checkpoint 
inhibitors as the effect is on trafficking T-Cells which can migrate peripherally to the brain. [15] 
Nonetheless, in the setting of contrast enhancement, the BBB is leaky, allowing drug penetration.
Taken together, these data support the rationale that the combination of an autologous cancer 
vaccine and an anti-PD-1 inhibitor may synergistically result in an increase in tumor specific 
immune response with downregulation of tumor immunosuppression resulting in important 
clinical responses.  There is pre-clinical and some clinical precedence for using an immune 
educating strategy with a release of tumoral immunosuppression.  Several studies have shown 
a benefit of the combination over check point modulators alone or vaccine alone in several 
types of solid tumors. [19, 40]
This study will be the first to evaluate this combination of vaccine (HSPPC-96) and PD-1 
inhibition (Pembrolizumab) in newly diagnosed GBM with unmethylated MGMT promoter 
and will provide important data on immune-modulatory effect of this combination. This may 
be of particular value in patients with high peripheral PD-L1 expression, but also there also be 
value adding PD-1 to standard GBM therapy.  We will be assessing OS-12 and other PFS and OS 
rates.
A phase I study adding Pembrolizumab (200 mg) to RT+TMZ using standard starting doses was 
found to be safe and without a DLT.[41] The DLT window was from the start of RT until 4 
weeks post Radiation. There were no grade 3 or 4 toxicities seen. Related grade 1 and 2 toxicities 
were anemia, lymphopenia, neutropenia, thrombocytopenia, fatigue, rash, and GI upset/poor PO 
intake. Pseudo-progression and inflammatory responses were not seen in in a phase I of RT + 
TMZ + Pembrolizumab. We do not believe there will be any added toxicity of adding HSPPC-96 
to RT + TMZ + Pembrolizumab; while an increased inflammatory reaction might occur, these 
patients will all have achieved ≥ 80% resection.
Tumor tissue will be analyzed to assess for MGMT, PDL-1 levels and T-cell infiltration as well 
as collection of peripheral markers of T-Cell activation and tryptophan metabolites. Patients who 
progress and will benefit from further surgery will have their tumor tissue collected and 
analyzed.
1.2.6
Rationale for the patient-reported outcomes:  
This study seeks to establish effective therapies.  We hypothesize that using a combination of 
pembrolizumab, temozolomide and HSPPC-96 will result in improved survival.  However, given 
the intensive nature of this regimen, it will be important to determine whether any determined 
survival benefit is associated with improvements in symptoms or whether a worsening of 
symptoms offsets the increase in survival. 
Precedence for measuring “non-therapeutic” endpoints exists in oncology research.  For 
example, Gemcitabine was approved by the FDA partially as a consequence of the decrease in 
pain reported in pancreatic patients who were treated, not on the basis of survival improvement 
which was modest at best [42]. There have been efforts in neuro-oncology to evaluate secondary 
endpoints using validated instruments as an additional indicator of benefit.  


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The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) allows the self-
reporting of symptom severity and interference with daily activities.  The MDASI-BT has 
demonstrated reliability and validity in the adult primary brain tumor patient population. [43]  
This tool represents a modification of the widely used and validated M.D. Anderson Symptom 
Inventory, with particular attention to symptoms common in patients with brain tumors.   The 
availability of validated instruments provides an opportunity to prospectively assess the impact 
of treatment, both positive and negative, on patients.  The evaluation of symptom burden in this 
study will assist in finding the best possible treatment with the least toxicity.
2
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1
ELIGIBILITY CRITERIA
The target population for this study is patients with newly diagnosed GBM with an un-
methylated MGMT promoter and IDH wild type.  NOTE: Enrollment to this protocol is closed. 
See Study Implementation (Section 3.1) regarding study termination and procedures for 
unblinding participants . 
Eligibility will be evaluated by the study team according to the following criteria: 
Eligibility waivers are not permitted. 
Subjects must meet all of the inclusion and none of the exclusion criteria to be registered to the 
study. Study treatment may not begin until a subject is registered. Please refer to Section 2.2 for 
complete instructions regarding registration procedures.
2.1.1
Inclusion Criteria
Pre-Surgery (Step 1) Inclusion:
2.1.1.1
MRI findings consistent with a suspected GBM or a histologically confirmed newly 
diagnosed GBM that has not been treated and would benefit from further surgical 
resection. As vaccine needs to be generated from the patient’s tumor, patients will need 
to be identified prior to definitive surgery.
2.1.1.2
Preliminary assessment by the neurosurgeons that >80% of the tumor can be resected 
with an expectation that >7gm of tissue would be resected
2.1.1.3
Age ≥ 18 years on day of signing informed consent.
2.1.1.4
Karnofsky performance status ≥ 70%.
2.1.1.5
Tumor must be supratentorial only.
2.1.1.6
Stereotactic biopsy will not be allowed unless there is plans for second surgery to 
remove ≥ 80 % of the tumor.
2.1.1.7
No prior treatment with radiation or chemotherapy for their GBM.
2.1.1.8
No prior treatment with carmustine wafers.


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Post-Surgery (Step 2) Inclusion:
2.1.1.9
Pathology must be a GBM, MGMT promoter region determined to be unmethylated and 
IDH wild type,  >80 % resection of contrast enhanced tumor on post operative MRI and 
> 7 grams of tumor resected are required  otherwise patient is ineligible .
2.1.1.10 Treatment must be initiated > 14 days and < 6 weeks from surgery.
2.1.1.11 Craniotomy site must be adequately healed and free of drainage or cellulitis, and the 
underlying cranioplasty must appear intact at the time of radiation. Radiation must start 
within 6 weeks of surgery.
2.1.1.12 Dexamethasone dose should be < 4 mg/day or steroid equivalent prior to starting 
treatment. If higher doses are needed, consult with Study Chair.
2.1.1.13 Female subjects of childbearing potential should have a negative urine or serum 
pregnancy within 7 days prior to receiving the first dose of study medication. If the 
urine test is positive or cannot be confirmed as negative, a negative serum pregnancy 
test will be required.
2.1.1.14 Patients must have adequate organ and bone marrow function within 14 days prior to 
step 2 registration, as defined below:
2.1.1.15 Absolute neutrophil count (ANC) > 1.5 × 109/L; platelet count > 100 × 109/L; and 
hemoglobin (Hb) >9.0 g/dL within 7 days prior to step 2 registration. Note: The use of 
transfusion or other intervention to achieve Hb ≥ 9.0 g/dL is acceptable.
2.1.1.16 Total bilirubin < 1.5 × ULN (except in patients diagnosed with Gilbert’s disease)
2.1.1.17 AST (SGOT), ALT (SGPT), and alkaline phosphatase (ALP) < 2.5 × ULN
2.1.1.18 Serum creatinine < 1.5 × ULN
2.1.1.19 International normalized ratio (INR), prothrombin time (PT), or activated partial 
thromboplastin time (APTT) as follows: In the absence of therapeutic intent to 
anticoagulate the patient: INR < 1.5 or PT < 1.5×ULN or aPTT < 1.5×ULN. In the 
presence of therapeutic intent to anticoagulate the patient: INR or PT and aPTT within 
therapeutic limits (according to the medical standard in the institution) and the patient 
has been on a stable dose of anticoagulants for at least 2 weeks before registration.
2.1.1.20 Females of child-bearing potential (FOCBP) and males must agree to use two adequate 
contraception methods (give examples, e.g. hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 120 days 
following completion of therapy. Should a female patient become pregnant or suspect 
she is pregnant while participating in this study, she should inform her treating 
physician immediately. Male patients who father a child should notify the treating 
physician.
NOTE: A FOCBP is any woman (regardless of sexual orientation, having undergone 
a tubal ligation, or remaining celibate by choice) who meets the
following criteria:
o
Has not undergone a hysterectomy or bilateral oophorectomy
o
Has had menses at any time in the preceding 12 consecutive months (and 
therefore has not been naturally postmenopausal for > 12 months)


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2.1.1.21 Patients must have the ability to understand and the willingness to sign a written 
informed consent prior to registration on study.
2.1.1.22 Diagnosis must be made by surgical excision.
2.1.1.23 Patients should not be on antibiotics for any infection but post operative antibiotics are 
allowed if used prophylactically but should be completed prior to starting RT.
2.1.2
Exclusion Criteria 
Pre-Surgery (Step 1) Exclusion:
2.1.2.1
Known history of immunodeficiency (HIV).  This medical entity can be exacerbated by 
PD-1 blockade.
2.1.2.2
History of another malignancy in the previous 3 years, with a disease-free interval of < 
3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 
Patients who have undergone a bone marrow or stem-cell transplant for any malignancy 
are excluded. 
2.1.2.3
Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome 
that requires chronic systemic steroids or immunosuppressive agents except as noted 
above in 2.1.2.13 and 2.1.2.14 Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. Subjects that require intermittent use 
of bronchodilators or local steroid injections will not be excluded from the study. 
Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome 
will not be excluded from the study.
2.1.2.4
Has a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis.
2.1.2.5
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  Examples include:
•
Hypertension (defined as 160/95) that is not controlled on medication
•
Ongoing or active infection requiring systemic treatment
•
Symptomatic congestive heart failure
•
Unstable angina pectoris
•
Cardiac arrhythmia
•
Psychiatric illness/social situations or substance abuse disorders that would 
limit compliance with study requirements
•
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints.


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2.1.2.6
Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
2.1.2.7
The effects of pembrolizumab and HSPPC-96 on the developing human fetus are 
unknown.  For this reason and because checkpoint inhibitors and immunotherapeutic 
vaccines as well as other therapeutic agents used in this trial are known to be 
teratogenic, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.
2.1.2.8
Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways).
2.1.2.9
On treatment for Hepatitis B or Hepatitis C or history of TB. 
2.1.2.10 Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to Pembrolizumab are not eligible. Known 
hypersensitivity to any excipients of Pembrolizumab.
Post-Surgery (Step 2) Exclusion:
2.1.2.11 Patients are ineligible if the tumor is not a GBM, MGMT promoter region determined 
to be unmethylated and IDH wild type, or if < 80 % resection of contrast enhanced 
tumor on post-operative MRI or < 7 grams of tumor is resected.
2.1.2.12 Patients who are receiving any other investigational agents.
2.1.2.13 Known history of immunodeficiency (HIV).  This medical entity can be exacerbated by 
PD-1 blockade.
2.1.2.14 Any form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment excluding steroids. Attempts should be made to have patient on lowest 
possible dose of steroids.  These medical entities can be exacerbated by PD-1 blockade.
2.1.2.15 History of another malignancy in the previous 3 years, with a disease-free interval of < 
3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin, or in situ cervical cancer that has undergone potentially curative therapy. 
Patients who have undergone a bone marrow or stem-cell transplant for any malignancy 
are excluded. 
2.1.2.16 Has an active autoimmune disease requiring systemic treatment within the past 3 
months or a documented history of clinically severe autoimmune disease, or a syndrome 
that requires chronic systemic steroids or immunosuppressive agents except as noted 
above in 2.1.2.13 and 2.1.2.14 Subjects with vitiligo or resolved childhood 
asthma/atopy would be an exception to this rule. Subjects that require intermittent use 
of bronchodilators or local steroid injections will not be excluded from the study. 


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Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome 
will not be excluded from the study.
2.1.2.17 Has a history of interstitial lung disease, non-infectious pneumonitis or pneumonitis.
2.1.2.18 Has an active infection requiring systemic antibiotics within 10 days of surgery.  
2.1.2.19 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.  Examples include:
•
Hypertension (defined as 160/95) that is not controlled on medication
•
Ongoing or active infection requiring systemic treatment
•
Symptomatic congestive heart failure
•
Unstable angina pectoris
•
Cardiac arrhythmia
•
Psychiatric illness/social situations or substance abuse disorders that would 
limit compliance with study requirements
•
Any other illness or condition that the treating investigator feels would 
interfere with study compliance or would compromise the patient’s safety or 
study endpoints.
2.1.2.20 Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment.
2.1.2.21 The effects of pembrolizumab and HSPPC-96 on the developing human fetus are 
unknown.  For this reason and because checkpoint inhibitors and immunotherapeutic 
vaccines as well as other therapeutic agents used in this trial are known to be 
teratogenic, women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study 
entry, and for the duration of study participation.  Should a woman become pregnant or 
suspect she is pregnant while she or her partner is participating in this study, she should 
inform her treating physician immediately.
2.1.2.22 Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti- Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways).
2.1.2.23 On treatment for Hepatitis B or Hepatitis C or history of TB. 
2.1.2.24 Has received a live vaccine within 30 days prior to the first dose of trial treatment (see 
Section 4.2)
2.1.2.25 Patients who have a history of allergic reactions attributed to compounds of similar 
chemical or biologic composition to Pembrolizumab are not eligible. Known 
hypersensitivity to any excipients of Pembrolizumab.


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2.1.3
Recruitment Strategies
This protocol may be abstracted into a plain language announcement posted on NIH websites 
and on NIH social media platforms. Patients will be referred by BTTC site PIs. An NIH/IRB 
approved patient flyer is used to recruit patients.   
2.2
SCREENING EVALUATION
2.2.1
Screening activities performed prior to obtaining informed consent
Minimal risk activities that may be performed before the subject has signed a consent include the 
following: 
•
Email, written, in person or telephone communications with prospective subjects 
•
Review of existing medical records to include H&P, laboratory studies, etc.  
•
Review of existing MRI, x-ray, or CT images
•
Review of existing photographs or videos
•
Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes
A waiver of consent for these activities has been requested in section 12.6.2.
2.2.2
Screening activities performed after a consent for screening has been signed
The following activities will be performed only after the subject has signed the consent for this 
study for screening. Assessments performed at outside facilities or on another NIH protocol 
within the timeframes below may also be used to determine eligibility once a patient has signed 
the consent.
The screening evaluation elements must be completed within (+/-) 14 days of signing consent  
unless otherwise noted:
Outside lab/procedure results for standard of care studies or another protocol that are performed 
within this timeframe may be used to determine eligibility.
•
Medical History
•
Prior and Concomitant medication review
•
Karnofsky performance status
•
Physical and Neurological Exam
•
Vital signs and Weight
•
Tumor Imaging (by MRI unless contraindicated) showing tumor consistent with a GBM.
•
Tumor Pathology (before Step 3)
•
Pregnancy Test
•
PT/INR or aPTT 
•
CBC with differential
•
Na, K, CL, Bicarbonate, BUN/Cr, AST, ALT, ALP, T. Bili, Calcium, Albumin
•
Urinalysis


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2.3
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES
Patients who are candidates for the study will first be evaluated for eligibility by the local 
investigator. All patients must be registered both locally and centrally with BTTC prior to 
surgery (see Section 3.3.1, Surgery).
BTTC patients will be registered with the BTTC Coordinating Center.  All subjects must be 
registered through the BTTC NCI Central Registration Office (CRO). The CRO is open from 
8:30 am to 5:00 pm EST Monday through Friday, excluding federal holidays.  
If any emails described in sections 2.3.2 through 2.3.6 contain protected health information 
(PHI), they must be encrypted.
2.3.1
Informed Consent/Authorization
Prior to protocol enrollment and initiation of treatment, subjects must sign and date an 
Institutional Review Board (IRB) approved consent form.
Registrations must be completed after the patient has signed the informed consent and has been 
determined to be eligible by the local investigator. 
At the time of registration, the following information will be requested by the BTTC 
Coordinating Center:
o
A copy of a completed and signed, protocol specific, Registration Form (eligibility checklist) 
o
One copy of the signed and dated Informed Consent/Authorization. 
o
Copies of all source documents to support protocol specific eligibility.  Please refer to the 
BTTC Operations Manual for specific source documents required.
2.3.2
Registration at the NCI
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here.
Registration will be a three part process as patients are screened on this protocol. Authorized 
staff must register an eligible candidate with NCI Central Registration Office (CRO) within 24 
hours of signing consent. See Section 2.3.5 for Step 3 of Registration Form (Randomization 
at NCI).
2.3.3
Registration at Participating BTTC Sites
Registration will be a three part process as patients are screened on this protocol. A protocol 
registration form and cover memo will be supplied by the Coordinating Center, NCI CCR and 
updates will be provided as needed. Registration will be completed within 2 business days of 
receipt of documents required for registration.   
Step 1: All patients must be registered both locally and centrally with BTTC prior to surgery. To 
initially register a subject, after the participant has signed the consent, site will complete and 
send Step 1 of the Registration Form, source documents, and consent form, indicating that the 
patient is being registered for screening and surgery, to the BTTC Coordinating Center via 
secure fax (240-541-4432) or send to the BTTC CC research nurse via Secure Email and File 
Transfer [SEFT] (preferred). Upon confirmation of consent and available slot, the BTTC CC 


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research nurse will send the Registration Form to NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov via encrypted email.  Within 1 business day, NCI Central 
Registration Office will send the Verification of Registration with the assigned subject ID 
number to the BTTC CC research nurse via encrypted email.  The BTTC CC research nurse will 
email the Verification of Registration to the site and Agenus (redacted with subject ID number 
and patient initials).  The subject ID number is unique to the patient and must be written on all 
data and correspondence for the patient and used to enter data into the NCI-designated eCRF 
database.   
Step 2: Study treatment may not begin until a subject is registered. After completion of 
screening and surgery, site will complete Step 2 of the Registration Form indicating that the 
patient has met all inclusion and no exclusion criteria.  The Registration Form and source 
documents will be sent to the BTTC CC via secure fax (240-541-4432) or send to the BTTC CC 
research nurse via Secure Email and File Transfer [SEFT] (preferred).   Upon confirmation of 
eligibility, the BTTC CC research nurse will sign the Registration Form (eligibility checklist) 
and send it via encrypted email to the CRO at NCI Central Registration Office 
ncicentralregistration-l@mail.nih.gov.  The CRO will send the Verification of Registration to the 
BTTC CC research nurse via encrypted email.  The BTTC CC research nurse will email the 
Verification of Registration to the site and Agenus (redacted with study ID number and patient 
initials).
When a participant has a status change (e.g., subject screened on the study, does not meet 
eligibility criteria and is removed from the study, participant is taken off protocol therapy or off 
study, etc.), the Participant Status Update Form will be supplied by the BTTC Coordinating 
Center research nurse coordinator. Send the completed form to the BTTC Research Nursevia 
secure fax: 240-541-4432, or via Secure Email and File Transfer (SEFT)..
See Section 2.3.6 for Step 3 of Registration Form (Randomization for Participating Sites).
2.3.4
Initiation of Therapy (Radiation Therapy, Temozolomide and Pembrolizumab)
Treatment may not be initiated until the participating institution receives a faxed or emailed copy 
of the patient’s Registration Verification Letter from the Central Registration Office. 
Treatment must be initiated > 14 days and < 6 weeks from surgery.
The BTTC Coordinating Center must be notified in writing of any exceptions to this policy.
2.3.5
Registration Step 3: Randomization for NCI
Following vaccine manufacture and completion of quality testing, Agenus will send the Vaccine 
Production Notification form to NCI.  This Form indicates whether manufacture of vaccine was 
successful. The site will send Step 3 of the Registration form and Vaccine Production 
Notification Form to BTTC CC research nurse via secure fax: 240-541-4432, hand-delivery, or 
encrypted email. BTTC CC will confirm verification and send via encrypted email to CRO and 
via Secure Email and File Transfer [SEFT] to Agenus.  CRO will send the Verification of 
Registration with the assigned sequence number to the site and the BTTC CC research nurse via 
encrypted email.  The BTTC CC research nurse will send the Verification of Registration with 
the assigned sequence number (vaccine assignment) to Agenus (redacted with subject ID number 


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and patient initials).  Agenus will send the blinded vaccine or placebo directly to the site.  In 
parallel, CRO will also notify the NCI Pharmacy to release blinded vaccine or placebo.
2.3.6
Registration Step 3: Randomization for Participating Sites
Following vaccine manufacture and completion of quality testing, Agenus will send the Vaccine 
Production Notification form to the site.  This Form indicates whether manufacture of vaccine 
was successful. The site will send Step 3 of the Registration form and Vaccine Production 
Notification Form to BTTC CC research nurse via secure fax: 240-541-4432 or via Secure Email 
and File Transfer [SEFT] (preferred).   BTTC CC will confirm verification and send via 
encrypted email to CRO and via Secure Email and File Transfer [SEFT] to Agenus.  CRO will 
send the Verification of Registration with the assigned sequence number to the BTTC CC 
research nurse.  The BTTC CC research nurse will send the Verification of Registration with the 
assigned sequence number (vaccine assignment) to the site and Agenus (redacted with subject ID 
number and patient initials).  Agenus will send the blinded vaccine or placebo directly to the site.  
2.3.7
Study Status Updates for Participating Sites
For participating BTTC Sites:  The Participant Status Updates Form will be supplied by the 
BTTC Coordinating Center, NCI, CCR. Send the completed Participant Status Updates Form via 
secure fax: 240-541-4432, or via Secure Email and File Transfer (SEFT). 
2.3.8
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE).


