Clinical trial NCT03690869
Conditions: Relapsed Solid Tumor Refractory Solid Tumor Relapsed Central Nervous System Tumor Refractory Central Nervous System Tumor Diffuse Intrinsic Pontine Glioma High Grade Glioma
Keywords: Newly Diagnosed Recurrent Refractory
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-09-24; Completion date: 2023-05-10
Enrollment: 57 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 1:

* To confirm the safety and anticipated recommended phase 2 dose (RP2D) of REGN2810 (cemiplimab) for children with recurrent or refractory solid or Central Nervous System (CNS) tumors
* To characterize the pharmacokinetics (PK) of REGN2810 given in children with recurrent or refractory solid or CNS tumors

Phase 2 (Efficacy Phase):

* To confirm the safety and anticipated RP2D of REGN2810 to be given concomitantly with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
* To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with conventionally fractionated or hypofractionated radiation among patients with newly diagnosed high-grade glioma (HGG)
* To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with re-irradiation in patients with recurrent HGG
* To assess PK of REGN2810 in pediatric patients with newly diagnosed DIPG, newly diagnosed HGG, or recurrent HGG when given in combination with radiation
* To assess anti-tumor activity of REGN2810 in combination with radiation in improving overall survival at 12 months (OS12) among patients with newly diagnosed DIPG
* To assess anti-tumor activity of REGN2810 in combination with radiation in improving progression-free survival at 12 months (PFS12) among patients with newly diagnosed HGG
* To assess anti-tumor activity of REGN2810 in combination with radiation in improving overall survival at OS12 among patients with recurrent HGG

Detailed description:

Arms: arm 1: Patients in both the Solid Tumor Cohort and the CNS Cohort will receive cemiplimab monotherapy. Each Cohort will have 2 subgroups by age (0 to \<12 years, 12 to \<18 years). arm 2: ≥ 3 to \< 12 years cohort and 12 to ≤ 25 years cohort with combination of cemiplimab and radiation therapy arm 3: ≥ 3 to \< 12 years cohort and 12 to ≤ 25 years cohort with combination of cemiplimab and radiation therapy arm 4: ≥ 3 to \< 12 years cohort and 12 to ≤ 25 years cohort with combination of cemiplimab and radiation therapy
Interventions: intervention 1: cemiplimab (monotherapy) intervention 2: cemiplimab (maintenance) intervention 3: Conventional or hypofractionated intervention 4: Re-irradiation
Intervention descriptions: intervention 1: To be administered intravenously as monotherapy in Phase 1 intervention 2: To be administered intravenously in combination with radiation and then used as maintenance therapy intervention 3: Combined with cemiplimab IV administration intervention 4: Combined with cemiplimab IV administration

Protocol documents:
Prot_000.pdf: 
Page 1 of 161 
CONFIDENTIAL 
IND 128123 
A Safety and Pharmacokinetic Study of Single Agent REGN2810 in Pediatric Patients with 
Relapsed or Refractory Solid or Central Nervous System (CNS) Tumors and a Safety and 
Efficacy Trial of REGN2810 in Combination with Radiotherapy in Pediatric Patients with 
Newly Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed High-Grade Glioma, 
or Recurrent High-Grade Glioma 
PNOC Protocol: PNOC 013 (CC#160825) 
Regeneron Study R2810-ONC-1690 
Amendment Number: 3 
Version Date: See appended electronic signature page 
Study Chair 
 
University of California, San Francisco 
550 16th Street, 4th Floor 
San Francisco, California, 94158 
Phone: 
 
 
Co-Chair 
 
, 
Brigham and Women’s / Dana Farber Cancer Center 
, 
Harvard Medical School
Telephone: 
 
Fax: 
 
 
PNOC-Project Leader 
 
University of California, San Francisco 
675 Nelson Rising Lane, Rm402 
San Francisco, California, 94158-0520 
Phone: 
 
 
PNOC-Project Co-Leader 
 
University of California, San Francisco 
1450 3rd Street, HD546, Box 0520 
San Francisco, California, 94158 
Phone: 
 
 
Coordinating Center 
Pacific Pediatric Neuro-Oncology Consortium 
Sandler Neurosciences Building 
675 Nelson Rising Lane, Rm405 
San Francisco, California, 94158-0520 
Phone: 415-502-1600 
PNOC_Regulatory@ucsf.edu 
Statistician 
 
44 Binney Street 
Dana-Farber Cancer Institute CLSB 11015 
Boston, Massachusetts 02115 
Phone: 
 
 
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CONFIDENTIAL 
Pacific Pediatric Neuro-Oncology Consortium Institutions 
Ann & Robert H. Lurie Children’s Hospital of Chicago 
PI: 
 
Co-PI: 
 
Telephone: 
 
Email: 
 
 
Children’s Hospital Los Angeles 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Children’s National Medical Center 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
Dana-Farber Cancer Institute 
Harvard University 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Doernbecher Children’s Hospital 
Oregon Health & Science University 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
Johns Hopkins Hospital 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
Nationwide Children’s Hospital 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Rady Children’s Hospital 
University of California, San Diego 
PI: 
 
Co-PI: 
 
Telephone: 
 
Email: 
 
 
Seattle Children’s Hospital 
University of Washington, Seattle 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
St. Jude Children’s Research Hospital 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
St. Louis Children’s Hospital 
Washington University in St. Louis 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Texas Children’s Hospital 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
The Children’s Hospital of Philadelphia 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
The Hospital for Sick Children 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
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CONFIDENTIAL 
UCSF Benioff Children’s Hospital 
University of California, San Francisco 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
University of Florida 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Children’s Hospital Minnesota 
PI: 
 
Co-PI: 
 
Telephone: 
 
 
 
University of Utah 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
University of Michigan 
C.S. Mott Children's Hospital 
PI: 
 
Co-PI: 
 
Telephone: 
 
E-mail: 
 
 
Participating Sites: 
Massachusetts General Hospital (in connection with DFCI) 
PI: 
 
Telephone: 
  
Email: 
 
 
UCSF Benioff Children’s Hospital Oakland (in connection with UCSF Benioff San Francisco) 
PI: Please see University of California, San Francisco information  
Telephone: 
 
 
University of Minnesota 
PI: 
 
Email: 
 
 
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CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE 
 
Protocol No.: PNOC 013 / Regeneron R2810-ONC-1690 
 
Version Date: See appended electronic signature page 
 
1. I agree to follow this protocol version as approved by the UCSF Protocol Review 
Committee (PRC), Institutional Review Board (IRB), and Data and Safety Monitoring 
Committee (DSMC).  
2. I will conduct the study in accordance with Good Clinical Practices (ICH-GCP) and the 
applicable IRB, ethical, federal, state, and local regulatory requirements.  
3. I certify that I, and the study staff, have received the required training to conduct this 
research protocol.  
4. I agree to maintain adequate and accurate records in accordance with IRB policies, 
federal, state and local laws and regulations. 
 
Study Chair 
 
_______________________________________ 
Printed Name 
 
_______________________________________ 
Signature 
__________ 
Date 
 
 
 
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CONFIDENTIAL 
PROTOCOL SIGNATURE PAGE – PARTICIPATING SITES 
 
Protocol No.: PNOC 013 / Regeneron R2810-ONC-1690 
 
Version Date: See appended electronic signature page 
Participating Site(s) 
 
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP) and the applicable IRB, ethical, federal, state, and local regulatory 
requirements.  
 
Principal Investigator 
Site 
_______________________________________ 
Printed Name 
______________________________ 
Institution Name 
_______________________________________ 
Signature 
__________ 
Date 
 
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CONFIDENTIAL 
AMENDMENT HISTORY  
Amendment 3 
The following is a summary of changes made for amendment 3 of the PNOC 013 (R2810-ONC-1690) protocol. 
The aim of this amendment is to streamline the structure and language of the protocol, to improve the clarity of 
the study design, and consistency of study conduct. Additionally, changes that impact the design of the study 
have been made. 
The changes in this amendment and their rationale are detailed below. Changes are categorized as changes to 
study design, clarifications of study design, structural changes, and other changes, and are listed by order 
of first appearance in the protocol. 
 
Changes to Study Design 
Changes to Study Design 
Change and Rationale 
Sections Changed 
If a patient treated with combination therapy 
experiences AE(s) that are likely to be related to only 
one of the therapies (in the opinion of the 
investigator), the patient may continue treatment 
with the therapy determined not to be the cause of the 
AE(s). In addition, if the AE is an infusion-related 
reaction that is likely only related to REGN2810 and 
not to combination therapy (in the opinion of the 
investigator), this will not be considered a DLT of 
the combination therapy. 
Section 4.5 Off-Treatment Criteria 
Amended the following regarding off-treatment 
criteria: 
 
Patients may be allowed to continue 
treatment after a treatment delay of ≥28 
days, after discussion with the sponsor and 
The Pacific Pediatric Neuro Oncology 
Consortium (PNOC) 
Section 4.5 Off-Treatment Criteria 
Patients who begin an anticancer therapy not 
specified in protocol will be considered off study. 
Section 4.6 Off-Study Criteria 
Patients with documented allergic or acute 
hypersensitivity reaction attributed to antibody 
treatments are now permitted entry into the study. 
Upon further consideration and in light of the fully 
human nature of REGN2810, it is unlikely that 
patients with prior allergic reaction to antibody 
treatment will have an increased risk of reaction to 
REGN2810 compared with other patients.  
Section 5.2 Exclusion Criteria 
Section 7.2.1 Allergic Reaction or Hypersensitivity in 
Patients with Prior Reaction(s) to Antibody Treatment 
Section 8.2.1.2 Medical History 
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Changes to Study Design 
Change and Rationale 
Sections Changed 
To ensure appropriate management of these patients 
who are now permitted in the study, prior history of 
antibody reaction will be documented as medical 
history. In addition, treatment will be temporarily 
suspended following any evidence of an allergic 
reaction or hypersensitivity to REGN2810, and the 
sponsor should be informed as soon as possible to 
discuss patient management.  
Amended exclusion criteria to clarify that, for 
patients with newly diagnosed HGG, the first study 
treatment should occur within 28 days of the date of 
definitive surgery. This criterion was implied but not 
explicitly stated. 
Section 5.1.3.2 Newly Diagnosed HGG (Cohorts G 
and H) Only 
Section 10.5 Timing 
Either serum or urine pregnancy test may be used to 
assess pregnancy during screening, and the window 
for a negative pregnancy test has been widened to 14 
days from cycle 1 day 1 (C1D1). In addition, all 
subsequent pregnancy tests are allowed a window of 
+/-14 days. 
Section 5.2 Exclusion Criteria 
S 
Table 11 Schedule of Events for Phase 1 
Table 12 Schedule of Events for the Efficacy Phase: 
REGN2810 + Conventionally Fractionated Radiation 
Table 13 Schedule of Events for the Efficacy Phase: 
REGN2810 + Hypofractionated Radiation or Re-
Irradiation 
Patients with prior idelalisib treatment are now 
permitted entry into the study. The cemiplimab risk-
benefit profile has evolved and is now considered 
positive for patients who have had prior treatment 
with idelalisib. 
Section 5.2 Exclusion Criteria 
The infusion time for REGN2810 has been amended 
to 
provide 
greater 
institutional 
flexibility. 
REGN2810 infusion should occur over at least 30 
minutes (window: +/-5 minutes). The infusion time 
may exceed 30 minutes as needed to conform with 
institutional standards. 
Section 6.1 REGN2810 Administration 
Table 9 REGN2810 Administration 
Clarified that patients may not receive live vaccines 
while on therapy and for 3 months after stopping 
therapy. Patients are currently prohibited from 
receiving live vaccines within 28 days of study 
registration; this prohibition clarified the original 
intent of the study (on-treatment and post-treatment 
prohibition). 
Section 6.3 Prohibited Therapies 
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Changes to Study Design 
Change and Rationale 
Sections Changed 
On-treatment serum C-reactive protein (CRP) 
collection will be required only on the first day of 
each cycle. 
Table 11 Schedule of Events for Phase 1 
Table 12 Schedule of Events for the Efficacy Phase: 
REGN2810 + Conventionally Fractionated Radiation 
Table 13 Schedule of Events for the Efficacy Phase: 
REGN2810 + Hypofractionated Radiation or Re-
Irradiation 
End of Treatment has been redefined as the day it is 
confirmed that a patient will discontinue future 
dosing, regardless of the reason for discontinuation. 
Table 11 Schedule of Events for Phase 1 
Table 12 Schedule of Events for the Efficacy Phase: 
REGN2810 + Conventionally Fractionated Radiation 
Table 13 Schedule of Events for the Efficacy Phase: 
REGN2810 + Hypofractionated Radiation or Re-
Irradiation 
Table 14 PK and ADA Collection Schedule for Phase 
1: Patients 0 to 2 Years of Age (or Per Institutional 
Guidelines) 
Table 15 and PK and ADA Collection Schedule for 
Phase 1: Patients >2 to <18 Years of Age 
Table 16 PK and ADA Collection Schedule for the 
Efficacy Phase 
Section 8.1.5 Footnotes for Table 14, Table 15, and 
Table 16 (PK and ADA Collection Schedules), 
footnote #2, #5 
Section 8.1.6 End of Treatment Visit 
The following changes and clarifications have been 
made regarding the collection of samples for 
Pharmacokinetic (PK) and Anti-drug Antibodies 
(ADA) analysis: 
 For patients who continue receiving REGN2810 
beyond cycle 12, on-treatment PK samples will 
be collected on cycles 16 and 24 (rather than 
every 3 cycles) 
 Clarified that in Phase 1, the time 1 PK sample 
should be collected pre-dose (rather than at the 
end of infusion) 
  
 Clarified that a PK sample will be taken at the 
first in-clinic follow-up visit. Additional PK 
samples will be taken at in-clinic visits after End 
Section 8.1.4 
Pharmacokinetic 
and 
Anti-Drug 
Antibody Sample Collection 
Table 14 PK and ADA Collection Schedule for Phase 
1: Patients 0 to 2 Years of Age (or Per Institutional 
Guidelines) 
Table 15 and PK and ADA Collection Schedule for 
Phase 1: Patients >2 to <18 Years of Age 
Table 16 PK and ADA Collection Schedule for the 
Efficacy Phase 
Section 8.1.5 Footnotes for Table 14, Table 15, and 
Table 16 (PK and ADA Collection Schedules), 
footnote #2, #5 
 
 
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Changes to Study Design 
Change and Rationale 
Sections Changed 
of Treatment (EOT) that are at least 3 weeks 
apart. 
Delineated that concomitant medications must be 
captured from signing of informed consent through 
the 30-day toxicity check. 
Section 8.2.1.8 Concomitant Medications 
 
 
Urinalysis will involve a dipstick urine test with 
reflex to microscopic urinalysis in the event of 
abnormal findings. 
Section 8.2.3 Laboratory Procedures 
Safety reporting requirements have been amended 
such that all AEs will be recorded/reported if they 
occur from the time the informed consent is signed 
until 90 days after the end of study treatment or until 
the patient receives another systemic anticancer 
therapy, whichever is earlier. In addition, clarified 
that AEs attributable to disease progression will not 
be recorded/reported. 
Section 9.4.1 Adverse Events 
Section 9.4.6 Follow-Up 
Study endpoints have been updated in order to better 
differentiate them from study objectives. Endpoints 
now provide an explicit description of the outcomes 
that will be measured and the methods or criteria that 
will be used to measure them. These updates are in 
line with the current planned outcome analyses of the 
study and are not intended to represent deviations 
from the study’s objectives.  
Abstract – Primary Endpoints, Secondary Endpoints, 
Exploratory Endpoints 
Section 12.1 Study Endpoints 
Section 12.1.1 Primary Endpoints 
Section 12.1.2 Secondary Endpoints 
Section 12.1.3 Exploratory Endpoints 
Section 12.7 Analysis of Primary Endpoints 
Section 12.8 Analysis of Secondary Endpoints 
Section 12.9 Analysis of Exploratory Endpoints 
Study reservation and registration procedures have 
been updated to reflect current process. 
Section 15.2 Reservation and Registration Process 
 
Clarifications of Study Design 
Clarifications of Study Design 
Change and Rationale  
Sections Changed 
Experimental design schema were updated to better 
clarify the design of the study. 
Figure 1 Trial Enrollment in Phase 1: Recurrent or 
Refractory Solid or Central Nervous System  
Figure 2 Trial Enrollment in the Efficacy Phase: Newly 
Diagnosed Diffuse Intrinsic Pontine Glioma 
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Clarifications of Study Design 
Change and Rationale  
Sections Changed 
Figure 3 Trial Enrollment in the Efficacy Phase: Newly 
Diagnosed High-Grade Glioma 
Figure 4 Trial Enrollment in the Efficacy Phase: 
Recurrent High-Grade Glioma 
Figure 5 Study Design, Phase 1 
Figure 6 Study Design, Efficacy Phase 
Amended exploratory quality of life objective to 
clarify that both younger and older cohorts will be 
assessed by quality of life instruments in this study. 
Abstract –  Exploratory Objectives 
Section 1.3 Exploratory Objectives 
Additional information was provided, and structural 
reorganizations were made, to clarify the design of 
the study, including: 
 Letter designations for each cohort 
 Dedicated sub-sections describing the dose 
escalation design (Phase 1 and Efficacy Phase), 
dose escalation rules (Phase 1 and Efficacy 
Phase), timing of enrollment (Efficacy Phase), 
and expansion cohorts (Efficacy Phase) 
 Description of the dose escalation review 
committee and review process 
 Description of the Simon two-stage design 
 Explicit delineation of dose escalation rules 
according to both age cohort and study phase 
 Dedicated sub-sections describing dose-limiting 
toxicity windows and definitions  
 Dedicated sub-sections describing off-treatment 
and off-study criteria 
Abstract – Study Design 
Section 4 Study Design (and all sections therein) 
Table 1 Patient Cohorts 
Table 2 Patient Cohorts in Phase 1 
Table 3 Patient Cohorts in the Efficacy Phase 
Table 4 Dose Escalation Rules: Cohorts Age <12 
Years, Phase 1 
Table 5 Dose Escalation Rules: Cohorts Age <12 
Years, Efficacy Phase 
Table 6 Dose Escalation Rules: Cohorts Age ≥12 
Years, Phase 1 and Efficacy Phase 
Table 7 Criteria for Dose-Limiting Toxicity 
Section 4.1 Characteristics (deleted) 
Section 6.2 Definition of Dose-Limiting Toxicity 
(deleted) 
Section 6.3 Dose Escalation Guidelines (deleted) 
Section 9.5 Off-Treatment Criteria (deleted) 
Section 9.6 Off-Study Criteria (deleted) 
Clarified that expansion enrollment will include at 
least 100 patients (at least 40 patients with newly 
diagnosed DIPG, at least 40 with newly diagnosed 
HGG, and at least 20 with recurrent HGG). 
Additionally, clarified the breakdown of patients 
within each cohort, for both Phase 1 and the Efficacy 
Phase. 
Abstract – Number of Patients 
Section 4.7 Number of Patients 
Section 12.2 Sample Size 
To ensure adequate imaging collection while 
minimizing duplicative data, imaging requirements 
Section 4 Study Design 
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Clarifications of Study Design 
Change and Rationale  
Sections Changed 
have been clarified as follows (applies to both study 
phases): 
 Imaging does not need to be taken or recorded 
every treatment cycle, but should occur once 
every 12 weeks (window: -2 weeks) while 
patients are on treatment 
 Imaging should be performed at the EOT visit, 
and during the off-treatment follow-up period 
approximately once every 12 weeks (or per 
institutional standards) for up to 52 weeks 
 Imaging should be performed at the time of 
disease progression 
 Imaging during C1D1 is only required if prior 
imaging occurred more than 14 days from C1D1. 
If imaging has been taken within 14 days of 
C1D1 (ie, during the screening period), imaging 
does not need to be performed on C1D1 
Section 8.1.2 Footnotes for Table 10 (Schedule of 
Events for Phase 1) - Footnote #6 
Section 8.1.3 Footnotes for Table 11 and Table 12 
(Schedules of Events for the Efficacy Phase) - Footnote 
#7 
 
Clarified that quality of life will be measured by 
Pediatric Quality of Life (PedsQL) for patients 2 to 
<18 years of age) and by Functional Assessment of 
Cancer Therapy-Brain (FACT-Br) for adult patients 
(>18 years of age). 
Section 4 Study Design 
Section 8.1.2 Footnotes for Table 11 (Schedule of 
Events for Phase 1) - Footnote #2 
Section 8.1.3 Footnotes for Table 12 and Table 13 
(Schedules of Events for the Efficacy Phase) - Footnote 
#3 
Section 8.2.1.9 Quality of Life Assessment 
Clarified that cohorts are defined by both age and 
tumor type. 
Section 4.1 Phase 1 Study Design 
Section 4.2 Efficacy Phase Study Design 
Clarified that cohort recommended phase 2 dose 
(RP2D) may be lower than the maximum tolerated 
dose (MTD) if indicated by pharmacokinetic 
analyses. 
Section 4.1.2 Dose Escalation Rules in Phase 1 
Section 4.2.2 Dose Escalation Rules in Efficacy Phase 
Clarified that radiation centers must be approved by 
PNOC.  
Section 4.2 Efficacy Phase Study Design 
Section 8.2.2.2 Radiation Therapy 
Section 10.1 General Guidelines 
Clarified that the timing of enrollment for age 3 to 
<12 Efficacy Phase cohorts will begin once the 
RP2D is determined for the corresponding age within 
the Central Nervous System (CNS) tumor cohorts. 
Section 4.2.3 Timing of Initial Enrollment 
 
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Clarifications of Study Design 
Change and Rationale  
Sections Changed 
Clarified that disease progression must be confirmed 
before patient will be taken off treatment for disease 
progression  
Section 4.5 Off-Treatment Criteria 
Clarified that archival tissue is acceptable to satisfy 
biopsy requirement for both Phase 1 and the Efficacy 
Phase. 
Section 5.1 Inclusion Criteria 
 
Removed duplicative inclusion criterion regarding 
corticosteroid use. Retained corticosteroid exclusion 
criterion. 
Section 5.1 Inclusion Criteria 
Section 5.2 Exclusion Criteria 
Clarification to inclusion/exclusion criteria: for 
newly diagnosed DIPG cohorts, patients should have 
no prior therapy or radiation before study registration 
Section 5.1.3.1 Newly Diagnosed DIPG (Cohorts E 
and F) Only 
Section 5.1.3.2 Newly Diagnosed HGG (Cohorts G 
and H) Only 
Clarified that patients are excluded from the study if 
they have received an investigational anticancer 
agent (ie, investigational agents not intended to 
treat/palliate cancer are not exclusionary). 
Section 5.2 Exclusion Criteria 
 
Exclusion 
criterion 
describing 
contraception 
requirements has been updated to comply with 
Clinical Trial Facilitation Group (CTFG) guidance. 
Section 5.2 Exclusion Criteria 
 
Clarified that lengthening of REGN2810 infusion 
time may be considered in managing Grade 2 
infusion-related reactions. 
Table 10 Guidelines for Dose Modification and Re-
Initiation of Treatment in Case of Suspected 
REGN2810 Toxicity 
Section 7.2 Infusion-Related Reactions 
To 
minimize 
redundancy 
and 
improve 
clarity/consistency 
regarding 
the 
required 
assessments and data collection timepoints in this 
study, the schedules of events have been updated as 
follows: 
 The Efficacy Phase schedules and corresponding 
footnotes have been consolidated. There are now 
two Efficacy Phase tables in total, based on 
treatment arm (conventionally fractionated 
radiation versus hypofractionated radiation) 
 Some assessments have been reordered to 
consolidate the number of assessment categories 
 Clarification has been made that, except where 
noted in the footnotes, all visit days (including 
Section 8 Schedule of Events and Procedures 
Section 8.1 Schedule of Events / Treatment Plan 
Table 11 Schedule of Events for Phase 1 
Section 8.1.2 Footnotes for Table 11 (Schedule of 
Events for Phase 1) 
Table 12 Schedule of Events for the Efficacy Phase: 
REGN2810 + Conventionally Fractionated Radiation 
Table 13 Schedule of Events for the Efficacy Phase: 
REGN2810 + Hypofractionated Radiation or Re-
Irradiation 
Section 8.1.3 Footnotes for Table 12 and Table 13 
(Schedules of Events for the Efficacy Phase) 
Section 9.1Study Calendar for Phase 1 (deleted) 
Section 9.2 Study Calendar for Efficacy Phase 
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Clarifications of Study Design 
Change and Rationale  
Sections Changed 
study drug administration and assessments) are 
allowed a window of +/-3 days 
 Line items have been added for height and 
weight 
  “Toxicity Assessment” has been renamed 
“Adverse Events” 
 To avoid duplicative data collection, the 
“baseline” column has been removed; these 
samples will be collected predose on C1D1 
 To avoid schedule overlaps, the toxicity check 
visit has been defined as 30 days after the end of 
treatment visit 
 The randomization column has been removed; 
randomization has been marked during the 
screening period 
 The “tissue collection” column has been 
removed; collection time points for tumor tissue, 
genomic DNA, and circulating tumor DNA have 
been marked within the corresponding clinic 
visits 
 All footnotes have been clarified to align sample 
collection requirements with the schedule 
provided in the tables 
 Clarified that the visit window for follow-up 
visits is +/-7 days 
 Various typographical, grammatical, formatting, 
and editorial changes were implemented 
Table 6: CYCLES 1 & 2: DIPG Cohort Arm 1 (XRT 
30 fractions, total 42 days) (deleted) 
Table 7: CYCLES 1 & 2: DIPG Cohort Arm 2 (XRT 
13 fractions, total 17 days) (deleted) 
Table 8: CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 1 (XRT 33 fractions, total 45 days) 
(deleted) 
Table 9: CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 2 (XRT 13 fractions, total 17 days) 
(deleted) 
Table 10: CYCLES 1 & 2: Recurrent HGG Cohort 
(XRT 10 fractions, 14 days) (deleted) 
Table 11: CYCLE 3 and Future Cycles Thereafter 
(deleted) 
Clarified that a) all patients must undergo a 30-day 
toxicity check, regardless of the reason for treatment 
cessation, and b) the 30-day toxicity check can be 
conducted by clinic visit, telemedicine encounter, or 
telephone encounter. 
Section 8.1.7 30-Day Toxicity Check 
Clarified that circulating tumor DNA (ctDNA) 
samples will be collected predose at C1D1 and at any 
time scheduled or repeat/confirmatory imaging is 
performed (except during screening). 
Table 11 Schedule of Events for Phase 1 
Section 8.1.2 Footnotes for Table 11 (Schedule of 
Events for Phase 1) - Footnote #9 
Table 12 Schedule of Events for the Efficacy Phase: 
REGN2810 + Conventionally Fractionated Radiation 
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Clarifications of Study Design 
Change and Rationale  
Sections Changed 
Table 13 Schedule of Events for the Efficacy Phase: 
REGN2810 + Hypofractionated Radiation or Re-
Irradiation 
Section 8.1.3 Footnotes for Table 12 and Table 13 
(Schedules of Events for the Efficacy Phase) - Footnote 
#10 
Clarified that periodic meetings of the study safety 
monitoring team will be conducted to review 
emerging safety data of the study treatments. 
Section 9.6 Safety Monitoring 
Clarified language surrounding statistical analysis; 
analysis will be conducted based on each radiation 
therapy arm irrespective of cohort or age group. 
Section 12.2 Sample Size 
Section 12.3 Sample Size Justification and Accrual 
Rate 
Clarified in the statistical analysis section that PK 
analysis is a primary objective in the Efficacy Phase. 
Section 12.7.3 Efficacy Phase: Pharmacokinetics 
Clarified the meaning of the term “enrollment” as 
appropriate (C1D1, screening, etc). 
Throughout the protocol. 
Clarified that data submission timelines represent 
targets, but may vary according to individual site. 
Appendix 3 REQUIRED DATA AND TIME TABLE 
FOR SUBMISSION 
 
Structural Changes 
Structural Changes 
Change and Rationale for Change 
Sections Changed 
Section headers were added and/or modified to the 
background and rationale sections of the protocol, 
and some text was reordered, to improve readability. 
Section 2 Background (and sections therein) Section 3 
Rationale (and sections therein) 
The rationale for radiation therapy fractionation 
schedules selected for this study was moved from the 
background section to the rationale section.  
Section 3.3 Radiotherapy Regimen Selection 
Section 2.3 Radiotherapy (deleted) 
Rationale, 
study 
procedures, 
and 
statistical 
considerations for correlative/biomarker analyses 
have been placed in the corresponding sections of the 
protocol related to rationale, study procedures, and 
statistical considerations. 
Section 3.5 Correlative Exploratory Studies 
Section 8.2.6 Exploratory Procedures  
Section 12.4 Exploratory Endpoints 
Section 12.9 Analysis of Exploratory Endpoints 
Section 13 Biomarker, Correlative, and Special Studies 
(deleted) 
To improve clarity of inclusion/exclusion criteria, 
the following changes have been made: 
Section 5.1 Inclusion Criteria 
Section 5.1.1 All Patients (Phase 1 and Efficacy Phase) 
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Structural Changes 
Change and Rationale for Change 
Sections Changed 
 Placed the criteria in a dedicated section of the 
protocol 
 Moved inclusion under “all patients” sub-section 
to the top of the inclusion/exclusion criteria 
section, to clarify that these criteria apply to 
patients in both Phase 1 and the Efficacy Phase 
 
Section 5.1.2 Phase 1 
Section 5.1.3 Efficacy Phase 
Section 5.1.3.1 5.1.3.1. Newly 
Diagnosed 
DIPG 
(Cohorts E and F) Only 
Section 5.1.3.2 Newly Diagnosed HGG (Cohorts G 
and H) Only 
Section 5.1.3.3 Recurrent HGG Cohorts (I and J) Only 
Section 5.2 Exclusion Criteria 
 
Section 4.3 Inclusion Criteria (deleted) 
Section 4.3.1. Phase 1 – Safety/RP2D (deleted)  
Section 4.3.2.1 DIPG Cohort (deleted) 
Section 4.3.2.2 HGG Cohort (deleted) 
Section 4.3.2.3 All Patients (deleted) 
Section 4.4 Exclusion Criteria (For All Patients) 
(deleted) 
To 
improve 
document 
organization, 
dosing 
modification guidelines have been merged with 
information concerning study drug administration. In 
addition, the section title was reworded to clarify that 
dose modification guidelines apply to both study 
phases. 
Section 6.2 REGN2810 Dose Modifications and 
Delays 
Section 8 Dosing Modifications and Delays for the 
Efficacy Phase of the Study (deleted) 
To improve clarity, section headings were added to 
the supportive care/adverse event management 
section. 
Section 6.3 Study Supportive Care and Adverse Event 
Management Guidelines 
To improve ease of use, the following changes to PK 
tables and descriptions have been made: 
 Sample collection tables for PK and ADA have 
been moved to the schedule of events section of 
the protocol 
 Information pertaining to PK and ADA 
procedures has been moved to the study 
procedures section of the protocol 
 Footnotes have been consolidated in a single set 
of footnotes for PK/ADA collection tables 
Section 8.1.4 
Pharmacokinetic 
and 
Anti-Drug 
Antibody Sample Collection 
Table 14 PK and ADA Collection Schedule for Phase 
1: Patients 0 to 2 Years of Age (or Per Institutional 
Guidelines) 
Table 15 and PK and ADA Collection Schedule for 
Phase 1: Patients >2 to <18 Years of Age 
Table 16 PK and ADA Collection Schedule for the 
Efficacy Phase 
Section 8.1.5 Footnotes for Table 14, Table 15, and 
Table 16 (PK and ADA Collection Schedules) 
Section 8.2.5 Pharmacokinetic and Immunogenicity 
Procedures 
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Structural Changes 
Change and Rationale for Change 
Sections Changed 
Section 3.1.2 Anti-drug Antibody Measurements and 
Samples (deleted) 
Section 12 PHARMACOKINETICS AND ANTI-
DRUG ANTIBODY STUDIES (deleted) 
Section 12.1. Drug Concentration Measurements and 
Samples (deleted) 
Section 12.2. Analysis of Anti-Drug Antibody Data 
(deleted) 
To avoid redundancy and internal inconsistencies, 
the study procedures section has been revised to 
include information concerning procedure execution 
and not timing of procedures. 
Section 8.2 Study Assessments and Procedures (and all 
sections therein) 
Section 9.3 Observations and Procedures (deleted) 
 
To improve document flow, the dedicated sections 
describing the procedural guidelines for radiation 
therapy and disease assessment per Response 
Evaluation Criteria in Solid Tumors (RECIST) have 
been placed near each other and earlier in the 
protocol. 
Section 10 Radiation Therapy Guidelines 
Section 11 Evaluation Criteria 
The per-protocol fractionation schedule for Efficacy 
Phase cohorts has been moved from the study 
procedures section to the radiation guidelines 
section, to avoid redundancy. Radiation therapy 
treatment lengths have also been moved into this 
section, from their previous location in the titles of 
schedules of events tables. 
Section 10.2 Protocol-Defined Dose and Fractionation 
Schedules 
Section 10.8.2 Prescribed Dose and Fractionation 
Section 9.3.4. Cycle 1 Day 1 Visit and Weekly During 
Cycle 1 and Through the DLT Period (Within 3 Days 
of Therapy Initiation and +/-3 Days Thereafter) – All 
Patients (deleted) 
Response criteria headings were renumbered to 
improve readability, and guidance schematic was 
reformatted. 
Section 11.4 Response Criteria (and sections therein) 
Figure 7 Additional Guidelines for Response Criteria 
for CNS Tumors 
To improve document flow, trial registration 
procedures have been moved to a later section of the 
protocol, adjacent to information regarding reporting 
and exclusions. 
Section 15 Registration Procedures 
Section 5 Registration Procedures (deleted) 
References and appendices have been reordered 
based on the order in which they are cited in the 
protocol. 
Section 18 References 
Appendix 1 PERFORMANCE STATUS CRITERIA 
Appendix 2 ADVERSE EVENT MANAGEMENT  
Appendix 3 REQUIRED DATA AND TIME TABLE 
FOR SUBMISSION 
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Structural Changes 
Change and Rationale for Change 
Sections Changed 
Appendix 4 PNOC INSTITUTIONS, REQUIRED 
REGULATORY DOCUMENTS 
Appendix 5 INFORMATION SHEET ON POSSIBLE 
DRUG INTERACTIONS 
 
Other Changes 
Other Changes 
Change and Rationale for Change 
Sections Changed 
Duration of Study in abstract has been defined on a 
per-patient basis. 
Abstract – Duration of Study (Per Patient) 
Background section was updated to reflect most 
recent cumulative safety data and marketing 
authorization status for REGN2810, with other 
editorial changes and updates made to improve 
readability. 
Section 2.3 REGN2810, a Human Monoclonal 
Antibody to Programmed Death-1 (PD-1) 
Section 2.5 REGN2810 Clinical Studies 
 
Specifications of REGN2810 infusion bag stability 
were removed; corresponding information can be 
found in the pharmacy manual. 
Section 13.2.6 Stability 
Typographical, grammatical, formatting, and other 
editorial updates were made as needed. 
Throughout the protocol. 
 
Amendment 2 
The following is a summary of changes made for amendment 2 of the PNOC 013 (R2810-ONC-1690) protocol. 
This study is being run in collaboration with the Pacific Pediatric Neuro-Oncology Consortium (PNOC). The 
primary objective of this amendment is to improve the applicability of our adverse event management guidelines 
to a pediatric population. The changes and rationale for changes in this amendment are detailed below. 
Change and Rationale for Change 
Sections Changed 
Guidelines for treatment-emergent adverse events 
(TEAEs) management are detailed in Appendix 5, 
and 
all 
other 
sections 
that 
discuss TEAE 
management were revised to refer to Appendix 5 
Section 7 General Supportive Care Guidelines (revised 
title) 
Section 8.1.1 Criteria for Dose-Modification in Case of 
Suspected REGN2810 Toxicity and Re-Initiation of 
Treatment 
Appendix 5 Adverse Event Management 
Table 5 Criteria for Dose Modification (deleted) 
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Change and Rationale for Change 
Sections Changed 
Updated the RECIST criteria with new references 
added to bring criteria to be more in line with the 
most recent RECIST guidelines and updated other 
imaging instructions as needed. 
Section 14.2.1 Solid Tumors 
Section 14.3.1 Chest X-Ray 
Section 14.3.2 Conventional CT and MRI 
Section 14.3.3 Ultrasound (addition)  
Section 14.3.4 Positron Emission Tomography-
Computed Tomography (formerly Section 14.3.3)  
Section 14.5.2 Complete Response 
Section 14.5.3 Non-complete response and Non-
progressive disease 
Section 14.5.4 Progressive Disease 
A special consideration was added in the General 
Supportive Care Guidelines for pseudoprogression 
Section 7 General Supportive Care Guidelines (revised 
title)  
Changed specification that tumor imaging must be 
performed within 14 days of enrollment. Imaging 
must be repeated if performed >14 days from 
enrollment  
Section 9.3.1 Screening Visit – Within 14 Days Prior 
to Enrollment – All Patients 
Section 9.3.3 Baseline Prior to Therapy Initiation – 
Within 3 Days Prior to Starting Therapy – All Patients 
Removed Surgery and Survival and removed weekly 
visits during 4-week post XRT DLT period from the 
Study Calendars 
Table 6 CYCLES 1 & 2: DIPG Cohort Arm 1 (XRT 30 
fractions, total 42 days) (formerly Table 7) 
Table 7 CYCLES 1 & 2: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days) (formerly Table 8) 
Table 8 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 1 (XRT 33 fractions, total 45 days) 
(formerly Table 9) 
Table 9 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 2 (XRT 13 fractions, total 17 days) 
(formerly Table 10) 
Table 10 CYCLES 1 & 2: Recurrent HGG Cohort 
(XRT 10 fractions, 14 days) (formerly Table 11) 
Added collection of ADA samples prior to infusion 
(pre-dose) at cycle 2 in response to request by health 
authorities for earlier ADA assessments  
Table 12 Blood PK and ADA Collection Schedule in 
Phase 1 for Patients 0 to 2 Years of Age 
Table 13 Blood PK and ADA Collection Schedule in 
Phase 1 for Patients >2 years of Age 
Table 14 Blood PK and ADA Collection Schedule for 
the Efficacy Phase 
Added a consent to the screening in the Study 
Calendar for the newly diagnosed HGG Cohort 
Arm 1, Arm 2, and the recurrent HGG Cohort 
Table 8 CYCLES 1 & 2: Newly Diagnosed HGG 
Cohort Arm 1 (XRT 33 fractions, total 45 days) 
(formerly Table 9) 
Table 9 CYCLES 1 & 2: Newly Diagnosed HGG 
Cohort Arm 2 (XRT 13 fractions, total 17 days) 
(formerly Table 10) 
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CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed 
Table 10 CYCLES 1 & 2: Recurrent HGG Cohort 
(XRT 10 fractions, 14 days) (formerly Table 11) 
Clarified that the younger age group applies to 
patients <12 years old 
Section 6.3.1 Dose Escalation for the <12 years Age 
Cohorts of the Phase 1 and Efficacy Phases (revised 
title) 
Table 2 Dose Escalation for the <12 Years Age Cohorts 
( revised title) 
Specified that tissue collection from biopsy or 
surgery will be performed per standard of care 
Section 9.3.1 Screening Visit – Within 14 Days Prior 
to Enrollment – All Patients 
Table 5 Study Calendar for Phase 1 (formerly Table 6) 
– Footnote a  
Table 6 CYCLES 1 & 2: DIPG Cohort Arm 1 (XRT 30 
fractions, total 42 days) (formerly Table 7) – Footnote 
a 
Table 7 CYCLES 1 & 2: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days) (formerly Table 8) – Footnote 
a 
Table 8 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 1 (XRT 33 fractions, total 45 days) 
(formerly Table 9) – Footnote a 
Table 9 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 2 (XRT 13 fractions, total 17 days) 
(formerly Table 10) – Footnote a 
Table 10 CYCLES 1 & 2: Recurrent HGG Cohort 
(XRT 10 fractions, 14 days) (formerly Table 11) – 
Footnote a  
Removed collection of blood for ADA and PK 
analysis at the screening visit 
Section 9.3.1 Screening Visit – Within 14 Days Prior 
to Enrollment – All Patients 
Clarified that disease status assessment on cycle 2 
day 1 was to be performed as indicated per 
randomization 
Section 9.3.5 Cycle 2 Day 1 Visit and Prior to Every 
Cycle Thereafter (Within 3 Days Prior to Each Cycle) 
– All Patients 
Added 
references 
to 
‘legally 
authorized 
representative,’ in addition to the patient, where 
applicable, since the study enrolls a pediatric patient 
population  
Section 3.2.2 Biomarker Procedures 
Section 4.3.2.3 All Patients 
Section 5.1 General Guidelines 
Section 9.5 Off-Treatment Criteria 
Section 9.6 Off-Study Criteria 
Section 13.2.2 Exploratory Biomarker Procedures 
Section 17.2.4 Regulatory Documentation 
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CONFIDENTIAL 
Change and Rationale for Change 
Sections Changed 
Revised, added, or removed text, including 
redundant text, for clarity and accuracy. Made 
editorial revisions throughout. 
List of Pacific Pediatric Neuro-Oncology Consortium 
Institutions) 
Abstract- Number of Patients 
Section 3 Rationale 
Section 3.2.2 Biomarker Procedures 
Section 3.2.3 Circulating Cytokine Procedures 
Section 4.1 Characteristics 
Section 4.3.2.3 All Patients 
Section 5.2 Reservation and Registration Process 
Section 7 General Supportive Care Guidelines (revised 
title) 
Section 9.3.4 Cycle 1 Day 1 Visit and Weekly During 
Cycle 1 and Through the DLT Period (Within 3 Days 
of Therapy Initiation and +/-3 Days Thereafter) – All 
Patients 
Section 9.3.5 Cycle 2 Day 1 Visit and Prior to Every 
Cycle Thereafter (Within 3 Days Prior to Each Cycle) 
– All Patients 
Section 9.3.7 End of Treatment Visit 
Section 9.5 Off-Treatment Criteria 
Section 9.6 Off-Study Criteria 
Section 10.7 Investigator Alert Notification 
Section 13.2.2 Exploratory Biomarker Procedures 
Section 13.2.3 Exploratory Circulating Cytokine 
Procedure 
Section 
14.1.1.3 
Immunotherapy 
Response 
Assessment in Neuro-Oncology Criteria 
Section 14.2.1 Solid Tumors 
Section 14.2.1.3 Non-Measurable Disease 
Section 14.2.2 Target Lesions 
Section 14.2.3 Non-Target Lesions 
Section 14.3 Methods for Evaluation of Measurable 
Disease 
Section 14.3.5 Tumor Markers 
Section 14.3.6 Cytology and Histology 
Section 14.3.7 FDG-PET 
Section 14.4 Response Criteria for Patients with Solid 
Tumors and Measurable Disease 
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Change and Rationale for Change 
Sections Changed 
Section 14.4.1.3 Progressive Disease 
Section 
14.6.1 
Metaiodobenzylguanidine-Positive 
Lesions 
Section 14.6.5 Overall Response 
Section 14.8 Response Criteria for Central Nervous 
System Tumors 
Section 17.2.4 Coordinating Center Documentation 
Distribution (deleted) 
Section 17.2.4 Regulatory Documentation 
Table 1 Dose Scheme for Phase 1 and Efficacy Phase  
Table 5 Study Calendar for Phase 1 (formerly Table 6) 
Table 6 CYCLES 1 & 2: DIPG Cohort Arm 1 (XRT 30 
fractions, total 42 days) (formerly Table 7) 
Table 7 CYCLES 1 & 2: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days) (formerly Table 8) 
Table 8 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 1 (XRT 33 fractions, total 45 days) 
(formerly Table 9) 
Table 9 CYCLES 1 & 2: Newly diagnosed HGG 
Cohort Arm 2 (XRT 13 fractions, total 17 days) 
(formerly Table 10) 
Table 10 CYCLES 1 & 2: Recurrent HGG Cohort 
(XRT 10 fractions, 14 days) (formerly Table 11) 
Table 11 CYCLE 2 and Future Cycles Thereafter 
Table 13 Blood PK and ADA Collection Schedule in 
Phase 1 for Patients >2 years of Age 
Table 14 Blood PK and ADA Collection Schedule for 
the Efficacy Phase 
Amendment 1 
The changes to the protocol are summarized in the table below and are primarily being 
implemented at the request of the FDA. 
Change and Rationale for Change 
Sections Changed 
Revised the 4+3 design to the standard 3+3 design  
Abstract: Study Design, Number of Patients  
Section 4.1 Characteristics  
Section 4.2 Number of Patients  
Section 6.2 Definition of Dose-Limiting  
Toxicity  
Table 2: Dose Escalation for the Younger Age Groups  
Table 3: Dose Escalation for the Older Groups  
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Change and Rationale for Change 
Sections Changed 
Section 15.2 Sample Size/Accrual Rate  
Added a physical examination on cycle 1 day 22, and 
cycle 2 days 1, 8, and 15 and weekly during the 4-
week post XRT dose-limiting toxicity (DLT) period 
(procedure days vary with each table)  
Table 7 Cycle 1: DIPG Cohort Arm 1 (XRT 30 
fractions, total 42 days)  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 9 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 1 (XRT 33 fractions, total 45 days)  
Table 10 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Table 11 Cycle 1: Recurrent HGG Cohort  
(XRT 10 fractions, 14 days)  
Added collection of blood samples for correlative 
studies (Peripheral blood mononucleated cell; 
[PBMC]) and cytokines at baseline  
Table 6 Study Calendar for Phase 1  
Added the following assessments on cycle 2 day 15: 
vital signs, toxicity assessment, performance status, 
concomitant medications, survival, serum thyroid-
stimulating hormone  
(TSH), serum amylase, serum lipase, serum  
C-reactive protein, serum chemistry  
(procedures vary with each table)  
Cycle 2 day 1 (aka day 29): disease status (Table 9)  
Table 7 Cycle 1: DIPG Cohort Arm 1 (XRT  
30 fractions, total 42 days)  
Table 9 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 1 (XRT 33 fractions, total 45 days)  
Added the following assessments:  
Cycle 1 day 22: survival, urinalysis, serum TSH, 
serum free thyroxine, serum amylase, serum 
lipase, serum C-reactive protein Cycle 2 day 1 
(aka day 29): survival, disease status  
Cycle 2 day 15: vital signs, toxicity assessment, 
performance status, concomitant medications, 
survival, urinalysis, serum TSH, serum free 
thyroxine, serum amylase, serum lipase, serum C-
reactive protein, serum chemistry  
  
(procedures vary with each table)  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 10 Cycle 1: Newly Diagnosed HGG Cohort Arm 
2 (XRT 13 fractions, total 17 days)  
Added administration of REGN2810 on  
Cycle 2 day 1 (aka day 29), Cycle 2 day 15  
(procedure days vary with each table)  
Table 7 Cycle 1: DIPG Cohort Arm 1 (XRT 30 
fractions, total 42 days)  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 10 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Table 11 Cycle 1: Recurrent HGG Cohort  
(XRT 10 fractions, 14 days)  
Added brain magnetic resonance imaging  
(MRI)/Spine MRI REGN2810 on Cycle 2 day 1 (aka 
day 29)  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 10 Cycle 1: Newly Diagnosed HGG  
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Change and Rationale for Change 
Sections Changed 
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Table 11 Cycle 1: Recurrent HGG Cohort  
(XRT 10 fractions, 14 days)  
Deleted radiation on cycle 1 day 22, Cycle 2 day 1 
(aka day 29)  
Table 10 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Deleted cycle 2 day 8 assessments due to redundancy 
with DLT period observations  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 10 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Table 11 Cycle 1: Recurrent HGG Cohort  
(XRT 10 fractions, 14 days)  
Added the following assessments:  
Cycle 1 day 22: survival, urinalysis, serum  
TSH,  
Cycle 2 day 1 (aka day 29): survival Cycle 2 day 15: 
vital signs, toxicity assessment, performance status, 
concomitant medications, survival, urinalysis, serum 
TSH, serum amylase, serum lipase, serum C-reactive 
protein  
Table 11 Cycle 1: Recurrent HGG Cohort (XRT 10 
fractions, 14 days)  
Added randomization to the recurrent High-grade 
glioma (HGG) cohort  
Table 11 Cycle 1: Recurrent HGG Cohort (XRT 10 
fractions, 14 days)  
Specified that physical examinations will include a 
full neurological exam  
Table 6 Study Calendar for Phase 1  
Table 7 Cycle 1: DIPG Cohort Arm 1 (XRT  
30 fractions, total 42 days)  
Table 8 Cycle 1: DIPG Cohort Arm 2 (XRT 13 
fractions, total 17 days)  
Table 9 Cycle 1: Newly Diagnosed HGG Cohort Arm 
1 (XRT 33 fractions,  
total 45 days)  
Table 10 Cycle 1: Newly Diagnosed HGG  
Cohort Arm 2 (XRT 13 fractions, total 17 days)  
Table 11 Cycle 1: Recurrent HGG Cohort (XRT 10 
fractions, 14 days)  
Table 12 Cycle 2 and Future Cycles Thereafter  
Section 9.3.5 Cycle 2 Day 1 Visit and Prior to Every 
Cycle Thereafter (Within 3 Days Prior to Each Cycle) 
– All Patients  
Section 9.3.7 End of Treatment Visit  
Updated information in the protocol regarding safety 
data on patients with DIPG treated concurrently with 
radiation  
Section 3 Rationale  
Added criteria to delay enrollment of children under 
1 year of age  
Section 4.1 Characteristics  
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Change and Rationale for Change 
Sections Changed 
Augmented safety oversight in the form of a safety 
monitoring team (SMT) and a Regeneron Safety 
Oversight Committee (RSOC)  
Section 10.6 Safety Monitoring  
Added a global stopping rule in the event of 
excessive toxicity  
Section 10.6.1 Safety Monitoring for Irreversible 
Neurological Events  
Clarified how disease response will be determined in 
patients 
with 
neuroblastoma 
with 
both 
Metaiodobenzylguanidine- (MIBG-) avid disease 
and bone marrow involvement  
Section 
14.6.1 
Metaiodobenzylguanidine-Positive 
Lesions  
Section 14.6.2 Primary Soft Tissue Disease  
Section 14.6.3 Metastatic Soft Tissue and Bone 
Disease  
Section 14.6.4 Bone Marrow Disease  
Section 14.6.5 Overall Response  
Added 
International 
Neuroblastoma 
Response 
Criteria  
Section 14.6.1 Metaiodobenzylguanidine-Positive 
Lesions  
Excluded 
urinary 
catecholamine 
levels 
from 
response assessment for patients with neuroblastoma  
Section 14.4.1.1 Complete Response  
Section 14.6.1 Metaiodobenzylguanidine-Positive 
Lesions  
Clarified how Immunotherapy Response Assessment 
in Neuro-Oncology (iRANO) criteria will be used to 
assess response in central nervous system tumors  
Section 14.8 Response Criteria for Central Nervous 
System Tumors  
Corrected the definition of progressive disease per 
the Response Assessment in  
Neuro-Oncology (RANO) criteria from a 50% 
increase to at least a 25% increase in the sum  
of the size of target lesions  
Section 14.8.3 Response Criteria, per RANO Criteria 
and Allowing for Integration of iRANO Criteria to 
Supplement RANO Criteria as Appropriate  
Added treatment criteria for determination of 
patient evaluability for efficacy and toxicity per 
Intention to Treat analyses, and Per Protocol 
Analyses  
Section 15.3 Criteria to be Evaluable for Efficacy and 
Toxicity  
Added replacement criteria for non-evaluable 
patients  
Section 15.4 Replacement Criteria  
Clarified the basis to support the assumption of the 
null hypothesis for the recurrent HGG cohort  
Section 15.2 Sample Size/Accrual Rate  
Section 15.2 Efficacy Phase-RP2D and Efficacy  
 
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CONFIDENTIAL 
ABSTRACT 
Title 
A Safety and Pharmacokinetic Study of Single Agent REGN2810 in Pediatric Patients with 
Relapsed or Refractory Solid or Central Nervous System (CNS) Tumors and a Safety and 
Efficacy Trial of REGN2810 in Combination with Radiotherapy in Pediatric Patients with Newly 
Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed High-Grade Glioma, or 
Recurrent High-Grade Glioma 
Patient 
Population 
Phase 1 will include patients age 0 to <18 years with recurrent/refractory solid tumors or 
recurrent/refractory CNS tumors.  
Efficacy Phase will include patients age 3 to 25 years with newly diagnosed diffuse intrinsic 
pontine glioma (DIPG), newly diagnosed high-grade glioma (HGG), or recurrent HGG. 
Study 
Rationale 
The median survival for newly diagnosed DIPG and recurrent HGG in pediatric patients is <1 year, 
while only 20% of pediatric patients with newly diagnosed HGG are alive at 2 years. 
Immunotherapy is a novel therapeutic approach emerging as effective therapy for a variety of 
malignancies and may have significant potential in treating pediatric DIPG, HGG, and other solid 
tumors. Preclinical data show that radiation “primes” the immune system, as evidenced by increases 
in antigen presentation, major histocompatibility complex expression, and antigen-specific T cells 
in the tumor microenvironment. The collective data suggest that combining radiation with 
Programmed Death-1 (PD-1) inhibitory immunotherapy in pediatric patients with DIPG, HGG, and 
other solid tumors is clinically and biologically feasible.  
 