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2.4
TREATMENT ASSIGNMENT AND RANDOMIZATION /STRATIFICATION PROCEDURES
Cohorts
Number
Name
Description
1
Patients with Glioblastoma 
eligible to receive radiation 
therapy 
GBM patients with MRI findings consistent with a suspected 
GBM or a histologically confirmed newly diagnosed GBM that 
has not been treated, have met all inclusion and no exclusion 
criteria, and have completed surgery (i.e., Step 2 of registration)
2
Patients with Glioblastoma 
with sufficient vaccine 
created
GBM patients with MRI findings consistent with a suspected 
GBM or a histologically confirmed newly diagnosed GBM that 
has not been treated, whose tumors have an unmethylated MGMT 
promoter and are IDH wildtype with sufficient vaccine created 
(i.e., Step 3 of registration) 
3
Patients with Glioblastoma 
without sufficient vaccine 
created
GBM patients with MRI findings consistent with a suspected 
GBM or a histologically confirmed newly diagnosed GBM that 
has not been treated, whose tumors have an unmethylated 
MGMT promoter and are IDH wildtype without sufficient 
vaccine created (i.e., Step 3 of registration)
Arms
Number
Name
Description
1
Radiation Therapy (RT)
Standard radiation therapy  
2
RT+TMZ + Pembrolizumab
Standard treatment with experimental 
treatment (pembro) added
3
RT+TMZ+Pembrolizumab+HSPPC-96 
Vaccine
Standard treatment with experimental 
treatment (pembro+ vaccine) added
4
RT+TMZ+Pembrolizumab+Placebo 
Vaccine
Standard treatment with experimental 
treatment and placebo added
Randomization and Arm Assignment
All study patients satisfying the eligibility criteria and who have completed surgery will be 
assigned to Cohort 1 and Arm 1, Radiation Therapy. All study patients that satisfy the eligibility 
criteria post-radiation therapy, will be assigned to Cohort 2 or 3, based on ability or inability to 
make sufficient vaccine. Study patients in Cohort 2 will then be randomized 1:1 in a blinded 
fashion between arms 3 and 4.  Patients in cohort 3 will be assigned directly to the ancillary arm, 
Arm 2.


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Stratifications
Name
Distinct Options
Notes
None
3
STUDY IMPLEMENTATION
3.1
EARLY TERMMINATION
On May 20, 2021 the NCI/CCR Data Safety and Monitoring Board met to review the progress of 
this protocol, including the results of an unscheduled interim analysis. 
Prior to the meeting, the board agreed to a request by the Lead NCI PI to look at outcome data by 
arm and agreed on principles for interpretation of outcome and accrual data. 
Based on the presented data, the board recommended the study be stopped because of poor 
accrual. The board deferred to the principal investigator on how to enact an orderly termination 
of the study including continued treatment and unblinding of patients. 
Because this is a multi-institutional trial, the IRBs of all institutions participating in this study 
must be informed by the Lead NCI PI about this DSMB’s decision.
Sections throughout the protocol have been revised to reflect that the study is closed to new 
enrollment and to describe the early termination procedures. The revisions include decisions for 
how long participants currently enrolled will remain on study after the unblinding. 
Below are guidelines for unblinding and follow up per Study Arm: 
•
Ancillary Arm 2: For participants assigned to RT+TMZ + Pembrolizumab, they will remain 
on treatment and will be followed for overall survival per Study Calendar.
•
Arm 3: For participants randomized to the RT+TMZ+Pembrolizumab+HSPPC-96 Vaccine, 
they will be unblinded but may remain on  treatment to receive TMZ, Pembro and/or 
HSPPC-96 vaccine and will be followed for overall survival per Study Calendar. 
•
Arm 4: For participants randomized to RT+TMZ+Pembrolizumab+Placebo Vaccine, they 
will be unblinded but may remain on treatment to receive TMZ and/or Pembro and will 
be followed for overall survival per Study Calendar. Placebo vaccine will be discontinued 
as permitted per Section 3.10.
Participants who decide to discontinue treatment will continue to be followed for overall 
survival.
3.2
STUDY DESIGN
This will be a randomized, double blind phase II trial of surgery, RT + TMZ + Pembrolizumab 
followed by TMZ + Pembrolizumab with HSPPC-96 vaccine or placebo vaccine in newly 
diagnosed GBM patients whose tumor has an unmethylated MGMT promoter and is IDH 
wildtype.


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Abbreviated Title: GBM Pembro HSPPC
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Subjects will be randomized without stratification on a 1:1 basis, using variable block sizes. The 
first block will be of size n=6 in order to facilitate the evaluation of toxicity and safety in the first 
3 patients on each arm.
The study will utilize the Recommended Phase 2 Dose (RP2D) for RT + TMZ + Pembrolizumab 
which was TMZ 75 mg/m2, RT approximately 60Gy and Pembrolizumab 200 mg every 3 weeks. 
HSPPC-96 is not expected to result in additional toxicity although the first 3 subjects treated in 
each arm will be observed for toxicity before further enrollment.
The primary endpoint is: 
o
To determine whether the one-year overall survival rate (OS) is improved in newly 
diagnosed GBM patients whose tumor is MGMT promoter unmethylated and is IDH 
wildtype treated with RT + TMZ + Pembrolizumab followed by Pembrolizumab + TMZ 
+ HSPPC-96 vaccine (or placebo vaccine) x 6 cycles (1 cycle is 9 weeks).
Nota Bene: Those patients whose tumor does not meet the criteria (unmethylated MGMT 
promoter and IDH wildtype by pathology) and with < 80% of contrast enhanced tumor or   
< 7grams of tumor resected are ineligible.  
All eligible patients will be treated with standard RT to approximately 60 Gy (180 cGy (1.8 Gy) 
x 33 or 200 cGy (2.0 Gy) x 30).  Initial dose of TMZ during radiation will be 75 mg/m2/day 7 
days per week and Pembrolizumab 200 mg every 3 weeks.
3.2.1
Blinding
This study will utilize a placebo control for the vaccine in order to fulfill the double blind design 
of the study.  This protocol design minimizes the risk of bias and enhances the impartial bias 
analysis of the study vaccine versus placebo effect.  However, it is important to note that in case 
this information is required for safety purposes (affects care or medically needed), it will be 
provided in an expedited manner.  
In this double blind study, neither the study personnel (including pharmacists) nor the subject 
will have knowledge of the vaccine assignment being administered.  Data analysis personnel and 
the Central Registration Office will have access to vaccine assignment.
Blinded vaccine (HSPPC-96 or placebo) will be prepared by Agenus and shipped directly to 
sites.  HSPPC-96 or placebo will be dispensed in identical appearing single-use vial as a clear, 
colorless solution.  Each vial of vaccine or placebo is labeled with the subject/patient number, 
subject/patient initials, and subject/patient date of birth (DOB).
Unblinding may occur at the discretion of the principal investigator and only where knowledge 
of treatment affects patient care.  Site would need to submit the document found in Appendix 
16.11 to request unblinding.  Unblinding will only be done upon approval by the lead PI as 
documented in Appendix 16.12.  
NOTE: Based on the DSMB’s May 2021 decision for early termination, unblinding treatment 
assignments for participants receiving HSPPC-96 vaccine or placebo will be provided to the 
Lead NCI PI by the NCI Central Registration Office (CRO) in consultation with and confirmed 
by Agenus, the vaccine manufacturer. The Lead NCI PI or designee at the BTTC Coordinating 


37
Abbreviated Title: GBM Pembro HSPPC
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Center will be responsible for notifying site PIs (at the participating BTTC site) of the unblinded 
treatment assignments for participants receiving HSPPC-96 vaccine or placebo.  Participants 
receiving pembrolizumab, temozolomide and/or HSPPC-96 vaccine will continue to receive 
those study treatments per Study Calendar (See Section 3.11). Participants who are on placebo 
will stop receiving placebo but may continue to receive pembrolizumab and/or temozolomide per 
Section 3.10.  Participants who decide to discontinue treatment will continue to be followed for 
overall survival, and the procedures for removal from protocol therapy will be followed (see 
Section 3.14).  Off-Study Procedures will be followed per protocol for patients who decide to 
withdraw from the study (see Section 3.14). 
3.2.1.1
Rationale for Double Blinding
This study has been designed to be double blinded despite having an objectively ascertained 
primary endpoint for the following reasons:  (1) This limits study defection due to randomization 
disappointment (so subjects randomized to placebo will not quit the study), (2) there will be no 
difference in the interpretation of biomarkers or lab tests due to knowing the intervention being 
delivered.  (3) Adverse event reporting will not be impacted with the knowledge of the treatment 
arm.  (4) Subject/patient responses in the MDASI will not be impacted with the knowledge of the 
treatment arm. 
3.3
SURGERY & TISSUE COLLECTION FOR VACCINE ADMINISTRATION
3.3.1
Surgery
Patients with presumed GBM based on MRI or if they require a more definitive surgery may be 
consented for the trial.  At the time of surgery, tissue will be collected for vaccine production (≥ 
7 grams is required) and processed per Appendix 16.2 Tumor must be confirmed to be MGMT 
promoter unmethylated and IDH wildtype prior to starting treatment.  
GBM patients whose tumor is MGMT promoter methylated and is not IDH wildtype are not 
eligible for treatment on this protocol and will be removed from the protocol.  
Those patients with < 80% of contrast enhanced tumor resected or < 7 grams of tissue will be no 
longer eligible for treatment with SOC (RT + TMZ) + Pembrolizumab. Tumor will be measured 
per RANO criteria. The determination of ≥ 80% resection will be based on the pre-operative and 
post operative cross sectional measurements, the residual tumor, if any, should be < 20% or 
original cross sectional measurements.
Post tumor resection, all patients must have a post-operative MRI done no more than 72 hours 
after surgery.  This MRI can be used as baseline prior to treatment.    
3.3.2
Tissue Collection for Vaccine Production at NCI
Tumor sample will be collected at time of surgery by the Laboratory of Pathology NCI. Tissue 
sections will be obtained and will be labeled with the Study Subject ID number. The relationship 
between the Study Subject ID number and the patient clinical information will be stored in a 
secure database that is maintained and regularly backed up by the Laboratory of Pathology NCI. 
The Laboratory of Pathology NCI will submit tumor tissue for vaccine manufacture according to 
Appendix 16.2.


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Abbreviated Title: GBM Pembro HSPPC
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Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or 
presence of IDH mutation will remain at or be returned to the site of origin.
Tissue will also be collected at NCI for Correlatives.  Refer to 5.1.2, 5.1.3, and 5.1.4 for tissue 
collection for Correlatives.
Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or 
presence of IDH mutation will remain at or be returned to the site of origin.
3.3.3
Tissue Collection for Vaccine Production at Participating BTTC Sites
Tumor sample will be collected at time of surgery at the participating sites. Tissue sections will 
be obtained and will be labeled with the Study Subject ID number. The participating BTTC site 
will submit tumor tissue for vaccine manufacture according to Appendix 16.2.     
Tumor tissue that does not qualify either because of incorrect diagnosis, MGMT status, or 
presence of IDH mutation will remain at or be returned to the site of origin.
Tissue will also be collected at the participating BTTC sites for Correlatives.  Refer to 5.1.2 and 
5.1.3 for tissue collection for Correlatives.
3.4
RADIATION THERAPY (RT) 
All eligible patients will be treated with standard RT to approximately 60 Gy (180 cGy (1.8 Gy) 
x 33 fractions or 200 cGy (2.0 Gy) x 30 fractions).  
3.5
DRUG ADMINISTRATION 
3.5.1
(RT+TMZ+Pembro) 
TMZ will be administered orally on day 1 of radiation therapy (RT) 1-2 hours before each 
session of radiotherapy or 1 night before RT (within 24 hours before Day 1); and it should be 
administered the same time throughout the course of RT. TMZ should continue throughout RT at 
the dose of 75 mg/m2/day.  During weekends without radiotherapy (Saturday and Sunday), the 
drug will be taken at the same time as on radiotherapy days. 
Pembrolizumab at 200 mg will be administered on day 1 as a 30 minute IV infusion (+/- 24 
hours day of RT) every 3 weeks during RT Phase on days 1, 22 and 43 (+/- 24 hours for each 
timepoint).  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 -10 
minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -10 min/+10 min). 
Observation for one hour after the infusion of the first dose of Pembrolizumab is recommended.  
3.5.2
HSPPC-96 Vaccine or Placebo
HSPPC-96 vaccine will be produced prior to the end of RT.  If > 4 doses can be made, the 
patient will then be randomized 1:1 to the treatment with TMZ + Pembrolizumab with HSPPC-
96 vaccine or placebo.


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3.6
POST RT TREATMENT REGIMEN 
3.6.1
For patients not randomized (ancillary arm 2)
Four weeks post end of RT, an MRI will be performed and then patients will start TMZ (days 1-
5 and 29-33) + Pembrolizumab (days 1, 22 and 43 of each cycle +/- 24 hours for each timepoint). 
1 cycle = 9 weeks.  Please note that if days 1-5 of TMZ is well tolerated, the dose of TMZ will 
be increased for days 29-33 as described below.
The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose 
escalation to 200 mg/m2/day for all subsequent treatment if no treatment-related adverse events 
greater than Grade 2 are noted. 
After completion of 6 cycles, patients may continue on Pembrolizumab for an additional 12 
months if felt to be of benefit by the treating physician. 
NOTE: For early terminationArm 2 ancillary participants that were not randomized and were 
assigned to Arm 2 will continue on treatment andfollowed for overall survival per Study 
Calendar (See Section 3.11).
3.6.2
For patients randomized to vaccine or placebo
One week post end of RT, patients will receive a dose of HSPPC-96 vaccine or placebo vaccine 
given as approximately 0.4mL intradermal weekly x 4 (see Section 14.3.8 details on intradermal 
administration).
Within 7 days of the last dose of HSPPC-96 vaccine or placebo, an MRI will be performed and 
then patients will start TMZ (days 1-5 and 29-33) + Pembrolizumab (days 1, 22 and 43 of each 
cycle +/- 24 hours for each timepoint). 1 cycle = 9 weeks.  
The starting TMZ dose will be 150 mg/m2/day for cycle 1, days 1-5, with a single dose 
escalation to 200 mg/m2/day for all subsequent treatment if no treatment-related adverse events 
greater than Grade 2 are noted. 
HSPPC-96 vaccine or placebo will then be given 21 days (+/- 24 hours) after the day 5 and day 
33 doses of TMZ. TMZ will be given for 6 cycles.  HSPPC-96 vaccine or placebo vaccine will 
be given for 6 cycles or until supply runs out. Patients who receive placebo will be matched for 
number of vaccine injections that were generated by their tumor tissue.  After the completion of 
6 cycles (54 weeks), they may continue pembrolizumab for 12 more months alone or in 
conjunction with HSPPC-96 or placebo vaccine if any is available, if felt to be of benefit by the 
treating physician.
NOTE: Early Termination procedures require that participants randomized to HSPPC-96 or 
placebo be unblinded. Participants randomized to HSPPC-96 vaccine may continue on treatment 
to receive TMZ, Pembro and/or HSPPC-96 vaccine. Patients randomized to placebo vaccine may 
continue on treatment to receive TMZ and Pembro. Placebo vaccine will be discontinued. 
Participants randomized to HSPPC-96 vaccine or placebo will be followed for overall survival 
per Study Calendar (see Section 3.11).


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Abbreviated Title: GBM Pembro HSPPC
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3.7
BASELINE ASSESSMENTS (POST-SURGERY AND PRE-TREATMENT RT+TMZ+PEMBRO)
Prior to RT, once patient has recovered from surgery, all patients will undergo the following 
baseline evaluations or procedures:
•
Karnofsky performance status
•
Physical and Neurological Exam
•
Vital signs and Weight
•
Pregnancy Test
•
PT/INR or aPTT 
•
CBC with differential 
•
Na, K, CL, Bicarbonate, BUN/Cr, AST, ALT, ALP, T. Bili, Calcium, Albumin  
•
Urinalysis
•
T3, T4, and TSH
•
MDASI-BT*
•
Correlative Studies Blood Collection (LabConnect Kit B refer to Appendix 16.3)
•
Baseline tumor imaging (by MRI unless contraindicated) to be performed within 72 
hours after surgery.
*The MDASI-BT (Appendix 16.9) will be administered at time of baseline MRI or up to 14 days 
prior to treatment initiation. 
Baseline assessments can be performed up to 7 days before RT+TMZ+Pembro treatment starts. 
If treatment is delayed (e.g. complications of wound healing, infection), repeat all baseline 
assessments (except for the MDASI-BT and Correlative research blood samples which do not 
need to be repeated). 
3.8
ASSESSMENTS WHILE ON TRIAL DURING AND POST RT
o
Patients will have a physical (including vital signs and weight), KPS, and neurological 
exam every 3 weeks (- 3 days to + 7 days) during RT and then every 4 weeks (+/- 7 days) 
after RT.
o
Patients on ancillary arm do not require vaccine associated physical exam. 
o
Adverse events will be assessed during Physical Exams and on treatment days.
o
For subjects not randomized: An MRI will be done pre surgery, post surgery (within 72 
hours), 4 weeks post RT (+/- 1 week), and then every 9 weeks +/- 1 week.  
o
For subjects who are randomized: An MRI will be done pre surgery, post surgery (within 
72 hours), within 7 days of last dose of vaccine or placebo induction, and then every 9 
weeks +/- 1 week.
o
Pregnancy test will be done at the start of each cycle.
o
A CBC with differential will be done weekly +/- 3 days during RT and then weekly +/- 3 
days after RT for the first year and then every 2 weeks for the year after if the patient 
remains on Pembrolizumab.


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
o
A Comprehensive Chemistry Panel with LFTs and TFTs, T3, T4, TSH will be done on 
day 21 of RT +\- 3 days, at the completion of RT and then day 1 (+/- 1 day) and day 29 (- 
7 days) of each cycle.
o
Blood for correlative labs will be collected for different immune monitoring assessments 
that may include, but are not limited to: whole exome sequencing (WES), immune 
phenotyping of immune cell subsets, functional characterization of immune cell subsets, 
measurement of immune mediators, peripheral lymphocyte, monocyte and tryptophan  
and the assessment of PD-L1 expression and circulating tumor at the following time 
points:  For subjects who are randomized:  Pre-RT treatment (RT+TMZ+Pembro), Post-
RT treatment (RT+TMZ+Pembro)/Pre-vaccine (or placebo) induction, Post Vaccine (or 
placebo) induction/Pre-cycle 1 maintenance, Every Day 1 on Cycle 2, C4, C6, C8 (if 
continuing on Pembrolizumab), then at discretion of Study Chair and BTTC Coordinating 
Center, every other cycle, at time of progression or at end of treatment and for subjects 
not randomized: Pre-RT treatment (RT+TMZ+Pembro), Post-RT treatment 
(RT+TMZ+Pembro)/Pre-cycle 1 maintenance, Every Day 1 on Cycle 2, C4, C6, C8 (if 
continuing on Pembrolizumab); then at discretion of Study Chair and BTTC 
Coordinating Center, every other cycle, at time of progression, or at end of treatment  
(See Study Calendar 3.11). 
o
Archival tissue for PDL1 expression and mutation analysis will be collected after surgery 
irrespective of whether the patient is randomized or not.
o
If a patient has tumor progression while on trial and undergoes surgery, patients will have 
their tumor evaluated for PDL1 expression and repeat mutational analysis.
3.8.1
Questionnaires
The MDASI-BT will be administered prior to the initiation of radiation, temozolomide and 
pembrolizumab (baseline) prior to initiation of adjuvant therapy and then at the time of each 
evaluation that also includes imaging.  Of note, every attempt should be made to administer the 
MDASI-BT prior to informing the patients about the results of the imaging study. The MDASI-
BT will be completed only by the patient, unless changes in vision or weakness make this 
difficult. If this occurs, then the caregiver or research assistant may read the questions to the 
patient or assist with marking the severity number or score as described by the patient. A 
caregiver may complete the questionnaires as a patient proxy if the patient’s deficits preclude 
self-report; however, this must be done at every assessment from baseline to end of treatment. 
Full instruments are provided in the Appendix 16.9.  In addition, information regarding 
demographics and treatment history will be collected as part of the larger study and used in this 
analysis.   
The MDASI-BT consists of symptoms rated on an 11-point scale (0 to 10) to indicate the 
presence and severity of the symptom, with 0 being “not present” and 10 being “as bad as you 
can imagine.” Each symptom is rated at its worst in the last 24 hours. Symptoms included on the 
instrument include those commonly associated with cancer therapies, those associated with 
increased intracranial pressure, and those related to focal deficits.  The questionnaire also 
includes ratings of how much symptoms interfered with different aspects of a patient’s life in the 
last 24 hours. These interference items include: general activity, mood, work (includes both work 
outside the home and housework), relations with other people, walking, and enjoyment of life. 