 
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Primary 
Objectives 
Phase 1 
 To confirm the safety and anticipated recommended phase 2 dose (RP2D) of REGN2810 
(cemiplimab) for children with recurrent or refractory solid or CNS tumors 
 To characterize the pharmacokinetics (PK) of REGN2810 given in children with recurrent or 
refractory solid or CNS tumors 
Efficacy Phase 
 To confirm the safety and anticipated RP2D of REGN2810 to be given concomitantly with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed diffuse intrinsic pontine glioma (DIPG) 
 To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed high-grade glioma (HGG) 
 To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
re-irradiation in patients with recurrent HGG  
 To assess PK of REGN2810 in pediatric patients with newly diagnosed DIPG, newly 
diagnosed HGG, or recurrent HGG when given in combination with radiation 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
overall survival at 12 months (OS12) among patients with newly diagnosed DIPG 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
progression-free survival at 12 months (PFS12) among patients with newly diagnosed HGG 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
overall survival at OS12 among patients with recurrent HGG 
Secondary 
Objectives 
Phase 1 
 To assess anti-tumor activity of REGN2810 monotherapy as identified by objective response 
in children with recurrent or refractory solid or CNS tumors 
 To assess immunogenicity 
Efficacy Phase 
 To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed DIPG 
 To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed HGG 
 To assess safety and tolerability profiles of REGN2810 given in combination with 
re-irradiation among patients with recurrent HGG 
 To assess immunogenicity 
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Exploratory 
Objectives 
Phase 1 and Efficacy Phase 
 To assess Quality of Life (QoL) in patients treated with REGN2810 as monotherapy or given 
concurrently with radiation followed by adjuvant monotherapy  
 To investigate the biologic activity of REGN2810 and potentially identify biomarkers 
predictive of drug response using DNA, serum, plasma, and tumor biopsy samples 
Primary 
Endpoints 
Phase 1 
 Safety, as measured by the incidence and severity of treatment-emergent adverse events 
(TEAEs)/immune-related adverse events (irAEs)/adverse events of special interest (AESIs) / 
serious adverse events (SAEs), deaths, and laboratory abnormalities (grade 3 or higher per 
version 4.0 of Common Terminology Criteria for Adverse Events (CTCAE v4.0), from 
initiation of study treatment until 90 days after the last study treatment (or until the patient 
receives another systemic anticancer therapy, whichever is earlier) 
 Tolerability, as measured by the incidence of dose-limiting toxicities (DLTs) from the first 
dose of REGN2810 through the end of the DLT observation period for cemiplimab given as 
monotherapy 
 PK for REGN2810 given as monotherapy in pediatric patients  
Efficacy Phase: 
 Incidence and severity of TEAEs, irAEs, AESIs, SAEs, deaths, and laboratory abnormalities 
(Grade 3 or higher per CTCAE v4.0) for REGN2810 given in combination with radiation 
therapy, from initiation of study treatment until 90 days after the last study treatment (or until 
the patient receives another systemic anticancer therapy, whichever is earlier) 
 Incidence of DLTs during the DLT observation period for REGN2810 given in combination 
with radiation therapy  
 PK for REGN2810 given as given in combination with radiation therapy in pediatric patients  
 Overall survival at 12 months (OS12) among newly diagnosed DIPG patients and recurrent 
HGG patients, respectively.  
 Progression-free survival at 12 months (PFS12) among newly diagnosed HGG patients.  
Secondary 
Endpoints 
Phase 1 
 Objective response rate (ORR). ORR is defined as the percentage of patients who have a best 
overall response (BOR) of confirmed complete response (CR) or partial response (PR).  
 Anti-drug antibody (ADA) assessments for REGN2810 given as monotherapy 
Efficacy Phase 
 ADA assessments for REGN2810 given in combination with radiation therapy 
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Exploratory 
Endpoints 
Phase 1 and Efficacy Phase: 
 Quality of Life (QoL), as measured using Pediatric Quality of Life (PedsQL) for younger age 
group 2 to <18 years  
 QoL, as measured using the Functional Assessment of Cancer Therapy-Brain (FACT-Br) for 
older age group 18 to 25 years 
 Circulating tumor cells, biomarker data, circulating cytokines, and peripheral blood 
mononucleated cells (PBMC), tumor expression of PD-L1 for biomarker and correlative 
studies 
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Study 
Design 
This is a multi-center safety and efficacy study conducted through The Pacific Pediatric Neuro 
Oncology Consortium (PNOC). This study will consist of 2 phases conducted in parallel. In both 
phases, treatment cycles will each last 28 days. Therapy will continue for a total of 12 cycles (or 
up to 24 cycles if, in the investigator’s opinion, the patient would continue to derive clinical 
benefit). Patients who discontinue or complete therapy will undergo evaluation at an end of 
treatment visit, followed by a 30-day toxicity check. Patients will then enter long-term follow up, 
which will occur every 12 weeks from the last day of treatment and will last for up to 52 weeks. 
To assess preliminary anti-tumor efficacy, patients will receive radiographic imaging (MRI/PET or 
CT) at least once every 12 weeks while on treatment and during follow up. Patients will also provide 
tumor tissue (either fresh or archival) at screening and will undergo biopsy at any time on-study at 
the time of disease progression. To assess the impact of treatment on quality of life (QoL), patients 
will also be asked to complete the PedsQL (age 2 to <18) or FACT-Br (age >18) questionnaire 
while on treatment and during follow up. 
Phase 1 will consist of 4 cohorts, consisting of patients with recurrent/refractory solid tumors 
(Cohorts A and B) or recurrent/refractory CNS tumors (Cohorts C and D), with each cohort defined 
according to patient age (age 0 to <12 and age 12 to <18). Phase 1 will use a 3+3 design to confirm 
the anticipated recommended phase 2 dose (RP2D) of REGN2810 as monotherapy in pediatric 
patients. Cohorts will escalate through a series of dose levels (DL0, 1 mg/kg/dose; DL1, 3 
mg/kg/dose; DL2, 4.5 mg/kg/dose), with dose escalation rules defined by age cohort. Younger 
cohorts (age 0 to <12) will begin at DL1 can escalate up to DL2 or de-escalate to DL0 based on 
toxicity. Older cohorts (age 12 to <18) will begin at DL1 and may not escalate further but may de-
escalate to DL0 based on toxicity.  
The DLT period for Phase 1 will be 28 days (2 doses of REGN2810 monotherapy). The RP2D will 
be determined separately for each of the 4 cohorts and may be lower than the identified maximum 
tolerated dose (MTD) if pharmacokinetically indicated. 
The Efficacy Phase will consist of 6 cohorts, including pediatric patients with either newly 
diagnosed DIPG (Cohorts E and F), newly diagnosed HGG (Cohorts G and H), or recurrent HGG 
(Cohorts I and J), defined according to patient age (age 3 to <12 and age 12 to 25). The Efficacy 
Phase will use a 3+3 design to confirm the RP2D of REGN2810 in combination with radiation 
therapy in pediatric patients. Patients in newly diagnosed DIPG and newly diagnosed HGG cohorts 
will be randomized 1:1 to receive REGN2810 + conventionally fractionated radiation therapy (Arm 
1) or REGN2810 + hypofractionated radiation therapy (Arm 2). Patients in recurrent HGG cohorts 
will receive REGN2810 + re-irradiation.  
Each cohort in the Efficacy Phase will escalate through a series of dose levels defined by age cohort. 
Younger cohorts (age 3 to <12) will begin at the RP2D identified in the Phase 1 younger CNS 
tumor cohort and may not escalate further but may de-escalate to a lower dose level based on 
toxicity. Older cohorts (age 12 to 25) will begin at DL1 and may not escalate further but may 
de-escalate to DL0 based on toxicity.  
The DLT period for the Efficacy Phase will be the length of radiation therapy + 28 days after 
completion of radiation therapy. DLT evaluation will occur according to both cohort and treatment 
arm. The RP2D will be confirmed for each of the 10 treatment arms and may be lower than the 
MTD if pharmacokinetically indicated. 
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Number of 
Patients 
In Phase 1, a minimum of 30 patients with recurrent/refractory solid tumors or CNS tumors will 
be enrolled, including at least 6 patients each in younger (age 0 to <12) cohorts and at least 3 
patients in older (age 12 to <18) cohorts. Solid tumor cohorts will enroll an additional 6 patients 
each (12 total) for treatment at the corresponding RP2D. 
In the Efficacy Phase, a minimum enrollment of 100 patients (at the respective confirmed RP2D 
for each cohort) is planned. This will include at least 40 patients with newly diagnosed DIPG 
patients, at least 40 patients with newly diagnosed HGG, and at least 20 patients with recurrent 
HGG. 
Duration of 
Therapy 
Patients in both Phase 1 and the Efficacy Phase will receive REGN2810 on study for 12 cycles 
from the time of study entry. REGN2810 may be continued for up to 24 cycles if a patient 
continues to derive clinical benefit. 
Duration of 
Follow-up 
Patients will be followed for at least 52 weeks from end of treatment or until death, whichever 
occurs first.  
Duration of 
Study (Per 
Patient) 
For each patient, the study is anticipated to last up to 3 years, which includes a maximum of 24 
cycles of treatment and a maximum of 52 weeks of follow up. 
Study Drugs REGN2810, a human monoclonal antibody targeting the PD-1 receptor, to be administered 
every 14 days via 30-minute intravenous (IV) infusion. 
Safety 
Assessments 
Safety assessments will include DLTs, adverse events (AEs), clinical laboratory evaluations, 
physical examination, and vital signs. 
PK 
Assessments 
PK assessments will be included in both Phase 1 and the Efficacy Phase of the study. 
Efficacy 
Assessments 
Objective response, 12-month overall survival (OS12), 12-month progression-free survival 
(PFS). 
Unique 
Aspects of 
this Study 
This is the first study to:  
 
Evaluate the safety of PD-1 inhibition given with radiation in pediatric patients with newly 
diagnosed DIPG, newly diagnosed HGG, or recurrent HGG 
 
Assess and describe preliminary efficacy of PD-1 inhibition given with conventionally 
fractionated or hypofractionated radiation in newly diagnosed DIPG and newly diagnosed 
HGG 
 
Determine the PK of REGN2810 in pediatric patients 
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EXPERIMENTAL DESIGN SCHEMA 
Figure 1: 
Trial Enrollment in Phase 1: Recurrent or Refractory Solid or Central Nervous System 
 
 
 
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Figure 2: 
Trial Enrollment in the Efficacy Phase: Newly Diagnosed Diffuse Intrinsic Pontine Glioma 
 
 
 
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Figure 3: 
Trial Enrollment in the Efficacy Phase: Newly Diagnosed High-Grade Glioma 
 
 
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Figure 4: 
Trial Enrollment in the Efficacy Phase: Recurrent High-Grade Glioma  
 
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Figure 5: 
Study Design, Phase 1  
 
 
 
 
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Figure 6: 
Study Design, Efficacy Phase  
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Table 1: 
Patient Cohorts  
Cohort 
Study Phase 
Tumor Type 
Age Range 
A 
1 
Solid Tumors 
0 to <12 
B 
1 
Solid Tumors 
12 to <18 
C 
1 
CNS Tumors 
0 to <12 
D 
1 
CNS Tumors 
12 to <18 
E 
Efficacy 
DIPG (Newly Diagnosed) 
3 to <12 
F 
Efficacy 
DIPG (Newly Diagnosed) 
12 to 25 
G 
Efficacy 
HGG (Newly Diagnosed) 
3 to <12 
H 
Efficacy 
HGG (Newly Diagnosed) 
12 to 25 
I 
Efficacy 
HGG (Recurrent) 
3 to <12 
J 
Efficacy 
HGG (Recurrent) 
12 to 25 
 
 
 
 
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LIST OF ABBREVIATIONS 
3D-CRT 
3D-conformal radiation therapy 
ADA 
Anti-drug antibody 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
AML 
Acute myelocytic leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve 
CBC 
Complete blood cell (count) 
cGy 
Centigray 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Clinical Research Organization 
CRP 
C-reactive protein 
CSCC 
Cutaneous squamous cell carcinoma 
CSF 
Cerebral spinal fluid 
CSI 
Craniospinal irradiation 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
CTEP 
Cancer Therapy Evaluation Program 
CTLA-4  
Cytotoxic T-lymphocyte-associated-4  
CTV 
Clinical target volume 
CTX 
Cyclophosphamide 
DFS 
Disease-free survival 
DIPG 
Diffuse intrinsic pontine glioma 
DLT 
Dose-limiting toxicity 
DVH 
Dose volume histogram 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
EGFR 
Estimated glomerular filtration rate 
EOI 
End of infusion 
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FACT-Br 
Functional Assessment of Cancer Therapy-Brain Inventory 
FDA 
Food and Drug Administration 
FFPE 
Formalin fixed-paraffin embedded 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GM-CSF 
Granulocyte Macrophage Colony-Stimulating Factor 
GTV 
Gross tumor volume 
hfRT 
Hypofractionated radiation therapy 
HGG 
High-grade glioma 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICRU 
International Commission on Radiation Units and Measurements 
IF 
Immunofluorescence 
IHC 
Immunohistochemistry 
IMRT 
Intensity modulated radiation therapy 
IND 
Investigational new drug application 
irAE 
Immune-related adverse event 
iRANO 
Immunotherapy Response Assessment in Neuro-Oncology 
IRB 
Institutional Review Board 
irRECIST 
Immune-related response evaluation criteria in solid tumors 
IV 
Intravenous 
IWRS 
Interactive web response system 
LAG-3 
Lymphocyte activation gene 3 
LAR  
Legally authorized representative 
LFT 
Liver function test 
MDS 
Myelodysplastic syndrome 
MIBG 
Metaiodobenzylguanidine 
mAb 
Monoclonal antibody 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no-observed-adverse-effect level 
NSCLC 
Non-small cell lung cancer 
OS 
Overall survival 
OS12 
Overall survival at 12 months 
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PBMC 
Peripheral blood mononucleated cell 
PedsQL 
Pediatric Quality of Life Inventory 
PD 
Progressive disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed death ligand 1 
PD-L2 
Programmed death ligand 2 
PET 
Positron Emission Tomography 
PET-CT 
Positron Emission Tomography-Computed Tomography 
PFS 
Progression-free survival 
PFS12 
Progression-free survival at 12 months 
PK 
Pharmacokinetics 
PNOC 
Pacific Pediatric Neuro Oncology Consortium 
PR 
Partial response 
PTV 
Planning target volume 
QOL 
Quality of Life 
Q2W 
Every 2 weeks 
RAPNO 
Response Assessment in Pediatric Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RCC 
Renal cell cancer 
RP2D 
Recommended phase 2 dose 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SGPT 
Serum glutamic pyruvic transaminase 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid-stimulating hormone 
t1/2 
Terminal half-life 
ULN 
Upper limit of normal 
VEGF 
Vascular endothelial growth factor 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................4 
PROTOCOL SIGNATURE PAGE – PARTICIPATING SITES ...................................................5 
AMENDMENT HISTORY .............................................................................................................6 
Amendment 3 ...................................................................................................................................6 
Changes to Study Design .................................................................................................................6 
Clarifications of Study Design .........................................................................................................9 
Structural Changes .........................................................................................................................14 
Other Changes ................................................................................................................................17 
Amendment 2 .................................................................................................................................17 
Amendment 1 .................................................................................................................................21 
ABSTRACT ...................................................................................................................................25 
1. 
OBJECTIVES .............................................................................................................51 
1.1. 
Primary Objectives .....................................................................................................51 
1.2. 
Secondary Objectives .................................................................................................51 
1.3. 
Exploratory Objectives ...............................................................................................52 
2. 
BACKGROUND ........................................................................................................52 
2.1. 
Unmet Need in Pediatric DIPG and HGG ..................................................................52 
2.2. 
Targeting of Programmed Death-1 (PD-1) as a Treatment Paradigm in 
Cancer .........................................................................................................................52 
2.3. 
REGN2810, a Human Monoclonal Antibody to Programmed Death-1 (PD-
1) .................................................................................................................................53 
2.4. 
REGN2810 Pre-Clinical Studies ................................................................................54 
2.5. 
REGN2810 Clinical Studies .......................................................................................54 
3. 
RATIONALE .............................................................................................................56 
3.1. 
Use of Anti-PD-1 Therapy in DIPG and HGG Patient Populations ...........................56 
3.2. 
REGN2810 Dose Selection ........................................................................................58 
3.3. 
Radiotherapy Regimen Selection ...............................................................................59 
3.4. 
Pharmacokinetic Assessment of REGN2810 .............................................................60 
3.5. 
Correlative Exploratory Studies .................................................................................60 
4. 
STUDY DESIGN .......................................................................................................60 
4.1. 
Phase 1 Study Design .................................................................................................61 
4.1.1. 
Dose Escalation Design in Phase 1 .............................................................................61 
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4.1.2. 
Dose Escalation Rules in Phase 1 ...............................................................................61 
4.2. 
Efficacy Phase Study Design ......................................................................................62 
4.2.1. 
Dose Escalation Design in the Efficacy Phase ...........................................................63 
4.2.2. 
Dose Escalation Rules in Efficacy Phase ...................................................................63 
4.2.3. 
Timing of Initial Enrollment .......................................................................................63 
4.2.4. 
Expansion Enrollment ................................................................................................64 
4.3. 
Dose Escalation Rules ................................................................................................64 
4.4. 
Dose-Limiting Toxicities ............................................................................................67 
4.4.1. 
DLT Period .................................................................................................................67 
4.4.2. 
Definition of Dose-Limiting Toxicity ........................................................................67 
4.5. 
Off-Treatment Criteria ................................................................................................68 
4.6. 
Off-Study Criteria .......................................................................................................69 
4.7. 
Number of Patients .....................................................................................................69 
4.7.1. 
Minimum Enrollment Requirements ..........................................................................69 
5. 
STUDY POPULATION .............................................................................................70 
5.1. 
Inclusion Criteria ........................................................................................................70 
5.1.1. 
All Patients (Phase 1 and Efficacy Phase) ..................................................................70 
5.1.2. 
Phase 1 ........................................................................................................................71 
5.1.3. 
Efficacy Phase ............................................................................................................71 
5.1.3.1. 
Newly Diagnosed DIPG (Cohorts E and F) Only ......................................................71 
5.1.3.2. 
Newly Diagnosed HGG (Cohorts G and H) Only ......................................................72 
5.1.3.3. 
Recurrent HGG (Cohorts I and J) Only: .....................................................................72 
5.2. 
Exclusion Criteria .......................................................................................................73 
6. 
STUDY DRUG ADMINSTRATION AND DOSE MODIFICATIONS ...................75 
6.1. 
REGN2810 Administration ........................................................................................75 
6.2. 
REGN2810 Dose Modifications and Delays ..............................................................75 
6.3. 
Prohibited Therapies ...................................................................................................76 
7. 
STUDY SUPPORTIVE CARE AND ADVERSE EVENT MANAGEMENT 
GUIDELINES .............................................................................................................77 
7.1. 
Supportive Care ..........................................................................................................77 
7.2. 
Infusion-Related Reactions .........................................................................................77 
7.2.1. 
Allergic Reaction or Hypersensitivity in Patients with Prior Reaction(s) to 
Antibody Treatment ....................................................................................................77 
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7.3. 
Management of Specific Organ-Related Toxicities ...................................................77 
7.4. 
Special Considerations: Pseudoprogression ...............................................................77 
8. 
SCHEDULE OF EVENTS AND PROCEDURES ....................................................78 
8.1. 
Schedule of Events / Treatment Plan ..........................................................................78 
8.1.1. 
Schedule of Events .....................................................................................................78 
8.1.2. 
Footnotes for Table 11 (Schedule of Events for Phase 1) ..........................................80 
8.1.3. 
Footnotes for Table 12 and Table 13 (Schedules of Events for the Efficacy 
Phase) ..........................................................................................................................83 
8.1.4. 
Pharmacokinetic and Anti-Drug Antibody Sample Collection ..................................85 
8.1.5. 
Footnotes for Table 14, Table 15, and Table 16 (PK and ADA Collection 
Schedules) ...................................................................................................................86 
8.1.6. 
End of Treatment Visit ...............................................................................................87 
8.1.7. 
30-Day Toxicity Check ...............................................................................................87 
8.1.8. 
Long Term/Survival Follow-up ..................................................................................87 
8.2. 
Study Assessments and Procedures ............................................................................87 
8.2.1. 
Clinical Procedures .....................................................................................................87 
8.2.1.1. 
Consent Form..............................................................................................................87 
8.2.1.2. 
Medical History ..........................................................................................................87 
8.2.1.3. 
Randomization (Efficacy Phase) ................................................................................88 
8.2.1.4. 
Physical Examination with Full Neurological Exam..................................................88 
8.2.1.5. 
Vital Signs, Height, and Weight .................................................................................88 
8.2.1.6. 
Toxicity Assessment ...................................................................................................88 
8.2.1.7. 
Performance Status .....................................................................................................88 
8.2.1.8. 
Concomitant Medications ...........................................................................................88 
8.2.1.9. 
Quality of Life Assessment ........................................................................................88 
8.2.1.10. 
Survival Data Collection .............................................................................................88 
8.2.2. 
Agent Administration .................................................................................................89 
8.2.2.1. 
REGN2810 .................................................................................................................89 
8.2.2.2. 
Radiation Therapy ......................................................................................................89 
8.2.3. 
Laboratory Procedures ................................................................................................89 
8.2.4. 
Imaging and Disease Status Assessment ....................................................................89 
8.2.5. 
Pharmacokinetic and Immunogenicity Procedures ....................................................89 
8.2.5.1. 
Pharmacokinetics Procedures .....................................................................................89 
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8.2.5.2. 
Immunogenicity Procedures .......................................................................................90 
8.2.6. 
Exploratory Procedures ..............................................................................................90 
8.2.6.1. 
Exploratory Biomarker and Cytokine Procedures ......................................................90 
8.2.6.2. 
Exploratory Biomarker Procedures ............................................................................91 
8.2.6.3. 
Exploratory Circulating Cytokine Procedures ............................................................91 
8.2.6.4. 
Peripheral Blood Mononucleated Cell Assay .............................................................91 
8.2.6.5. 
Tissue/Blood Banking ................................................................................................92 
9. 
SAFETY DEFINITIONS, REPORTING AND MONITORING ..............................92 
9.1. 
Obligations of Investigator .........................................................................................92 
9.2. 
Obligations of Regeneron ...........................................................................................92 
9.3. 
Definitions ..................................................................................................................92 
9.3.1. 
Adverse Event .............................................................................................................92 
9.3.2. 
Serious Adverse Event ................................................................................................93 
9.3.3. 
Adverse Events of Special Interest .............................................................................93 
9.3.4. 
Infusion Reactions ......................................................................................................94 
9.4. 
Recording and Reporting Adverse Events ..................................................................94 
9.4.1. 
Adverse Events ...........................................................................................................94 
9.4.2. 
Serious Adverse Events ..............................................................................................94 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................95 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................95 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................95 
9.4.6. 
Follow-Up ...................................................................................................................96 
9.5. 
Evaluation of Severity and Causality .........................................................................96 
9.5.1. 
Evaluation of Severity ................................................................................................96 
9.5.2. 
Evaluation of Causality ...............................................................................................97 
9.6. 
Safety Monitoring .......................................................................................................99 
9.6.1. 
Safety Monitoring for Irreversible Neurological Events ............................................99 
9.7. 
Investigator Alert Notification ..................................................................................100 
9.8. 
Secondary Malignancy .............................................................................................100 
9.9. 
Second Malignancy ..................................................................................................100 
10. 
RADIATION THERAPY GUIDELINES ................................................................100 
10.1. 
General Guidelines ...................................................................................................100 
10.2. 
Protocol-Defined Dose and Fractionation Schedules ...............................................101 
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10.3. 
Treatment Planning Specifics ...................................................................................102 
10.4. 
Indications for Radiation Therapy ............................................................................102 
10.5. 
Timing .......................................................................................................................102 
10.5.1. 
Emergency Irradiation ..............................................................................................102 
10.6. 
Equipment and Methods of Delivery and Verification .............................................102 
10.6.1. 
Treatment Planning ...................................................................................................103 
10.7. 
Target Volumes ........................................................................................................103 
10.7.1. 
General Comments ...................................................................................................103 
10.7.2. 
Definitions for Gross Tumor Volume, Clinical Target Volume, and Planning 
Target Volume ..........................................................................................................103 
10.8. 
Target Dose ...............................................................................................................104 
10.8.1. 
Dose Definition .........................................................................................................104 
10.8.2. 
Prescribed Dose and Fractionation ...........................................................................105 
10.8.3. 
Dose Uniformity .......................................................................................................105 
10.8.4. 
Tissue Heterogeneity ................................................................................................105 
10.8.5. 
Interruptions, Delays and Dose Modifications .........................................................105 
10.9. 
Treatment Technique ................................................................................................105 
10.9.1. 
Beam Configuration ..................................................................................................105 
10.9.2. 
Field Shaping ............................................................................................................106 
10.9.3. 
Simulation Including Patient Positioning and Immobilization .................................106 
10.9.3.1. 
Patient Positioning ....................................................................................................106 
10.9.3.2. 
Immobilization Devices ............................................................................................106 
10.9.3.3. 
Special Considerations ..............................................................................................106 
10.9.4. 
Motion Management and Margins to Account for Target Volume Changes 
During Treatment ......................................................................................................106 
10.10. 
Organs at Risk ...........................................................................................................106 
10.10.1. 
Dose Constraints .......................................................................................................106 
10.10.1.1. Cochleae ...................................................................................................................106 
10.10.1.2. Optic Globes .............................................................................................................107 
10.10.1.3. Right and Left Optic Nerves and Chiasm .................................................................107 
10.10.1.4. Spinal Cord ...............................................................................................................107 
10.10.1.5. Brainstem ..................................................................................................................108 
10.11. 
Dose Calculations and Reporting .............................................................................109 
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10.11.1. 
Prescribed Dose ........................................................................................................109 
10.11.2. 
Normal Tissue Dosimetry .........................................................................................109 
10.12. 
Quality Assurance Documentation ...........................................................................109 
10.12.1. 
External Beam Treatment Planning System .............................................................109 
10.12.2. 
Digital Data ...............................................................................................................110 
10.12.3. 
Supportive Data ........................................................................................................110 
11. 
EVALUATION CRITERIA .....................................................................................110 
11.1. 
Definitions ................................................................................................................110 
11.1.1. 
Evaluable for Toxicity ..............................................................................................110 
11.1.2. 
Evaluable for Objective Response ............................................................................111 
11.1.3. 
Immunotherapy Response Assessment in Neuro-Oncology (iRANO) Criteria .......111 
11.2. 
Disease Parameters ...................................................................................................111 
11.2.1. 
Solid Tumors ............................................................................................................111 
11.2.1.1. 
Measurable Disease ..................................................................................................111 
11.2.1.2. 
Malignant Lymph Nodes ..........................................................................................111 
11.2.1.3. 
Non-Measurable Disease ..........................................................................................111 
11.2.2. 
Target Lesions ..........................................................................................................112 
11.2.3. 
Non-Target Lesions ..................................................................................................112 
11.3. 
Methods for Evaluation of Measurable Disease .......................................................112 
11.3.1. 
Chest X-Ray ..............................................................................................................112 
11.3.2. 
Conventional CT and MRI .......................................................................................112 
11.3.3. 
Ultrasound .................................................................................................................113 
11.3.4. 
Positron Emission Tomography-Computed Tomography ........................................113 
11.3.5. 
Tumor Markers .........................................................................................................113 
11.3.6. 
Cytology and Histology ............................................................................................113 
11.3.7. 
FDG-PET ..................................................................................................................113 
11.4. 
Response Criteria ......................................................................................................114 
11.4.1. 
Response Criteria for Patients with Solid Tumors and Measurable Disease: 
Evaluation of Target Lesions ....................................................................................114 
11.4.2. 
Response Criteria for Patients with Solid Tumors and Evaluable Disease ..............114 
11.4.3. 
Response Criteria for Neuroblastoma Patients with 
Metaiodobenzylguanidine-Positive Lesions .............................................................115 
11.4.3.1. 
Metaiodobenzylguanidine-Positive Lesions .............................................................115 
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11.4.3.2. 
Primary Soft Tissue Disease .....................................................................................115 
11.4.3.3. 
Metastatic Soft Tissue and Bone Disease .................................................................116 
11.4.3.4. 
Bone Marrow Disease ...............................................................................................116 
11.4.3.5. 
Overall Response ......................................................................................................116 
11.4.3.6. 
Scoring Based on Relative Curie Score ....................................................................117 
11.4.4. 
Response Criteria for Solid Tumor Patients with Bone Marrow Involvement ........117 
11.4.5. 
Response Criteria for Central Nervous System Tumors ...........................................118 
11.4.5.1. 
Measurable Disease ..................................................................................................118 
Target Lesions ..............................................................................................................................118 
11.4.5.2. 
Non-Measurable Disease ..........................................................................................118 
11.4.5.3. 
Methods for Evaluation of Measurable Disease .......................................................118 
11.4.5.4. 
Response Criteria, per RANO Criteria and Allowing for Integration of 
iRANO Criteria to Supplement RANO Criteria as Appropriate ..............................119 
11.5. 
Evaluation of Best Overall Response .......................................................................120 
11.6. 
Duration of Response ...............................................................................................120 
11.7. 
Additional Guidelines for Response Criteria for CNS Tumors ................................121 
12. 
STATISTICAL CONSIDERATIONS .....................................................................122 
12.1. 
Study Endpoints ........................................................................................................122 
12.1.1. 
Primary Endpoints ....................................................................................................122 
12.1.2. 
Secondary Endpoints ................................................................................................123 
12.1.3. 
Exploratory Endpoints ..............................................................................................123 
12.2. 
Sample Size ..............................................................................................................123 
12.3. 
Sample Size Justification and Accrual Rate .............................................................124 
12.4. 
Criteria to be Evaluable for Efficacy and Toxicity ...................................................126 
12.5. 
Replacement Criteria ................................................................................................127 
12.6. 
Stratification Factors for the Efficacy Phase of the Study ........................................127 
12.7. 
Analysis of Primary Endpoints .................................................................................127 
12.7.1. 
Phase 1: RP2D and Pharmacokinetics ......................................................................127 
12.7.2. 
Efficacy Phase: RP2D and Efficacy .........................................................................128 
12.7.3. 
Efficacy Phase: Pharmacokinetics ............................................................................128 
12.8. 
Analysis of Secondary Endpoints .............................................................................128 
12.8.1. 
Phase 1: Objective Response ....................................................................................128 
12.8.2. 
Efficacy Phase: Toxicity Profile ...............................................................................128 
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12.8.3. 
Phase 1 and Efficacy Phase: ADA ............................................................................129 
12.9. 
Analysis of Exploratory Endpoints ...........................................................................129 
12.9.1. 
Phase 1 and Efficacy Phase: Quality of Life ............................................................129 
12.9.2. 
Phase 1 and Efficacy Phase: Biology Studies ...........................................................129 
13. 
PHARMACEUTICAL INFORMATION ................................................................130 
13.1. 
Agent .........................................................................................................................130 
13.1.1. 
Agent - REGN2810 ..................................................................................................130 
13.2. 
Treatment Logistics and Accountability ...................................................................130 
13.2.1. 
Drug Ordering ...........................................................................................................130 
13.2.2. 
Packaging, Labeling and Storage .............................................................................130 
13.2.3. 
Supply and Disposition .............................................................................................131 
13.2.4. 
Solution Preparation .................................................................................................131 
13.2.5. 
Storage Requirements ...............................................................................................131 
13.2.6. 
Stability .....................................................................................................................131 
13.2.7. 
Route of Administration ...........................................................................................131 
13.2.8. 
Accountability ...........................................................................................................131 
13.2.9. 
Treatment Compliance ..............................................................................................131 
14. 
REPORTING AND EXCLUSIONS ........................................................................132 
14.1. 
Evaluation of Toxicity ..............................................................................................132 
14.2. 
Evaluation of Response ............................................................................................132 
15. 
REGISTRATION PROCEDURES ..........................................................................133 
15.1. 
General Guidelines ...................................................................................................133 
15.2. 
Reservation and Registration Process .......................................................................133 
16. 
DATA REPORTING / REGULATORY REQUIREMENTS ..................................134 
16.1. 
Data Reporting ..........................................................................................................134 
16.1.1. 
Method ......................................................................................................................134 
16.1.2. 
Responsibility for Data Submission .........................................................................134 
16.2. 
Oversight and Monitoring Plan ................................................................................134 
16.2.1. 
Source Document Requirements ..............................................................................135 
16.2.2. 
Multicenter Communication .....................................................................................135 
16.2.3. 
Record Keeping and Record Retention ....................................................................135 
16.2.4. 
Regulatory Documentation .......................................................................................136 
17. 
DEFINITIONS OF DEVIATIONS IN PROTOCOL PERFORMANCE ................137 
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18. 
REFERENCES .........................................................................................................138 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................161 
 
LIST OF TABLES 
Table 1: 
Patient Cohorts ............................................................................................................37 
Table 2: 
Patient Cohorts in Phase 1 ..........................................................................................61 
Table 3: 
Patient Cohorts in the Efficacy Phase .........................................................................62 
Table 4: 
Dose Escalation Rules: Cohorts Age <12 Years, Phase 1 ..........................................65 
Table 5: 
Dose Escalation Rules: Cohorts Age <12 Years, Efficacy Phase ..............................66 
Table 6: 
Dose Escalation Rules: Cohorts Age ≥12 Years, Phase 1 and Efficacy Phase ..........67 
Table 7: 
Criteria for Dose-Limiting Toxicity ...........................................................................68 
Table 8: 
REGN2810 Dose Levels .............................................................................................75 
Table 9: 
REGN2810 Administration ........................................................................................75 
Table 10: Guidelines for Dose Modification and Re-Initiation of Treatment in Case of 
Suspected REGN2810 Toxicity ..................................................................................76 
Table 11: Schedule of Events for Phase 1 ..................................................................................79 
Table 12: Schedule of Events for the Efficacy Phase: REGN2810 + Conventionally 
Fractionated Radiation ................................................................................................81 
Table 13: Schedule of Events for the Efficacy Phase: REGN2810 + Hypofractionated 
Radiation or Re-Irradiation .........................................................................................82 
Table 14: PK and ADA Collection Schedule for Phase 1: Patients 0 to 2 Years of Age 
(or Per Institutional Guidelines) .................................................................................85 
Table 15: PK and ADA Collection Schedule for Phase 1: Patients >2 to <18 Years of 
Age ..............................................................................................................................85 
Table 16: PK and ADA Collection Schedule for the Efficacy Phase .........................................86 
Table 17: NCI-CTCAE Grading System (v4.0) .........................................................................97 
Table 18: Required DVH data ..................................................................................................109 
 
LIST OF FIGURES 
Figure 1: 
Trial Enrollment in Phase 1: Recurrent or Refractory Solid or Central 
Nervous System ..........................................................................................................31 
Figure 2: 
Trial Enrollment in the Efficacy Phase: Newly Diagnosed Diffuse Intrinsic 
Pontine Glioma ...........................................................................................................32 
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Figure 3: 
Trial Enrollment in the Efficacy Phase: Newly Diagnosed High-Grade 
Glioma ........................................................................................................................33 
Figure 4: 
Trial Enrollment in the Efficacy Phase: Recurrent High-Grade Glioma ....................34 
Figure 5: 
Study Design, Phase 1 ................................................................................................35 
Figure 6: 
Study Design, Efficacy Phase .....................................................................................36 
Figure 7: 
Additional Guidelines for Response Criteria for CNS Tumors ................................121 
 