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Abbreviated Title: GBM Pembro HSPPC
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The interference items are also measured on 0 - 10 scales. The average time to complete these 
instruments is 5 minutes. The MDASI-BT has been translated into multiple languages, but the 
English language version will be used for this study. [43]
3.9
TELEHEALTH/REMOTE VISITS 
In the extenuating event that a subject cannot travel to be seen in person at the study site, or any 
other crisis causing travel and staffing restriction, the provider assessment may occur via 
telehealth visits. Telehealth visits (synonyms: telemedicine, videoconferencing, virtual visits, 
video phone call or remote visits) will be allowed for patients on-study unless these visits are 
essential to maintaining patient safety while on-study, refer to study calendar section 3.11 for 
more details.  Decisions regarding the use of telehealth will be based on the patient’s physician’s 
decision regarding the risk of an in-person clinic visit compared with the potential benefit of a 
comprehensive in-person evaluation. The medical record or progress note for the telehealth visit 
should state that the risks were greater than the benefit.
Telehealth visits for clinical assessments will be conducted in compliance with local guidelines 
and FDA regulations.  For example, to ensure privacy, the patients will confirm their identities 
before the interaction or exchange of private information begins; guidance on this issue can be 
found in the National Institute of Standards and Technology (NIST) Digital Identity Guidelines, 
Special Publication 800-63A —Enrollment and Identity Proofing Requirements When 
Developing an Identity Verification Plan.  In addition, documentation of telehealth visits must 
comply with local requirements (e.g., date and time of the real-time video interaction, location of 
the subject, individuals present, assessments performed, etc.).
General interviews may be conducted adequately via telehealth visits. For example, to obtain a 
patient’s medical history, check-in with a participant regarding their current health status, or to 
administer a questionnaire to a participant related to their level of functioning or activities of 
daily living. 
Clinical assessments via telehealth visits for patients on study will not compromise either the 
primary or secondary objectives and will likely have minimal impact on the ability to complete 
this study as long as administration of treatment (e.g., radiation, temozolomide, pembrolizumab 
and vaccine/placebo) is not compromised.  Given that the study requires only standard, clinical 
laboratory assessments and imaging per routine radiologic parameters/procedures, any possible 
interlaboratory or facility variability is not expected to be a concern.  If any question about 
possible progression, a patient may be asked to have repeat imaging and/or additional 
assessments to confirm response. 
Further, a patient may be referred to another local provider or asked to come to the NIH for an 
in-person assessment, if clinically indicated, and at the discretion of the investigator.  In the case 
of any visits with participants’ local providers, records will be obtained for the research records. 
The following clinical assessments generally obtained during a physical examination (i.e., 
H&P) can be conducted via telehealth visits through discussion and remote/video 
observation: 
•
Karnofsky Performance Status.


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
•
Neurological exam to assess cognition remotely will use the American Academy of 
Neurology Telemedicine guidance document for evaluation of memory, attention, 
concentration, language, eye movements, facial weakness, strength, walking and 
coordination. 
•
Physical exam to observe rashes, thrust, surgical scar, and swelling will use the American 
Academy of Dermatology Teledermatology guidance document for physical evaluation 
during telehealth vistis. 
The following clinical assessments are not feasible via telehealth visits:
•
Hearing and vision 
•
Listening to your heart and lungs 
•
Assessing weakness
•
Checking reflexes 
•
Checking for abnormalities in sensation 
•
Feeling lymph nodes, areas of swelling 
3.10 DOSE MODIFICATIONS
If Pembrolizumab and/or HSPPC-96 are stopped or discontinued, the patient can continue 
treatment on TMZ alone.  If TMZ is stopped or discontinued, Pembrolizumab or HSPPC-
96/placebo can continue. If HSPPC-96/Placebo is stopped or discontinued, TMZ and 
Pembrolizumab can continue. 
3.10.1 Pembrolizumab Dose Modifications
Adverse events (AE) (both non-serious and serious) associated with pembrolizumab exposure, 
including coadministration with additional compounds, may represent an immunologic etiology. 
These immune-related adverse events (irAEs) may occur shortly after the first dose or several 
months after the last dose of treatment and may affect more than one body system 
simultaneously. Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per  Table 1: Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab.  
See Section  3.10.3 for supportive care guidelines, including use of corticosteroids.
3.10.1.1 Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to a 
single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event [to the combination, to Temozolomide alone or to pembrolizumab alone, for 
adverse events listed in [Table 1], both interventions must be held according to the criteria in 
[Table 1 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse 
Events Associated with Pembrolizumab].


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
3.10.1.2 Holding Study Interventions:
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications.
3.10.1.3 Restarting Study Interventions:
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in [Table 1].
•
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions.
If the toxicities do resolve and conditions are aligned with what is defined in [Table 1], the 
combination of temozolomine and pembrolizumab may be restarted at the discretion of the 
investigator.[In these cases where the toxicity is attributed to [the combination or to 
temozolomine alone, re-initiation of pembrolizumab as a monotherapy may be considered at the 
principal investigator’s discretion .


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
Table 1: Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General 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.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
•  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
Diarrhea/Colitis 
Grade 2 or 3
Withhold
•  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) 


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 3 or 
Grade 4
Permanently 
discontinue
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
Grade 2 a
Withhold
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
•  Administer corticosteroids (initial dose of 
1 to 2 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)
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
Withhold d
•  Initiate insulin replacement therapy for 
participants with T1DM
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
evidence of 
-cell failure
•  Administer antihyperglycemic in 
participants with hyperglycemia
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold or 
permanently 
discontinue d
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold or 
permanently 
discontinue d
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
•  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
•  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according to 
increased 
creatinine or 
acute kidney 
injury
Grade 3 or 4
Permanently 
discontinue
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
•  Monitor changes of renal function
Grade 2
Withhold


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Version Date:   06/25/2025
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
•  Based on severity of AE administer 
corticosteroids
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
•  Based on severity of AE administer 
corticosteroids
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Suspected SJS, 
TEN, or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, or 
DRESS
Permanently 
discontinue
•  Based on severity of AE administer 
corticosteroids
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
•  Based on severity of AE administer 
corticosteroids
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes
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: Non-irAE will be managed as appropriate, following clinical practice recommendations.


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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
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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3.10.2 Guidelines for Drug-Related Adverse Events due to Pembrolizumab  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Study Chair. The reason for 
interruption should be documented in the patient's study record.
3.10.3 Pembrolizumab Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse events 
with potential immunologic etiology are outlined below. Where appropriate, these guidelines 
include the use of oral or intravenous treatment with corticosteroids as well as additional anti-
inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note 
that several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab. 
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). Refer to Section 3.10 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
•
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.
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.
•
Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  
o
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 


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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.
•
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
For T1DM or Grade 3-4 Hyperglycemia
▪
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 
▪
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
•
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.
•
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated based 
on clinical evaluation) and for clinical signs and symptoms of thyroid disorders.
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.


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•
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.
•
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. 
•
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. 
Refer to Infusion Reaction Treatment Guidelines Appendix 16.8 for subjects who experience 
an infusion reaction associated with administration of pembrolizumab.
3.10.4 Temozolomide Dose Modifications
NOTE: TMZ dose is modified ONLY if toxicity is specifically attributed to TMZ.
TMZ can be delayed at the beginning of a cycle (e.g., C2D1) and then restarted when the reason 
for a delay has resolved. If TMZ is held (e.g., for toxicity) at mid-cycle (e.g., C2D29) it can be 
delayed up to 2 weeks. When TMZ is restarted, for example, 1 week later (e.g., D36) the cycle 
date entered in the CRF will automatically be labelled as D36, not D29; please enter a comment 
in the CRF that TMZ was held for X amount of days. 
If during a TMZ dosing period, there is a drop in ANC to < 1.5 or platelets < 75 000 a dose 
reduction should occur in the subsequent cycle. See tables.
RT Phase
Dose level
Temozolomide dose
Dose reduce to
0 (starting dose)
75 mg/m2
60 mg/m2
-1b
60 mg/m2
50 mg/m2
-2b
50 mg/m2
40 mg/m2


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Abbreviated Title: GBM Pembro HSPPC
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Post RT phase
Dose level
Temozolomide dose
Dose reduce to
0
(starting dose for cycle 2 and 
beyond)
200 mg/m2
150 mg/m2
-1
(starting dose for cycle 1)
150 mg/m2
125 mg/m2
-2
125 mg/m2
100 mg/m2
3.10.5 HSPPC-96/Placebo Dose Modifications
For grade 1 or 2 reactions considered related to HSPPC-96/Placebo, manage symptoms 
according to institutional procedures. Continue on study. 
For grade 3 or 4 allergic reactions considered related to HSPPC-96/Placebo, discontinue HSPPC-
96/Placebo.
3.10.6 Vaccine Injection Site Reactions
For grade 1 or 2 injection site reactions, continue on study; make sure to rotate injection sites as 
instructed in Administration Section 14.3.8.  Manage symptoms according to institutional 
procedures. 
For grade 3 or 4 injection site reactions, discontinue HSPPC-96/Placebo. 
For other grade 1 or 2 non-hematologic toxicity, continue on protocol once toxicity is 
resolved to < grade 1. 
For other grade 3 or 4 non-hematologic toxicity considered at least possibly related to 
HSPPC-96, discontinue HSPPC-96/Placebo. 


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3.11 STUDY CALENDAR
Screening7
Treatment
Follow Up
Time Period
Pre-
Surgery 
Screening
RT + TMZ +
Pembrolizumab16
TMZ+Pembrolizumab 
+/- HSPPC-96/Vaccine 
(6 cycles)
End of Treatment 
or Discontinuation
Long-term
Follow-up
8
Scheduling Window 
(Days)
+/-14 of 
signing 
consent
Surgery
- 7
(before treatment)
HSPPC-96/Vaccine
Induction or Break14
(4 weeks)
- 7
(before treatment)
+/- 3
30 days 
after last 
dose
Every 8-16 
weeks
Informed Consent
X
Medical history
X
Prior & concomitant 
medications review
X
Assess and 
document first post-
protocol treatment 
X
Assess and 
document Adverse 
Events
12
X
12
X
12
X
12
X 
X
Physical, KPS & 
neurological exam
13
X
X
13
X
13
X
13
X
X
Vital Signs and 
Weight
1
X
X
X
X
X
X
Pregnancy test
2
X
X
2
X
2
X
2
PT/INR or aPTT
X
X
CBC with diff
X
X
4
X
4
X
4
X
X
Comprehensive 
Chemistry panel
9 
X
X
5
X
5
X
5
X
Urinalysis
X
X
T3, T4, and TSH
X
5
X
5
X
5
X
X
Tumor Imaging
3
X
X3
X3
X3
X
X
Archival or 
Collection Tumor 
X
MDASI-BT11
X
X
X
X
Correlative Studies 
Blood Collection
X6
X6
X6
X6


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Abbreviated Title: GBM Pembro HSPPC
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Screening7
Treatment
Follow Up
Time Period
Pre-
Surgery 
Screening
RT + TMZ +
Pembrolizumab16
TMZ+Pembrolizumab 
+/- HSPPC-96/Vaccine 
(6 cycles)
End of Treatment 
or Discontinuation
Long-term
Follow-up
8
Scheduling Window 
(Days)
+/-14 of 
signing 
consent
Surgery
- 7
(before treatment)
HSPPC-96/Vaccine
Induction or Break14
(4 weeks)
- 7
(before treatment)
+/- 3
30 days 
after last 
dose
Every 8-16 
weeks
Drug Administration
X15
X10
X10
Assess and 
document Survival 
Status
X
1 Includes vital signs (pulse, respirations, blood pressure) and height (baseline only) and weight.
2 Serum or urine test for females of child-bearing potential prior to the start of RT+TMZ+Pembro and at the start of every cycle. 
3 By MRI (unless contraindicated): For subjects not randomized: An MRI will be done pre surgery, post surgery (within 72 hours), 4 
weeks post RT, and then every 9 weeks +/- 1 week.  For subjects who are randomized: An MRI will be done pre surgery, post surgery 
(within 72 hours), within +/- 10 days of last dose of vaccine or placebo induction, and then every 9 weeks +/- 1 week. This schedule of 
MRIs is consistent with standard of care.
4 A CBC with differential will be done weekly during RT and then weekly after RT for the first year and then every 2 weeks for the 
year after if the patient remains on Pembrolizumab.
5 Chemistry should be done at beginning of RT, Day 21 of RT +/- 3 days, at completion of RT, and on Days 1(+/- 1 day) and Day 29 
(- 7 days) of each cycle. 
6 Randomized - 8x8mL CPT blue and black top tubes (LabConnect Kit B) will be used to collect correlative blood samples at the 
following time points for patients randomized to study vaccine or placebo: 1) Pre-RT treatment (RT+TMZ+Pembro) 2) Post-RT 
treatment (RT+TMZ+Pembro)/Pre-vaccine (or placebo) induction 3) Post Vaccine (or placebo) induction/Pre-cycle 1 maintenance 4) 
Every Day 1 on Cycle 2, C4, C6, C8 (if continuing on Pembrolizumab); then, at discretion of Study Chair and BTTC Coordinating 
Center, every other cycle; 5) At time of progression or at End of Treatment.
Ancillary - 8x8mL CPT blue and black top tubes (LabConnect Kit B) will be used to collect correlative blood samples at the following 
time points for patients not randomized (ancillary cohort): 1) Pre-RT treatment (RT+TMZ+Pembro) 2) /Pre-cycle 1 maintenance 3) 
Every Day 1 on Cycle 2, C4, C6, C8 (if continuing on Pembrolizumab); then, at discretion of Study Chair and BTTC Coordinating 
Center, every other cycle 4) At time of progression, or at End of Treatment.
7 Screening labs will be completed within (+/-) 14 days of signing consent. 
8 Patients will be followed for overall survival. Patients withdrawn from treatment will follow the same schedule.
9 Comprehensive Serum Chemistry panel=Na, K, CL, Bicarbonate, BUN/Cr, AST, ALT, ALP T. Bili, Calcium, Albumin.


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10 HSPPC-96 Vaccine/Placebo given weekly post RT x 4 weeks, then 21 days (+/- 24 hours) after the day 5 and day 33 doses of TMZ 
of each cycle. TMZ doses Cycle 1, days 1-5 at 150 mg/m2. If tolerated, the dose will be escalated to  200 mg/m2 for all remaining 
doses (This would begin with Cycle 1 days 29-33.). Pembrolizumab dosed on day 1, 22, and 43 (+/- 24 hours for each timepoint) of 
RT then day 1, 22, 43 (+/- 24 hours for each timepoint) of each 9 week cycle.  
11 MDASI-BT assessments will take place along with imaging studies. MDASI-BT will need to be given prior to informing the 
patients about the results of the imaging study, within +/- 1 week of the MRI assessment date. 
12 Assess patients for adverse events during Physical Exam and treatment days.
13 Physical, KPS and neurological exam every 3 weeks (- 3 days to + 7 days) during RT and then every 4 weeks (+/- 7 days) after RT.  
If needed, telehealth assessments will be allowed for the physical, KSP & neurological exams. For additional details on allowed 
telehealth assessments, please see Section 3.9. 
14 For those not randomized (ancillary arm), no drug administration during the 4 weeks prior to Pembro and TMZ, therefore no 
laboratory tests or scheduled assessments are required.
15 TMZ may be given night before RT (within 24 hours before day 1).
16 Baseline assessments will be done prior to the start of RT+TMZ+Pembro (see 3.7).


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3.12 SURGICAL GUIDELINES
Surgical guidelines will be according to Standard of Care at each institution.
3.13 COST AND COMPENSATION 
3.13.1 Costs
Subjects costs will be based on local guidelines as described in the site specific consent.
3.13.2 Compensation
Participants will not be compensated on this study.
3.13.3 Reimbursement 
Reimbursement is based on site policy.
At the NCI site, the NCI will cover the costs of some expenses associated with protocol 
participation.  Some of these costs may be paid directly by the NIH and some may be reimbursed 
to the participant/guardian as appropriate.  The amount and form of these payments are 
determined by the NCI Travel and Lodging Reimbursement Policy.
3.14 CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA
Patients can be taken off the protocol therapy and/or study as a whole at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. 
Prior to documenting removal from study, effort must be made to have all subjects complete a 
safety visit approximately 30 days following the last dose of study therapy.  The following 
evaluation will occur:
•
KPS
•
Toxicity Assessment
•
Physical & Neurological Exam
•
Vital Signs and Weight
•
CBC with Diff, Comprehensive Chemistry Panel, T3, T4, and TSH
•
Tumor Imaging
•
MDASI-BT
•
Correlative Blood Collection
3.14.1 Criteria for Removal from Protocol Therapy
The reason(s) for discontinuation must be clearly documented on the appropriate eCRF and may 
include:
•
Patient voluntarily withdraws from treatment (follow-up permitted)
•
Patient demonstrates disease progression after beginning treatment 
•
Patient experiences unacceptable toxicity
•
Treating physician determines that continuation with treatment on the study would not be 
in the patient’s best interest


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•
Patient develops a second malignancy that requires treatment which would interfere with 
this study 
•
Patient becomes pregnant
•
Patient completes treatment as outlined in section 3.3
•
Screen failure
3.14.2 Off Study Criteria
The reason(s) for discontinuation must be clearly documented on the appropriate eCRF and may 
include:
•
Screen failure
•
Tumor is identified as a methylated MGMT promoter 
•
Tumor is not IDH wildtype by pathology
•
Investigator decision to end study
•
Patient withdraws consent (no follow-up permitted)
•
Patient is unable to comply with protocol requirements
•
Patient becomes lost to follow-up (LTF)
•
Death
3.14.3 Lost to Follow-up
A participant will be considered lost to follow-up if he or she fails to return for 3 scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
•
The site will attempt to contact the participant and reschedule the missed visit within 24 
hours, and reschedule within 7 days and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain if the participant wishes to and/or 
should continue in the study.
•
Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record or study file. 
•
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.
4
CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & 
PROHIBITED)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  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 investigator should discuss any questions regarding this with 


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the coordinating center. The final decision on any supportive therapy or vaccination rests with 
the investigator and/or the subject's primary physician.
4.1
ACCEPTABLE CONCOMITANT MEDICATIONS
All treatments that the investigator considers necessary for a subject’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 8.1. 
4.2
PROHIBITED CONCOMITANT MEDICATIONS
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:
•
Antineoplastic systemic chemotherapy or biological therapy 
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab and HSPPC-96
•
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. 
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. The 
exception is for cerebral edema, but dose should be < 4 mg once treatment begins.
•
Bevacizumab can be used to control edema, but not as a biologic treatment intended for 
the patient’s disease under study. 
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial.  Subjects may receive 
other medications that the investigator deems to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.


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4.3
DIET/ACTIVITY/OTHER CONSIDERATIONS
4.3.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting.
4.3.2
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects 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).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative medical 
cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not using 
hormonal contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
o
intrauterine device (IUD)
o
vasectomy of a female subject’s male partner 
o
contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
o
diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
o
cervical cap with spermicide (nulliparous women only)  
o
contraceptive sponge (nulliparous women only) 


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o
male condom or female condom (cannot be used together)
o
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception 
if it is consistently employed as the subject’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence (e.g., calendar, 
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable 
methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study subjects of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study.
5
BIOSPECIMEN COLLECTION
5.1
CORRELATIVE STUDIES FOR RESEARCH/PHARMACOKINETIC STUDIES
The purpose of the correlative studies is to determine if there is a correlation with clinical 
outcome of PD1 or PDL1 expression and T-Cell infiltrate in pathology from first, and if 
applicable, second surgical specimens with outcome.
o
To assess tumor tissue for neo-antigens (initial tumor pathology).
o
To collect peripheral monocytes for PD-L1 levels to confirm that low level expression 
leads to better outcome and if higher levels that are treated with Pembrolizumab might 
improve outcome. To perform other immune monitoring assessments including, but are 
not limited to: whole exome sequencing (WES), immune phenotyping of immune cell 
subsets, functional characterization of immune cell subsets, measurement of immune 
mediators and the assessment of circulating tumor DNA (ctDNA).
o
To correlate MGMT and IDH status with outcome (local pathology report).
At each timepoint noted in the study calendar, correlative blood will be collected in 8 
mononuclear cell preparation tubes (LabConnect Kit B, 8mL CPT™ blue and black top tubes) 
and processed for the isolation of both PBMCs and plasma.  As detailed in the LabConnect lab 
manual, Correlative blood will be collected at NCI and participating BTTC sites and sent to:
NCI Frederick Lab
Leidos Biomedical Research


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
Attn:  Theresa Burks
1050 Boyles Street
Bldg. 469/Room 121
Frederick, MD 21702
Phone 301-846-5125, or 301-846-6865
Email: burkst@mail.nih.gov, cc: jon.inglefield@nih.gov
5.1.1
Collection of correlative blood time points:
NOTE: The schedule of correlative blood sample collection should be held/delayed when 
treatment dosing is held. See section 5 Biospecimen Collection, and at the end of Table 1, and/or 
the calendar. 
For participants randomized to study vaccine or placebo:
1) Pre-RT treatment (RT+TMZ+Pembro)
2) Post-RT treatment (RT+TMZ+Pembro)/Pre-vaccine (or placebo) induction
3) Post Vaccine (or placebo) induction/Pre-cycle 1 maintenance
4) Every Day 1 on Cycle 2, C4, C6, C8 (if continuing on Pembrolizumab); then, at discretion 
of Study Chair and BTTC Coordinating Center, every other cycle
5) At time of progression or at end of treatment
For participants not randomized (ancillary cohort 3):
1) Pre-RT treatment (RT+TMZ+Pembro)
2) Pre-cycle 1 maintenance
3) Every Day 1 on Cycle 2, C4, C6, C8 (if continuing on Pembrolizumab); then, at discretion 
of Study Chair and BTTC Coordinating Center, every other cycle
4) At time of progression or at end of treatment
LabConnect (Fee for Service Provider) will supply kits and track shipments for correlative blood 
collection.  (See LabConnect lab manual.)
5.1.2
PD-L1 expression on tumor cells
A collection of sectioned slides from tumor samples for the purpose of immunohistochemical 
(IHC) analysis will be sent for PD-L1 analysis at the end of the study. Sectioned slides from 
formalin-fixed, paraffin-embedded (FFPE) samples will be stained for the biomarker(s) of 
interest, and then evaluated by a pathologist for review of biomarker staining expression levels.
This sample will be taken at time of surgery. At the end of the study, the BTTC CC Research 
Nurse will contact the participating site to request the slides.  
5.1.3
Tissue will be interrogated by Next Generation Sequencing for tumor antigens 
Generation of the HSPPC-96 vaccine requires > 7 grams of tissue. All available tumor aside 
from what will be used for routine pathologic studies and diagnosis should be sent for HSPPC-96 
vaccine preparation. At the end of the study, up to 18 FFPE unstained slides (formalin fixed 


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paraffin embedded) may be collected. If subsequent tumor biopsies are obtained, including at 
time of progression, additional tissue specimens may be collected following the same method 
described above.  These tissue collections for next generation sequencing are at the 
investigator’s discretion.  
The FFPE Tumor Tissue Slide specimens are maintained at room temperature and shipped 
ambient by the site upon request by BTTC Coordinating Center to:
Attn: BTTC Coordinating Center Research Nurse Coordinator
NCI / Neuro-Oncology Branch / Brain Tumor Trials Collaborative
National Institutes of Health
Building 82 , Room 215
Bethesda, MD 20892
Phone: 240-858-7083 
Email: ukeme.ikiddeh-barnes@nih.gov
5.1.4
Tissue Collection at NCI
Tumor samples will be collected at time of surgery by the Laboratory of Pathology NCI. Tissue 
sections will be obtained and will be labeled with the Study Subject ID number. The relationship 
between the Study Subject ID number and the patient clinical information will be stored in a 
secure database that is maintained and regularly backed up by the Laboratory of Pathology NCI.
The Laboratory of Pathology at NCI will process the tissue samples per Appendices 16.2, 16.3, 
16.4, 16.5. 
5.1.5
Sample Storage, Tracking and Disposition
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that 
are remaining at the completion of the protocol will be stored in the conditions described below. 
The study will remain open so long as sample or data analysis continues.  Samples from 
consenting subjects will be stored until they are no longer of scientific value or if a subject 
withdraws consent for their continued use, at which time they will be destroyed. 
If the patient withdraws consent the participant’s data will be excluded from future distributions, 
but data that have already been distributed for approved research use will not be able to be 
retrieved.
The PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will 
be per the requirements of section 7.2.
5.2
SAMPLES FOR GENETIC/GENOMIC ANALYSIS
5.2.1
Scope of the analysis
Patients’ tissue specimens will be analyzed for exploratory tumor-derived biomarkers. Assays 
performed may include, but are not limited to: a) immunohistochemistry (IHC) of FFPE samples 
to determine the frequency of tumor infiltrating lymphocytes (TILs) such as CD8 T cells and 
CD4 regulatory T cells, as well as the expression of predictive biomarkers such as PD-L1; b) 
whole exome sequencing (WES) and transcriptome analysis (RNAseq) of flash frozen/OCT 


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samples to evaluate mutational burden and expression of neo-epitopes; and c) functional and 
phenotypic characterization of vitally frozen immune cell subsets.
5.2.2
Certificate of Confidentiality 
As part of study efforts to provide confidentiality of subject information, this study has obtained 
a Certificate of Confidentiality, which helps to protect personally identifiable research 
information. The Certificate of Confidentiality allows investigators on this trial to refuse to 
disclose identifying information related to the research participants, should such disclosure have 
adverse consequences for subjects or damage their financial standing, employability, insurability 
or reputation. The informed consent includes the appropriate coverage and restrictions of the 
Certificate of Confidentiality.
5.2.3
Incidental Findings
Subjects will be contacted if a clinically actionable gene variant is discovered. Clinically 
actionable findings for the purpose of this study are defined as disorders appearing in the 
American College of Medical Genetics and Genomics recommendations for the return of 
incidental findings that is current at the time of primary analysis. (A list of current guidelines is 
maintained on the CCR intranet: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Incidental+Findings+Lists).  Subjects will 
be contacted at this time with a request to provide a blood sample to be sent to a CLIA certified 
laboratory. If the research findings are verified in the CLIA certified lab, the subject will be 
offered the opportunity to come to NIH (at our expense) to have genetic education and 
counseling to explain this result.  If the subject does not want to come to NIH, a referral to a 
local genetic healthcare provider will be provided (at their expense). Subjects enrolled at 
participating BTTC sites will be referred to a local genetics health care provider.  
This is the only time during the course of the study that incidental findings will be returned. No 
interrogations regarding clinically actionable findings will be made after the primary analysis.
6
DATA COLLECTION AND EVALUATION 
6.1
DATA COLLECTION
The PI will be responsible for overseeing entry of data into a 21 CFR Part 11-compliant data 
capture system provided by the NCI CCR and ensuring data accuracy, consistency and 
timeliness. The MDASI-BT Survey responses will be entered by study subjects directly into 
Scribe/Labmatrix.  The principal investigator, associate investigators/research nurses and/or a 
contracted data manager will assist with the data management efforts. All data will have 
identifiers so that research data can be attributed to an individual human subject participant.
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event.   Such 
events will be recorded at each examination on the Adverse Event case report forms/worksheets. 
The investigator will make every attempt to follow all subjects with non-serious adverse events 
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For the time period beginning at treatment initiation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject 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 study treatments, must be 
reported.
6.1.1
Exceptions to Data Collection
Adverse events that occur after the consent form is signed but before treatment (RT, 
Pembrolizumab, TMZ) must be collected by the investigator only if they cause the subject to be 
excluded from the trial. Sites (NCI or participating BTTC sites) will be responsible for entering 
data collected at their site.
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, onset of menses or menopause occurring at a 
physiologically appropriate time.
An abnormal laboratory value will be considered an AE if the laboratory abnormality is 
characterized by any of the following:
•
Results in discontinuation from the study
•
Is associated with clinical signs or symptoms 
•
Requires treatment or any other therapeutic intervention
•
Is associated with death or another serious adverse event, including hospitalization. 
•
Is judged by the Investigator to be of significant clinical impact
•
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome.
End of study procedures: Data will be stored according to HHS, FDA regulations and NIH 
Intramural Records Retention Schedule as applicable. 
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1. 
6.1.2
Source Documentation Timeframes
The following information will be entered into a 21 CFR Part 11-compliant data capture system 
provided by the NCI CCR and Scribe/Labmatrix within the indicated timeframes. In addition, the 
source documents should be provided to the BTTC Coordinating Center’s Research Nurse at 
secure fax: 240-541-4432, encrypted email, or Secure Email and File Transfer  within the 
indicated timeframe. The MDASI-BT responses will be entered by study subjects directly into 
Scribe/LabMatrix.
Data Set / Source Documents
Schedule for Submission
Regulatory Documents
(as described in the BTTC Operations Manual)
Prior to Step 1 of registration


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Data Set / Source Documents
Schedule for Submission
Registration Form (eligibility checklist) 
Within 24 hours of signing Informed 
Consent (Step 1 registration)
Following surgery and confirmation of 
diagnosis (Step 2 registration)
Prior to end of RT in order to randomize 
subject (Step 3 registration)
Copy of signed & dated Informed Consent w/ 
HIPAA Authorization 
Within 24 hours of signing Informed 
Consent (Step 1 registration)
Pathology Report (from the most recent pre-
registration diagnostic biopsy or surgery)
At time of Step 2 of registration
Baseline MDASI – BT Questionnaire
Within 14 days (+ 3 working days) after 
enrollment
Screening/Baseline Source Documents
At time of registration (step 1 or 2, as 
applicable)
Other Source Documents 
With Participant Status Updates Form
6.1.3
Database Entry Timeframes
The following data should be entered into a 21 CFR Part 11-compliant data capture system 
provided by the NCI CCR and Scribe/Labmatrix within the specified timeframes.  Source 
documentation will be kept at the participating site.
Sites (NCI or participating BTTC sites) will be responsible for entering data collected at their 
site.


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Data Set
Schedule for Data Entry
Screening data
Within 14 days of Step 1 Registration
Baseline data
No later than 14 days after Day 1 of radiation 
(RT cycle)
Treatment (Course/Cycle) Data
(To include treatment, response, AE, and 
clinical evaluation information)
Course initiation case report form (CRF) no 
later than 7 days after the cycle begins
All other course/cycle CRFs must be entered 
no later than 21 days after the cycle is 
complete
Off Treatment Data
Within 21 days after the:
•
last date of any modality of protocol 
treatment; or,
•
study discontinuation visit.
Follow-up (Survival) Data
(To include post-protocol treatment and long-
term follow up survival data)
Note: Long-term follow up is required every 8-
16 weeks for two years until patient is off 
study.
No later than 21 days after follow up visit or 
survival call or post-treatment medication 
begins.
Non-Treatment Data
(May include Quality of Life questionnaires 
(MDASI-BT), Specimen Tracking information, 
Pathology Specimen Submission, etc.)
Within 10 days after each scheduled 
assessment, event, or activity
Off Study Data
No later than 21 days after the date the 
patient is removed from the study.
6.1.4
Confidentiality
All documents, investigative reports, or information relating to the patient are strictly 
confidential. Any source documents submitted to the BTTC Coordinating Center with protected 
health information or personally identifiable information (e.g. patient’s name) must be sent via 
Secure Email and File Transfer (SEFT) or secure fax.  For NIH only, documents can also be sent 
via hand-delivery or encrypted email.  
6.1.5
Safety Data
All patients receiving study agents will be evaluated for safety.  The safety parameters include all 
laboratory tests and hematological abnormalities, CNS observations, physical examination 
findings, and spontaneous reports of adverse events reported to the investigator by patients.  
Life-threatening toxicities that are unexpected and assessed to be possibly related to the study 
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Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and followed as 
appropriate. 
Medical conditions/diseases present before starting study treatment are only considered adverse 
events if they worsen after starting study treatment (any procedures specified in the protocol). 
Adverse events occurring before starting study treatment but after signing the informed consent 
form are recorded on the Baseline Evaluations Case Report Form. 
6.1.6
Data Monitoring
All submitted data will be monitored by the BTTC Clinical Research Nurse specifically assigned 
to this protocol.  Requests for correction of data deficiencies will be sent via emailed to the 
Institutional Coordinator.  Any major deficiencies will be corrected by telephone and email 
communication.  All data will be monitored for completeness.  Key parameters such as drug 
dosages including attenuations and escalations, toxicity documentation and tumor measurements 
will be analyzed.  All data deficiencies will be corrected within two weeks.
6.2
DATA SHARING PLANS
6.2.1
Human Data Sharing Plan
What data will be shared?
I will share human data generated in this research for future research as follows: 
•
Coded, linked data in an NIH-funded or approved public repository.  
•
Coded, linked data in another public repository.  
•
Coded, linked data in BTRIS (automatic for activities in the Clinical Center)
•
Coded, linked or identified data with approved outside collaborators under appropriate 
agreements.
How and where will the data be shared? 
Data will be shared through:
•
An NIH-funded or approved public repository:  clinicaltrials.gov.
•
BTRIS (automatic for activities in the Clinical Center)
•
Approved outside collaborators under appropriate individual agreements.
•
Publication and/or public presentations.
When will the data be shared? 
•
Before publication.
•
At the time of publication or shortly thereafter.
6.2.2
Genomic Data Sharing Plan
Unlinked genomic data will be deposited in public genomic databases such as dbGaP in 
compliance with the NIH Genomic Data Sharing Policy.


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6.3
RESPONSE CRITERIA
6.3.1
Definitions
6.3.1.1
Evaluable for toxicity:  All patients will be evaluable for toxicity from the time of their 
first treatment with Pembrolizumab and/or HSPPC-96.
6.3.1.2
Evaluable for objective response: Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their 
disease re-evaluated will be considered evaluable for response.  These patients will have 
their response classified according to the definitions stated below.  (Note:  Patients who 
exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.)
6.3.1.3
Evaluable Non-Target Disease Response:  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received 
at least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.
6.3.2
Disease Parameters
6.3.2.1
Measurable disease:  Based on RANO criteria  [44]
6.3.3
RANO Criteria for Response
Table 2: RANO Criteria for Response
RANO Criteria for Response [44]
CR
PR
SD
PD
T1 gadolinium enhancing disease
None
≥ 50% ↓
< 50% ↓ but 
< 25% ↑
≥ 25% 
T2/FLAIR
Stable or ↓
Stable or ↓
Stable or ↓
↑1
New lesion
None
None
None
Present
1
Corticosteroids
None
Stable or ↓
Stable or ↓
n/a†
Clinical status
Stable or ↑
Stable or ↑
Stable or ↑
↓1
Requirement for response
All
All
All
Any1


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RANO Criteria for Response [44]
CR
PR
SD
PD
1 Progression occurs when this criterion is present
†Increase in corticosteroids alone will not be taken into account in determining progression in the 
absence of persistent clinical deterioration.
↓ = decreased, ↑ = increased,
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease. If PD is 
unclear based on white matter changes, patients may be kept on trial.
FLAIR, fluid-attenuated inversion recovery; NA, not applicable.
6.3.4
iRANO (Exploratory)[45]
Table 3: iRANO


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6.3.5
Evaluation of Best Overall Response
6.3.5.1
Duration of overall response: The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started).
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented.
6.3.5.2
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.
6.3.6
Dose Limiting Toxicity 
Any of the following adverse events not due to disease progression or any underlying disease 
will be documented as a DLT during the first 4 weeks of treatment with Pembrolizumab, TMZ 
and HSPPC-96/Placebo (attribution should be assigned to drug most suspected) during the first 
post RT cycle, after completion of induction:
•
Grade 4 neutropenia for more than 7 days
•
Grade 3 or 4 febrile neutropenia during the first 4 weeks
•
Grade 3 or 4 thrombocytopenia for more than 7 days
•
Grade 4 anemia for more than 7 days
•
Grade 3 or 4 non-hematologic adverse events. 
•
Exceptions include:
•
Grade 3 nausea, vomiting or diarrhea will only be considered a DLT if not adequately 
managed with maximum supportive care within 48 hours.
•
More than 14 days of treatment delay due to the failure to recover from attributable 
toxicity.
Subjects experiencing irAEs due to Pembrolizumab and are successfully treated for toxicity, 
and able to be re-dosed will not be considered to have experienced DLTs. The frequency, grade, 
and nature of irAE will be recorded.
6.3.7
Progression-Free Survival
Progression free survival will be defined from the time of registration to the time of confirmed 
progression.  In cases where this might be unclear, patients may continue on trial.  
6.3.8
Overall survival
Defined as the time from registration to the time of death 
6.3.9
Response Review
Response review will be done locally and by Study Chair if response is questionable.


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6.4
TOXICITY CRITERIA
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE 
reporting.  An investigator who is a qualified physician will evaluate all adverse events 
according to (CTCAE), version 5.0. 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.
All appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  A copy 
of the CTCAE version 5.0 can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm ). 
7
NIH REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN
7.1
DEFINITIONS
Please refer to definitions provided in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.2
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING
7.2.1
Expedited Reporting
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. Note: Only IND Safety 
Reports that meet the definition of an unanticipated problem will need to be reported per these 
policies.
7.2.2
IRB Requirements for NCI PI Reporting at Continuing Review
Please refer to the reporting requirements in Policy 801: Reporting Research Events found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements. 
7.3
NCI CLINICAL DIRECTOR REPORTING 
NIH site only:
Problems expeditiously reviewed by the OHSRP in the NIH eIRB system will also be reported to 
the NCI Clinical Director/designee; therefore, a separate submission for these reports is not 
necessary.  


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In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to 
progressive disease.  
To report these deaths, please send an email describing the circumstances of the death to 
NCICCRQA@mail.nih.gov within one business day of learning of the death.
7.4
NCI GUIDANCE FOR REPORTING EXPEDITED ADVERSE EVENTS FOR MULTI-CENTER 
TRIALS
The site PI (at the participating BTTC site) must immediately report to the BTTC Coordinating 
center PI any serious adverse event, whether or not considered drug related, including those 
listed in the protocol or investigator brochure and must include an assessment of whether there is 
a reasonable possibility that the drug caused the event within 24 hours of PI awareness of the 
event.  
CCR Reportable Event Form (REF) will be used to submit Serious Adverse Events to both the 
CCR Office of Sponsor and Regulatory Oversight at OSROSafety@mail.nih.gov  and the BTTC 
Coordinating Center. https://ccrod.cancer.gov/confluence/display/CCRCRO/Templates
Participating BTTC sites must also report events to the Reviewing IRB as per its policy. 
For IND studies, the site PI will also directly submit reports to the CCR as IND sponsor per 
section 8.3. Please also notify the coordinating center PI and study coordinator of your 
submission at the time you make it. 
The BTTC Coordinating Center will maintain documentation of all Serious Adverse Events from 
each institution. The BTTC Coordinating Center will notify all investigators of any serious and 
unexpected adverse experiences that are possibly related to the study agent/s.  The investigators 
are to file a copy with their protocol file and send a copy to their IRB according to their local 
IRB’s policies and procedures.
•
For the time period beginning when the consent form is signed until treatment initiation, 
any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause that occurs to any subject must be reported within 24 hours to the Sponsor 
(NCI) if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.  
•
For the time period beginning at treatment initiation through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject 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 
study treatments, must be reported within 24 hours to the Sponsor (NCI).
•
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to study treatment 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 the Sponsor.