LIST OF APPENDICES 
APPENDIX 1. PERFORMANCE STATUS CRITERIA .........................................................143 
APPENDIX 2. ADVERSE EVENT MANAGEMENT ............................................................144 
APPENDIX 3. REQUIRED DATA AND TIME TABLE FOR SUBMISSION .....................158 
APPENDIX 4. PNOC INSTITUTIONS, REQUIRED REGULATORY DOCUMENTS .......159 
APPENDIX 5. INFORMATION SHEET ON POSSIBLE DRUG INTERACTIONS ............160 
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1. 
OBJECTIVES 
Study objectives are provided below. Study endpoints are provided in Section 12.1. 
1.1. 
Primary Objectives 
Phase 1 
 To confirm the safety and anticipated recommended phase 2 dose (RP2D) of 
REGN2810 (cemiplimab) for children with recurrent or refractory solid or CNS tumors 
 To characterize the pharmacokinetics (PK) of REGN2810 given in children with 
recurrent or refractory solid or CNS tumors 
Efficacy Phase 
 To confirm the safety and anticipated RP2D of REGN2810 to be given concomitantly 
with conventionally fractionated or hypofractionated radiation among patients with 
newly diagnosed diffuse intrinsic pontine glioma (DIPG) 
 To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed high-grade glioma (HGG) 
 To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
re-irradiation in patients with recurrent HGG  
 To assess PK of REGN2810 in pediatric patients with newly diagnosed DIPG, newly 
diagnosed HGG, or recurrent HGG when given in combination with radiation 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
overall survival at 12 months (OS12) among patients with newly diagnosed DIPG 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
progression-free survival at 12 months (PFS12) among patients with newly diagnosed 
HGG 
 To assess anti-tumor activity of REGN2810 in combination with radiation in improving 
overall survival at OS12 among patients with recurrent HGG 
1.2. 
Secondary Objectives 
Phase 1 
 To assess anti-tumor activity of REGN2810 monotherapy as identified by objective 
response in children with recurrent or refractory solid or CNS tumors 
 To assess immunogenicity 
Efficacy Phase 
 To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed DIPG 
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 To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed HGG 
 To assess safety and tolerability profiles of REGN2810 given in combination with 
re-irradiation among patients with recurrent HGG 
 To assess immunogenicity 
1.3. 
Exploratory Objectives 
Phase 1 and Efficacy Phase 
 To assess Quality of Life (QoL) in patients with solid or CNS tumors treated with 
REGN2810 as monotherapy or given concurrently with radiation followed by adjuvant 
monotherapy  
 To investigate the biologic activity of REGN2810 and potentially identify biomarkers 
predictive of drug response using DNA, serum, plasma, and tumor biopsy samples 
2. 
BACKGROUND 
2.1. 
Unmet Need in Pediatric DIPG and HGG 
Brain tumors are the most common solid pediatric malignancy and result in more deaths than any 
other pediatric cancer. Diffuse intrinsic pontine gliomas (DIPG) and high-grade gliomas (HGG) 
account for the majority of these deaths. Pediatric HGGs are relatively rare, comprising 
approximately 4% of all brain tumors diagnosed in children age 0-14 and up to 14% in children 
age 10-191. Histologically, the vast majority of pediatric HGGs are either anaplastic astrocytomas 
(World Health Organization [WHO] grade III) or glioblastomas (WHO grade IV). Diffuse intrinsic 
gliomas are gliomas (typically grade II-IV) arising in the brainstem. Even with multi-modality 
therapies, survival curves remain dismal and stagnant for these diagnoses2-5. The 2-year survival 
for patients with DIPG and HGG is less than 10% and 20%, respectively6,7. The median survival 
for DIPG and other brainstem HGG remains less than 1 year8. For children with HGG older than 
3 years of age, combination therapy with surgical resection, radiation, and chemotherapy remains 
the standard of care2,5. Radiation is typically spared in children younger than 3 years due to the 
deleterious effects on neurocognition. Regardless, extent of surgical resection best correlates with 
both progression-free and overall survival2,6,9. Surgical resection though is not a viable option for 
patients with DIPG due to the brainstem location and infiltrative nature of the tumor. In these 
patients, radiation has proven to have the most lasting effect at slowing tumor growth; however, 
even this intervention does not prolong overall survival beyond 1 year2,6.  
2.2. 
Targeting of Programmed Death-1 (PD-1) as a Treatment Paradigm 
in Cancer 
Enhancement of the anti-tumor immune response with cancer immunotherapy agents has emerged 
as a highly effective and complementary approach to the therapeutic mainstays of surgery, 
cytotoxic drugs, targeted therapeutics, and radiation. Moreover, induction of durable and extensive 
tumor regressions suggest that immunotherapy may convert previously fatal diseases into chronic, 
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manageable ones for some patients. Under chronic stimulation, T-cells lose proliferative and 
effector function capacity, often due to signal down-modulation via the increased expression of 
proteins such as PD-1, an inhibitory checkpoint receptor of the CD28 receptor family. The ligand 
for the PD-1 receptor, PD-L1, is expressed in a variety of human malignancies, and its high level 
of expression has been previously correlated with poor patient prognosis and resistance to 
treatment in non-small-cell lung cancer10, glioblastoma multiforme11, and squamous-cell 
carcinoma of head and neck12. Binding of ligand (PD-L1 or PD-L2), often expressed on tumor 
cells, to PD-1 imparts an inhibitory signal to the T-cell, thus down-modulating the anti-tumor 
T-cell response13. Blockade of the PD-1/PD-L1/PD-L2 T-cell checkpoint pathway is an effective 
and well-tolerated approach to stimulating the immune response and has achieved significant 
objective responses in advanced melanoma, renal cell cancer (RCC), and non-small-cell lung 
cancer (NSCLC), among others14. However, optimal therapy will likely require combining anti-
PD-1 monoclonal antibody (mAb) treatment with conventional therapies and novel 
immunotherapy approaches. Combinatorial approaches to stimulate convergent aspects of host 
immunity by employing complementary immunomodulators as well as immune-stimulatory 
aspects of conventional modalities such as radiation and chemotherapy may result in the 
development of more effective cancer therapies. Combination blockade of PD-1 and the cytotoxic 
T-lymphocyte antigen 4 (CTLA-4) is effective in controlling growth of syngeneic mouse tumors 
of ID8-VEGF ovarian carcinoma and CT26 colon carcinoma cell lines in immune-competent mice, 
providing support to this notion15. Furthermore, adding blockade of CTLA-4 to PD-1 blockade in 
melanoma patients achieves response rates twice of that achieved with anti-PD-1 alone 
(ie, >50%)16. In a subset of patients with PD-L1+ tumors, preliminary results demonstrated an 
enhanced systemic response when treatment with an anti-PD-L1 antibody (MPDL3280A) 
coincided with palliative local irradiation17. 
2.3. 
REGN2810, a Human Monoclonal Antibody to Programmed Death-1 
(PD-1) 
Investigational agent: REGN2810 
IND: 123950 
IND Sponsor: Regeneron Pharmaceuticals, Inc. 
For more information on this agent, please refer to the current Investigator’s Brochure.  
REGN2810 (cemiplimab) is a high-affinity, human, hinge-stabilized IgG4P antibody directed to 
the PD-1 receptor that potently blocks the interaction of PD-1 with its ligands, PD-L1 and PD-L2. 
In syngeneic tumor models in immunocompetent mice humanized for PD-1, the anti-tumor activity 
of REGN2810 delivered as a monotherapy against a mouse colon adenocarcinoma tumor line is 
similar to that observed with antibodies generated in-house based on the publicly-available genetic 
sequences of pembrolizumab and nivolumab, anti-PD-1 antibodies approved for the treatment of 
melanoma, RCC, NSCLC, and in late-stage development for use against several other 
malignancies. 
Libtayo® (cemiplimab) has received marketing authorization and is now approved in the United 
States (US), the European Union (EU), Canada, and Brazil for the treatment of patients with 
metastatic CSCC or patients with locally advanced CSCC who are not candidates for curative 
surgery or curative radiation. In the US, it is approved as cemiplimab-rwlc.  
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This study is a multi-center study with the aim of assessing the safety, pharmacokinetics, and 
preliminary efficacy of REGN2810 as monotherapy and in combination with radiation therapy, in 
pediatric patients with newly diagnosed DIPG, newly diagnosed HGG, and recurrent HGG. 
2.4. 
REGN2810 Pre-Clinical Studies 
The starting dose chosen for the first-in-human study using REGN2810 was based on the similar 
in vitro and in vivo potency of REGN2810 compared to antibodies generated with publicly 
available sequences of 2 approved anti-PD-1 antibodies, nivolumab and pembrolizumab. When 
compared to REGN1672 (primary sequence identical to nivolumab) and REGN2626 (primary 
sequence identical to pembrolizumab) in both in vitro and cell-based assays, REGN2810 
demonstrated similar in vitro PD-1 binding affinity, blocking efficiency for PD-1/PD-L1 and 
PD-L2 interactions in vitro, and ability to antagonize PD-1-induced T-cell inhibitory signaling in 
a cell-based bioassay. Additionally, REGN2810 demonstrated similar in vivo anti-tumor efficacy 
to REGN1672 and REGN2626 in humanized-PD-1 mouse tumor model bioassays. Furthermore, 
the PK profile for REGN2810 in monkeys is similar to that of nivolumab18.  
In a 4-week toxicology study in monkeys at the no-observed-adverse-effect level (NOAEL) of 
50 mg/kg per week, the area under the concentration-time curve (AUC) over the last dosing 
interval was estimated at 6170 day•mg/mL, a greater than 12-fold higher exposure than 
steady-state exposures predicted with 1 mg/kg, and a 14% higher exposure than that anticipated 
with 10 mg/kg administered to human patients every 14 days. Based on preclinical activity and 
toxicology data and greater than 10-fold exposure margin over 1 mg/kg REGN2810, in addition 
to the clinical efficacy and safety data from other anti-PD-1 mAbs at similar doses/dosing intervals, 
a dosage of 1 mg/kg REGN2810 every 14 days was expected to have an acceptable safety profile 
and to be active, and was therefore chosen as a starting dosage in the first human trials, with plans 
to de-escalate if necessary. Experience with other anti-PD-1 antibodies suggested that REGN2810 
dosage can be escalated safely. In PK studies of 1, 5, and 15 mg/kg REGN2810 administered to 
cynomolgus monkeys, estimates of the beta-phase terminal half-life (t½) of REGN2810 were 
comparable across dose groups: 9.84, 10.9, and 12.4 days, respectively. Accordingly, REGN2810 
will be administered every 14 days in this study to maintain targeted blood concentrations over the 
dosing interval.  
2.5. 
REGN2810 Clinical Studies 
REGN2810 is being evaluated in several phase 1, 2 and 3 clinical studies, as monotherapy and in 
combination with other antibodies, bispecific antibodies, radiation, and chemotherapy, among 
other treatment modalities. For an up-to-date list, please refer to the current Investigator’s 
Brochure(s).  
R2810˗ONC˗1423 is a Phase 1, first-in-human study of repeat dosing with REGN2810 as single 
therapy and in combination with other anticancer therapies in patients with advanced malignancies. 
The study has 10 dose escalation cohorts in patients with advanced solid tumors, followed by 26 
expansion cohorts explored in select indications. The primary objective of this investigation is to 
characterize the safety, tolerability, and dose-limiting toxicities (DLT) of REGN2810 as 
monotherapy or in combination with hypofractionated radiation therapy (hfRT) and/or 
cyclophosphamide (CTX), with hfRT, CTX, and Granulocyte Macrophage Colony-Stimulating 
Factor (GM-CSF), or in combination with chemotherapy agents (low dose carboplatin plus 
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docetaxel, low dose docetaxel, full dose carboplatin plus paclitaxel or carboplatin plus 
pemetrexed) (IND 123950; Study REGN2810-ONC-1423). Fifty-two (52) weeks is the proposed 
study length for the current study, similar to the treatment duration in the first-in-human study of 
REGN2810.  
As of 20 Jan 2017, a total of 353 (dose escalation, n = 60; expansion, n = 293) patients have been 
enrolled in this first-in-human study and treated at 4 different dose levels (1 mg/kg, 3 mg/kg, 10 
mg/kg, and a flat dose of 200 mg) of REGN2810 as monotherapy as well as in combination. There 
were no protocol defined dose limiting toxicities observed. REGN2810 was generally well 
tolerated; the most common treatment emergent adverse events (TEAEs) occurring in 10% or more 
patients were fatigue, nausea, anemia, decreased appetite, arthralgia, constipation diarrhea, 
dyspnea, cough, pyrexia, vomiting, asthenia and back pain.  
REGN2810 has demonstrated promising efficacy in a variety of tumor types, most notably as 
monotherapy in cutaneous squamous cell carcinoma, as presented at ASCO 201719. 
Cumulative Safety Profile of REGN2810 
 The emerging safety profile of REGN2810 is consistent with that described for other antibodies 
directed against PD-1 and evidence of rapid and durable responses with REGN2810 has been 
similar to the observations with other PD-1 inhibitors20,16.  
As of 20 January 2019, 885 patients have been treated with REGN2810 either as monotherapy or 
in combination with radiotherapy and/or other cancer therapy in 7 of the ongoing studies. A total 
of 615 patients (69.5%) experienced at least 1 treatment-related adverse event (AE) of which 
121 patients (13.7%) experienced grade 3 or higher treatment-related AEs. Seventy-six patients 
(8.6%) experienced investigator-attributed treatment-related serious adverse events (SAEs). Nine 
patients (1.0%) experienced fatal treatment-related AEs: hepatic failure (1 patient with 
hepatocellular carcinoma [HCC]) and acute hepatic failure (1 patient with diffuse large B-cell 
lymphoma [DLBCL]), paraneoplastic encephalomyelitis (1 patient with soft tissue sarcoma), toxic 
epidermal necrolysis (TEN), 1 patient with follicular lymphoma [FL] ), nosocomial pneumonia 
secondary to grade 4 mucositis (1 patient with FL), pneumonitis (2 patients: 1 with NSCLC and 1 
with cervical cancer), myelodysplastic syndrome (1 patient with NSCLC and subsequent treatment 
with KEYTRUDA), and unknown cause of death that could not rule out REGN2810 (1 patient 
with locally advanced head and neck CSCC). 
Additional details regarding the REGN2810 clinical development program and safety profile can 
be found in the Investigator’s Brochure. 
Studies of REGN2810 in Glioblastoma 
In the R2810-ONC-1423 study, there are 2 cohorts of adult patients with glioblastoma: 1 with 
newly diagnosed patients and 1 with patients with recurrent disease. In these cohorts, patients are 
treated with a starting dose of REGN2810 at 1 mg/kg/dose every 14 days and dose escalated to 
3 mg/kg/dose every 14 days and in combination with hypofractionated radiation of 6 Gy x 5 doses.  
Newly Diagnosed Glioblastoma: As of 20 Jan 2017, 6 patients with newly diagnosed 
glioblastoma (GBM) were treated (3 patients at 1 mg/kg and 3 patients at 3 mg/kg REGN2810). 
The first 3 run-in patients in this cohort, at the starting dose level of 1 mg/kg REGN2810 
experienced no DLTs; therefore the dose was escalated to 3 mg/kg REGN2810 for the next 3 
patients. Patients at the 3 mg/kg dose level experienced CNS necrosis probably related to radiation 
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therapy (RT), a serious grade 3 infusion related reaction after receiving first dose of REGN2810, 
and a grade 3 SAE of Nervous System Disorder Inflammation, and have recovered from these 
reactions. As of the data cut, 2/5 patients received treatment with bevacizumab in the newly 
diagnosed GBM cohorts.  
A total of 47 TEAEs of all grades occurred in 5/6 (83%) patients with newly diagnosed GBM, 
treated with either dose level of REGN2810 in combination with RT (1 patient receiving 1 mg/kg 
REGN2810 did not experience any AE thus far). Seven of the 47 TEAEs are suspected to be caused 
by REGN2810 occurring in 4/6 (66%) patients: grade 1 aspartate aminotransferase (AST) [1] and 
alanine aminotransferase (ALT) elevation [1]; grade 2 headache [2] and inflammation [1]; grade 
3 inflammation [1] and infusion related reaction [1].  
Two patients came off treatment: 1 patient in the 3 mg/kg REGN2810 cohort due to infusion 
related reaction and 1 in the 1 mg/kg REGN2810 cohort due to progressive disease. 
Recurrent Glioblastoma: As of 20 January 2017, 9 patients were treated (6 patients at 1 mg/kg 
and 3 patients at 3 mg/kg REGN2810). One patient treated with 1 mg/kg REGN2810 developed 
grade 2 inflammation in the brain, which was considered by the investigator to be related to both 
RT and REGN2810. Due to the nature of the first AE of grade 2 inflammation of the brain, a 
decision was made to expand the 1 mg/kg cohort from 3 patients to 6 patients prior to escalating 
to 3 mg/kg. Among the 3 patients enrolled in the 3 mg/kg dose level, there have been no protocol-
defined DLTs and the cohort has been expanded to enroll an additional 3 patients. Five of the 9 
patients came off treatment due to progressive disease. Of these 5 patients, 4 received 1 mg/kg and 
1 received 3 mg/kg REGN2810. One patient had progressive disease at the end of the first cycle 
(study day 54) and died on study day 105.  
A total of 78 TEAEs of all grades occurred in 8/9 (88.9%) patients with recurrent GBM, treated 
with either dose level of REGN2810 in combination with RT (1 patient receiving 3 mg/kg 
REGN2810 did not experience any AE thus far). Among the 78 TEAEs, 19 are suspected to be 
related to REGN2810 alone or in combination with RT occurring in 5/9 (55.6%) patients. Most of 
these treatment-related TEAEs are grade ½ with 3 grade 3 events: headache, worsening back pain 
and hyponatremia. There are 17/78 TEAEs considered to be related to radiotherapy alone 
occurring in 4/9 (44%) patients. Among these, 15 of the TEAEs are grade 1 or 2, and 1 grade 3 
headache and 1 grade 3 CNS necrosis, which have been resolved with bevacizumab treatment. 
3. 
RATIONALE 
3.1. 
Use of Anti-PD-1 Therapy in DIPG and HGG Patient Populations 
Given the stagnant survival curves of pediatric DIPG and recurrent HGG, despite multi-modal 
therapies over decades, this population remains a high-risk group deserving of novel, 
investigational therapeutic approaches. Previous therapeutic attempts have included tumor 
resection or debulking, re-irradiation, standard chemotherapy, and targeted approaches22-28. 
Additionally, multiple phase 1 and 2 clinical trials have demonstrated poor outcomes for patients 
with these high-risk tumors. There remains limited published data on population-based outcomes 
of recurrent pediatric HGGs, but anecdotal evidence and some published data support an estimated 
50% overall survival at 12 months for this high-risk group.  
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Immunotherapy is a novel therapeutic approach that is emerging as effective therapy for a variety 
of malignancies and may have significant potential in the treatment of pediatric DIPG and HGG. 
PD-1 receptors are expressed predominantly on T-cells and the corresponding ligands, PD-L1 and 
PD-L2, modulate T-cell function and diminish immune responses29. Evidence of PD-L1 and 
PD-L2 expression on various cancers as well as on tumor-infiltrating immune cells offers a 
potential pathway that can be targeted with anti-neoplastic immunotherapy. Recent preclinical 
studies have demonstrated that immunotherapy with PD-1 blockade prolongs overall survival and 
leads to durable responses in glioma mouse models30,31. These responses seem to correlate with T-
cell lymphocyte infiltration and PD-L1 and –L2 expression in the tumor microenvironment.32,33 A 
high percentage of human glioma cell lines express PD-L1, supporting that this inhibitory pathway 
is a key mechanism in HGG subversion of the immune system34-37. This is further supported 
through studies illustrating that PD-L1 levels within cerebral spinal fluid (CSF) and tumor tissues 
positively correlate with both grade and malignancy of gliomas38. The culmination of the above 
evidence, combined with findings of tumor-infiltrating lymphocytes and PD-L1 expression in 
HGG, reinforce use of PD-1 inhibitors in DIPG and HGG treatment31,39. 
Preliminary studies and animal models have suggested that PD-1 inhibition and radiation may 
synergize to produce local and systemic effects40-45. More specifically, preclinical data have shown 
that radiation “primes” the immune system as evidenced by increased antigen presentation, 
increased major histocompatibility complex expression, and antigen-specific T-cells in the tumor 
microenvironment43. Hypofractionated radiation may capitalize on these immune stimulating 
effects46. This priming of the immune system can then be further exploited by PD-1 inhibition, 
which is supported by prolonged survival in mouse models undergoing combined PD-1 inhibition 
and radiation compared to mice undergoing monotherapy with either agent45. Children may be 
particularly suited to exploit inherent immunity against tumor cells through the plasticity and 
robustness of their developing immune systems47.  
Early analyses of adult patients with melanoma, lung, or renal cancers at the Dana-Farber Cancer 
Institute treated with radiation and PD-1 pathway inhibitors concurrently or in close temporal 
proximity have revealed no unexpected or severe toxicities. This includes several patients treated 
with hypofractionated stereotactic radiosurgery to the brain or whole brain radiation therapy 
(PMID 28463153). Similarly, a recently published experience of patients treated with stereotactic 
radiosurgery and PD-1 inhibition revealed promising evidence in brain control with no unexpected 
toxicity or radionecrosis requiring surgery (PMID 26712903). At the University of California, San 
Francisco, a small cohort of patients with recurrent DIPG has been treated with nivolumab 
administered concurrently with reirradiation. To date, no patients have experienced significant 
toxicity. One patient experienced subacute onset of ataxia, dysarthria, and dysphagia early in 
treatment. Symptoms were treated with a 7-day course of oral dexamethasone, no doses of 
nivolumab were held and the patient went on to receive several months of therapy with nivolumab 
before again experiencing disease progression. The patient also experienced an acneiform rash that 
was treated with topical steroids48. Various studies evaluating combinations of PD-1 pathway 
blockade and radiation in adult patients are recently open or currently in development, including 
the combination of radiation and PD-L1 inhibition for the treatment of newly diagnosed 
glioblastoma (NCT02336165), also supporting this approach. 
In the R2810-ONC-1423 study, there are 2 dose escalation cohorts of adult patients with GBM — 
1 cohort of patients with newly diagnosed GBM and 1 cohort of patients with recurrent GBM. In 
both cohorts, patients are treated with a starting dose of REGN2810 1 mg/kg/dose every 14 days 
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and escalated to 3 mg/kg/dose every 14 days and in combination with hypofractionated radiation 
of 6 Gy for 5 fractions (total 30 Gy). As of 20 January 2017, 6 patients with newly diagnosed GBM 
and 9 patients with recurrent GBM have been treated, as discussed above.  
Given the evidence, there is strong rationale to treat children with DIPG and newly diagnosed and 
recurrent HGG with hypofractionated radiation in combination with PD-1 inhibition.  
3.2. 
REGN2810 Dose Selection 
As REGN2810 has not yet been evaluated in children, Phase 1 of this investigation will include 
children with relapsed or refractory solid or CNS tumors in order to confirm the anticipated RP2D 
dose for our target population. Inclusion of children with refractory or recurrent solid or CNS 
tumors will allow more rapid definition of the dose of REGN2810 to be used in combination with 
radiation. The starting dose of 3 mg/kg/dose was chosen for Phase 1 and the Efficacy Phase based 
on similar dosing in the commercially available anti-PD-1 antibodies, nivolumab and 
pembrolizumab, and on the comparable in vitro and in vivo potency of REGN2810 to these 
compounds, as well as on the safety and tolerability of 3 mg/kg/dose that was demonstrated in the 
first-in-human and phase 1 expansion cohorts using REGN2810 (see Section 2.5). The efficacy 
phase of this study will evaluate the feasibility, safety, and potential efficacy of administering the 
PD-1 inhibitor, REGN2810 in combination with radiation therapy and adjuvantly in three cohorts 
of pediatric patients with high-risk intracranial malignancies: newly diagnosed diffuse intrinsic 
pontine gliomas randomized to conventionally fractionated or hypofractionated radiation, newly 
diagnosed HGG randomized to conventionally fractionated or hypofractionated radiation and 
recurrent high-grade gliomas receiving hypofractionated dosing in the re-irradiation setting.  
Based on the phase 1 data, dose escalation experience with REGN2810, preclinical activity, 
toxicology data with greater-than-10-fold exposure margin over 1 mg/kg/dose REGN2810, and 
clinical efficacy and safety data from other anti-PD-1 monoclonal antibodies at similar 
doses/dosing intervals in global populations; a dosage of 3 mg/kg/dose every 14 days is expected 
to have an acceptable safety profile and to be active, and was therefore chosen as the anticipated 
RP2D in pediatrics. Additionally, at UCSF, PD-1 inhibition with nivolumab has been used 
concomitantly with upfront or reirradiation in nearly 10 pediatric patients with high-grade brain 
tumors. A 3 mg/kg/dose every 14 days has been employed at UCSF in all patients, with good 
tolerability observed for this regimen. Only 1 patient experienced symptomatic pseudoprogression 
including dysphagia and worsening ataxia; symptoms were alleviated with a 7-day course of oral 
dexamethasone and did not require holding of any drug. Ongoing multi-institutional trials also use 
similar dosing of PD-1 inhibitors in pediatric patients including trials led by the Children’s 
Oncology Group and Pediatric Brain Tumor Consortium, further supporting the anticipated RP2D 
dose for REGN2810 in pediatrics. 
Body weight-adjusted dosing of monoclonal antibodies may result in lower exposure in children 
with low body weight than in adults. This can lead to under-exposure in young pediatric patients 
with low body weight. In addition, based on REGN2810 clinical data and data in literature, toxicity 
of PD-1 inhibitors does not appear to correlate with increased dose14,21. Thus, the current study 
proposes a starting dose of REGN2810 of 3 mg/kg every 14 days, with a planned dose escalation 
to 4.5 mg/kg in younger children. If pharmacokinetics and drug exposure data suggest that dosing 
could be adjusted, then dosing may be altered. The 3 mg/kg every 2 weeks (Q2W) is consistent 
with the dose used for maintenance therapy in adult patient populations, and was found to be 
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clinically efficacious in several adult indications in study R2810-ONC-1423. This dose is 
consistent with current dosing used at UCSF for the similar PD-1 inhibitor, nivolumab, in 
conjunction with radiation and other pediatric protocols using nivolumab (NCT02304458). 
The results of this study will provide insight to optimally guide the development of REGN2810 
for DIPG and newly diagnosed and recurrent HGG and in combination with radiation, and 
potentially as treatment for other pediatric brain tumors.  
3.3. 
Radiotherapy Regimen Selection 
The optimal fractionated regimen for augmenting immunogenicity of tumors in human patients is 
unknown, therefore we propose four fractionated regimens in this current study, varying according 
to the arm and cohort of enrollment. We include both conventionally fractionated and 
hypofractionated regimens in this protocol, all of which represent acceptable standards of care in 
these populations.  
Patients with newly diagnosed DIPG will be randomized to receive either conventionally 
fractionated radiation as 1.8 Gy administered 5 times a week for 30 fractions to a total of 54 Gy 
(DIPG cohort-arm 1), or hypofractionated radiation delivered as 3 Gy administered 5 times a week 
for 13 fractions for a total of 39 Gy (DIPG cohort-arm 2). This hypofractionated schema is 
supported by other pediatric studies that have found hypofractionation radiation alone for DIPG to 
be well tolerated49-51.  
Patients with newly diagnosed HGG will be randomized to receive either conventionally 
fractionated radiation as 1.8 Gy administered 5 times a week for 33 fractions to a total of 59.4 Gy, 
or hypofractionated radiation delivered as 3 Gy administered 5 times a week for 13 fractions for a 
total of 39 Gy.  
In the recurrent HGG cohort, targeted focal re-irradiation is currently planned as 3.5 Gy 
administered 5 times a week for 10 fractions for a total of 35 Gy in recurrent HGG. This regimen 
has previously been used in patients with recurrent HGG who have received prior radiation 
therapy.  
While both treatment regimens in the DIPG and HGG cohort are acceptable standards of practice, 
the hypofractionated regimens being evaluated may offer advantages in terms of 
immunopotentiating effects52. In contrast, more extremely hypofractionated regimens such as 
25 Gy in 5 fractions have not been as well tolerated in this population and are therefore, not being 
tested in this study, despite their potential immune stimulating effects.  
In this study, radiation will be administered within +/-3 days of initial administration of 
REGN2810. The time course between radiation and REGN2810 initiation is based on previous 
literature illustrating that concomitant radiation with PD-1 inhibition, as opposed to sequential 
pairing of these therapies, leads to increased immune response and survival in mouse models41. 
The study proposes a single course of radiation, as the objective is to provide this treatment as the 
equivalent of a potent, autologous tumor vaccine aimed to augment the response achieved by PD-1 
blockade and as part of standard of care approach for our selected brain tumor populations.  
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3.4. 
Pharmacokinetic Assessment of REGN2810  
Assessment of REGN2810 PK in blood will be performed in all patients enrolled in the Phase 1 
and efficacy phases of this study. Because the PK profile of this agent is unknown in the pediatric 
population, this information will be essential to relate drug exposure in blood to toxicity and 
disease response in pediatrics and for refining dosing in future clinical trials of REGN2810.  
3.5. 
Correlative Exploratory Studies 
There is great utility to identifying mechanisms of response and resistance to PD-1 blockade as 
well as evaluating potential biomarkers that may be associated with clinical benefit. REGN2810 
is thought to work by stimulating an immune mediated attack on cancer cells, and based on prior 
preliminary studies conducted in patients across several disease types, PD-L1 expression and 
greater numbers of infiltrating lymphocytes may predict response to PD-1 / PD-L1 / PD-L2 
inhibitors in certain settings14,32,53,54. Systemic immune responses engendered by immunologic 
checkpoint blockade therapy may be predictive of response53,55,56. However, it is unknown to what 
degree tumor and circulating factors such as PD-L1 and PD-L2 expression, infiltrating and 
circulating T-cell populations, myeloid derived suppressor cells, and immunologic cytokines may 
predict responses to combined radiation-PD-1 blockade in patients with pediatric brain tumors. 
Tumor mutational burden may also be predictive of response to immune therapy and specifically 
PD-1 blockade, as has been observed in patients with lung cancer, glioblastoma, and mismatch 
repair deficient tumors.  
Patients enrolled in this trial will have tissue samples collected at baseline when feasible, and 
therefore available for potential correlative analyses. In recurrent disease cohorts, archival tissue 
collected from initial diagnoses will be acceptable. Additionally, serial blood collections of serum 
and peripheral blood mononuclear cells will evaluate additional correlative endpoints. 
We hypothesize that PD-L1 expression and CD8+ T-cell infiltration in baseline tumor biopsies 
will correlate with response to combined immunotherapy radiation approaches. We further 
hypothesize that CD8+ T-cell infiltration and PD-L1 expression as well as other immunologic 
factors such as PD-L2 expression, number of infiltrating CD68+ macrophages, and CD4+/FoxP3+ 
regulatory T cells may differ in biopsies taken in responding and non-responding patients and may 
therefore help guide future combination therapies. Favorable clinical responses may also be 
associated with measurable changes in circulating immune factors such as T-cell subsets, and 
immune chemokines/cytokines that may be of potential value in monitoring responses in future 
patients treated with this regimen. 
Procedures and descriptions of the proposed analyses can be found in Section 8.2.6. Statistical 
considerations can be found in Section 12.4. 
4. 
STUDY DESIGN 
This is a multi-center safety and efficacy study conducted through The Pacific Pediatric Neuro 
Oncology Consortium (PNOC). This study will consist of 2 phases conducted in parallel. After a 
screening period of 14 days, therapy will begin for a total of 12 cycles (or up to 24 cycles if, in the 
investigator’s opinion, the patient would continue to derive clinical benefit). In both phases, 
treatment cycles will each last 28 days. Patients who discontinue therapy or complete therapy will 
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undergo evaluation at an end of treatment visit, followed by a 30-day toxicity check. Patients will 
then enter long-term follow up, which will occur every 12 weeks from the last day of treatment 
and will last for up to 52 weeks. 
To assess preliminary anti-tumor efficacy, patients will receive radiographic imaging (MRI/PET 
or CT) once every 12 weeks while on treatment and during follow up. Patients will also provide 
tumor tissue (either fresh or archival) at screening and will undergo biopsy at any time on-study at 
the time of disease progression. To assess the impact of treatment on quality of life (QoL), patients 
will also be asked, while on treatment and during follow up, to complete the PedsQL (age 2 to 
<18) or FACT-Br (age >18) questionnaire. 
4.1. 
Phase 1 Study Design 
Phase 1 will consist of 4 cohorts (Cohort A through Cohort D), consisting of patients with 
recurrent/refractory solid tumors or recurrent/refractory CNS tumors and defined according to 
patient age (see the Experimental Design Schema and Table 2; for more information on patient 
population criteria, see Section 5). Cohorts are divided by age because drug metabolism and 
exposure may vary between younger and older patients. In this phase of the study, REGN2810 will 
be given as monotherapy (ie, no radiation therapy will be given). The Schedule of Events for 
Phase 1 is provided in Table 11. 
4.1.1. 
Dose Escalation Design in Phase 1 
Cohorts will escalate through a series of dose levels (DLs), which are provided in Table 8. For all 
cohorts, doses will be given every 14 days (see dose administration information in Table 9). All 
cohorts in Phase 1 will start REGN2810 at DL1 (3 mg/kg/dose). If DL1 is tolerated, the subsequent 
age cohorts 0 to <12 years may escalate to DL2 (4.5 mg/kg/dose). Age cohorts 0 to <12 years may 
also de-escalate to DL0 (1 mg/kg/dose) if de-escalation criteria are met (see Table 4). Age cohorts 
12 to <18 years cannot escalate beyond DL1, but may de-escalate to DL0 if de-escalation criteria 
are met (see Table 6). 
Table 2: 
Patient Cohorts in Phase 1 
Recurrent or refractory solid tumors 
Recurrent or refractory CNS tumors 
Cohort A: Age 0 to <12 years 
Cohort B: Age 12 to <18 years 
Cohort C: Age 0 to <12 years 
Cohort D: Age 12 to <18 years 
4.1.2. 
Dose Escalation Rules in Phase 1 
Phase 1 will use a 3+3 design to confirm the anticipated RP2D of REGN2810 as a single agent 
among children with solid or CNS tumors. Dose escalation rules for Phase 1 are provided in 
Table 4 (age cohorts <12 years) and Table 6 (age cohorts ≥12 years). A minimum of 3 patients 
will be required at each DL to be evaluable for DLT. Tolerability of a dose level will be achieved 
if all 3 DLT-evaluable patients complete the 28-day DLT period and 0 out of 3 experience a DLT. 
If 1 out of 3 DLT-evaluable patients experience a DLT, 3 more patients will be enrolled for a total 
of 6 patients. If 1 out of 6 evaluable patients experience a DLT, the DL will be considered tolerable. 
If ≥2 out of 6 evaluable patients experience a DLT, the DL will have exceeded the maximum 
tolerated dose (MTD). The RP2D will be confirmed separately for each of the 4 cohorts and may 
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be lower than the MTD if pharmacokinetically indicated. DLT windows for this study are provided 
in Section 4.4.1; DLT definitions are provided in Section 4.4.2.  
Dose escalation, de-escalation, and/or confirmation of RP2D will occur once all initial patients 
enrolled in a cohort have been observed for the DLT period and the data have been reviewed at a 
dose escalation review meeting. This meeting will include (at a minimum) the Regeneron 
medical/study director, the Regeneron risk management lead, the PNOC chair or co-chair, and a 
representative PNOC statistician. Other individuals, such as the individual site investigators, may 
also be included. Note that screening for the next dose cohort may begin prior to the dose escalation 
review meeting. 
For any cohort, if a dose level is considered tolerable but data from PK analyses indicate blood 
levels are above desired levels, a lower pre-specified dose level (Table 8) may be considered for 
that cohort. 
For each of the solid tumor cohorts, an additional 6 patients will be enrolled at the corresponding 
identified RP2D. 
Enrollment of patients <1 year of age will be allowed only after at least 3 patients ≥1 to <12 years 
of age have been enrolled and have demonstrated tolerability in the DLT period (ie, no DLTs).  
4.2. 
Efficacy Phase Study Design 
The Efficacy Phase will consist of 6 cohorts (Cohort E through Cohort J) of pediatric patients with 
either newly diagnosed DIPG, newly diagnosed HGG, or recurrent HGG, and defined according 
to patient age (see the Experimental Design Schema and Table 3; for more information on patient 
populations criteria see Section 5). In this phase of the study, REGN2810 will be given in 
combination with radiation therapy. The Schedule of Events for the Efficacy Phase is provided in 
Table 12 (REGN2810 + conventionally fractionated radiation) and Table 13 (REGN2810 + 
hypofractionated radiation).  
Table 3: 
Patient Cohorts in the Efficacy Phase  
Newly diagnosed DIPG 
Newly diagnosed HGG 
Recurrent HGG 
Cohort E: Age 3 to <12 years 
Cohort F: Age 12 to 25 years 
Cohort G: Age 3 to <12 years 
Cohort H: Age 12 to 25 years 
Cohort I: Age 3 to <12 years 
Cohort J: Age 12 to 25 years 
In the Efficacy Phase of the study, patients in newly diagnosed DIPG and newly diagnosed HGG 
cohorts will be randomized 1:1 to receive REGN2810 + conventionally fractionated radiation 
therapy (Arm 1) or REGN2810 + hypofractionated radiation therapy (Arm 2). Patients in recurrent 
HGG cohorts will receive REGN2810 + re-irradiation. After radiation therapy (in combination 
with REGN2810) is complete, patients will continue to receive REGN2810 according to the 
respective Schedule of Events.  
Radiation therapy guidelines, including dose schedules for each cohort, are provided in Section 9. 
All radiation will be done in a PNOC institution or PNOC-approved radiation center, due to 
frequent safety monitoring and the need to follow protocol radiation guidelines. 
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4.2.1. 
Dose Escalation Design in the Efficacy Phase 
Similar to Phase 1, in the Efficacy Phase cohorts (and treatment arms, as applicable) will need to 
establish a RP2D for REGN2810 in combination with radiation. For all cohorts, doses will be 
given every 14 days (see dose administration information in Table 9).  
Age cohorts 3 to <12 years (Cohorts E, G, and I) will start at the RP2D for this age group as 
determined by the corresponding CNS tumor cohort (Cohort C) in Phase 1, which is anticipated to 
be DL2 (4.5 mg/kg/dose). These cohorts may de-escalate if de-escalation criteria are met (see 
Table 5) but may not dose escalate above the Phase 1 RP2D of REGN2810.  
Age cohorts 12 to 25 years will start REGN2810 at DL1 (3 mg/kg/dose). Age cohorts 12 to 25 
years cannot escalate beyond DL1, but may de-escalate to DL0 if de-escalation criteria are met 
(see Table 6).  
4.2.2. 
Dose Escalation Rules in Efficacy Phase 
Similar to Phase 1, the Efficacy Phase will use a 3+3 design. This design will assess safety by 
observing for toxicity in the same manner as Phase 1 of the study. Dose escalation will proceed 
separately for each of the 6 cohorts per the dose escalation rules provided in Table 4 (age cohorts 
<12 years) and Table 6 (age cohorts ≥12 years). A minimum of 3 patients will be required at each 
DL to be evaluable for DLT. Tolerability of a dose level will be achieved if all 3 potentially 
DLT-evaluable patients complete the DLT period (length of radiation plus 28 days) and 0 out of 3 
experience a DLT. If 1 out of 3 DLT-evaluable patients experience a DLT, 3 more patients will be 
enrolled for a total of 6 patients. If 1 out of 6 evaluable patients experience a DLT, the DL will be 
considered tolerable. If ≥2 out of 6 evaluable patients experience a DLT, the DL will have 
exceeded the maximum tolerated dose (MTD). DLT evaluation will occur according to both cohort 
and treatment arm. The RP2D will be confirmed for each of the 10 treatment arms and may be 
lower than the MTD if pharmacokinetically indicated. DLT windows for this study are provided 
in Section 4.4.1; DLT definitions are provided in Section 4.4.2.  
Similar to Phase 1, dose escalation, de-escalation, or confirmation of MTD/RP2D will occur once 
all initial patients enrolled in a cohort have been observed for the DLT period and the data have 
been reviewed at a dose escalation review meeting or discussion, as appropriate. This will include 
(at minimum) the Regeneron medical/study director, the Regeneron risk management lead, the 
PNOC chair or co-chair, and a representative PNOC statistician. Other individuals, such as the 
individual PNOC site investigators, may also be included. Note that screening for the next dose 
cohort may begin prior to the dose escalation review meeting. 
As in Phase 1, if a dose level is considered tolerable but data from PK analyses indicate blood 
levels are above desired levels, a lower pre-specified dose level (Table 8) may be considered for 
that cohort. 
 
4.2.3. 
Timing of Initial Enrollment 
For cohorts enrolling patients 3 to <12 years, Efficacy Phase enrollment (and for newly diagnosed 
DIPG or newly diagnosed HGG cohorts, randomization) will begin once the RP2D of REGN2810 
is determined in Phase 1 for their corresponding age group in the CNS tumor cohort (Cohort C). 
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For cohorts enrolling patients 12 to 25 years of age, Efficacy Phase enrollment (and for newly 
diagnosed DIPG or newly diagnosed HGG cohorts, randomization) will begin immediately (in 
parallel with Phase 1). These cohorts will begin treatment at DL1. 
Once PK, tolerability, and preliminary efficacy of REGN2810 + radiation therapy are established 
in patients >3 years of age, patients ≤3 years and will also be enrolled, if appropriate, at the 
corresponding RP2D for their age group.  
4.2.4. 
Expansion Enrollment 
Once the RP2D of REGN2810 in combination with radiation is confirmed for a given cohort, 
enrollment of expansion cohorts will open to further investigate the safety and efficacy of 
REGN2810 + radiation therapy. Patients in expansion cohorts will follow the same Schedule of 
Events as patients in the initial 3+3 enrollment of the Efficacy Phase (Table 12, REGN2810 + 
conventionally fractionated radiation, and Table 13 , REGN2810 + hypofractionated radiation).  
During expansion, the total number of patients enrolled will be based on treatment arm, 
irrespective of patient age or cohort. Patients will be enrolled until at least 20 evaluable patients 
are reached per treatment arm, based on a Simon two-stage design. During the first stage, 7 patients 
will be enrolled per treatment arm. For DIPG and recurrent HGG, if no more than 3 deaths occur 
within 12 months, the second stage will be opened. If 4 or more deaths occur within 12 months, 
the arm will be temporarily closed for review. For newly diagnosed HGG, if no more than 2 
patients experience disease progression or death, the second stage will be opened, but if 3 or more 
patients experience disease progression or death, the arm will be temporarily closed for review. 
For more information on expansion enrollment and statistical considerations, see Section 12. 
4.3. 
Dose Escalation Rules 
Dose escalation will follow the rules provided below. Dose escalation rules for both Phase 1 and 
the Efficacy Phase of the study are subdivided according to age cohorts. Younger cohorts (<12 
years of age) will follow the rules outlined in Table 4 (Phase 1) and Table 5 (Efficacy Phase). All 
older cohorts (≥12 years of age) will follow the rules outlined in Table 6. 
 