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All subjects with serious adverse events must be followed up for outcome.
7.4.1
Reporting Deviations and Unanticipated Problems for Multi-Center Trials
Deviation or Unanticipated Problem Reports and any accompanying documentation (to include 
the local IRB acknowledgement of the event when applicable) are to be submitted by the 
participating BTTC site to the BTTC Coordinating Center using the CCR Reportable Event 
(REF) Form in Appendix 16.10 by email nci_bttc@mail.nih.gov or via fax at: 240-541-4432.
Deviations or Unanticipated problems must be submitted to the BTTC Coordinating Center 
within 5 days after becoming aware of the event. When Deviations or Unanticipated Problems 
are reported to BTTC, but, the local IRB does not require a report, the report that is submitted to 
the BTTC Coordinating Center must be accompanied by a formal memo explaining the local 
policy and the rationale for not reporting the event to the local IRB.
Neither the FDA nor the ICH GCP guidelines define the term “protocol deviation.”  The 
definition is often left to the Lead Institution IRB.  Accordingly, since NCI, Center for Cancer 
Research is the Coordinating Center and the Lead PI must adhere to those policies set by the 
NIH Intramural IRB, the definitions for unanticipated problem and protocol deviation as 
described by the NIH Intramural IRB will be applied for reporting purposes for all institutions 
participating in this study. Definitions are listed in Section 7.1.
Protocol Deviations or Unanticipated problems occurring at a participating institution will be 
submitted to that institution’s own IRB in accordance with local policies and procedures.   
However, the participating institution must submit a report to the BTTC Coordinating Center 
even in instances where the local IRB does not require a report. 
NCI Center for Cancer Research BTTC Coordinating Center:  Upon receipt of the 
deviation/unanticipated reportable event report from the participating institution, the BTTC 
Coordinating Center will submit the report to the Study Chair for review. Subsequently, the 
participating institution’s IRB deviation/unanticipated reportable event report will be submitted 
to the NIH Intramural IRB if it meets the criteria under Policy 801: Reporting Research Events 
found at: 
https://irbo.nih.gov/confluence/pages/viewpage.action?pageId=36241835#Policies&Guidance-
800Series-ComplianceandResearchEventReportingRequirements.
7.5
NIH REQUIRED DATA AND SAFETY MONITORING PLAN
The clinical research team will have a teleconference every other week when patients are being 
actively treated on the trial to discuss each patient. 
All data will be collected in a timely manner and reviewed by the Principal investigator or a lead 
associate investigator. Events meeting requirements for expedited reporting as described in 
section 7.2.1 will be submitted within the appropriate timelines. 
The Principal Investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The Principal Investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.


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7.5.1
Data Safety Monitoring Board (DSMB)
As this is a prospective, double-blinded, randomized controlled trial, the NCI/CCR DSMB will 
be used to monitor the trial. This monitoring will be done for futility, as well as for safety. Since 
the meetings of the NCI DSMB are annual, futility monitoring may be performed by the DSMB 
at a special meeting requested by the study team.   These ad-hoc DSMB meetings may convene 
by phone in the event of rapid accrual. 
The interim data analyses needed for the DSMB futility monitoring will be performed by the 
BTTC biostatistician.
Subjects will be randomized without stratification on a 1:1 basis, using variable block sizes. The 
first block will be of size n=6 in order to facilitate the evaluation of toxicity and safety in the first 
3 patients on each arm. 
The futility monitoring will be performed as follows:  at the first DSMB meeting after which 22 
patients have been enrolled into each of the experimental arms, given an experimental arm, 
(i) if 16 or more patients survive at 8 months, additional 23 patients will be enrolled into that 
arm; 
(ii) if 7 or more patients fail to survive at 8 months, the experimental arm will be terminated 
early. 
If neither of these two conditions are satisfied, in other words, some patients are followed less 
than 8 months and their survival at 8 month is unknown, the posterior probability Pr(OS8 < 0.75 
| data) will be evaluated using the method of Cai, Liu and Yuan (2014) [48]. If Pr(OS8 < 0.75 | 
data) > 0.6, the experimental arm will be terminated early; otherwise additional 23 patients will 
be enrolled into that arm. Note that this posterior stopping rule is consistent with rules (i) and 
(ii). Interim outcome results will not be revealed to the investigators of the trial; results will be 
presented to the investigators prior to final accrual to the trial only if the DSMB recommends 
early termination of the trial.    The DSMB will review the rules for early termination for toxicity 
and provide feedback to the BTTC Biostatistician, the Study Chair, and lead PI who will confirm 
the condition for early termination. Once confirmed, the Biostatistician will then communicate to 
CRO (Central Registration Office) to break the blind and provide the listing to the BTTC 
Biostatistician and Study Chair.  
The evaluation for safety will be performed independently for each of the two experimental arms 
as follows: 
For each of the experimental arms, stop the enrollment if [# of patients with DLT]/[# of 
patients evaluated] ≥ 2/3, 4/6, 5/10 or 8/20; otherwise continue the enrollment.
In the case that one arm is discontinued due to futility or safety, enrollment would shift to the 
remaining arm as the primary objective of this trial is not to compare two arms. 
7.5.2
Patient-Reported Outcomes
Received MDASI-BT forms will be checked versus the timing schedule and considered as valid 
if they fall within  14 days of the scheduled assessment window.  Compliance rates will be 
calculated as the number of received valid forms over the number of expected forms. Differences 
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We will use descriptive statistics to describe how patients rate symptom severity and interference 
with function at each time point.  Error bar graphs for each of the symptoms will be constructed 
at each time point.  The proportion of patients rating their symptoms to be 5 or greater (on a 0-10 
scale) will also be reported.  We will construct individual patient profiles for each of the selected 
symptoms to describe the individual patients’ patterns of change over time. We will calculate the 
mean symptom severity and mean symptom interference at the time of clinical evaluation. 
Estimates of differences in the mean symptom severity and mean symptom interference between 
responders and non-responders will be estimated in the intent to treat population.  All patients 
with at least one valid questionnaire will be included in the analyses.  Questionnaires completed 
at study registration will be considered baseline.  All questionnaire data received after 
randomization will be used in the primary analyses.
Differences of at least 2 points will be classified as the minimum clinically meaningful change in 
the symptom severity and symptom interference measures. For example, an increase of 2 points 
or more would mean a moderate improvement, whereas a decrease of 2 points or more would be 
interpreted as moderate worsening. For individual symptoms, a rise in a symptom score means 
deterioration, whereas a reduced score means improvement of the specific symptom.
7.6
EXPLORATORY OBJECTIVES & ENDPOINTS
PDL1 expression and T-Cell infiltrate in tumor will be correlated using Spearman correlation 
coefficients. Peripheral T-Cell activation and tryptophan metabolites will be summarized by 
reporting descriptive statistics such as median and inter-quartile range for all time points. 
8
SPONSOR PROTOCOL/SAFETY REPORTING
8.1
DEFINITIONS
8.1.1
Adverse Event
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An adverse event (AE) can therefore be unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease, temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product (ICH E6 (R2)).
8.1.2
Serious Adverse Event (SAE)
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following:
•
Death,
•
A life-threatening adverse event (see section 8.1.3)
•
Inpatient hospitalization or prolongation of existing hospitalization
o
A hospitalization/admission that is pre-planned (i.e., elective or scheduled surgery 
arranged prior to the start of the study), a planned hospitalization for pre-existing condition, 
or a procedure required by the protocol, without a serious deterioration in health, is not 
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o
A hospitalization/admission that is solely driven by non-medical reasons (e.g., 
hospitalization for patient or subject convenience) is not considered a serious adverse 
event. 
o
Emergency room visits or stays in observation units that do not result in admission to the 
hospital would not be considered a serious adverse event. The reason for seeking medical 
care should be evaluated for meeting one of the other serious criteria.
•
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions
•
A congenital anomaly/birth defect.
•
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.
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, these events are considered serious by 
Merck for collection purposes.
•
Is a new cancer (that is not a condition of the study);
•
Is associated with an overdose.
Refer to Section 8.1.1  “Adverse Events” for additional details regarding each of the above 
criteria.
8.1.2.1
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Immediate Reporting of Adverse Events to the Sponsor (NCI), unless there is evidence 
suggesting a causal relationship between the drug and the event. Any such event will be 
submitted to the Merck within 24 hours.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
Hospitalization related to convenience (e.g. transportation issues, etc.) will not be considered a 
SAE.
8.1.3
Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. (21CFR312.32)
8.1.4
Severity
The severity of each Adverse Event will be assessed utilizing the CTCAE version 5.


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8.1.5
Relationship to Study Product
All AEs will have their relationship to study product assessed using the terms:  related or not 
related.  
•
Related – There is a reasonable possibility that the study product caused the adverse 
event. Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event.
•
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event.
8.1.6
Events Of Clinical Interest (ECI) For This Trial Include:
•
an overdose of Merck product, as defined in Section 8.1.7 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. 
•
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.
8.1.7
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
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. Appropriate supportive treatment should be provided if clinically 
indicated. In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met.
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 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 within 24 hours to 
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8.2
ASSESSMENT OF SAFETY EVENTS
AE information collected will include event description, date of onset, assessment of severity 
and relationship to study product and alternate etiology (if not related to study product), date of 
resolution of the event, seriousness and outcome. The assessment of severity and relationship to 
the study product will be done only by those with the training and authority to make a diagnosis 
and listed on the Form FDA 1572 as the site principal investigator or sub-investigator.  AEs 
occurring during the collection and reporting period will be documented appropriately regardless 
of relationship.  AEs will be followed through resolution.
SAEs will be:
•
Assessed for severity and relationship to study product and alternate etiology (if not 
related to study product) by a licensed study physician listed on the Form FDA 1572 as 
the site principal investigator or sub-investigator.
•
Recorded on the appropriate SAE report form, the medical record and captured in the 
clinical database.
•
Followed through resolution by a licensed study physician listed on the Form FDA 1572 
as the site principal investigator or sub-investigator.
For timeframe of recording adverse events, please refer to section 6.1. All serious adverse events 
recorded from the time of first investigational product administration must be reported to the 
sponsor with the exception of any listed in section 8.4. 
8.3
REPORTING OF SERIOUS ADVERSE EVENTS
Any AE that meets protocol-defined serious criteria or meets the definition of Adverse Event of 
Special Interest that require expedited reporting must be submitted immediately (within 24 hours 
of awareness) to OSRO Safety using the CCR SAE report form. Any exceptions to the expedited 
reporting requirements are found in section 8.4.
All SAE reporting must include the elements described in section 8.2.
SAE reports will be submitted to the NCI Center for Cancer Research (CCR) at: 
OSROSafety@mail.nih.gov and to the BTTC PI and study coordinator.  CCR SAE report form 
and instructions can be found at: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions
Following the assessment of the SAE by OSRO, other supporting documentation of the event 
may be requested by the OSRO Safety and should be provided as soon as possible.
8.4
SAFETY REPORTING CRITERIA TO THE PHARMACEUTICAL COLLABORATORS 
8.4.1
To be Sent by OSRO Safety
OSRO Safety will only provide the following: SAEs, SUSARs, overdoses and pregnancies.  
OSRO Safety will not send routine AEs or periodic reports. 


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8.4.2
To be Sent by BTTC study team
8.4.2.1
Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events.
8.4.2.2
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate 
length of time and units.
8.4.2.3
Action taken 
Did the adverse event cause Merck product to be discontinued?
8.4.2.4
Relationship to Merck Product
Did Merck product cause the adverse event? The determination of the likelihood that Merck 
product caused the adverse event will be provided by an investigator who is a qualified 
physician. The investigator’s signed/dated initials on the source document or worksheet that 
supports the causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in 
assessing the likelihood of a relationship between the test drug and the adverse event based upon 
the available information.
The following components are to be used to assess the relationship between Merck product and 
the AE; the greater the correlation with the components and their respective elements (in number 
and/or intensity), the more likely Merck product caused the adverse event (AE):
8.4.2.5
Exposure
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, 
acceptable compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or 
measurement of drug/metabolite in bodily specimen?
8.4.2.6
Time Course
Did the AE follow in a reasonable temporal sequence from administration of Merck product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with 
investigational medicinal product)?
8.4.2.7
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
8.4.2.8
 Dechallenge
Was Merck product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.


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(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 Sponsor’s product; or (3) the trial is a 
single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
8.4.2.9
Rechallenge
Was the subject re-exposed to Merck product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor’s 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 MERCK PRODUCT, OR IF 
REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL.
8.4.2.10 Consistency with Trial Treatment Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding 
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 Merck product relationship).
1. Yes, there is a reasonable possibility of Merck product relationship. There is 
evidence of exposure to Merck product.  The temporal sequence of the AE onset relative 
to the administration of Merck product is reasonable.  The AE is more likely explained by 
Merck product than by another cause.
2. 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 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.)
8.4.3
Events of Clinical Interest
These selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be reported within 24 hours to Merck. For reporting of ECI refer to 
section 8.3.
For the time period beginning when the consent form is signed until treatment initiation, any 
ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 hours to the 


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Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
For the time period beginning at treatment initiation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to study 
treatment, must be reported within 24 hours to the Sponsor (NCI).
Merck Global Safety facsimile number:  +1-215-993-1220 (Sponsor [NCI] will contact Merck)
8.4.4
Reporting Serious Adverse Events to Merck and Agenus
Upon receipt, Sponsor (NCI) will forward SAE reports and any other relevant safety information 
to the Merck Global Safety facsimile number:  +1-215-993-1220 and to Agenus 
Pharmacovigilance via email: adverse.events@agenusbio.com or fax: 1-781-674-4261.
A copy of all 15 Day Reports and Annual Progress Reports will be submitted to Merck & Co., 
Inc. (Attn: Worldwide Product Safety; FAX 215 993-1220) and to Agenus Pharmacovigilance 
(email: adverse.events@agenusbio.com or fax: 1-781-674-4261) at the time of submission to 
FDA.
For the time period beginning at treatment initiation through 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the subject initiates new anticancer 
therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related to study 
treatment, must be reported within 24 hours to the Sponsor (NCI).
Sites will submit all reportable events to the Sponsor (NCI), and NCI will submit to Agenus and 
Merck within 2 working days. 
The DSMB Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data 
to ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety and Agenus 
Pharmacovigilance as a SAE within 2 working days of determination that the event is not 
progression of the cancer under study.
For reporting pregnancy: The designated Sponsor representative will work with the investigator 
to ensure that all relevant information is provided to Merck and Agenus within 1 to 5 calendar 
days for SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.5
REPORTING PREGNANCY
All required pregnancy reports/follow-up to OSRO will be submitted to: 
OSROSafety@mail.nih.gov and to the CCR PI and study coordinator.  Forms and instructions 
can be found here: 
https://ccrod.cancer.gov/confluence/display/CCRCRO/Forms+and+Instructions.
8.5.1
Maternal exposure
If a participant becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately, and the pregnancy reported to the Sponsor no later than 24 hours of 


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when the Investigator becomes aware of it. The Investigator should notify the Sponsor no later 
than 24 hours of when the outcome of the Pregnancy becomes known,
Pregnancy itself is not regarded as an SAE. However, congenital abnormalities or birth defects 
and spontaneous miscarriages that meet serious criteria (section 8.3) should be reported as SAEs. 
The outcome of all pregnancies should be followed up and documented.
8.5.2
Paternal exposure
Male participants should refrain from fathering a child or donating sperm during the study and 
for 120 days after the last dose of pembrolizumab.
Pregnancy of the participant’s partner is not considered to be an AE. The outcome of all 
pregnancies occurring from the date of the first dose until 120 days after the last dose should, if 
possible, be followed up and documented. Pregnant partners may be offered the opportunity to 
participate in an institutional pregnancy registry protocol (e.g., the NIH IRP pregnancy registry 
study) to provide data about the outcome of the pregnancy for safety reporting purposes.
8.6
REGULATORY REPORTING FOR STUDIES CONDUCTED UNDER CCR SPONSORED IND
Following notification from the investigator, CCR, the IND sponsor, will report any suspected 
adverse reaction that is both serious and unexpected in expediated manner to the FDA in 
accordance to 21 CFR 312. 32.  CCR will report an AE as a suspected adverse reaction only if 
there is evidence to suggest a causal relationship between the study product and the adverse 
event.  CCR will notify FDA and all participating investigators (i.e., all investigators to whom 
the sponsor is providing drug under its INDs or under any investigator’s IND) in an IND safety 
report of potential serious risks from clinical trials or any other source, as soon as possible, in 
accordance to 21 CFR Part 312.32. 
All serious events will be reported to the FDA at least annually in a summary format.
9
CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure:
•
that the rights of the participants are protected; 
•
that the study is implemented per the approved protocol, Good Clinical Practice and 
standard operating procedures; and, 
•
the quality and integrity of study data and data collection methods are maintained.  
Monitoring for this study will be performed by NCI CCR Office of Sponsor and Regulatory 
Oversight (OSRO) Sponsor and Regulatory Oversight Support (SROS) Services contractor. 
Clinical site monitoring activities will be based on OSRO standards, FDA Guidance E6(R2) 
Good Clinical Practice: Integrated Addendum to ICH E6(R1) March 2018, and applicable 
regulatory requirements.
Details of clinical site monitoring will be documented in a Clinical Monitoring Plan (CMP) 
developed by OSRO. CMPs will be protocol-specific, risk-based and tailored to address human 
subject protections and integrity of the study data. OSRO will determine the intensity and 
frequency of monitoring based on several factors, including study type, phase, risk, complexity, 


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expected enrollment rate, and any unique attributes of the study and the site. The Sponsor will 
conduct a periodic review of the CMP to confirm the plan's continued appropriateness. A change 
to the protocol, significant or pervasive non-compliance with GCP, or the protocol may trigger 
CMP updates.
OSRO SROS Monitoring visits and related activities will be conducted throughout the life cycle 
of each protocol. The first activity is before the study starts to conduct a Site Assessment Visit 
(SAV) (as warranted), followed by a Site Initiation Visit (SIV), Interim Monitoring Visit(s) 
(IMVs), and a study Close-Out Visit (COV).
Some monitoring activities may be performed remotely, while others will occur at the study site(s). 
Monitoring visit reports will describe visit activities, observations, and associated action items or 
follow-up required for resolution of any issues, discrepancies, or deviations. Monitoring reports 
will be distributed to the study PI, NCI CCR QA, CCR Protocol Support Office, coordinating 
center (if applicable), and the Sponsor regulatory file.
The site Monitor will inform the study team of any deviations observed during monitoring visits. 
If unresolved, the Monitor will request that the site Staff enter the deviations in the CCR Protocol 
Deviation Tracking System (PDTS) for deviation reporting to the Sponsor and as applicable per 
institutional and IRB guidance.
10 STATISTICAL CONSIDERATIONS  
This is a phase II blinded, randomized trial in newly diagnosed GBM. Evaluable patients must 
complete 1 cycle of treatment post RT. A Bayesian two-stage design will be used to monitor the 
efficacy of two experimental arms independently based on the OS at 8 months (OS8) using the 
following Bayesian rule (Thall and Simon, 1994) [46]:
Stop the experimental arm for futility if Pr (OS8 < 0.75 | data ) > 0.6.
That is, if the observed data indicate that there is greater than 60% chance that the OS8 is smaller 
than 0.75, we stop the experimental arm. We choose 0.75 as the threshold because that is the 
estimate of OS8 for the standard of care (RT+TMZ). In order to speed up the trial, we use the 
OS8, rather than the OS at 12 months (i.e., the primary endpoint), for the purpose of interim 
monitoring. Assuming vague Beta prior Beta (0.25, 0.25) for the OS8, the two-stage Bayesian 
design can be described as follows:
Enroll 22 patients for each of the experimental arms, if 16 or more patients 
survive at 8 months, we continue to enroll the remaining 23 patients; otherwise 
stop that experimental arm. 
At the interim analysis, if some patients are followed less than 8 months, we will calculate Pr 
(OS8 < 0.75 | data) based on the methodology of Cai, Liu and Yuan (2014) by imputing the OS8 
for these patients. The following table shows the operating characteristics of the Bayesian phase 
II design:
True OS8
0.6
0.7
0.8
0.9


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Stopping probability
0.845
0.507
0.135
0.004
Average sample size
25.6
33.3
41.9
44.9
Similar Bayesian method will also be used to monitor the rate of DLT. We monitor two 
experimental arms independently-patients that are randomized. Specifically, for each of the arms, 
we will stop enrolling patients and inspect the safety data if the Pr(DLT > 25% | data) > 0.9. That 
is, we will stop enrolling patients if the data indicate that there is more than 90% chance that the 
true DLT rate is higher than 25%. This decision rule gives the following stopping rule, assuming 
a Beta(0.1, 0.4) prior distribution for DLT rate, 
Stop enrolling pts if [# of pts with DLT] / [# of pts evaluated] ≥ 2/3, 4/6, 5/10 or 8/20.
Below are the operating characteristics of the toxicity monitoring rule.
True toxicity rate
0.1
0.2
0.3
0.4
0.5
Early stop 
probability
0.028
0.136
0.372
0.692
0.906
Average 
sample size
27.3
25.0
20.6
14.9
9.8
In the case that one arm is discontinued due to futility or safety, enrollment would shift to the 
remaining arm as the primary objective of this trial is not to compare two arms. 
10.1 SAMPLE SIZE AND ACCRUAL
Based on previous experience of newly diagnosed (ND) unmethylated GBM patients treated 
with Pembrolizumab, the estimated one-year OS for the RT+TMZ+Pembrolizumab arm is 
70%, and the estimated one-year OS for the RT+TMZ+Pembrolizumab +HSPPC-96 arm is 
90%. Given one-sided significance level of 0.10, the sample size of 45 patients per arm 
provides 80% power to detect the difference between two experimental arms. 
Treatment accrual for the randomization arms will be 90 patients (45 patients per arm). 
Considering vaccine production failures  for patients when HSPPC-96 is not produced, accrual 
in the ancillary cohort is up to 18 patients.  Therefore, the randomized treatment accrual ceiling 
will be 108 patients. Assuming a screen failure rate of 65%, the total accrual ceiling will be 310 
patients. 
Approximately 8 potentially eligible patients are seen per month, and it is anticipated that at least 
1-2 per month will be accrued per site. NOTE: DSMB recommended in May 2021 to terminate 
study early due to slow accrual. Study is closed to enrolment. Patients will be unblinded but will be 
kept on treatment  until completion of TMZ, Pembro, and/or HSPPC-96 and followed for overall 
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10.2 DATA ANALYSES PLANS
Progression-free and overall survival will be determined using a Kaplan-Meier survival curve. 
Median PFS and OS will be determined from this curve. A one-sided lower 90% confidence 
limit for median PFS and OS will be determined by the method of Brookmeyer and Crowley 
[47]. The Chi-square test will be used to compare the one-year OS between two experimental 
arms. In addition, the weighted log rank test will also be used to compare the OS and PFS 
between two experimental arms. 
10.3 SECONDARY OBJECTIVES & ENDPOINTS
•
PFS-6 (percentage of subjects alive and progression-free at 6 months post-registration): 
determined from the value of the Kaplan-Meier curve at 6 months.
•
Response rate: determined as described by RANO Table 2. Rates and 95% confidence 
intervals will be determined using exact binomial probability distributions.
•
Overall survival: Kaplan-Meier curves will be used to analyze overall survival.
•
OS-6, 12 and 24 (overall survival at 6, 12, and 24 months post-registration, respectively): 
determined from the level of the Kaplan-Meier curves at these time points.
•
Safety of Pembrolizumab in GBM: Adverse events will be described descriptively by 
giving frequencies of each event by type, severity, frequency, timing, and attribution.
•
To evaluate the occurrence of symptoms and correlate to disease progression and 
tolerance to treatment using the MD Anderson Symptom Inventory-Brain Tumor Module 
(MDASI-BT).  
11 COLLABORATIVE AGREEMENTS
11.1 AGREEMENT TYPE
There is a BTTC consortia agreement in place between all of the participating institutions listed 
in the NIH IRB system.  In addition, there are CRADA agreements in place with Merck (03128), 
and Agenus (03127) who are supporting this study.  
Transfers that are associated with correlative studies conducted under an approved protocol: 
Investigators in the NIH intramural program may participate in multi-site clinical trials (either as 
a site or as the coordinating center) under which human materials are transferred from the 
intramural program to another site for correlative studies that are part of the approved protocol. 
In such a situation, the protocol clearly documents the tests conducted under the correlative 
studies, and each institution participating in the clinical study is bound by the terms of their 
Protocol and their obligations under the statutes and regulations.  In addition, intramural 
protocols are cleared by the IC Clinical Director.  In such a situation, use of an HM-MTA is not 
necessary for these transfers.
11.2 MULTI-INSTITUTIONAL GUIDELINES
11.2.1 Participating Institution Site Initiation
Before an institution may begin participating in a BTTC protocol, they must complete the 
following steps:


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•
Submit all required regulatory documents to the BTTC Coordinating Center
•
Participate in a site initiation visit, webcast, or conference call
•
Receive training regarding study specific CRF’s and/or databases
After these requirements have been fulfilled, the participating institution will receive by fax, e-
mail, or hard copy, a Site Activation Memo. Once the Site Activation Memo has been received, 
the participating institution may begin to register patients to the protocol.
11.2.2 IRB Approvals 
The lead PI will provide the NIH Intramural IRB with a copy of the participating institution’s 
initial approval and approved yearly continuing review.  Registration will be halted at any 
participating institution in which a current continuing approval is not on file at the NIH 
Intramural IRB.
12 HUMAN SUBJECTS PROTECTIONS 
12.1 RATIONALE FOR SUBJECT SELECTION
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects.  Males and females will be recruited with no preference to 
gender.  No exclusion to this study will be based on race.  Minorities will actively be recruited to 
participate.  High grade gliomas occur in patients of all races and although there is a slight 
predominance in men, this is a disease that is also common in women.  The molecular targets of 
pembrolizumab and HSPPC-96 within the tumor are not known to be different among patients 
based on gender or race; hence this study will be open to all adults.
12.2 PARTICIPATION OF CHILDREN
Individuals under the age of 18 will not be eligible to participate in this study because they are 
unlikely to have glioblastoma, and because of unknown toxicities of the study agents in the 
pediatric patient.  Furthermore, the targets of pembrolizumab and HSPPC-96 are not as prevalent 
in pediatric malignant gliomas and therefore, the efficacy of this regimen will be initially 
determined in the adult population before consideration of its use in pediatrics.
12.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT (NCI)
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. In circumstances where the subject becomes decisionally impaired due to 
disease progression, the subject will be taken off-treatment per protocol, but may continue in 
long term follow-up.  In long term follow-up, the risks associated with study related 
interventions are no more than minimal.
However, because in other circumstances, there is a prospect of direct benefit from research 
participation, all subjects ≥ age 18 will be offered the opportunity to fill in their wishes for 
research and care, and assign a substitute decision maker on the “NIH Advance Directive for 
Health Care and Medical Research Participation” form so that another person can make 
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impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to 
Consent Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and 
to identify an LAR, as needed. Please see section 12.6.1 for consent procedure.  
12.4 PARTICIPATION OF ADULTS UNABLE TO GIVE CONSENT (BTTC)
Each institution will follow their own procedure for re-consenting subjects unable to re-consent 
and will notify the Coordinating Center at time of continuing review of these occurrences.
12.5 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS
12.5.1 Risks
12.5.1.1 Study Agents
The primary risk to patients participating in this research study is from the toxicity of 
pembrolizumab or HSPPC-96 or all drugs as described in section 14 and the consent document.   
Pembrolizumab and HSPPC-96 are investigational agents in the treatment of gliomas.  The 
protocol provides for detailed and careful monitoring of all patients to assess for toxicity.  
Toxicity data from the current dose level will be collected and reviewed to ensure that there were 
no severe toxicities that would preclude further patient enrollment.  Patients will be treated with 
therapeutic intent and response to the therapy will be closely monitored. 
12.5.1.2 Imaging risks
The MRIs to be done in this study will involve contrast.  The risks associated with MRIs and 
contrast are discussed in the consent form.
Although MR imaging with gadolinium has been used as part of the standard care for patients 
with high grade gliomas, long term toxicities of gadolinium as a consequence of gadolinium 
accumulation in the body has been reported. All investigators will ascertain the MR imaging 
history of all prospective study participants to determine the extent of prior exposure to 
gadolinium contrast.  Radiology will be consulted if there is a history of repeated gadolinium 
exposure.
12.5.1.3 Blood Collection
The risk of blood draws in this study is that it may cause pain, bleeding, and/or bruising.  The 
risks associated with blood collection are discussed in the consent form. Participants may faint 
and/or develop an infection with redness and irritation of the vein at the site where blood is 
drawn. Frequent blood collection may cause anemia (low red blood cell count), which may 
create a need for blood transfusions.
12.5.1.4 Questionnaires
The risk of questionnaires in this study is that they may contain questions sensitive in nature. 
Participants may refuse to answer any question that makes them feel uncomfortable.  The 
primary use of the information collected is to assess the severity of symptoms related to study 
treatment. Submission of this information is voluntary.  
12.5.1.5 Non-Physical Risks of Genetic Research
12.5.1.5.1 Risk Of Receiving Unwanted Information


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Anxiety and stress may arise as a result of the anticipation that unwanted information regarding 
disease related DNA sequencing or disease tendencies, or misattributed paternity. Patients will 
be clearly informed that the data related to DNA sequencing and genetic analysis is coded, 
investigational and will not be shared with patients, family members or health care providers.
12.5.1.5.2 Risk Related To Possibility That Information May Be Released
This includes the risk that data related to genotype, DNA sequencing or risk for disease tendency 
or trait can be released to members of the public, insurers, employers, or law enforcement 
agencies. Although there are no plans to release results to the patients, family members or health 
care providers, this risk will be included in the informed consent document.
12.5.2 Benefits
The potential benefit to a patient on this study is a reduction in the bulk of their tumor and 
improvement in cancer lesions, which may or may not have favorable impact on symptoms 
and/or survival.  
12.6 CONSENT PROCESS AND DOCUMENTATION
The informed consent document will be provided as a physical or electronic document to the 
participant or consent designee as applicable, for review prior to consenting.  A designated study 
investigator will carefully explain the procedures and tests involved in this study, and the 
associated risks, discomforts, and benefits. In order to minimize potential coercion, as much time 
as is needed to review the document will be given, including an opportunity to discuss it with 
friends, family members and/or other advisors, and to ask questions of any designated study 
investigator. A signed informed consent document will be obtained prior to entry onto the study.
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other site approved remote platforms used in compliance with 
policy, including HRPP Policy 303)   per discretion of the designated study investigator and with 
the agreement of the participant/consent designee(s).  Whether in person or remote, the privacy 
of the subject will be maintained. Consenting investigators (and participant/consent designee, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant/consent designee will be informed of the private nature of 
the discussion and will be encouraged to relocate to a more private setting if needed.
Note: When required, witness signature will be obtained similarly as described for the investigator 
and participant as described below.
Consent will be documented with required signatures on the physical document (which includes 
the printout of an electronic document sent to participant.  Signatures on electronic documents 
are described below.  Note: FDA only regulates electronic signatures (i.e., an electronic 
timestamp is generated at the time of signature) in FDA regulated research.  
Manual (non-electronic) signature on electronic document:
When a manual signature on an electronic document is used for the documentation of consent at 
the NIH Clinical Center, this study will use the Adobe platform (which is not 21 CFR Part 11 
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During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations.  
Both the investigator and the subject will sign the document using a finger, stylus or mouse. 
Electronic signature on electronic document:
When permitted by the NIH Clinical Center, an electronic signature may be obtained using the 
iMedConsent platform to obtain the required signatures.
During the consent process, participants and investigators will view individual copies of the 
approved consent document on screens at their respective locations.  
The identity of the participant will be determined by a prompt which will require the provision of 
information from a form of government-issued identification prior to obtaining the signature.  If 
participant does not have such identification available, security questions will be used to confirm 
identity.
Both the investigator and the subject will sign the document electronically per system prompts.
For BTTC Participating multicenter sites:
Each institution will follow their own local procedure for electronic signature requirements at 
participating site. 
12.6.1 Consent Process for Adults Who Lack Capacity to Consent to Research 
Participation
For NIH participants addressed in section 12.3, an LAR will be identified consistent with Policy 
403 and informed consent obtained from the LAR, as described in Section 12.6. 
12.6.2 Request for Waiver of Consent for Screening Activities
Prior to the subject signing the consent for this study pre-screening activities listed in section 
2.2.1 may be performed. 
We request a waiver of consent for these activities as they involve only minimal risk to the 
subjects.  A waiver will not adversely affect the rights and welfare of the subjects given that the 
activities are only intended to determine suitability for screening for participation in research 
protocols.  These activities could not practicably be carried out without the wavier as central 
recruiting services, utilized in the NIH Clinical Center, perform pre-screening activities for 
multiple studies and obtaining consent for each one is beyond their resources.  The subjects will 
be provided with additional pertinent information after participation as they will be informed 
whether or not they are eligible to sign a consent for additional screening.
12.6.3 Reconsent via phone at BTTC Sites (outside of NCI)
Each institution will follow their own procedure for reconsenting subjects.


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13 REGULATORY AND OPERATIONAL CONSIDERATIONS 
13.1 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, site 
investigators, funding agency, the Investigational New Drug (IND) or Investigational Device 
Exemption (IDE) sponsor and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the 
Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the termination 
or suspension.  Study participants will be contacted, as applicable, and be informed of changes to 
study visit schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to participants
•
Demonstration of efficacy that would warrant stopping   
•
Insufficient compliance to protocol requirements
•
Data that are not sufficiently complete and/or evaluable
•
Determination that the primary endpoint has been met
•
Determination of futility
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and as applicable, Food and Drug Administration (FDA).
13.2 QUALITY ASSURANCE AND QUALITY CONTROL
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management 
plan will be developed to describe a site’s quality management.
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution.
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Council for 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local 
and regulatory authorities.
13.3 CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
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required to have such conflicts managed in a way that is appropriate to their participation in the 
design and conduct of this trial.  The study leadership in conjunction with the National Cancer 
Institute has established policies and procedures for all study group members to disclose all 
conflicts of interest and will establish a mechanism for the management of all reported dualities 
of interest.
Participating sites will adhere to local conflict of interest policy guidelines. 
13.4 CONFIDENTIALITY AND PRIVACY
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible.
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical 
records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records.
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements.
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored at the BTTC Coordinating Center. This will not 
include the participant’s contact or identifying information. Rather, individual participants and 
their research data will be identified by a unique study identification number. The study data 
entry and study management systems used by clinical sites and by BTTC Coordinating Center 
research staff will be secured and password protected. At the end of the study, all study databases 
will be archived at the BTTC Coordinating Center. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been 
issued by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any 
civil, criminal, administrative, legislative, or other proceeding, whether at the federal, state, or 
local level. By protecting researchers and institutions from being compelled to disclose 
information that would identify research participants, Certificates of Confidentiality help achieve 
the research objectives and promote participation in studies by helping assure confidentiality and 
privacy to participants.


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14 PHARMACEUTICAL INFORMATION  
14.1 PEMBROLIZUMAB/KEYTRUDA ®
14.1.1 Chemical Name 
Humanized X PD-1_mAb (H409A11) IgG4
14.1.2 CAS Name and Number
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 / 1374853-91-4
14.1.3 Molecular Formula: C6534H10004N1716O2036S46 (peptide) 
14.1.4 Molecular Weight: 149 kDa.
14.1.5 Appearance
Sterile, preservative-free, white to off-white lyophilized powder in single-use vials. Each vial is 
reconstituted and diluted for intravenous infusion. Each 2 mL of reconstituted solution contains 
50 mg of pembrolizumab and is formulated in L-histidine (3.1 mg), polysorbate-80 (0.4 mg), 
sucrose (140 mg). May contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5
14.1.6 Storage and Stability
KEYTRUDA is supplied in a carton containing one 50 mg single-use vial (NDC 0006-3029-02). 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F).
14.1.7 Supplier
Pharmacy will receive Merck Marketed Drug (MMD) (i.e., commercial supply) of 
pembrolizumab for use after 30 April 2020. This will replace the previous arrangement in which 
Merck was providing Pembrolizumab Lot R022867, which expires on 30 Apr 2020.
14.1.8 Mechanism of Action
Pembrolizumab (previously known as SCH 900475) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of 
the target lymphocytes to facilitate tumor regression and ultimately immune rejection.
14.1.9 Administration for this study
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14.1.10 Preparation
Product Name & Potency
Dosage Form
Pembrolizumab 50 mg
Lyophilized Powder for Injection
Pembrolizumab 100 mg/ 4mL
Solution for Injection
Drug will be supplied either as powder for injection, 50 mg single-use vial, or a liquid, DP 100 
mg/vial (25 mg/mL), both in Type I glass vials intended for single use only.
Reconstitution of Pembrolizumab Lyophilized Powder for Injection:
Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the vial 
and not directly on the lyophilized powder (resulting concentration 25 mg/mL).
Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial.
Pembrolizumab Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the fully 
formulated DS), and has the identical formulation as that of the reconstituted lyophilized vial.
14.1.11 Preparation for Intravenous Infusion
The liquid drug product is a clear to opalescent solution which may contain proteinaceous and 
extraneous particulates. Do not shake or freezer the vial(s). 
The liquid product is intended for IV administration. 
The liquid DP can be further diluted with 0.9% Sodium Chloride (normal saline) in IV containers 
made of polyvinyl chloride (PVC) or non-PVC material. The final concentration of the diluted 
solution should be between 1 mg/ml to 10 mg/ml. Do not dilute or combine product as an 
infusion with other medicinal products. Do not co-administer other drugs through the same 
infusion line. Administer infusion solution intravenously over 30 minutes through an intravenous 
line containing a sterile, non-pyrogenic, low- protein binding 0.2 micron to 5 micron in-line or 
add-on filter. The infusion solution should be immediately administered. If not used 
immediately, vials and/or IV bags may be stored at 2-8 °C for up to a cumulative time of 20 
hours. If refrigerated, the vials and/or IV bags should be allowed to equilibrate to room 
temperature prior to subsequent use. Pembrolizumab solutions may be stored at room 
temperature for a cumulative time of up to 6 hours. This includes room temperature storage of 
reconstituted or liquid DP solution in vials, room temperature storage of infusion solution in the 
IV bag and the duration of infusion.
14.1.12 Incompatibilities
No formal pharmacokinetic drug interaction studies have been conducted with Pembrolizumab. 
Live vaccines should be prohibited within 30 days prior to the first dose of trial treatment and 
while participating in the trial.