 
 
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Table 4: 
Dose Escalation Rules: Cohorts Age <12 Years, Phase 1 
DL1 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
May stop enrollment at this level and escalate to DL2 
1 out of 3 
Enroll 3 more patients at DL1 
1 out of 6 DL1 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
>2 out of 3 
Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
DL0 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL0 
≤1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
1 out of 3 
Enroll 3 more patients at DL0  
1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
>2 out of 3 
Trial will be stopped for toxicity and discussed with sponsor 
DL2 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL2 
≤1 out of 6 DL2 will be considered the MTD for the cohort 
≥2 out of 6 DL1 will be considered the MTD for the cohort 
1 out of 3 
Enroll 3 more patients at DL2  
1 out of 6 DL2 will be considered the MTD for the cohort 
≥2 out of 6 DL1 will be considered the MTD for the cohort 
>2 out of 3 
DL1 will be considered the RP2D for the cohort 
 
 
 
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Table 5: 
Dose Escalation Rules: Cohorts Age <12 Years, Efficacy Phase 
Note that, during the Efficacy Phase, patients <12 years will initially be enrolled to confirm the 
RP2D identified in Phase 1, which is anticipated to be DL2. Patients may not escalate above their 
respective Phase 1 RP2D, but may de-escalate. See Section 4.2 for more information. 
DL2 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL2 
≤1 out of 6 DL2 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL1 and subsequent patients will follow DL1 rules 
1 out of 3 
Enroll 3 more patients at DL2 
1 out of 6 DL2 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL1 and subsequent patients will follow DL1 rules 
>2 out of 3 
Dose will de-escalate to DL1 and subsequent patients will follow DL1 rules 
DL1 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL1 
≤1 out of 6 DL1 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
1 out of 3 
Enroll 3 more patients at DL1  
1 out of 6 DL1 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
>2 out of 3 
Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
DL0 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL0 
≤1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
1 out of 3 
Enroll 3 more patients at DL0 
1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
>2 out of 3 
Trial will be stopped for toxicity and discussed with sponsor 
 
 
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Table 6: 
Dose Escalation Rules: Cohorts Age ≥12 Years, Phase 1 and Efficacy Phase 
DL1 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL1 
≤1 out of 6 DL1 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
1 out of 3 
Enroll 3 more patients at DL1  
1 out of 6 DL1 will be considered the MTD for the cohort 
≥2 out of 6 Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
>2 out of 3 
Dose will de-escalate to DL0 and subsequent patients will follow DL0 rules 
DL0 Rules 
No. of Patients 
with DLT 
Dose Decision Rule 
0 out of 3 
Enroll 3 more patients at DL0 
≤1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
1 out of 3 
Enroll 3 more patients at DL0 
1 out of 6 DL0 will be considered the MTD for the cohort 
≥2 out of 6 Trial will be stopped for toxicity and discussed with sponsor 
>2 out of 3 
Trial will be stopped for toxicity and discussed with sponsor 
4.4. 
Dose-Limiting Toxicities 
4.4.1. 
DLT Period 
Phase 1: The DLT period for Phase 1 is defined as the first cycle of therapy (cycle length 28 days, 
having received 2 doses of REGN2810) and will include weekly toxicity monitoring (physical 
examination, vital signs, adverse event monitoring, CBC with differential, and serum chemistry).  
Efficacy Phase: The DLT period for the Efficacy Phase is defined as the length of radiation 
therapy + 28 days after completion of radiation therapy. All patients in the DIPG and HGG cohorts 
of the efficacy phase will undergo weekly toxicity monitoring (described above) for the entire 
length of the DLT period.  
4.4.2. 
Definition of Dose-Limiting Toxicity 
Criteria for establishing dose-limiting toxicity are presented in Table 7. Treatment-emergent 
adverse events that appear to meet the DLT definition will be discussed between Regeneron and 
the investigator. The final decision of whether or not the AE meets the DLT definition will be 
based on a careful review of all relevant data and consensus between the medical monitor and the 
designated risk management lead from the Pharmacovigilance & Risk Management department. 
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The investigator will also be consulted. A minimum of 3 patients at each dose level will be required 
to be evaluable for DLT. Tolerability of a dose level will only be determined when all potentially 
DLT-evaluable patients complete the entire DLT period.  
Management and dose modifications associated with the AEs described below are outlined 
in Section 6.2.  
 
Table 7: 
Criteria for Dose-Limiting Toxicity 
Non-
Hematologic 
 Any grade 3 or 4 non-hematologic toxicity considered related to REGN2810. 
 Any REGN2810-related AE during the first cycle of therapy that leads to a dose 
reduction, or results in delay of treatment ≥7 days, or results in permanent 
cessation of therapy  
Hematologic  Any grade 4 hematologic toxicity considered related REGN2810, with the 
exception of lymphopenia and anemia  
 Grade 3 neutropenia with fever considered related to REGN2810 
 Grade 3 thrombocytopenia considered related to REGN2810 
Immune-
Related 
 Grade 3 immune-related AE considered related to REGN2810. Examples 
include, but are not limited to, neurological toxicities, uveitis, endocrine 
toxicity, and colitis 
Interruption 
of 
Planned 
Radiation 
(Efficacy 
Phase Only) 
 For newly diagnosed DIPG and HGG receiving conventionally fractionated 
radiation: interruption of radiation for 5 consecutive fractions, or 10 fractions 
total, due to REGN2810-related toxicity (and not due to technical issues) 
 For newly diagnosed DIPG and HGG receiving hypofractionated radiation: 
interruption of radiation for 2 consecutive fractions, or 4 fractions total, due to 
REGN2810-related toxicity (and not due to technical issues) 
 Recurrent HGG, reirradiation: 2 consecutive fractions or 3 fractions total due 
to REGN2810-related toxicity (and not due to technical issues) 
 
4.5. 
Off-Treatment Criteria 
REGN2810 treatment may occur for up to 12 cycles (or up to 24 cycles if, in the opinion of the 
investigator, the patient would continue to derive clinical benefit from extended treatment). 
Patients must discontinue therapy if 1 or more of the following criteria are met: 
 Confirmed disease progression 
 General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator 
 Treatment delays (≥28 days) from anticipated dosing schedule of REGN2810; 
however, note that treatment may be continued after discussion with the sponsor and 
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 Unacceptable AE(s) 
 The patient or LAR refuses further treatment on this protocol 
 Pregnancy 
Note that, in the Efficacy Phase, if a patient treated with combination therapy experiences 
unacceptable AE(s) that are (in the opinion of the investigator) reasonably likely to be related to 
only one of the therapies, the patient may continue treatment with the therapy determined not to 
be the cause of the AE(s). In addition, if the AE is an infusion-related reaction that (in the opinion 
of the investigator) is reasonably likely to be related to REGN2810 and not combination therapy, 
this will not be considered a DLT of the combination therapy. 
The off-treatment information and reason for discontinuation must be documented by the attending 
investigator in the medical record and recorded in the eCRF. 
4.6. 
Off-Study Criteria 
Patients will be considered off study for the following reasons: 
 Patients begins new anticancer therapy not specified in protocol 
 Patient is determined to be ineligible 
 Patient or LAR withdraws consent for continued participation 
 Patient dies while on study 
 Completion of the follow-up period specified in the protocol 
The date and reason for the patient coming off study must be documented in the eCRF. No data 
will be collected after the “off study” date. 
4.7. 
Number of Patients 
In Phase 1, a minimum of 30 patients will be enrolled. In the Efficacy Phase, a minimum of 100 
patients will be enrolled. A complete description of patient sample size can be found in 
Section 12.2.  
4.7.1. 
Minimum Enrollment Requirements 
Cohorts in the Efficacy Phase will have minimum enrollment requirements for certain age groups. 
DIPG cohorts will include a minimum of 30 patients age <18 years (15 in each treatment arm) and 
a minimum of 20 patients age <12 years (10 in each treatment arm). Newly diagnosed HGG 
cohorts will include a minimum of 20 patients age <18 years (10 in each treatment arm) and a 
minimum of 4 patients age <12 years (2 in each treatment arm). Recurrent HGG cohorts will 
include a minimum of 5 patients <18 years, with no minimum requirement for patients age <12 
years. These minimum cutoffs are tailored to the age-related incidence of each tumor type. 
 
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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
To be eligible for this study, all patients must meet the criteria outlined in Section 5.1.1. Inclusion 
criteria applicable only to Phase 1 or the Efficacy Phase are provided in Section 5.1.2 and 
Section 5.1.3, respectively. Performance status criteria can be found in Appendix 1. For mandatory 
radiation dose constraints, see Section 10. 
The inclusion criteria provided below are to be interpreted literally and cannot be waived. 
5.1.1. 
All Patients (Phase 1 and Efficacy Phase) 
 Karnofsky performance status 50 (patients >16 years) or Lansky performance status 
50 (patients 16 years) 
 Patients who are unable to walk due to paralysis, but who are able to use a 
wheelchair, will be considered ambulatory for the purpose of assessing 
performance score 
 Life expectancy >8 weeks 
 Adequate bone marrow function, defined as: 
a. Peripheral absolute neutrophil count (ANC) 1000/mm3  
and 
b. Platelet count 100,000/mm3 (transfusion independent, defined as not receiving 
platelet transfusions for ≥7 days prior to study registration)  
and 
c. Hemoglobin ≥8 g/dL (transfusion independent) 
 Adequate renal function, defined as: 
a. Creatinine clearance or radioisotope glomerular filtration rate (GFR) 70 
mL/min/1.73 m2  
or 
b. Serum creatinine based on age/gender as follows: 
 
Age 
Maximum Serum Creatinine (mg/dL) 
Male 
Female 
0 to 2 months 
0.9 
0.9 
2 months to <2 years 
0.6 
0.6 
2 to <6 years 
0.8 
0.8 
6 to <10 years 
1 
1 
10 to <13 years 
1.2 
1.2 
13 to <16 years 
1.5 
1.4 
≥16 years 
1.7 
1.4 
Threshold creatinine values derived from the Schwartz formula for GFR estimation, 
which utilizes child body length/stature data from the Centers for Disease Control57 
 Adequate liver function, defined as: 
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a. Bilirubin (sum of conjugated + unconjugated) 1.5x upper limit of normal (ULN) 
for age  
and 
b. Alanine transaminase (ALT, also referred to as SGPT) 110 U/L  
and 
c. Serum albumin 2 g/dL 
 Adequate neurologic function: patients with seizure disorder may be enrolled if well 
controlled  
 Patient or legally authorized representative (LAR) able to understand, and willing to 
sign, a written informed consent 
5.1.2. 
Phase 1  
 Age 0 to <18 years  
 Diagnosis of recurrent or refractory solid or CNS tumor  
 Histologic confirmation of malignancy at original diagnosis or relapse  
 Multifocal DIPG will be eligible for Phase 1 
 Exception: patients with metastatic spine disease and gliomatosis, as documented 
by diffuse involvement of >2 lobes, are not eligible 
 Available tumor tissue from biopsy or resection; archived tissue is acceptable 
 Radiation therapy: for solid tumors outside of the CNS, an interval of ≥14 days between 
local palliative radiation therapy and study registration; for CNS tumors, interval of 
≥12 weeks between radiation therapy and study registration  
 Note: these requirements are due to concerns of pseudo-progression in the CNS and 
challenges that may arise from delineating toxicity related to radiation versus drug 
5.1.3. 
Efficacy Phase 
5.1.3.1. 
Newly Diagnosed DIPG (Cohorts E and F) Only 
 Age 3 to 25 years  
 Histological confirmation of newly diagnosed DIPG  
 Patients with or without H3K27M mutations are eligible 
 Patients with infiltrating astrocytomas within the pons, consistent with DIPG, are 
eligible 
 Patients with disseminated spine disease are not eligible. Magnetic resonance 
imaging (MRI) of the spine must be performed if the treating physician suspects 
disseminated disease 
 Available tumor tissue from biopsy or resection; archived tissue is acceptable 
 No prior therapy before study registration 
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 No prior radiation before study registration 
 First study treatment administration ≤28 days from the date of radiographic diagnosis 
5.1.3.2. 
 Newly Diagnosed HGG (Cohorts G and H) Only 
 Age 3 to 25 years 
 Histological confirmation of newly diagnosed high-grade glioma (WHO grade III-IV) 
within the cerebrum and/or the cerebellum, including but not limited to infiltrating 
astrocytomas outside of the pons 
 Patients with or without H3K27M mutations are eligible 
 Patients with disseminated disease anywhere outside of the cerebrum or cerebellum 
are not eligible 
 Patients whose primary diagnosis is high-grade glioma of the spinal cord are not 
eligible 
 Patients with DIPG are excluded from this cohort 
 Available tumor tissue from biopsy or resection; archived tissue is acceptable 
 No prior therapy before study registration 
 No prior radiation before study registration 
 First study treatment administration ≤28 days of the date of definitive surgery 
5.1.3.3. 
Recurrent HGG (Cohorts I and J) Only: 
 Age 3 to 25 years 
 Diagnosis of recurrent high-grade glioma (WHO grade III-IV) within the cerebrum 
and/or the cerebellum, including but not limited to infiltrating astrocytomas outside of 
the pons 
 Patients with or without H3K27M mutations are eligible 
 Recurrent lesions must be treatable within a single radiation field that can meet 
mandatory radiation dose constraints 
 Patients will be limited to first or second recurrence 
 Patients with disseminated disease anywhere outside of the cerebrum or 
cerebellum are not eligible. Patients whose primary diagnosis included high-grade 
glioma of the spinal cord are not eligible. Patients with DIPG are excluded from 
this cohort 
 Histological confirmation of recurrent high-grade glioma (WHO grade III-IV) is 
preferred  
 Available tumor tissue from biopsy or resection; archived tissue is acceptable 
 Patients must have had previous irradiation as therapy for HGG diagnosis 
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 Patients are allowed to have undergone prior therapy including surgery, chemotherapy, 
and radiation therapy. Patients must have fully recovered from acute side effects related 
to previous anticancer therapies 
 Patients must have:  
 Had their last fraction of local irradiation to primary tumor ≥6 months prior to 
study registration; investigators are reminded to review potentially eligible cases 
to avoid confusion with pseudo-progression 
 Had their last dose of myelosuppressive chemotherapy ≥21 days prior to study 
registration (≥42 days if nitrosourea therapy) 
 Had their last dose of hematopoietic growth factor ≥14 days (long-acting growth 
factor) or ≥7 days (short-acting growth factor) prior to study registration, or 
beyond the time during which adverse events (AEs) are known to occur 
 Had their last dose of biologic (anti-neoplastic agent) ≥7 days prior to study 
registration, or beyond the time during which AEs are known to occur 
 Had their last dose of monoclonal antibodies ≥21 days prior to study registration 
5.2. 
Exclusion Criteria 
The exclusion criteria below apply to all patients in this study, in both Phase 1 and the Efficacy 
Phase.  
The exclusion criteria provided below are to be interpreted literally and cannot be waived. 
 Patients with bulky metastatic disease of the CNS causing any of the following: 
 Uncal herniation or symptomatic midline shift 
 Significant, symptomatic mass effect 
 Uncontrolled neurological symptoms such as seizures or altered mental status 
 Patients with metastatic spine disease and gliomatosis as documented by diffuse 
involvement of >2 lobes  
 Patients who are receiving any other investigational anticancer agent(s) 
 Patients on greater than dexamethasone 0.1 mg/kg/day (maximum 4 mg/day) or 
equivalent dose in alternate corticosteroid, or actively undergoing corticosteroid dose 
escalation in the last 7 days 
 Patients with a history of allogeneic stem cell transplant 
 Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements 
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 Human immunodeficiency virus (HIV)-positive patients are ineligible if HIV therapy 
regimen has not been stable for ≥4 weeks, or there is intent to change the regimen 
within 8 weeks prior to study registration 
 Patients who are unable to return for follow-up visits or obtain follow-up studies 
required to assess toxicity to therapy 
 Ongoing or recent (within 5 years) evidence of significant autoimmune disease that 
required treatment with systemic immunosuppressive treatments, which may suggest 
risk for immune-related AEs 
 Prior treatment with an agent that blocks the PD-1/PD-L1/PD-L2 pathway 
 History of pneumonitis within the last 5 years or any history of thoracic radiation 
 Patients who have received prior craniospinal irradiation (CSI) or have prior radiation 
fields that overlap the lung 
 History of documented allergic reactions or acute hypersensitivity reaction attributed 
to agents used in the study 
 Patients who have received live vaccines within 28 days (4 weeks) prior to study 
registration 
 Continued sexual activity in males or women of childbearing potential (WOCBP)1 who 
are unwilling to practice highly effective contraception prior to the initial dose/start of 
the first treatment, during the study, and for at least 6 months after the last dose  
Examples of highly effective contraceptive measures in WOCBP include: intrauterine 
device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal ligation; 
vasectomized partner2; stable use of combined (estrogen and progestogen containing) 
hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal 
contraception (oral, injectable, implantable) associated with inhibition of ovulation 
initiated 2 or more menstrual cycles prior to screening; and/or sexual abstinence3,4 
Male study participants with WOCBP partners are required to use condoms unless they 
are vasectomized2 or practice sexual abstinence3,4 
1 WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless 
permanently sterile. Pregnancy testing and contraception are not required for women with documented hysterectomy 
or tubal ligation. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy 
2 Vasectomized partner or vasectomized study participant must have received medical assessment of the surgical 
success 
3 Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient 
4 Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female 
condom and male condom should not be used together 
 WOCBP who are pregnant or breast-feeding. WOCBP must have a negative pregnancy 
test (serum or urine) within 14 days prior to study registration 
 
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6. 
STUDY DRUG ADMINSTRATION AND DOSE 
MODIFICATIONS 
6.1. 
REGN2810 Administration 
REGN2810 dosing and information is provided in Table 8 and Table 9. Appropriate dose 
modifications are described in Section 6.2. REGN2810 will be infused intravenously every 2 
weeks. REGN2810 infusion should occur over at least 30 minutes (window: +/-5 minutes). The 
infusion time may exceed 30 minutes as needed to conform with institutional standards. Patients 
should be observed post-infusion as per institutional standards. Post-infusion observations should 
be documented in the eCRF. 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy. REGN2810 should be initiated 
within 14 days of screening and within +/-3 days of radiation start. 
 
Table 8: 
REGN2810 Dose Levels  
Dose Level 
Dose of REGN28101 
DL0 
1 mg/kg/dose 
DL1 
3 mg/kg/dose 
DL2 
4.5 mg/kg/dose 
1 The dose of REGN2810 must be adjusted at the start of each cycle for changes in body weight of ≥10%. 
Dose adjustments for changes in body weight of <10% will be at the discretion of the investigator. 
 
Table 9: 
REGN2810 Administration 
Agent (Phase 1 and 
Efficacy Phase) 
Premedications 
or Precautions Dose 
Route 
Schedule Cycle 
Length 
REGN2810 
None 
See 
Table 8  
IV for at least 30 minutes 
(+/-5 minutes); may 
exceed 30 minutes per 
institutional standards  
Dose on 
days 1 and 
15 of 28-
day cycles 
28 days  
(4 
weeks) 
6.2. 
REGN2810 Dose Modifications and Delays  
All toxicities will be graded per Common Terminology Criteria for Adverse Events (CTCAE) v4.0 
(see Section 9.5.1). Table 10 provides general guidelines for dose modification in the event of 
suspected toxicity related to REGN2810. Please see Appendix 2 for dose-modification guidelines 
for specific organ-related toxicities.  
NOTE: If a patient experiences several AEs and there are conflicting recommendations, the 
investigator should use the recommended dose adjustment that reduces the dose the most.  
The PNOC Study Chair, Co-Chair, and Medical Monitor must be notified prior to any dose 
modifications and prior to the implementation of a dose modification. 
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Table 10: 
Guidelines for Dose Modification and Re-Initiation of Treatment in Case of 
Suspected REGN2810 Toxicity 
Toxicity 
Grade 
Recommended Action 
Non-
hematologic 
toxicity1 
1 
No change in REGN2810 dose 
2 
 Consider holding REGN2810 until grade ≤1 
 Discontinue REGN2810 if toxicity is intolerable to 
patient 
 Discontinue REGN2810 if toxicity remains and does not 
return to grade ≤1 within 4 weeks 
3/4 
Discuss with study chairs regarding specific recommendations 
for REGN2810 dose modification. 
Infusion-
related 
reactions 
1 
 No change in REGN2810 dose 
 Consider premedication with acetaminophen and 
diphenhydramine, as per institutional standards, prior to 
future infusions 
 For patients with a documented history of allergic 
reaction/hypersensitivity to antibody therapy, temporarily 
suspend study treatment and notify sponsor 
2 
 No change in REGN2810 dose 
 Recommend premedication with acetaminophen and 
diphenhydramine, as per institutional standards, prior to 
future infusions 
 For patients with a documented history of allergic 
reaction/hypersensitivity to antibody therapy, temporarily 
suspend study treatment and notify sponsor 
2 (Recurrent)2 
Discontinue REGN2810 
3/4 
Discontinue REGN2810 
1 Outside of specific organ-related toxicities listed in Appendix 2. 
2 Recurrent grade 2 that occurs a second time despite premedication. 
6.3. 
Prohibited Therapies 
Patients may not receive live vaccines while on therapy and for 3 months after stopping therapy. 
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7. 
STUDY SUPPORTIVE CARE AND ADVERSE EVENT 
MANAGEMENT GUIDELINES 
7.1. 
Supportive Care 
Supportive care may include, but is not limited to, antibiotics, antiemetics, antidiarrheals, topical 
treatments, blood products, intravenous or oral fluids, and electrolyte repletion. These measures 
will be used as clinically indicated.  
7.2. 
Infusion-Related Reactions 
Guidance for managing infusion-related reactions is provided in Table 10. Infusion-related 
reactions should be managed per institutional guidelines with treatment including, but not limited 
to, corticosteroids, antihistamines, epinephrine, and intravenous fluids. Lengthening of the 
infusion time for subsequent REGN2810 administration may also be considered, after discussion 
with the sponsor. 
7.2.1. 
Allergic Reaction or Hypersensitivity in Patients with Prior Reaction(s) to 
Antibody Treatment 
For patients with a documented allergic reaction or hypersensitivity attributed to antibody therapy, 
study treatment will be temporarily suspended following any evidence of an allergic reaction or 
hypersensitivity to REGN2810. The sponsor should be informed as soon as possible to discuss 
further management of the patient. 
7.3. 
Management of Specific Organ-Related Toxicities  
In general, treatment emergent adverse events should be provided symptomatic care per 
institutional standards. For grade 2 to 4 adverse events, corticosteroids may be considered, as 
described in Appendix 2. Grade 3 to 4 irAEs can be fatal if not aggressively treated. In most cases, 
this means instituting systemic corticosteroid therapy before ruling out all competing diagnoses. 
For adult patients, recommended initial systemic corticosteroid therapy is 0.5 to 1 mg/kg daily for 
grade 3 irAEs and 1 to 2 mg/kg daily for grade 4 irAEs. For pediatric patients, initiation of 
corticosteroids per institutional standards is appropriate. See Appendix 2 for additional AE 
management guidelines. 
7.4. 
Special Considerations: Pseudoprogression 
For symptoms and imaging consistent with pseudoprogression of tumors in the CNS, use of 
supportive care measures including bevacizumab and corticosteroids will be allowed, with 
recommended dosing as follows and in order of study preference, as possible per institutional 
availability and acuity of symptoms: 
 Bevacizumab for up to 3 doses, dosing per institutional standard 
 Dexamethasone, per institutional standard 
For symptoms of pseudoprogression of solid tumors outside of the CNS (Phase 1 only), use of 
supportive care measures including corticosteroids will be allowed, with recommended type and 
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dosing as follows: methylprednisolone intravenous (IV) or oral equivalent per institutional 
standards, depending on severity of symptoms 
8. 
SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events / Treatment Plan 
8.1.1. 
Schedule of Events 
The Schedule of Events is provided below for Phase 1 (Table 11) and the Efficacy Phase (Table 12 
and Table 13). Table 12 describes cohorts in the Efficacy Phase receiving REGN2810 + 
conventionally fractionated radiation. Table 13 describes cohorts in the Efficacy Phase receiving 
REGN2810 + hypofractionated radiation. Additional information on long-term follow-up is 
provided in Section 8.1.8. Detailed descriptions of study observations and procedures are provided 
in Section 8.2. Specific fractionation schedules for each cohort/tumor type are provided in 
Section 10.2. 
Windows for each visit are provided in the Schedule of Events. The window for REGN2810 
administration is +/-3 days. Unless otherwise noted, the window for assessments is also +/-3 days. 
REGN2810 should be initiated within 14 days of screening and (for Efficacy Phase cohorts) +/-3 
days of radiation start. 
 