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14.1.13 Side Effects
14.1.13.1
Non-Clinical Toxicology Summary of Results
In the 1-month and 6-month toxicology study in cynomolgus monkeys, Pembrolizumab 
administered once a week and once every other week respectively, intravenously up to 200 
mg/kg resulted in no adverse treatment related effects. The exposure multiple based on a 
predicted AUC 0-tau of 4464 μg.day/mL at the maximum anticipated human clinical dose of 10 
mg/kg Q2W or Q3W is 15-fold at 200 mg/kg, the NOAEL for the 6-month monkey study. 
Additionally, in the tissue cross-reactivity study of Pembrolizumab with human and monkey 
tissues demonstrated the expected on-target staining of the membranes of mononuclear 
leukocytes in both species. Off-target cross-reactivity staining was also noted in both species but 
was limited to cytoplasm of various cell types/tissues and the stroma (extracellular connective 
tissue matrix), and was considered related to the experimental method artifacts, i.e. tissue 
processing for IHC, that are well recognized limitations of tissue cross-reactivity studies and, 
thus not considered toxicologically relevant.
No reproductive or developmental toxicity studies are planned with Pembrolizumab. Therefore, 
inclusion of women of childbearing potential in clinical trials should be in accordance with the 
study protocol and applicable regulatory guidance (e.g., ICH M3(R2): Nonclinical Safety Studies 
for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals).
14.1.13.2
Clinical Summary of Results
As of 18-Oct-2013, 1,000 patients have been treated with Pembrolizumab at several dose 
schedules, including 10 mg/kg every 2 weeks. Pembrolizumab has been generally well tolerated, 
as expected based on preclinical findings and other anti-PD-1 monoclonal antibodies. As of 18-
Oct-2013 no serious infusions reactions have been reported in PN001, however, since the 
potential exists in anti-PD-1 monoclonal antibodies, investigators should be vigilant to this 
possibility. Less than 1% of patients thus far assayed had confirmed positive ADA samples and 
among these, no or no clear impact on exposure has been observed.          
There is no contraindication to further clinical investigation with Pembrolizumab. 
Pharmacokinetics were as expected, based on Pembrolizumab being an IgG mAb and based on 
preclinical data, which support dosing once every 2 or 3 weeks. Pembrolizumab monotherapy 
induces an ORR of 25%/27% in patients with ipilimumab exposed melanoma by central 
independent RECIST and oncology review/investigator assessed irRC, respectively. 
Pembrolizumab monotherapy induces an ORR of 39%/43% in patients with ipilimumab-naive 
melanoma by central independent RECIST and oncology review/investigator assessed irRC, 
respectively. These responses are remarkably durable. The preliminary 1-year survival rate for 
patients, many of whom have had multiple therapies, including ipilimumab, who receive 
Pembrolizumab is 81%. Pembrolizumab monotherapy induces an ORR of 21%/24% in patients 
with previously-treated NSCLC by central independent RECIST/investigator assessed irRC, 
respectively, with these responses also remarkably durable. Preliminary data suggest higher 
levels of PD-L1 expression in tumors of NSCLC are associated with increased activity (ORR 
67% by investigator assessed irRC/57% by central independent RECIST); additional data are 
required to define the optimal PD-L1 cut point. The most commonly reported treatment emergent 
AEs experienced are fatigue (43.8%), nausea (26.7%), cough (25.3%), pruritus (24.6%), 
diarrhoea (22.3%) and rash (21.5%). Immune-related adverse events were reported in 21.4% of 
melanoma patients; most of these events (15.8%) were considered drug-related by the 


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investigator. The most commonly reported, immune-related adverse events across the dose-
schedules are rash (3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia 
(2.2%), diarrhoea (2.2%), and pneumonitis (1.9%). Review of the overall benefit: risk ratio of 
Pembrolizumab favors enrollment of eligible patients into clinical trials of Pembrolizumab. The 
preliminary data suggest that a dose of Pembrolizumab at 2 mg/kg Q3W is appropriate for 
patients with melanoma.
14.1.13.3
Important Safety Considerations
Based on results from the nonclinical studies, there are currently no specific safety 
considerations. Pembrolizumab is a humanized monoclonal Ab. Thus far, no serious infusion 
reactions have been reported however, patients should be closely monitored for potential AEs 
during antibody infusion and potential AEs throughout the study. In the event that a subject 
experiences an allergic reaction to Pembrolizumab, treatment (i.e., vasopressors, H2-blockers, 
antihistamines, H1-blockers, steroids) should be administered, as appropriate, and prophylaxis 
should be considered. Surveillance for the appearance of ADAs is included in all protocols.
Pembrolizumab has the same mechanism of action as other anti-PD-1 monoclonal antibodies. 
Preclinical studies have suggested similar potency, and PK modeling has suggested similar 
human PK in the class. Accordingly, the AEs observed with other anti-PD-1 antibodies may 
serve as in indicator for the AEs to expect for Pembrolizumab in cancer patients. Furthermore, 
AEs from other immunotherapies for cancer were considered in the Events of Clinical Interest 
(Section ) and Immune-Related Guidance.
14.1.13.4
Immune-Related Adverse Events (I-R AE)
An I-R-AE is defined as a clinically significant AE of any organ that is associated with study 
drug exposure, is of unknown etiology, and is consistent with an immune-related mechanism. 
Immune-related adverse events were reported in 21.4% of melanoma patients; most of these 
events (15.8%) were considered drug- related by the investigator.
The most commonly reported, immune-related adverse events across the dose-schedules are rash 
(3.2%), pruritus (2.9%), vitiligo (2.9%), hypothyroidism (2.7%), arthralgia (2.2%), diarrhoea 
(2.2%), and pneumonitis (1.9%). The organ most frequently affected by irAEs with 
Pembrolizumab is the skin. Less frequently affected tissues include thyroid gland, colon, lung, 
kidney, and liver. Based on the mechanism of action of Pembrolizumab and similar 
immunomodulatory agents, the sponsor is keenly interested in potential events of colitis, 
hepatitis, hyper/hypothyroidism, nephritis, pneumonitis. Therefore, the sponsor encourages 
appropriate academic investigation of signs and symptoms suggestive of any of the above events. 
Consultation with the appropriate medical specialist should be considered when investigating a 
possible irAE. These events can occur after the first dose to several months after the last dose of 
treatment. Mild irAEs are usually treated symptomatically and do not require dosing delays or 
discontinuation. Higher grade and persistent lower grade irAEs typically necessitate withholding 
or discontinuing treatment and administration of systemic steroids or other immunosuppressive 
agents (such as tumor necrosis factor blockers), when systemic steroids are not effective. Early 
recognition of irAEs and initiation of treatment are critical to reduce the risk of complications, 
since the majority of irAEs are reversible with the use of steroids and other immune 
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14.1.13.4.1
Other immune-mediated adverse reactions
The following additional clinically significant, immune-mediated adverse reactions
were reported in less than 1% of patients treated with KEYTRUDA (pembrolizumab) in 
KEYNOTE-001, KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010: 
uveitis, myositis, Guillain-
Barré syndrome, pancreatitis, encephalitis, sarcoidosis, myasthenic syndrome/myasthenia gravis 
(including exacerbation) and), myelitis., and vasculitis.
The following were reported in other clinical studies with KEYTRUDA or in
postmarketing use: myocarditis and sclerosing cholangitis.
Cases of these immune-mediated adverse reactions, some of which were severe, have been 
reported in clinical trials or in postmarketing use.
14.1.13.5
Nursing Implications
Standard treatment protocols per hospital guidelines will be used for this Pembrolizumab. Dose 
will be administered prior to RT.
14.2 TEMOZOLOMIDE
Temozolomide during Concomitant Radiation Therapy (RT)
TMZ will be administered orally on day 1 of radiation therapy (RT) 1-2 hours before each 
session of radiotherapy or night before RT; and it should be administered the same time 
throughout the course of RT. TMZ should continue throughout RT at the dose of 75 mg/m2/day.  
During weekends without radiotherapy (Saturday and Sunday), the drug will be taken at the 
same time as radiotherapy days.
14.2.1 Chemical Name  
Temozolomide is 3,4-dihydro-3methyl-4-oxoimidazo[5,1-d]-as-tetrazine-8-carboxamide
14.2.2 Molecular Formula: C6H6N6O2
14.2.3 Molecular Weight: 194.15
14.2.4 Appearance 
white to light tan/light pink powder
14.2.5 Supply: Commercially Available.
14.2.6 Pill Diary
Temozolomide will be properly accounted for, handled, and disposed in accordance with existing 
federal regulations and principles of Good Clinical Practice. All oral study drugs will be 
recorded in the patient diaries found in Appendix 16.14. This will be used as a memory aide for 
subjects. A clinical research team maintains the primary source record.


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14.2.7 Storage and Stability 
The capsules are packaged in amber glass bottles and should be stored at 25°C. Temperature 
excursions between 15 and 30°C are permissible. Refer to the commercially labeled bottles for 
expiration dating.
Temozolomide is rapidly and completely absorbed after oral administration; peak plasma 
concentrations occur in 1 hour. Food reduces the rate and extent of temozolomide absorption. 
Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and Tmax 
increased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a modified 
high-fat breakfast.
Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hours and exhibits 
linear kinetics over the therapeutic dosing range. Temozolomide has a mean apparent volume of 
distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean 
percent bound of drug- related total radioactivity is 15%.
14.2.8 Metabolism and Elimination 
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-
(triazen-1-yl)imidazole-4-carboxamide (MTIC) and to temozolomide acid metabolite. MTIC is 
further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an 
intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to 
be the active alkylating species.
Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and 
MTIC.
14.2.9 Mechanism of Action
An oral cytotoxic alkylating agent is the lead agent in a new class of compounds known as 
imidazotetrazines. Cytotoxic agents are designed to prevent the replication of cells that divide 
rapidly, including those in tumors.
14.2.10 Special Populations 
14.2.10.1
Creatinine Clearance: 
Caution should be exercised when temozolomide is administered to patients with severe renal 
impairment. Temozolomide has not been studied in patients on dialysis.
14.2.10.2
Hepatically Impaired Patients: 
In a pharmacokinetic study, the pharmacokinetics of temozolomide in patients with mild to 
moderate hepatic impairment (Child’s-Pugh Class I-II) were similar to those observed in patients 
with normal hepatic function. Caution should be exercised when temozolomide is administered 
to patients with severe hepatic impairment.
14.2.10.3
Gender: 
Population pharmacokinetic analysis indicates that women have an approximately 5% lower 
clearance (adjusted for body surface area) for temozolomide than men. Women have higher 
incidences of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than men.


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14.2.10.4
Age: 
Population pharmacokinetic analysis indicates that age (range 19-78 years) has no influence on 
the pharmacokinetics of temozolomide.
14.2.11 Drug-Drug Interactions
In a multiple dose study, administration of temozolomide with ranitidine did not change the 
Cmax or AUC values for temozolomide or MTIC. Population analysis indicates that 
administration of valproic acid decreases the clearance of temozolomide by about 5%. The 
clinical implication of this effect is not known. Population analysis failed to demonstrate any 
influence of co-administered dexamethasone, prochlorperazine, phenytoin, carbamazepine, 
ondansetron, H2-receptor antagonists, or phenobarbital on the clearance of orally administered 
temozolomide.
14.2.12 Adverse Events: 
•
Hematologic: Thrombocytopenia, leukopenia, myelodysplastic syndrome
•
Gastrointestinal: Nausea, vomiting, anorexia
•
Hepatic: Elevated liver enzymes (reversible)
•
Skin: Rash
•
Neurologic: Convulsions, weakness on one side of the body, abnormal coordination, 
paralysis
•
Other: Constipation, diarrhea, stomatitis, fatigue, decreased performance status, headache
14.2.13 Special Handling and Precautions
Capsules should not be opened or damaged. Rigorous precautions should be taken to avoid 
capsule contents having contact with skin or mucous membranes. Capsule contents may be 
irritating to skin and eyes. Mutagenic and prolonged exposure may cause serious health effects 
(outside of prescribed dosage in this trial).
Temozolomide is potentially mutagenic and should be handled with appropriate precautions by 
both staff and patients. Capsules should not be opened. If capsules are accidentally opened or 
damaged, rigorous precautions should be taken with the capsule contents to avoid inhalation or 
contact with the skin or mucous membranes. Procedures for proper handling and disposal of 
anticancer drugs should be considered.
14.2.14 Contraindications
Temozolomide is contraindicated in patients who have a history of a hypersensitivity reaction to 
any of its components or to DTIC.
14.2.15 Pregnancy Category D
Temozolomide may cause fetal harm when administered to a pregnant woman. There are no 
adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, 
or if the patient becomes pregnant while taking this drug, the patient should be apprised of the 
potential hazard to the fetus. Women of childbearing potential should be advised to avoid 
becoming pregnant during therapy with temozolomide.


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14.2.16 Fertility 
Treatment of a man with temozolomide may increase the risk of birth defects if he causes a 
woman to become pregnant while he is taking temozolomide. Men treated with temozolomide 
may have difficulty causing a woman to become pregnant after their treatment is completed. 
Men receiving temozolomide should be directed to use effective contraception while they are 
being treated. There is insufficient data to know what the risk of subsequent problems with 
fertility will be. Similarly, women who are treated with temozolomide may have difficulty 
becoming pregnant in the future and may at be at increased risk of having children with birth 
defects. There is insufficient evidence to determine what the risk of these complications will be.
14.3 HEAT SHOCK PROTEIN-PEPTIDE COMPLEX-96 VACCINE (HSPPC-96) 
HSPPC-96 is an autologous tumor-derived vaccine under clinical investigation for the treatment 
of a variety of cancer types. It is composed of the 96-kDa heat shock protein gp96 in complex 
with autologous tumor-derived peptides. The gp96 in HSPPC-96 is a highly conserved, 
abundant, nonpolymorphic stress protein found in every cell type of the body. The gp96 isolated 
from normal or tumor tissues is found in complex with a diverse repertoire of peptides, which are 
specific to the tissue of origin. Published studies in mouse tumor models have shown that 
HSPPC-96 confers protective immunity only to the tumor from which it is derived and not to 
antigenically distinct tumors. The specific immunogenicity of the HSP preparations can be 
attributed to the unique repertoire of antigenic peptides that exists in different cancers. 
When injected into the host, HSPPC-96 interacts with antigen presenting cells (APCs) such as 
macrophages, dendritic cells or Langerhans cells, which take up HSPPCs via HSP receptors, 
including CD91. Once internalized by APCs, the peptides chaperoned by the HSPs are 
transferred to major histocompatibility complex (MHC) class I and II molecules in intracellular 
compartments and subsequently expressed at the cell surface. The cells then migrate to lymph 
nodes, where the complexes are processed so that the peptides chaperoned by the HSPs are re-
presented to naive T cells. The T cells recognize the peptides and, as a result, are stimulated by 
them. Vaccination with HSPPCs thus elicits both a CD8+ and CD4+ T-cell response targeting 
potentially all relevant tumor antigens. The interaction of HSPs with receptors on APCs also 
leads to activation of various components of innate immunity, including cytokine and chemokine 
release by macrophage and dendritic cells, maturation of dendritic cells and activation of natural 
killer cells, as shown in both murine and human systems. Tumor immunity is largely mediated 
by T cells and the ability of HSPPC-96 to stimulate both T-cell arms to recognize a large variety 
of tumor antigens, coupled with the ability to activate innate immune responses, uniquely 
positions the product among other cancer vaccine strategies.
14.3.1 Molecular Formula
The molecular formula of HSPPC-96 is unknown since the antigenic peptide repertoire isolated 
from tumor cells is patient specific.
14.3.2 Peptide Component
The peptide component of HSPPC-96 is not characterized on a patient specific basis due to the 
limited quantity of product available and the technical challenges in performing this type of 
peptide analysis.


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14.3.3 Appearance
HSPPC-96 is supplied in a single-use vial as a clear, colorless solution. Each vial contains 25 μg 
of HSPPC-96 in a solution of 9% sucrose-potassium phosphate for intradermal (ID) injection. 
The total volume of each vial of HSPPC-96 is 0.47 mL. The total volume that should be 
administered is approximately 0.4 mL.
14.3.4 Availability 
Blinded vaccine (HSPPC-96 or placebo) will be prepared by Agenus Inc. and shipped directly to 
sites within approximately 4-6 weeks of Agenus’ receipt of tumor tissue for randomized patients. 
The number of vaccine treatments will be based on the amount of vaccine generated. Although 
HSPPC-96 vaccine will be prepared for patients on the placebo arm, it will not be shipped to 
sites. Vaccine produced for patients randomized to placebo will be used for quality evaluation 
and will not be available for clinical use. 
14.3.5 HSPPC-96 Vaccine Label
Each vial of vaccine vial is labeled with the subject/patient study number, subject/patient initials, 
and subject/patient date of birth (DOB).
14.3.6 Storage and Stability
Following successful production of HSPPC-96 vaccine at Agenus Inc. and randomization, vials 
of blinded vaccine are shipped overnight on dry ice and must be stored at -80 °C ± 20 °C until 
administration to the patient. 
NOTE: Once HSPPC-96 is drawn up into the syringe, the vaccine is stable for up to 2 hours at 
ambient temperature if immediate administration is not possible.  Please refer to the 
Investigator’s Brochure for further details.
Any unused or expired vaccine remaining after a patient has completed vaccine treatment should 
be returned to Agenus or destroyed at the site upon approval from Agenus. Destruction records 
are to be forwarded to Agenus. The shipping kit used to send vaccine from Agenus to the site 
may be stored until the patient has completed vaccine therapy and utilized for return of any 
unused or expired vaccine.  See Appendix 16.6 for further detail.
14.3.7 Preparation
Withdraw the vial from the freezer and roll gently between two fingers until it is completely 
thawed (5-10 minutes). Withdraw approximately 0.4 mL, using a low hold up TB or insulin 
syringe.
14.3.8 Administration
The route of administration is intradermal injection. Inject into 1 site or into 2 adjacent sites (0.2 
mL each) a few centimeters apart. Appropriate sites for vaccination include the anterior deltoid 
regions or subclavicular region bilaterally. 
Do not administer HSPPC-96/placebo to any side where lymph nodes have been removed or 
damaged.  Rotate the injection sites so that injections are not repeated at the same site at 2 
consecutive administrations, and utilize all potential sites for the patient before repeating 


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injections at a previously used injection site. Syringes with slip-tip detachable needles or luer 
hubs with greater than 0.1 mL dead space should not be utilized.
14.3.9 Toxicities
Local injection-site reactions can occur and are usually of minimal extent and mild severity. If a 
local injection-site reaction requires medical attention, the investigator can provide local therapy 
as needed. Occasional systemic toxicities have been reported that have been mild in severity. The 
most frequently reported events include injection- site reactions of erythema and induration, 
fatigue, nausea, pyrexia, headache, back pain, arthralgia, constipation, and asthenia. 
14.4 PLACEBO
14.4.1 Supply
Placebo will be prepared by Agenus Inc. and shipped directly to sites within approximately 4-6 
weeks of Agenus’ receipt of tumor tissue for randomized patients. The number of placebo 
treatments will be based on the amount of vaccine generated. 
14.4.2 Product Description
Each dose of placebo is supplied in a single-use vial as a clear, colorless solution. Each vial 
contains a solution of 9% sucrose-potassium phosphate for intradermal (ID) injection. The total 
volume in each vial of placebo is 0.47 mL. The total volume that should be administered is 
approximately 0.4 mL.
14.4.3 Placebo Label
Each vial of vaccine vial is labeled with the subject/patient study number, subject/patient initials, 
and subject/patient date of birth (DOB).
14.4.4 Storage
Vials of blinded vaccine are shipped overnight on dry ice and must be stored at–-80 °C ± 20 °C 
until administration to the patient. 
NOTE: Once the placebo is drawn up into the syringe, it is stable for up to 2 hours at ambient 
temperature if immediate administration is not possible.  
14.4.5 Administration 
Withdraw the vial from the freezer and roll gently between two fingers until it is completely 
thawed (5-10 minutes). Withdraw approximately 0.4 mL, using a low hold up TB or insulin 
syringe.
14.4.6 Dose 
The route of administration is intradermal injection. Inject into 1 site or into 2 adjacent sites (0.2 
mL each) a few centimeters apart. Appropriate sites for vaccination include the anterior deltoid 
regions or subclavicular region bilaterally. 


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Do not administer placebo to areas distal to lymph node basins that have been resected or in 
areas just distal to a surgical scar. Rotate the injection sites so that injections are not repeated at 
the same site at 2 consecutive administrations, and utilize all potential sites for the patient before 
repeating injections at a previously used injection site. Syringes with slip-tip detachable needles 
or luer hubs with greater than 0.1 mL dead space should not be utilized.
14.5 ORDERING STUDY AGENT
14.5.1 Heat Shock Protein-Peptide Complex-96
Following vaccine manufacture and completion of quality testing, Agenus will send the site the 
Vaccine Production Notification form indicating whether manufacture of vaccine was successful. 
Upon randomization, Agenus will then send the appropriate blinded vaccine to the site.  
Agenus Contact Information for Tissue Procurement and Kit Ordering: 
supply&logistics@agenusbio.com  or fax: 781-674-4220.
See Appendix 16.3 and Appendix 16.4 for more details.
14.5.2 Pembrolizumab
Pembrolizumab may be requested by the Principal Investigator (or their authorized designees) at 
each participating institution. All regulatory document requirements, as described in the BTTC 
Operations Manual, must be current and up to date in the BTTC Coordinating Center.  A Study 
Drug Order Form and Pharmacy Initiation Worksheet Form will need to be completed; these 
forms can be obtained from the BTTC Coordinating Center.  The participating institution must 
have received a Site Activation Memo from the BTTC Coordinating Center prior to requesting 
study agents.  
Signed and Dated drug requests should be emailed to:
Merck
Attn:  Eleonora Veglia, PhD 
Email: nciisdrugorder@merck.com 
Cc: eleonora.veglia@msd.com
Phone:  +44 (0) 7824524450
When a number of investigators are participating on a clinical study at the same institution, one 
investigator should be considered or designated the principal or lead investigator under whom all 
investigational agents for that protocol should be ordered.
14.5.3 Temozolomide 
Temozolomide is commercially available.  
14.5.4 Agent Storage and Accountability:
The investigator is responsible for the proper and secure physical storage and record keeping of 
investigational agents received for BTTC protocols. Specifically, the investigator must:  


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o
Maintain a careful record of the receipt, use and final disposition of all investigational 
agents received, using the NCI Investigational Agent Accountability Record Form 
(DARF), http://ctep.cancer.gov/forms/index.html 
o
Store the agent in a secure location, accessible to only authorized personnel, preferably in 
the pharmacy.
o
Maintain appropriate storage of the investigational agent to ensure the stability and 
integrity of the agent.
o
Return or destroy any unused investigational agents at the completion of the study or 
upon notification that an agent is being withdrawn.
The intent of the agent accountability procedures described in this section is to assist the 
investigator in making certain that agents received from BTTC are used only for patients entered 
onto an approved protocol. The record keeping described in this section is required under FDA 
regulation. Investigators are responsible for the use of investigational agents shipped in their 
name. Even if a pharmacist or chemotherapy nurse has the actual task of handling these agents 
upon receipt, the investigator is the responsible individual and has agreed to accept this 
responsibility by signing the FDA 1572: https://www.fda.gov/science-research/clinical-trials-
and-human-subject-protection/clinical-trial-forms
14.5.5 BTTC Procedures for Agent Accountability and Storage
o
Each investigational agent should be stored separately by protocol. If an agent is used for 
more than one protocol, there should be separate physical storage for each protocol. 
Remember that agents are provided and accounted for on a protocol-by-protocol basis.
o
Each agent should be accounted for separately by protocol. If an agent is used for more 
than one protocol, there should be a separate Investigational Agent Accountability 
Record Form (DARF) for each protocol, http://ctep.cancer.gov/forms/index.html. There 
should be a separate DARF for each agent in a multi-agent protocol.
o
Separate accountability forms should be maintained for each different strength or dosage 
form of a particular agent (e.g., an agent with a 1-mg vial and a 5-mg vial would require a 
different DARF for the 1-mg vial than for the 5-mg vial).
o
The DARF has been designed for use at each location where agents are stored, e.g., main 
pharmacy, satellite pharmacy, physician's office, or other dispensing areas.
o
The DARF is also designed to accommodate both dispensing records and other agent 
transaction documentation (e.g., receipt of agent, returns, broken vials, etc.). A copy of 
the DARF may be found at http://ctep.cancer.gov/forms/index.html.
o
Unauthorized inter-institutional transfer of BTTC investigational agents from one 
participating institution to another is not permitted.  For some protocols the lead 
institution may enter into contractual agreements to forward agents to participating 
institutions (Refer to the BTTC Operations Manual).
o
BTTC Supplied agents must not be repackaged and forwarded to patients on a routine 
basis. Refer to the BTTC Operations Manual for BTTC polices on forwarding BTTC 
supplied agents under certain limited circumstances.


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14.5.6 Verification of Compliance
Investigators are reminded that compliance with procedures to ensure proper agent usage will be 
reviewed during site visits conducted under the monitoring program. Specifically, site visitors 
will check that the agent accountability system is being maintained, and will spot-check the 
agent accountability records by comparing them with the patients' medical records to verify that 
the agents were administered to a patient entered in the recorded protocol.
14.6 RETURNING OR DESTROYING UNUSED AND/OR DEFECTIVE AGENT: 
14.6.1 Pembrolizumab Return Procedure
All unused and returned pembrolizumab may be destroyed on site.  The site must follow their local 
drug destruction policy and procedure.  A copy of the drug destruction record must be submitted 
to BTTC to send to Merck.. 
Contact: Eleonora Veglia, PhD
Scientific Leadership & Research Manager (EU SLRM)
Merck Investigator Initiated Studies Program/ Scientific Engagements
MSD, MRL Innovation Hub
Two Pancras Square, Kings Cross
London N1C 4AG
Tel:  +44 (0) 7824524450
Email:  eleonora.veglia@msd.com  
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 used 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.
14.6.2 HSPPC-96 or Placebo Return Procedure
If a subject is randomized to receive placebo or if there is any remaining vaccine after the subject 
has finished treatment, it will be coded and linked and used by Agenus or other approved 
investigators for development and research purposes. Refer to section 16.6 for HSPPC-96 or 
Placebo return instructions.


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16 APPENDICES
16.1 PERFORMANCE STATUS CRITERIA
ECOG Performance Status Scale
Karnofsky Performance Scale
Grade
Descriptions
Percent
Description
100
Normal, no complaints, no 
evidence of disease.
0
Normal activity.  Fully active, 
able to carry on all pre-disease 
performance without restriction.
90
Able to carry on normal activity; 
minor signs or symptoms of 
disease.
80
Normal activity with effort; 
some 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).
70
Cares for self, unable to carry on 
normal activity or to do active 
work.
60
Requires occasional assistance, 
but is able to care for most of 
his/her needs.
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.
50
Requires considerable assistance 
and frequent medical care.
40
Disabled, requires special care 
and assistance.
3
In bed >50% of the time.  
Capable of only limited self-care, 
confined to bed or chair more 
than 50% of waking hours.
30
Severely disabled, 
hospitalization indicated.  Death 
not imminent.
20
Very sick, hospitalization 
indicated. Death not imminent.
4
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair.
10
Moribund, fatal processes 
progressing rapidly.
5
Dead.
0
Dead.


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16.2 TUMOR TISSUE SUBMISSION FOR VACCINE MANUFACTURE 
See Appendix 16.3 for detailed instructions for handling, preparation, and submission of tumor 
tissue for HSPPC-96 vaccine manufacture. 
The Tumor Procurement Form (TPF) must be included with the tissue sent to Agenus Inc. 
Kits for shipping tissue will be supplied by Agenus and should be ordered at time of IRB 
approval because they will be needed at time of surgery:
 
Supply and Logistics
Agenus Inc. 
Primary Contact: Tel: +1 (781) 674-4400 x4486 (office) 
Email:  supply&logistics@agenusbio.com
The dimensions of the kits are 17" x 17" x 15". Please order one or two kits at a time, based on 
your anticipated use, and please allow 3-4 days for shipping.  Upon receipt of a kit with patient 
tumor at Agenus, a new kit will automatically be replenished for the site.


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Version Date:   06/25/2025
16.3 VACCINE TISSUE PROCUREMENT AND SHIPPING INSTRUCTIONS
Tissue procurement kits provided by Agenus Inc. include:
 
o
50-mL nonpyrogenic tubes and patient information labels 
o
Dry Ice Contents Sticker
o
Absorbent paper 
o
Plastic bags 
o
Orange-capped pressure vessels (with foam insert) 
o
Cardboard pieces (to support base of pressure vessel and top of dry ice)
o
Tumor Procurement Form (TPF) 
o
Shipping box and all shipping/address labels Sites must provide the dry ice 
(8kg). 
o
The site should contact Agenus at supply&logistics@agenusbio.com to request courier 
documents (pre-paid shipping label for tumor shipment from site to Agenus) 1 day in 
advance of the desired shipment and the shipping label will be emailed to the site.
The shipment of tissue to Agenus for vaccine creation should be delayed until confirmation of 
histologic diagnosis, MGMT status and IDH mutational status that would make the tumor 
eligible for vaccine production. Tumor specimens for vaccine production must be frozen and 
stored at -80°C ± 20°C. The tumor specimen must not arrive on the weekend or a holiday unless 
this has been agreed to in advance by Agenus. 
If the tumor specimen will not be shipped immediately, it should be placed into an -80° (+/- 20°) 
C freezer until ready to pack and ship. Do this within a maximum of 30 minutes of removal. 
For tumor specimen stored at sites prior to shipping to Agenus (i.e. overnight or for 
weekends/holidays), the freezer does not need to be sterile, but it is recommended that it be 
monitored for temperature (24/7) with alarms or other mechanism for identifying when 
temperature goes out of specification. The freezer or its location should have controlled access 


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(locked with specified group members having access). The freezer should also be on a 
preventative maintenance program and ideally be hooked up to a back-up power system. 
In the OR, wrap or place the tumor specimen in a sterile specimen cup, cloth or towel, and place 
in a basin, on ice (not dry ice). Transport the specimen immediately to the pathology/frozen 
section suite. 
Share the following steps with the surgical pathologist, along with the tissue procurement 
kit: 
a.
Use basic sterile technique. Care should be taken to avoid any possible cross-
contamination with tissues or fluids from other patients. 
b. As small a section of tumor as possible should be kept for routine pathologic studies and 
diagnosis. Tumor for routine pathologic diagnosis should be processed according to 
institutional standards. 
c.
The pathologist should assess viability of the tumor. 
d. When there is necrosis and/or cystic degeneration in the tumor specimen, the necrotic 
tissue and/or cystic component should be removed and should not be sent to Agenus. 
e.
All available tumor aside from what will be used for routine pathologic studies and 
diagnosis should be sent for HSPPC-96 vaccine preparation. A minimum of ≥ 7 grams of 
fresh, non-necrotic tumor should be sent (if <7 grams, may not produce sufficient 
vaccine).
Tumor procurement and shipping procedure 
a.
The pathologist should section the tissue into 1-2 cm2 sections. The sections should 
then be placed carefully, maintaining sterility, into the 50-mL nonpyrogenic tubes. 
Each tube should be filled no more than ½-⅔ full to allow for expansion of tumor 
during freezing.
b. Each tube must be properly labeled (patient/subject identifiers are a match on all 
tubes).
c.
Each tube should be placed in a plastic pouch, and the pouch sealed closed.
d. Wrap the tubes in bubble wrap or place in the foam insert in the upright position.
e.
Absorbent paper should be placed in the bottom of the orange capped pressure 
vessel.  The sealed tubes in the foam insert are then placed into the pressure vessel 


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and the vessels lid is screwed shut. Dry ice should NOT be placed inside the 
pressure vessel.
f.
Place some dry ice in the bottom of the insulated shipper box.
g. The pressure vessel should be placed above the dry ice, with the base seated in the 
cardboard support, and more dry ice packed surrounding the container.
h. Dry ice should be added to about 10 cm from the top of the box, a second cardboard 
insert placed above the ice, and the foam plug placed into the box. If an insufficient 
amount of dry ice is placed in the box, and the tissue is not frozen on arrival, it 
cannot be processed and the patient must be withdrawn from the study.
i.
The Tumor Procurement Form (top sections) must be completed with all required 
information ensuring patient/subject identifiers are a match on the form and tube 
labels.
The form should be scanned and e-mailed to: supply&logistics@agenusbio.com so 


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
that the shipment is expected and can be traced by airbill number if it does not 
arrive. A copy of the form should also be kept for the records of the study center.
j.
The original Tumor Procurement Form should be placed in the clear 
documentation holder on the inside carboard flap of the box. Close the cardboard 
flaps and securely taped shut.
k. A copy of the TPF should be kept for site records.
l.
The following labels should be over the appropriate areas:
1. Dry Ice (#9) With Weight
2. “Shipping To” label
3. “Shipped From” label
m. Record the amount (in kilograms) of dry ice placed in the package on the Dry Ice 
label.
Attach the courier air bill to the box. The shipment should be sent to: 
Supply and Logistics
Agenus Inc. 
3 Forbes Road 
Lexington, MA 02421 
United States 
Tel: +1 (781) 674-4486 
Below is a list of some common issues that have been encountered with completing the 
Tumor Procurement Form (TPF). 
Please take great care in filing out this form correctly, as any such issues may lead to delays in 
vaccine production and potential rejection of the material if the correct identity cannot be 
confirmed. 
o
Study subject ID number does not match – tube labels vs. procurement form 
o
Patient/subject date of birth does not match – tube labels vs. procurement form 
o
Patient/subject initials do not match – tube labels vs. procurement form (i.e., A-C ≠ C-A) 
Side of box
_______
_______
Dry Ice 
“Shipped from” label
“Shipped to” label
9


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
o
Study subject ID number, date of birth or patient initials are illegible on procurement 
form or tube labels 
o
Tube labels used are not the same as those issued by Agenus 
o
Tubes are not labeled at all, or information is recorded directly onto body of tube and is 
then smeared upon receipt 
o
Pen or marker used to record information on tube label is not indelible ink, and 
information is then smeared upon receipt 
o
Tubes for more than 1 patient/subject are placed into one pressure vessel 
o
Initials and date of correction are not recorded when cross-outs are made on tube labels 
or Tumor Procurement Form


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.4 TUMOR PROCUREMENT FORM


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.5 LABCONNECT MANUAL FOR WHOLE BLOOD PBMC PROCESSING AND SHIPPING 
This manual is a separate document.


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.6 HSPPC-96 VACCINE OR PLACEBO RETURN INSTRUCTIONS
1. Any unused or expired vaccine remaining after a subject has completed vaccine treatment, 
should be returned to Agenus Inc. according to the following instructions. 
2. Please contact the Agenus Team at BTTC17C0034@agenusbio.com in advance (i.e., 
minimum of 1 day) to inform Agenus when you plan to return unused or expired vaccine. 
Also copy nci_bttc@mail.nih.gov on this return request communication.
3. Agenus will provide a pre-paid courier air-way bill via email for this shipment to your site. 
4. Use the qualified HSPPC-96 shipping kit that was received with the original shipment of 
vaccine from Agenus. The shipping kit should have the following materials, which came as 
part of the vaccine shipment from Agenus: 
•
Outer cardboard shipping box. 
•
Insulated liner and foam plug. 
•
Pressure vessel container (with foam inserts).
•
Cardboard pieces (2: 1 for upright positioning of base of pressure vessel and 1 for 
placement on top of pressure vessel surrounded with dry ice).
•
Absorbent paper (on bottom of pressure vessel)
5. Place vials to be returned inside of the pressure vessel, inserted upright in the holes of the 
foam inserts. Screw the lid shut on the pressure vessel. Multiple subjects’ /patients’ vaccines 
may be returned in 1 one pressure vessel. 
6. Place a layer of dry ice on the bottom of the insulated liner that is within the outer cardboard 
shipping box. The pressure vessel container should then be placed above this layer of dry ice, 
with the base of the pressure vessel inserted into the cardboard support. Additional dry ice is 
then packed around the closed pressure vessel. The shipping container must be filled with at 
least 8 kg of dry ice (i.e., level with the top of the pressure vessel). A second cardboard insert 
should be placed above the dry ice, and the foam plug placed into the box. The box is then 
sealed with packing tape. 
7. The following labels should be placed on the exterior of the outer cardboard shipping box:
•
Dry ice (#9) with weight (8 kg).
•
Shipping address/content label (where the package is being sent).
•
Shipped from label (Where the package is shipping from)
8. Contact the courier to arrange for a pick-up, if a standard pick- up time is not established for 
your site or if this was not done in advance. 
9. Attach the courier air bill to the top of the box. The shipment should be sent overnight to: 
Supply and Logistics 
Agenus Inc. 
3 Forbes Road 
Lexington, MA 02421 
United States
Tel: +1 (781) 674-4486
supply&logistics@agenusbio.com


119
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.7 HSPPC-96 Intradermal Injection Instructions


120
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
HSPPC-96 Intradermal Injection Instructions
The route of administration is intradermal injection. Using a 25 g needle or equivalent, inject into 
1 site or into 2 adjacent sites (0.2 mL each) a few centimeters apart. Appropriate sites for 
vaccination include the anterior deltoid regions, subclavicular region bilaterally, and medial 
inguinal regions of the upper thighs (please see the figure below). 
Intradermal injections are administered into the outer layers of the skin.  The needle should be 
inserted at a 
10-15 degree angle so that it just punctures the skin’s surface.  Insert the needle about 0.3 cm 
below the epidermis and stop when the needle’s tiup is under the skin.  You should feel some 
resistance as you make the injection and a wheal should form as you complete the injection.  If 
the needle tip moves freely, you have inserted the needle too deeply. At this point, withdraw 
needle slightly and check again for resistance.  The appearance of a wheal indicates that the 
vaccine has entered the area between the intradermal tissues. If a wheal does not appear, 
withdraw the needle and repeat the procedure in another site a few centimeters apart.
Do not administer HSPPC-96 to areas distal to lymph node basins that have been resected or in 
areas just distal to a surgical scar. 
Rotate the injection sites so injections are not repeated at the same site forat 2 consecutive 
administrations and utilize all potential sites for the patient before repeating injections at a 
previously used injection site. 
Syringes with slip-tip detachable needles or luer hubs with greater than 0.1 mL dead space 
should not be utilized.


121
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025


122
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.8 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 subject is deemed 
medically stable in the opinion 
of the investigator.
None
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs
Stop Infusion and monitor 
symptoms.
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator.
If symptoms resolve within 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.
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued 
from further trial treatment 
administration.
Subject may be 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).


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Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
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:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital 
signs as medically indicated 
until the subject is deemed 
medically stable in the opinion 
of the investigator.
Hospitalization may be 
indicated.
Subject is permanently 
discontinued from further 
trial treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily 
available during the period of drug administration.


124
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.9 MD ANDERSON SYMPTOM INVENTORY (MDASI-BT)
This questionnaire is a separate document.


125
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.10 CCR REPORTABLE EVENT FORM (REF)
NCI Protocol #: 
Protocol Title: 
Report version: (select one)
☐
Initial Report 
☐
Follow-up 
Site Principal Investigator:  
 
Date site PI was notified of the 
problem:    
Date of problem: 
If delay in reporting to the coordinating center, please explain:
Location of problem: (e.g.,  patient’s home, doctor’s office )
Description of Subject
Does this problem apply to a subject?
☐ yes
☐ not applicable (more than one subject is involved)
If yes, enter details below:
Subject ID:   (do not use medical record number)
Sex:  ☐Male  ☐ Female
Age:  


126
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
Diagnosis: 
Name the problem: (select all that apply)  
☐ Specimen collection issue  
☐ Informed consent issue  
☐ Ineligible for enrollment  
☐ Breach of PII 
☐ Other, briefly state the nature of the problem: 
Detailed Description of the problem: (Include any relevant treatment, outcomes 
or pertinent history): 
What are you reporting?
☐
unanticipated problem
☐
death
☐
non-compliance (other than a protocol deviation)
☐
protocol deviation
☐
new information that might affect the willingness of subjects to enroll 
or continue     participation in this study
If interventional or expanded access study, please answer the following 
questions about your site:


127
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
How many participants are still receiving the study intervention? 
How many participants completed study interventions but remain in follow up?
How many participants are enrolled but not yet receiving study interventions?
Have similar problems occurred on this protocol at your site?
☐ Yes      ☐ No
Describe what steps you have already taken or will be taking as a result of 
this problem:
INVESTIGATOR’S SIGNATURE: 
DATE:  


128
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.11 UNBLINDING REQUEST MEMO
MEMORANDUM
DATE:      
TO:
Lead PI
FROM:             __________________________MD
Phone Number:_____________________________
Email address:______________________________
Site:______________________________________
RE:  
Patient Unblinding Request for A randomized, double blind phase II trial of Surgery, 
Radiation Therapy plus Temozolomide and Pembrolizumab with and without HSPPC-96 in 
newly diagnosed Glioblastoma (GBM)
I am requesting the following patient to be unblinded: 
Subject ID # ________ 
I am requesting this patient to be unblinded because: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
_____________________
 
Thank you, 
____________________________ 
__________________________
Signature of requesting physician
Date 
I have reviewed this request and agree that the circumstances warrant patient unblinding 


129
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
_______________________ 
_________________________
Signature of approving MD
Date
 
I have reviewed this request but do not agree that the circumstances warrant patient unblinding. 
The reason I am denying this request is: 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
_____________________ 
_______________________ 
_________________________
Signature of disapproving MD
Date


130
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.12 UNBLINDING NOTIFICATION MEMO
MEMORANDUM
DATE:      
_______________  
TO:
__________________________MD
Site:_______________________
FROM:
Lead PI, MD
RE:  Patient Unblinding Notification for protocol titled - A randomized, double blind phase II 
trial of Surgery, Radiation Therapy plus Temozolomide and Pembrolizumab with and without 
HSPPC-96 in newly diagnosed Glioblastoma (GBM)
With concurrence from the Data Safety Monitoring Board, the Lead PI MD has requested 
unblinding for the following patient: 
Subject ID #________ 
Date of unblinding: _________
The patient’s treatment assignment is:
 ________HSPPC-96
 ________Placebo 
Be sure to place this memo in the patient’s clinic or hospital chart following your institution’s 
guidelines. 
Thank you, 
_______________________
 _______________________ 
SIGNATURE
DATE


131
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.13 STUDY PHASES AND CORRELATIVE BLOOD DRAWS


132
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.14 PILL DIARY


133
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025


134
Abbreviated Title: GBM Pembro HSPPC
Version Date:   06/25/2025
16.15  INVESTIGATOR AGREEMENT
I have received and reviewed the Investigator Brochure for Pembrolizumab and HSPPC-96.
I have read this protocol and agree that the study is ethical.
I agree to conduct the study as outlined and in accordance with all applicable regulations and 
guidelines. 
I agree to maintain the confidentiality of all information received or developed in connection 
with this protocol.  
Protocol Title: A randomized, double blind phase II trial of Surgery, Radiation Therapy plus 
Temozolomide and Pembrolizumab with and without HSPPC-96 in newly diagnosed 
Glioblastoma (GBM)
Protocol Version Date:  06/25/2025
_______________________________________           
___________________     
Signature of Principal Investigator
Date
_________________________________________
Name of Principal Investigator (printed or typed)

ICF_001.pdf: 
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