 
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Table 11: 
Schedule of Events for Phase 1 
Visit 
Screening 
Treatment Cycles (28 days) 
End of 
Treatment 
(EOT) 
Toxicity 
Check 
Follow-up2 
C1 
C2 to C121 
Day 
-14 to -1 
1 
+/-3d 
8  
+/-3d 
15  
+/-3d 
22  
+/-3d 
1  
+/-3d 
15  
+/-3d 
Day of 
decision to 
stop 
treatment 
+14d 
30 days 
after 
EOT 
+7d 
Every 12 weeks 
after last 
treatment +/-7d 
CLINICAL PROCEDURES 
Consent Form 
X 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical w/Full Neurologic Exam 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
X 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Quality of Life Assessment3 
 
X3 
 
 
 
X3 
 
X3 
 
X3 
Survival 
 
 
 
 
 
 
 
 
 
X 
AGENT ADMINISTRATION 
REGN2810 (cemiplimab) 
 
X4 
 
X4 
 
X4 
X4 
 
 
 
LABORATORY PROCEDURES 
CBC w/Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistry5 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum or Urine Pregnancy Test 
(women of childbearing potential 
only)6 
X 
X 
 
 
 
X 
 
 
 
 
Urinalysis  
 
X 
 
 
 
X 
 
X 
 
 
Serum TSH 
 
X 
 
 
 
X 
 
X 
 
 
Serum Free Thyroxine, T4 
 
X 
 
 
 
X 
 
X 
 
 
Serum Amylase 
 
X 
 
 
 
X 
 
X 
 
 
Serum Lipase 
 
X 
 
 
 
X 
 
X 
 
 
Serum C-reactive Protein (CRP) 
 
X 
 
 
 
X 
 
X 
 
 
IMAGING AND DISEASE ASSESSMENT PROCEDURES 
MRI/PET or CT 
X7 
X7 
 
 
 
X7 
 
X7 
 
X7 
Disease Status Assessment 
X7 
X7 
 
 
 
X7 
 
X7 
 
X7 
PHARMACOKINETIC (PK) AND ANTI-DRUG ANTIBODY (ADA) PROCEDURES 
PK and ADA  
 
Sample collection schedule varies by cohort. See Section 8.2. 
EXPLORATORY PROCEDURES 
Tumor Tissue8 
X8 
 
 
 
 
 
 
 
 
 
Genomic DNA (Saliva/Buccal) 
X9 
 
 
 
 
 
 
 
 
 
Circulating Tumor DNA 10 
 
X10 
 
 
 
X10 
 
X10 
 
X10 
Peripheral Blood Mononuclear 
Cells11 
 
X11 
 
 
 
X11 
 
 
 
 
Cytokines/Biomarkers12 
 
X12 
 
 
 
X12 
 
 
 
 
 
 
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8.1.2. 
 Footnotes for Table 11 (Schedule of Events for Phase 1) 
1. Patients who continue beyond 12 cycles should undergo all observations listed under C2 
to C12 with the exception of PBMC and cytokine sample collection. 
2. All indicated follow-up assessments, with the exception of QoL assessments, should occur 
every 12 weeks after a patient has stopped receiving treatment, up to 52 weeks.  
3. Quality of life assessment should occur at the following visits: prior to the first dose of 
REGN2810, prior to receiving REGN2810 on cycle 7, day 1, at the end of treatment visit, 
and during every other follow up visit (ie, every 24 weeks) during the off-treatment period. 
Quality of life will be measured using PedsQL (patients 2 to <18 years of age) or FACT-
Br (patients >18 years of age) as described in Section 8.2.1.9. 
4. REGN2810 should be given every 14 days, starting on cycle 1 day 1, for up to 12 cycles. 
REGN2810 may continue to be given every 14 days for up to 24 cycles if, in the 
investigator’s opinion, the patient would continue to derive clinical benefit. On days when 
REGN2810 is given, all other assessments and procedures should be performed first. In 
Phase 1, the DLT period occurs during the first two doses of REGN2810 (ie, cycle 1 day 1 
[C1D1] to C1D28). 
5. For more information on serum chemistry tests that must be performed, see Section 8.2.3. 
6. For all visits in which pregnancy testing is required, the procedure window is +/-14 days. 
7. Imaging does not need to be taken or recorded every treatment cycle, but should occur once 
every 12 weeks (window: -2 weeks) while patients are on treatment. Imaging should also 
be performed during the EOT visit (window: +/-30 days) and during the off-treatment 
follow-up period approximately once every 12 weeks (or per institutional standards) for up 
to 52 weeks. Imaging should also be performed at the time of disease progression.  
Imaging during C1D1 is only required if prior imaging occurred more than 14 days from 
C1D1. If imaging has been taken within 14 days of C1D1 (ie, during the screening period), 
imaging does not need to be performed on C1D1.  
For a given patient, the same imaging modality should be used throughout the study. 
Details on imaging procedures and disease assessment are provided in Section 11.  
8. Available tumor tissue, either archival or fresh, must be confirmed prior to study eligibility. 
Tumor tissue will also be collected if the patient undergoes repeat surgical resection or 
biopsy at any time while the patient is on-study, including in the setting of disease 
progression. See Section 5.1 for tumor biopsy requirements. 
9. Saliva/buccal sample for genomic DNA may be collected at any time. Saliva/buccal sample 
is only required if a tumor sample (either archival or from biopsy) is taken. 
10. Blood for circulating tumor DNA (ctDNA) should be collected pre-dose on C1D1 and at 
any time scheduled or repeat/confirmatory imaging is performed (except during screening).  
11. Blood for correlative peripheral blood mononuclear cell (PBMC) studies should be 
collected pre-dose on day 1 of cycles 1, 2, and 3.  
12. Blood for correlative serum/plasma biomarker studies should be collected pre-dose on day 
1 of cycles 1 through 5 and at the time of disease progression.
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Table 12: 
Schedule of Events for the Efficacy Phase: REGN2810 + Conventionally Fractionated Radiation 
Visit 
Screening 
Treatment Cycles (28 days) 
End of Treatment 
(EOT) 
Toxicity 
Check 
Follow-up2 
C1 
C2 
C3 to C121 
Day 
-14 to -1 
1 
+/-3d 
8 
+/-3d 
15 
+/-3d 
22 
+/-3d 
1 
+/-3d 
8 
+/-3d 
15 
+/-3d 
1 
+/-3d 
15 
+/-3d 
Decision to stop 
future dosing +14d 
30 days after 
EOT +7d 
Every 12 weeks after 
last treatment +/-7d 
CLINICAL PROCEDURES 
Consent Form 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
Physical w/Full Neurologic Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Quality of Life Assessment4 
 
X4 
 
 
 
 
 
 
X4 
 
X4 
 
X4 
Survival 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AGENT ADMINISTRATION 
REGN2810 (cemiplimab) 
 
X5 
 
X5 
 
X5 
 
X5 
X5 
X5 
 
 
 
Radiation6 
 
C1D1 to C2D8: 5 times each week w/ 
cohort-specific dosing (Section 10.2) 
 
 
 
 
 
 
LABORATORY PROCEDURES 
CBC w/Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum or Urine Pregnancy Test7 
X 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Urinalysis 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
Serum TSH, Serum Free T4 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Serum Amylase 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Serum Lipase 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
 
Serum C-reactive Protein (CRP) 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
IMAGING AND DISEASE STATUS ASSESSMENT PROCEDURES 
Brain MRI/Spine MRI8 
X8 
X8 
 
 
 
 
 
 
X8 
 
X8 
 
X8 
Disease Status Assessment 
X8 
X8 
 
 
 
 
 
 
X8 
 
X8 
 
X8 
PHARMACOKINETIC (PK) AND ANTI-DRUG ANTIBODY (ADA) PROCEDURES 
PK and ADA 
 
Sample collection schedule varies by cohort. See Section 8.2. 
EXPLORATORY PROCEDURES 
Tumor Tissue9 
X9 
 
 
 
 
 
 
 
 
 
 
 
 
Genomic DNA (Saliva/Buccal) 
X10 
 
 
 
 
 
 
 
 
 
 
 
 
Circulating Tumor DNA11 
 
X11 
 
 
 
 
 
 
X11 
 
X11 
 
X11 
Peripheral Blood Mononuclear Cells12 
 
X12 
 
 
 
X12 
 
 
X12 
 
 
 
 
Cytokines/Biomarkers13 
 
X13 
 
 
 
X13 
 
 
X13 
 
X13 
 
 
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Table 13: 
Schedule of Events for the Efficacy Phase: REGN2810 + Hypofractionated Radiation or Re-Irradiation 
Visit 
Screening 
Treatment Cycles (28 days) 
End of Treatment 
(EOT) 
Toxicity 
Check 
Follow-up2 
C1 
C2 
C3 to C121 
Day 
-14 to -1 
1 
+/-3d 
8 
+/-3d 
15 
+/-3d 
22 
+/-3d 
1 
+/-3d 
15 
+/-3d 
1 
+/-3d 
15 
+/-3d 
Decision to stop 
future dosing +14d 
30 days after 
EOT +7d 
Every 12 weeks after 
last treatment +/-7d 
CLINICAL PROCEDURES 
Consent Form 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X3 
 
 
 
 
 
 
 
 
 
 
 
Physical w/Full Neurologic Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Quality of Life Assessment4 
 
X4 
 
 
 
 
 
X4 
 
X4 
 
X4 
Survival 
 
 
 
 
 
 
 
 
 
 
 
X 
AGENT ADMINISTRATION 
REGN2810 (cemiplimab) 
 
X5 
 
X5 
 
X5 
X5 
X5 
X5 
 
 
 
Radiation6 
 
C1D1 to C1D15: 5 times each week w/ 
cohort-specific dosing (Section 10.2) 
 
 
 
 
 
 
 
 
LABORATORY PROCEDURES 
CBC w/Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
  
Serum Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum or Urine Pregnancy Test7 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
Urinalysis 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
Serum TSH, Serum Free T4 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
Serum Amylase 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
Serum Lipase 
 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
Serum C-reactive Protein (CRP) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
IMAGING AND DISEASE STATUS ASSESSMENT PROCEDURES 
Brain/Spine MRI8 
X8 
X8 
 
 
 
X8 
 
X8 
 
X8 
 
X8 
Disease Status Assessment 
X8 
X8 
 
 
 
X8 
 
X8 
 
X8 
 
X8 
PHARMACOKINETIC (PK) AND ANTI-DRUG ANTIBODY (ADA) PROCEDURES 
PK and ADA 
 
Sample collection schedule varies by cohort. See Section 8.2. 
EXPLORATORY PROCEDURES 
Tumor Tissue9 
X9 
 
 
 
 
 
 
 
 
X9 
 
X9 
Genomic DNA (Saliva/Buccal) 
X10 
 
 
 
 
 
 
 
 
 
 
 
Circulating Tumor DNA11 
 
X11 
 
 
 
X11 
 
X11 
 
X11 
 
X11 
Periph. Blood Mononuclear Cells12 
 
X12 
 
 
 
X12 
 
X12 
 
 
 
 
Cytokines/biomarkers13 
 
X13 
 
 
 
X13 
 
X13 
 
X13 
 
X13 
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8.1.3. 
Footnotes for Table 12 and Table 13 (Schedules of Events for the Efficacy Phase)  
1. Patients who continue beyond 12 cycles should undergo all observations listed under C2 
to C12 with the exception of PBMC and cytokine sample collection. 
2. All follow-up assessments, with the exception of QoL assessments, should occur every 12 
weeks after a patient has stopped receiving treatment, up to 52 weeks.  
3. For more information on randomization in this study, please refer to Section 4.2. 
4. Quality of life assessment should occur at the following visits: prior to the first dose of 
REGN2810, prior to receiving REGN2810 on cycle 7, day 1, at the end of treatment visit, 
and every 24 weeks during the off-treatment follow-up period. Quality of life will be 
measured using PedsQL (patients 2 to <18 years of age) or FACT-Br (patients >18 years 
of age) as described in Section 8.2.1.9. 
5. REGN2810 should be given every 14 days starting on cycle 1 day 1, for up to 12 cycles. 
REGN2810 may continue to be given every 14 days for up to 24 cycles if, in the 
investigator’s opinion, the patient would continue to derive clinical benefit. On days when 
REGN2810 is given, all other assessments and procedures should be performed first.  
6. Radiation will be given 5 times weekly according to a fractionation and dosing schedule 
specific to each disease cohort. Radiation should be administered within +/-3 days of initial 
administration of REGN2810, and should be started no more than 3 days after initial 
administration of REGN2810. See Section 10.2 for more information. 
During the DLT period (the length of radiation therapy + 28 days), weekly toxicity 
monitoring must be performed, including physical examination, vital signs, adverse event 
monitoring, CBC with differential, and serum chemistry. For more information on serum 
chemistry tests that must be performed, see Section 8.2.3. 
7. For all visits in which pregnancy testing is required, the procedure window is +/-14 days. 
8. MRI should occur within 2 to 4 weeks after completion of radiation. Subsequently, imaging 
does not need to be taken or recorded every treatment cycle, but should occur once every 
12 weeks (window: -2 weeks) while patients are on treatment. Imaging should also be 
performed during the EOT visit (window: +/-30 days) and during the off-treatment follow-
up period approximately once every 12 weeks (or per institutional standards) for up to 52 
weeks. Imaging should also be performed at the time of disease progression. Spine imaging 
should be performed as clinically indicated and should occur during the same visits as brain 
MRI. 
Imaging during C1D1 is only required if prior imaging occurred more than 14 days from 
C1D1. If imaging has been taken within 14 days of C1D1 (ie, during the screening period), 
imaging does not need to be performed on C1D1.  
For a given patient, the same imaging modality should be used throughout the study. 
Details on imaging procedures and disease assessment are provided in Section 11.  
9. Available tumor tissue, either archival or fresh, must be confirmed prior to study eligibility. 
Tumor tissue will also be collected if the patient undergoes repeat surgical resection or 
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biopsy at any time while the patient is on-study, including in the setting of disease 
progression. See Section 5.1 for tumor biopsy requirements.  
10. Saliva/buccal sample for genomic DNA may be collected at any time. Saliva/buccal sample 
is only required if a tumor sample (either archival or from biopsy) is taken. 
11. Blood for circulating tumor DNA (ctDNA) should be collected pre-dose on C1D1 and at 
any time scheduled or repeat/confirmatory imaging is performed (except during screening).  
12. Blood for correlative peripheral blood mononuclear cell (PBMC) studies should be 
collected pre-dose on day 1 of cycles 1, 2, and 3. 
13. Blood for correlative serum biomarker studies should be collected pre-dose on day 1 of 
cycles 1 through 5 and at the time of disease progression.
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8.1.4. 
Pharmacokinetic and Anti-Drug Antibody Sample Collection 
Collection time points for PK and ADA samples are provided in Table 14, Table 15, and Table 16. For details on procedures for PK and 
ADA collection and analysis, refer to Section 8.2.5. 
Table 14: 
PK and ADA Collection Schedule for Phase 1: Patients 0 to 2 Years of Age (or Per Institutional Guidelines) 
Visit1 
Cycle 1 
Cycles 2, 4, 6, 8, 10, 12, 16, 242 
End of Treatment (EOT)3 
Follow-up3 
Day 1 
Day 2 
Day 8 
Day 15 
Day 1 
Decision to stop future 
dosing 
Every 12 weeks after last 
treatment 
Time 1 
PK 
X 
(pre-dose) 
X 
(24 hours  
post-dose)4 
X 
(any time 
during visit) 
X 
(pre-dose) 
X 
(pre-dose) 
X 
(pre-dose, if applicable) 
X 
(any time during visit)5 
Time 1 
ADA 
X 
(pre-dose) 
 
 
 
X 
(pre-dose, cycles 2, 4, 8, 12, 16, and 24 only)7 
X 
(pre-dose, if applicable) 
X 
(first visit only; any time during 
visit)6 
Time 2 
PK 
X 
(EOI)4 
 
 
 
X 
(EOI)4 
 
 
EOI=end of infusion. 
 
 
Table 15: 
PK and ADA Collection Schedule for Phase 1: Patients >2 to <18 Years of Age 
Visit1 
Cycle 1 
Cycles 2, 3, 4, 5, 6, 8,  
10, 12, 16, 242 
End of Treatment 
(EOT)3 
Follow-up3 
Day 1 
Day 2 
Day 8 
Day 15 
Day 1 
Day 15  
(ages 12 to 
<18 only)8 
Decision to stop future 
dosing 
Every 12 weeks after last 
treatment 
Time 1 
PK 
X 
(pre-dose) 
X 
(24 hours 
post-dose)4 
X 
(any time 
during visit) 
X 
(pre-dose) 
X 
(pre-dose) 
X 
(pre-dose) 
X 
(pre-dose, if applicable) 
X 
(any time during visit)5 
Time 1 
ADA 
X 
(pre-dose) 
 
 
 
X 
(pre-dose, cycles 2, 4, 8, 12, 16, 
and 24 only)7 
 
X 
(pre-dose, if applicable) 
X 
(first visit only; any time during 
visit)6 
Time 2 
PK 
X 
(EOI)4 
 
 
 
X 
(EOI)4 
 
 
 
Time 3 
PK 
X 
(8 hours 
post-dose)4 
 
 
 
 
 
 
 
EOI=end of infusion. 
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Table 16: 
PK and ADA Collection Schedule for the Efficacy Phase 
Visit1 
Cycle 1 
Cycles 2, 3, 4, 5, 6, 8,  
10, 12, 16, 242 
End of Treatment 
(EOT)3 
Follow-up3 
Day 1 
Day 2 
Day 8 
Day 15 
Day 1 
Decision to stop future 
dosing 
Every 12 weeks after last treatment 
Time 1 
PK 
X 
(pre-dose) 
X 
(24 hours 
post-dose)4 
X 
(any time 
during visit) 
X 
(pre-dose) 
X 
(pre-dose) 
X 
(pre-dose, if applicable) 
X 
(any time during visit)5 
Time 1 
ADA 
X 
(pre-dose) 
 
 
 
X 
(pre-dose, cycles 2, 4, 8, 12, 16, 
and 24 only)7 
X 
(pre-dose, if applicable) 
X 
(first visit only; any time during visit)6 
Time 2 
PK 
X 
(EOI)4 
 
 
 
X 
(EOI)4 
 
 
Time 3 
PK 
X 
(8 hours post-
dose)4 
 
 
 
 
 
 
EOI=end of infusion. 
8.1.5. 
Footnotes for Table 14, Table 15, and Table 16 (PK and ADA Collection Schedules) 
1. Visit windows are as follows: on-treatment cycles: +/-3 days; end of treatment (EOT), day of decision to stop treatment +14 
days; toxicity check: 30 days after EOT +7 days; follow-up visit: every 12 weeks after last treatment +/-7 days.  
2. On-treatment PK and ADA samples will only be collected at cycles 16 and 24 for patients who continue receiving REGN2810. 
3. End of treatment (EOT) and follow-up visits are the same visits as those listed in the Schedules of Events. 
4. Windows for PK sample collection time are as follows: end of infusion, +15 to 30 minutes; 8 hours post-dose, +/-1 hour; 24 
hours post-dose, +/-3 hours. 
5. A PK sample will be taken at the first in-clinic follow-up visit. Additional PK samples will be taken at in-clinic visits after EOT 
that are at least 3 weeks apart. 
6. An ADA sample will be taken at the first in-clinic follow-up visit.  
7. On-treatment ADA samples should only be collected on cycles 1, 2, 4, 8, 12, and (for patients receiving REGN2810 beyond 
cycle 12) at cycles 16 and 24.  
8. In Phase 1, PK samples on day 15 of cycles 2 and beyond should only be collected from patients age 12 to <18. 
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8.1.6. 
End of Treatment Visit  
The End of Treatment visit is defined as the day it is confirmed that a patient will discontinue 
future dosing, regardless of the reason for discontinuation (window: +14 days). 
8.1.7. 
30-Day Toxicity Check 
All patients who discontinue therapy (for any reason) or who complete therapy will have a 30-day 
toxicity check, consisting of an evaluation of adverse events and concomitant medications. This 
evaluation can be conducted via a clinic visit, telemedicine encounter, or telephone encounter. 
Toxicity assessment-related AEs must be followed until resolution or until return to baseline. For 
more information on AE management and reporting, see Section 7 and Section 9.  
8.1.8. 
Long Term/Survival Follow-up 
All patients in Phase 1 and the Efficacy Phase who have completed therapy or are off treatment 
(as defined in Section 4.5) will enter the follow-up period of the study. Patients will be followed 
every 12 weeks, up to 52 weeks or when a patient starts a new therapy or comes off study (as 
defined by criteria in Section 4.6). The follow-up period may end at any time per investigator 
discretion. Information will be collected by chart review and/or by telephone.  
Information to be collected during the follow-up period is provided in the Schedules of Events 
(Table 11, Table 12, and Table 13). In addition, the following information should be collected as 
applicable: disease status information, the date of progression, date of commencement of any new 
anticancer therapy, date of last contact, and date of death. Patients who die without confirmation 
of disease status will be considered to have had PD at the time of death. 
8.2. 
Study Assessments and Procedures 
The section below provides information on performing study assessments and procedures. For 
frequency of assessments and procedures at each visit, see the Schedules of Events and PK/ADA 
collection tables listed in Section 8.1. 
8.2.1. 
Clinical Procedures 
8.2.1.1. 
Consent Form  
Informed consent/assent must be obtained in accordance with the guidelines described in 
Section 16.2. 
8.2.1.2. 
Medical History 
A complete medical history should be taken and should include baseline symptoms, history of 
prior treatments, and any residual toxicity related to prior treatment. Any history of prior allergic 
reaction or hypersensitivity to antibody treatment should also be documented, including the name 
of the antibody therapy and a description of the reaction. 
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8.2.1.3. 
Randomization (Efficacy Phase) 
Newly diagnosed DIPG and newly diagnosed HGG patients will be randomized to either 
conventional radiotherapy (Arm 1) or hypofractionated radiation (Arm 2). The recurrent HGG 
cohort assignment is to re-irradiation therapy; there is no randomization for these patients. For 
more information, please refer to Section 4.2.  
8.2.1.4. 
Physical Examination with Full Neurological Exam 
Physical examination should include an examination of head and neck, lungs, heart, abdomen 
(including liver and spleen), lymph nodes, extremities, and skin, as well as a complete neurologic 
examination, according to the visits listed in the Schedule of Events. 
8.2.1.5. 
Vital Signs, Height, and Weight 
Vital signs should include temperature, blood pressure, pulse, and respiration rate. Height and 
weight will also be measured, as indicated in the Schedules of Events. 
8.2.1.6. 
Toxicity Assessment 
Adverse events should be managed and reported as described in Section 7 and Section 9. 
8.2.1.7. 
Performance Status 
Patients should be measured using Karnofsky criteria if >16 years of age, or Lansky criteria if ≤16 
years of age). Performance status criteria are provided in Appendix 1. To be eligible for the study 
patients must have a Karnofsky or Lansky (as applicable) score of ≥50 at the time of screening. 
8.2.1.8. 
Concomitant Medications 
Any procedure performed or treatment administered (both prescription medications and over-the-
counter preparations), from the time of informed consent until the 30-day toxicity check, will be 
considered concomitant treatment. All concomitant treatments must be recorded in the study CRF 
with the generic name, dose, dose unit, frequency, indication, and start/stop date, as appropriate. 
8.2.1.9. 
Quality of Life Assessment 
In patients 2 to <18 years of age, quality of life will be measured using the Pediatric Quality of 
Life Inventory (PedsQL). In patients 18 to 25 years of age, quality of life will be measured using 
the Functional Assessment of Cancer Therapy-Brain (FACT-Br) instrument. 
8.2.1.10. Survival Data Collection 
Every effort will be made to collect survival data (by phone or chart review) on all patients, 
including patients who withdraw from the study for any reason but have not withdrawn consent to 
collect survival information. Follow up will continue until death, loss to follow up, or withdrawal 
of consent. If a patient is lost to follow-up, they will be considered to have died of progressive 
disease after their last completed survival assessment. 
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8.2.2. 
Agent Administration 
8.2.2.1. 
REGN2810 
Dosing information for REGN2810 is provided in Section 6.1 and Section 6.2. For additional 
information pertaining to REGN2810 dosing in combination with radiation therapy, see 
Section 10. 
8.2.2.2. 
Radiation Therapy 
Radiation therapy guidelines, including dose schedules for each cohort, are provided in Section 10. 
All radiation must be done in a PNOC-approved radiation center, due to the frequent safety 
monitoring and need to follow protocol radiation guidelines.   
8.2.3. 
Laboratory Procedures 
Complete Blood Count: should include differential and platelet count 
Serum Chemistry: should include alkaline phosphatase, ALT, AST, total bilirubin, calcium, 
phosphorus, blood urea nitrogen (BUN/urea), creatinine, total protein, albumin, glucose, 
potassium, sodium, chloride, bicarbonate (carbon dioxide), and magnesium. 
Urinalysis: a dipstick urine test should be performed, with reflex to microscopic urinalysis in the 
event of abnormal findings.  
Serum or Urine Pregnancy Test: must be collected for women of childbearing potential.  
Additional laboratory tests may also include urinalysis, serum TSH, serum thyroxine/T4, serum 
amylase, serum lipase, and serum CRP. 
8.2.4. 
Imaging and Disease Status Assessment 
A detailed description of imaging procedures and disease/response assessment is provided in 
Section 11. 
In Phase 1 of the study, MRI/PET is the preferred imaging modality, but CT scans may be used 
for patients with a solid tumor diagnosis. In the Efficacy Phase, brain MRI (and spine MRI where 
clinically indicated) will be performed. 
In all cases, imaging should be based on institutional guidelines appropriate for underlying tumor 
diagnosis and should include the primary site of disease as well as known measurable sites of 
metastases. For a given patient, the same imaging modality should be used throughout the study.  
8.2.5. 
Pharmacokinetic and Immunogenicity Procedures 
Sample collection time points for PK and ADA analysis are provided in Table 14, Table 15, and 
Table 16. 
8.2.5.1. 
Pharmacokinetics Procedures 
REGN2810 PK parameters will be determined by measuring REGN2810 concentrations in blood 
samples using a validated assay. Blood samples for PK should be taken as close as feasible to the 
indicated PK sampling times. The actual time of each blood draw must be recorded. On days when 
study drug is not administered, all PK sampling times will be based on time of last administered 
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study drug dose. If for any reason a blood sample cannot be drawn at the proposed PK time point, 
then draw blood for PK as soon as possible and the actual time of PK sampling should be recorded.  
Any unused blood samples collected for drug concentration measurements may be used for future 
research, which may include but are not limited to: exploratory biomarker research or to investigate 
unexpected AEs. 
8.2.5.2. 
Immunogenicity Procedures 
Formation of ADA will be assessed in individual patients by dose level/dose cohort. The actual 
time of each blood draw must be recorded. 
Any unused samples collected for ADA assessment may be used for future research, which may 
include but is not limited to exploratory biomarker research and/or investigation of unexpected 
SAEs. 
8.2.6. 
Exploratory Procedures 
Blood samples, saliva/buccal samples, and tumor tissue samples will be used for exploratory 
analyses as described in the sub-sections below. 
Tissue biopsy/resection, as per standard of care therapy, is required for study enrollment. Surgical 
samples collected prior to screening including archived tissue will be acceptable. Tissue from this 
standard of care surgery will be submitted per sample processing standard operating procedure 
(SOP) found on the PNOC SharePoint Members Site. Tissue samples to be sent with sample for 
genomic DNA when possible.  
8.2.6.1. 
Exploratory Biomarker and Cytokine Procedures 
Exploratory predictive and pharmacodynamic biomarkers related to REGN2810 treatment 
exposure, clinical activity, or underlying disease will be investigated from collected DNA, serum, 
plasma, PBMC, archived tumor tissue (as available) and tumor biopsy samples (as available). 
These results may be used to: 
 Explore biomarkers of REGN2810 activity 
 Identify ctDNA and cytokines that may have prognostic or predictive utility 
 Assess tumor expression of PD-L1 
 Analyze changes in the tumor microenvironment 
 Perform immunohistochemistry for PD-L1 pathway components 
 Identify somatic mutations through targeted mRNA sequencing to discover other 
factors that may modulate responses to immune therapy through PD-1/PD-L1 
pathway interactions 
Gene expression panels including the defined “tumor inflammation gene signature” panel, as well 
as a broader tumor immune-related expression profile will be investigated. 
Formalin fixed-paraffin embedded (FFPE) tumor slides will be prepared and H&E stained for 
assessment of tumor infiltrating lymphocytes in all tumor samples. To identify subsets of different 
immune populations (effector/memory CD8 cells, T-regulatory cells, tumor-associated 
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macrophages, and potentially others such as dendritic cells, and Tie-2 expressing monocytes), IHC 
staining will be performed on FFPE tumor slices using some or all of the following antibodies: 
Core set: CD3, CD4, CD8, PD-1, PD-L1, PD-L2, CD68, FoxP3, and Ki67.  
Other potential antibodies to be used: CD25, Indoleamine 2,3 deoxygenase-1 (IDO1), CD11c, 
CD83, CD86, CD56, CD14, CD16, and Tie2  
8.2.6.2. 
Exploratory Biomarker Procedures 
Protein expression of a set of pre-specified markers of immune cell infiltration and activity may 
be analyzed by IHC on evaluable archival samples taken at baseline and biopsies on study (as 
available). During the screening period, after patients or their LARs have given informed consent, 
they will be requested to arrange to provide any available archival tumor samples. Samples will 
be collected according to directions in the study Sample Processing SOP in the PNOC Members 
SharePoint Site. 
For correlative studies, samples will be collected and prepared according to directions in the study 
reference manuals. The following markers may be assayed in archived and/or biopsy tumor tissue 
samples using IHC: CD3, CD4, CD8, FoxP3, CD274 (PD-L1), CD279 (PD-1), TIM-3, LAG-3, 
IDO, and GZMB. PD-L1 expression on tumor-associated immune cells, tumor associated 
macrophages and myeloid suppressor cells may be performed. Additional immune cell markers 
and/or tumor markers specific to DIPG and HGG may be included. 
8.2.6.3. 
Exploratory Circulating Cytokine Procedures 
Circulating cytokine levels that may relate to REGN2810 treatment exposure, clinical activity, or 
underlying disease will be assessed at time points according to the Schedules of Events. Serum 
and plasma samples will be collected for measurement of cytokines. Cytokines to be analyzed may 
include, but are not limited to, IL-1β, IL-2, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, IFNγ, and 
TNFα. Serology analysis for anti-tumor specific antibody responses may include, but are not 
limited to survivin, 5T4, galectin-3, estimated glomerular filtration rate (EGFR), and MUC-1. 
Serum antibody levels in patients receiving Prevnar as standard of care will be used for positive 
controls. 
8.2.6.4. 
Peripheral Blood Mononucleated Cell Assay 
Peripheral blood mononucleated cells will be assessed by fluorescence-activated cell sorting for 
changes in cell subsets including, but not limited to, naïve and memory CD8 and CD4 T-cells, 
MDSCs, NK, and B cells. Any unused blood samples collected for drug concentration 
measurements may be used for future research, which may include but are not limited to: 
exploratory biomarker research or to investigate unexpected AEs. 
Baseline and post-treatment PBMC will be collected in cell preparation tubes (CPT) and red top 
blood collection tubes to monitor peripheral immunologic changes in response to therapy during 
the course of the trial. Primary analyses will be performed to quantify specific T-cell populations 
(composition and functioning), using flow cytometry in conjunction with peripheral markers such 
as CD3/CD4/CD8, and checkpoint receptors such as PD-1, Tim-3, and Lag-3. Baseline and post-
treatment blood will be collected to identify potential therapeutic targets, biomarkers, and 
predictors of response. 
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8.2.6.5. 
Tissue/Blood Banking 
All leftover tissue or blood specimens will be banked, such that they can be used for additional or 
future analyses as needed. These analyses may include exploratory biomarker research, 
investigation of unexpected AEs, and RNA analyses using the most current and informative 
methodologies at the time that correlative science is performed on all specimens. NanoString 
signatures and comprehensive RNA sequencing may be used.  
Additionally, available specimens, may be used for whole exome sequencing to determine 
mutational burden and neoantigen detection, T-cell receptor sequencing to determine intratumoral 
T-cell receptor diversity and flow cytometry to quantify immune populations.  
9. 
SAFETY DEFINITIONS, REPORTING AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the IRB/Ethics Committee (EC) any information as 
required by local IRB/ECs. This includes all unanticipated events involving risks to patients. An 
unanticipated event is defined as any unexpected, serious event that has implications for the 
conduct of the study (e.g., requiring a significant and usually safety-related change in the protocol, 
such as revising inclusion/exclusion criteria or including a new monitoring requirement, informed 
consent, or Investigator’s Brochure).  
9.2. 
Obligations of Regeneron 
During the course of the study, the sponsor and/or the Clinical Research Organization (CRO) will 
inform health authorities, ECs/IRBs, and the participating investigators of any suspected 
unexpected serious adverse reactions (SUSARs), occurring in other study centers or other studies 
of the active study drug, REGN2810, as appropriate per local reporting requirements. In addition, 
the sponsor and/or CRO will comply with any additional local safety reporting requirements. All 
notifications to investigators will contain only blinded information.  
Event expectedness for study drug (REGN2810) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure, using the version that is effective for expedited 
safety reporting.  
At the completion of study, the sponsor will report all safety observations made during the conduct 
of the trial in the clinical study report to health authorities and ECs/IRBs as appropriate.  
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug, which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease that is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
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Progression of underlying malignancy will not be considered an AE if it is clearly consistent with 
the typical progression pattern of the underlying cancer (including time course, affected organs, 
etc.). Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit the 
expected pattern of progression for the disease under study. 
If there is any uncertainty about an AE being due only to progression of the underlying malignancy, 
it should be reported as an AE or SAE as outlined in Section 9.4.  
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose:  
 Results in death – includes all deaths, even those that appear to be completely 
unrelated to study drug (e.g., a car accident in which a patient is a passenger). 
 Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
 Requires inpatient hospitalization or prolongation of existing hospitalization. 
Inpatient hospitalization is defined as a hospital admission (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing 
hospitalization is defined as a hospital stay that is longer than was originally 
anticipated for the event or is prolonged due to the development of a new AE as 
determined by the investigator or treating physician. 
 Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions).  
 Is a congenital anomaly/birth defect. 
 Is an important medical event — Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(e.g., intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse). 
Hospitalization or death due solely to manifestations consistent with typical progression of 
underlying malignancy will not be considered an SAE.  
Criteria for reporting SAEs must be followed for these events. See Section 9.4.2 for more 
information on recording and reporting SAEs.  
9.3.3. 
Adverse Events of Special Interest 
An AE of special interest (AESI; serious or non-serious) is one of scientific and medical concern 
specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
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event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 9.4.3).  
9.3.4. 
Infusion Reactions 
Infusion-related reactions are known to occur with protein therapeutic infusions and have been 
observed in REGN2810 studies.  
Acute infusion reactions can include cytokine release syndrome, angioedema, or anaphylaxis, and 
differ from allergic/hypersensitive reactions, although some of the manifestations are common to 
both AEs. Signs and symptoms usually develop during or shortly after drug infusion 
and generally resolve completely within 24 hours of completion of infusion. 
Infusion reactions are defined as any relevant AE that occurs during the infusion or within 2 hours 
after the infusion is completed. All infusion reactions must be reported as AEs (defined in 
Section 9.3.1) and graded using the grading scales as instructed in Section 9.5.1. Refer to 
Section 6.2 for guidelines on management of infusion reactions. 
9.4. 
Recording and Reporting Adverse Events 
9.4.1. 
Adverse Events 
The investigator (or designee) will seek information on AEs at each patient contact, and record all 
AEs that occur from the time the informed consent is signed until 90 days after the end of study 
treatment (or until the patient receives another systemic anticancer therapy, whichever is earlier), 
except in cases where the AE is attributable to disease progression (see Section 9.3.1). Prior to 
initiation of study treatment, only the following categories of AEs should be reported on the AE 
eCRF: 
 SAEs 
 Non-SAEs associated with a protocol-mandated intervention (eg, AEs related to an 
invasive procedure such as a biopsy) 
Other AEs that occur prior to first treatment should be reported on the medical history CRF.  
All AEs after initiation of study treatment and until 90 days after the last study treatment (or until 
the patient receives another systemic anticancer therapy, whichever is earlier) will be reported on 
the AE CRF, except in cases where the AE is attributable to disease progression (see Section 9.3.1). 
Additionally, any SAE or other AE of concern that the investigator believes may be related to 
study treatment and that occurs later than 90 days after last study treatment should be reported. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or 
electrocardiogram (ECG) abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours.  
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Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
 All SAEs within the safety follow-up window should be reported. After this window, 
only SAEs that are deemed related should be reported. The investigator should make 
every effort to obtain follow-up information on the outcome until the event is 
considered chronic and/or stable.  
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: Accidental or intentional overdose of at least 2 times the 
intended dose of study drug within the intended therapeutic window, if associated with an AE 
Pregnancy: Although pregnancy is not considered an AE, it is the responsibility of the investigator 
to report to the sponsor (or designee), within 24 hours of identification, any pregnancy occurring 
in a female or female partner of a male, during the study or within 6 months of the last dose of 
study drug. Any complication of pregnancy affecting a female study patient or female partner of a 
male study patient, and/or fetus and/or newborn that meets the SAE criteria must be reported as an 
SAE. Outcome for all pregnancies should be reported to the sponsor. 
Adverse Events of Special Interest: All AESI, serious and nonserious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, per Section 9.4.2. 
Adverse events of special interest for this study include the following:  
 Any AE that meets DLT criteria 
 Grade 2 or greater infusion-related reactions 
 Grade 2 or greater allergic/hypersensitivity reactions 
 Grade 3 or greater immune-related AE (irAE) (or grade 2 or greater Uveitis). Note: An 
irAE can occur shortly after the first dose or several months after the last dose of 
treatment. All AEs of unknown etiology associated with drug exposure should be 
evaluated to determine possible immune etiology. If an irAE is suspected, efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic 
causes prior to labeling an AE as an irAE. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
medical monitor within 30 days.  
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
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 The test result is associated with accompanying symptoms, and/or 
 The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
 Other criterion; for example, all grade 3 or higher lab abnormalities – if required for a 
particular study 
Contact the medical monitor in the event the investigator feels that an abnormal test finding should 
be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1.  
9.4.6. 
Follow-Up 
Information for any non-SAE that starts during the treatment period or within 90 days after last 
treatment will be collected from the time of the event until resolution of the event, or until the 
patient’s last study visit, whichever comes first. Information does not need to be collected for any 
non-SAE attributable to disease progression (see Section 9.3.1) 
Serious adverse event information will be collected until the event is considered chronic and/or 
stable.  
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The descriptions and grading scales found in the revised National Cancer Institute (NCI) CTCAE 
version 4.0 will be utilized for AE grading of severity. All appropriate treatment areas should have 
access to a copy of the CTCAE version 4.0. This can be downloaded from the CTEP web site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
When specific AEs are not listed in the CTCAE they will be graded by the Investigator according 
to the following grades and definitions: 
 
 
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Table 17: 
NCI-CTCAE Grading System (v4.0) 
Grade 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL1 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL2 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
1 Instrumental activities of daily living (ADL) refer to preparing meals, shopping for groceries 
or clothes, using the telephone, managing money, etc. 
2 Self-care activities of daily living (ADL) refer to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden. 
Infusion Reactions 
The severity of infusion reactions will be graded NCI CTCAE version 4.0.  
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug?  
The possible answers are: 
 Not Related: There is no reasonable possibility that the event may have been caused 
by the study drug 
 Related: There is a reasonable possibility that the event may have been caused by the 
study drug 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
No: 
 Due to external causes such as environmental factors or other treatment(s) being 
administered 
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 Due to the patient’s disease state or clinical condition 
 Does not follow a reasonable temporal sequence following the time of administration 
of the dose of study drug 
 Does not reappear or worsen when dosing with study drug is resumed 
 Is not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
 
 Could not be explained by environmental factors or other treatment(s) being 
administered 
 Could not be explained by the patient’s disease state or clinical condition 
 Follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
 Resolve or improve after discontinuation of study drug  
 Reappear or worsen when dosing with study drug  
 Are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Conduct:  
The relationship of AEs to study conduct will be assessed by the investigator, and will be a clinical 
decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by study conduct? 
The possible answers are: 
 Not Related: There is no reasonable possibility that the event may have been caused 
by study conduct 
 Related: There is a reasonable possibility that the event may have been caused by study 
conduct 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the AE may have been caused by the study conduct? 
No: 
 Due to external causes such as environmental factors or other treatment(s) being 
administered 
 Due to the patient’s disease state or clinical condition 
 Does not follow a reasonable temporal sequence following the course of the study 
 Does not reappear or worsen when dosing with study participation is resumed 
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Yes: 
 Could not be explained by environmental factors or other treatment(s) being 
administered 
 Could not be explained by the patient’s disease state or clinical condition 
 Follow a reasonable temporal sequence following the course of the study  
 Resolve or improve after discontinuation from study participation. 
 Reappear or worsen when study participation is resumed 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with Regeneron or delegate(s) in a timely fashion. Regeneron or 
delegate(s) will monitor the safety data from across all study sites. Regeneron will have primary 
responsibility for the emerging safety profile of the compound. Safety monitoring will be 
performed on an ongoing basis (e.g., individual review of SAEs) and on a periodic cumulative 
aggregate basis. 
Periodic (at least semi-annually or ad hoc as needed) meetings of the study safety monitoring team 
(SMT) will be conducted to review emerging safety data of the study treatments. The SMT will 
include at a minimum the Regeneron study monitor, Regeneron Risk Management lead for the 
study and the PNOC study chair or their designee. Other members of PNOC leadership may attend 
on an as needed basis.  
Safety issues identified by the SMT can be escalated to the Regeneron Safety Oversight Committee 
(RSOC) per Regeneron’s usual procedures. The RSOC is a standing committee that meets 
periodically or on an ad hoc basis, and includes senior leadership from clinical development, 
regulatory affairs, and pharmacovigilance. The RSOC serves as the Safety Oversight Committee 
for all Regeneron studies. The RSOC is empowered to require changes to a study, up to and 
including stopping a study or a specific cohort of a study, based on its assessment of the risks and 
potential benefits to study subjects. Any changes to this study will be communicated to Health 
Authorities and IRBs/ECs per regulatory requirements. 
In addition, for this study, Regeneron is modifying their usual procedures in 2 ways: 1) any case 
of irreversible focal or non-focal neurologic toxicity, as described below, will be automatically 
escalated to RSOC for further consideration and 2) RSOC membership for safety matters related 
to this study will include, at a minimum, the PNOC study chair, or their designee. Other members 
of PNOC may attend on an as needed basis. The latter will ensure expertise at RSOC relevant to 
this study. 
9.6.1. 
Safety Monitoring for Irreversible Neurological Events 
A potential toxicity that is relatively unique to the pediatric brain tumor population set forth in this 
study is the potential for treatment-related (radiation + PD-1 blockade) intracranial swelling/edema 
that can result in irreversible focal or non-focal neurologic toxicity. This toxicity can occur/persist 
even after standard of care therapy for brain swelling, i.e., steroids and anti-angiogenic agents, has 
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been initiated. It is unknown if and how often such toxicity may occur. The natural history of these 
diseases also frequently involves irreversible neurologic deficit. Therefore, particular attention will 
be paid to the emergence of this potential toxicity. 
For the purposes of this study, neurologic toxicity will be defined as intolerable grade 2 or any 
grade 3 or worse, treatment emergent focal or non-focal neurological toxicity that is not clearly 
due to either pseudo-progression or disease progression. Irreversible will be defined as toxicity 
that remains unimproved after 8 weeks of therapy including steroids and anti-angiogenic agents as 
described in Section 6.2.  
Distinguishing irreversible neurologic toxicity that is directly related to drug versus disease status 
is difficult and best left to experts in this field. For this study, the primary responsibility for making 
this determination will be the PNOC study chair and co-chair or their designees. 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug by either investigator or sponsor). 
9.8. 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (eg, treatment 
with investigational agent/intervention, radiation, or chemotherapy). A secondary malignancy is 
not considered a metastasis of the initial neoplasm.  
 Leukemia secondary to oncology chemotherapy (eg, acute myelocytic leukemia 
[AML])  
 Myelodysplastic syndrome (MDS)  
 Treatment-related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol.  
9.9. 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine reporting via 
CDUS unless otherwise specified.  
10. 
RADIATION THERAPY GUIDELINES 
10.1. 
General Guidelines 
This study includes an efficacy study of REGN2810 in combination with radiation in patients with 
newly diagnosed DIPG and newly diagnosed and recurrent HGG. All patients in the efficacy phase 
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will receive radiation therapy with the targeted volume based on the extent of disease defined by 
neuroimaging prior to radiation therapy. This study specifies a 0 to 2 cm clinical target volume 
(CTV) margin (described in Section 10.7.2) and mandates the use of computed tomography-
magnetic resonance (CT-MR) registration to define the target volume. The allowed treatment 
methods are restricted to conformal or intensity-modulated radiation therapy using photons and 
electronic data submission is required. Proton therapy is not allowed. All radiation is required to 
be done within a PNOC institution or PNOC-approved radiation center, due to the frequent safety 
monitoring and the need to follow protocol radiation guidelines. 
10.2. 
Protocol-Defined Dose and Fractionation Schedules 
The protocol-defined radiation therapy dose is specified according to tumor type and treatment 
arm. 
Newly Diagnosed DIPG Cohorts: 
 Arm 1, conventionally fractionated radiation:  
 Dose: 1.8 Gy fraction administered 5 times a week for 30 fractions; 54 Gy 
administered in total  
 Treatment Length: 42 days 
 Arm 2, hypofractionated radiation delivered:  
 Dose: 3 Gy fraction administered 5 times a week for 13 fractions; 39 Gy 
administered in total 
 Treatment Length: 17 days  
Newly Diagnosed HGG Cohorts: 
 Arm 1, conventionally fractionated radiation:  
 Dose: 1.8 Gy fraction administered 5 times a week for 33 fractions; 59.4 Gy 
administered in total  
 Treatment Length: 45 days 
 Arm 2: hypofractionated radiation:  
 Dose: 3 Gy fraction administered 5 times a week for 13 fractions; 39 Gy 
administered in total  
 Treatment Length: 17 days 
Recurrent HGG Cohorts: 
 Focal re-irradiation:  
 Dose: 3.5 Gy fraction administered 5 times a week for 10 fractions; 35 Gy 
administered in total  
 Treatment Length: 14 days  
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10.3. 
Treatment Planning Specifics 
The goal of the treatment planning process is to develop a plan to deliver a uniform dose to the 
planning target volume that includes all known tumor plus the specified clinical target volume 
margin. The protocol-specified total dose for each cohort is listed in Section 10.2. The total dose 
does not exceed the recommended dose limits for the spinal cord and optic chiasm for the DIPG 
cohorts and so for these cohorts, volume reductions are not required nor recommended. Radiation 
therapy will be administered using photons. Required photon methods include 3D-conformal 
radiation therapy (3D-CRT) or intensity modulated radiation therapy (IMRT). Investigators using 
IMRT will be required to comply with the guidelines developed for the use of IMRT in National 
Cancer Institute sponsored cooperative group trials. These guidelines are available through 
www.qarc.org. These guidelines require that the protocol explicitly state their requirements and 
methods for localization and immobilization; the use of volumetric imaging; target and organ 
motion management; nomenclature, definitions and rationale for targets and organs at risk; target 
volume coverage and normal tissue dose constraints; effects of heterogeneity in tissues; and quality 
assurance.  
10.4. 
Indications for Radiation Therapy 
All patients enrolled on the efficacy phase of this protocol will receive concurrent REGN2810 and 
radiation therapy.  
10.5. 
Timing 
All patients should be seen in consultation by a radiation oncologist at the time of study enrollment. 
The purpose of the consultation is to participate in the initial evaluation and to review the adequacy 
of the initial diagnostic imaging studies that will be used for subsequent RT planning and the 
feasibility of reirradiation in the recurrent HGG cohort to the dose mandated in the protocol while 
maintaining brainstem, optic, and spinal cord tolerance. If additional imaging studies are pursued, 
thin section MR (T2-weighted and FLAIR) sequences should be obtained for registration to the 
CT dataset to assist in treatment planning.  
Radiation should be administered within +/-3 days of initial administration of REGN2810.  
Bevacizumab or corticosteroids should be used as clinically indicated and tapered as soon as 
possible.  
Please see Section 6 and Section 6.2 for details of timing of REGN2810 administration. 
REGN2810 will be administered intravenously every 14 days and can be administered before or 
after each day’s radiation therapy fraction.  
10.5.1. 
Emergency Irradiation 
Patients are not allowed to have received radiation therapy prior to enrollment on this protocol and 
urgent irradiation is not envisioned under any circumstance.  
10.6. 
Equipment and Methods of Delivery and Verification  
Equipment 
Photons (any energy) 
IMRT (4-10MV) 
Linear Accelerator 
X 
X 
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10.6.1. 
Treatment Planning 
Computed tomography (CT) (volumetric)-based planning is required to optimize dose to the 
planning target volume (PTV) while protecting normal tissues. Organs at risk within the irradiated 
volume should be contoured. A dose volume histogram (DVH) is necessary to determine target 
coverage and evaluate dose to normal tissues. Computed tomography section thickness should be 
≤5 mm although 1-3 mm is preferred.  
Portal imaging is the most common system used to verify patient position, in particular when the 
target volume is believed to possess a fixed spatial relationship with visualized bony anatomy. 
Orthogonal paired (AP and lateral) portal images (MV or kV) are required for IMRT and 3D-CRT 
to verify that the isocenter is in correct alignment relative to the patient position.  
Volumetric imaging is allowed in this study. This includes in-room kV or cone beam or 
conventional CT imaging. Please submit DICOM representative axial images showing the 
isocenter and the correct alignment in relationship to the patients’ position. For CT here isocenters 
are not used, isodoses overlaid on the fused CT images can be submitted to demonstrate in-room 
verification.  
10.7. 
Target Volumes 
10.7.1. 
General Comments 
International Commission on Radiation Units and Measurements (ICRU) Reports 50 and 62 
(www.icru.org) define prescription methods and nomenclature that will be utilized for this study 
where applicable. Although the MRI obtained immediately prior to radiation therapy should be 
used for treatment planning, the target volumes for this study will be determined by the collective 
information that delineates the extent of disease before and after surgical resection or CSF shunting 
procedure. The investigators recognize that resection and shunting are unlikely for these patients. 
The sequence that best defines the extent of disease and post- operative tumor bed (when 
applicable) should be used to determine the gross tumor volume (GTV) and registered to the 
treatment planning CT. Most patients with DIPG and HGG require a combination of MR 
sequences to delineate the extent of disease. MR T2 and FLAIR sequences are most likely to be 
those chosen for registration to the treatment planning CT data set. The GTV, CTV, PTV and 
normal tissues must be outlined on all axial imaging slices on which the structures exist.  
10.7.2. 
Definitions for Gross Tumor Volume, Clinical Target Volume, and Planning 
Target Volume 
Gross tumor volume is based on the most recent MRI and/or post-operative MRI examination (if 
resection was done) and includes gross residual tumor and the tumor bed at the primary site. In 
defining the GTV, the investigator should consider all imaging studies that have defined the extent 
of tumor and the tissues involved anatomically. The GTV in most cases will be the T2 or FLAIR 
abnormality on the appropriate MR sequence. Tissue defects resulting from surgical approaches, 
when undertaken, will not be included as part of the GTV when not previously involved by tumor. 
Investigators should register the immediate pre-irradiation MR imaging sequences that 
demonstrated tumor and contour the GTV.  
For patients enrolled in the newly diagnosed HGG cohort and randomized to conventional 
radiation, GTV1 and GTV2 can be developed as follows:  
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 The GTV1 is the enhancing and non-enhancing primary tumor volume as visualized on 
the treatment planning scan plus additional volume as characterized by tumor 
infiltration on the presurgical imaging. This should be outlined by translating the extent 
of presurgical infiltration using anatomical references onto the current treatment 
planning scans. The GTV2 is the enhancing and non-enhancing primary tumor volume 
as visualized on the treatment planning scan plus the surgical bed. This volume may be 
larger or smaller than the tumor visualized at diagnosis. Both GTV1 and GTV2 should 
only include imaging highly suspicious for gross tumor.  
 Clinical target volume includes the GTV with an added margin of 1 cm for the DIPG 
cohort (DIPG patients) and an optional 0.5 cm for the recurrent HGG cohort (recurrent 
HGG patients). For the newly diagnosed HGG cohort, patients randomized to 
conventional fractionation will have a 2 cm CTV1 margin added to the GTV1 volume 
and a 1cm margin added to the CTV2 volume. For patients randomized to the 
hypofractionated regimen, the CTV will be created with an individualized 1-2 cm 
margin at the discretion of the treating radiation oncologist. For all cohorts the CTV 
expansion is meant to treat subclinical microscopic disease and is anatomically 
confined (ie, the CTV is limited to the confines of the bony calvarium, falx and 
tentorium where applicable, or extends up to but not beyond neuroanatomic structures 
through which tumor extension or invasion is certain not to have occurred). The CTV 
may be manually moved inward to the inner table of the bony calvarium. When the 
GTV approaches the boundary of an anatomic compartment, the CTV will extend up 
to and include the boundary. The CTV margin chosen for this study requires treatment 
planning MR and/or diagnostic MR imaging data with image section thickness ≤5 mm.  
 PTV includes a margin that is added to the CTV in 3-dimensions. For the newly 
diagnosed HGG cohort randomized to conventional fractionation, a PTV1 
corresponding to CTV1 and a PTV2 corresponding to CTV2 will be generated. PTVs 
are geometric and not anatomically defined. The PTV has two components, the internal 
margin (IM) and the set- up margin (SM). The IM is meant to compensate for all 
movements and variations in size and shape of the tissues contained within the CTV. 
The SM is meant to account for set-up, mechanical and dosimetric uncertainties related 
to daily patient positioning, treatment equipment and software. For this study, the PTV 
margin should be 3 or 5 mm. The use of a PTV margin of 3 mm requires written 
documentation that image-guided radiation therapy (IGRT) methods are used on a daily 
basis or alternatively that a head fixation system or verification system is used with 
weekly or more frequent imaging. For this study, IGRT is defined as 2- or 3-
dimensional digital imaging positioning. Given that the CTV is generally confined to 
the intracranial space, the PTV may extend into or beyond bone but is unlikely to extend 
beyond the surface of the patient. The PTV margin chosen by the treating investigator 
requires treatment planning MR and/or diagnostic MR imaging data with imaging 
section thickness ≤ the chosen PTV margin.  
10.8. 
Target Dose 
10.8.1. 
Dose Definition 
Photon dose is to be specified in centigray (cGy)-to-water.  
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10.8.2. 
Prescribed Dose and Fractionation 
The total dose to the isodose surface encompasses the PTV will be as follows: 
 Newly diagnosed DIPG Cohorts (Arm 1): 5400 cGy administered in 30 fractions of 
180 cGy 
 Newly diagnosed DIPG Cohorts (Arm 2): 3900 cGy administered in 13 fractions of 
300 cGy 
 Newly diagnosed HGG Cohorts (Arm) 1: 5940 cGy administered in 33 fractions of 
180 cGy for PTV2, and 4500 in 25 fractions to PTV1 
 Newly diagnosed HGG Cohorts (Arm 2): 3900 cGy administered in 13 fractions of 
300 cGy 
 Recurrent HGG Cohorts: 3500 cGy administered in 10 fractions of 350 cGy 
The patient should be treated with 1 fraction per day. All fields should be treated each day.  
10.8.3. 
Dose Uniformity 
At least 95% of the protocol-specified dose should encompass 100% of the PTV and no more than 
10% of the PTV should receive greater than 110% of the protocol dose as evaluated by DVH. The 
100% isodose should be equal to the protocol specified dose. Wedges, compensators and other 
methods of generating more uniform dose distributions are encouraged.  
10.8.4. 
Tissue Heterogeneity 
Calculations must take into account tissue heterogeneity and should be performed with CT-based 
treatment planning to generate dose distributions and treatment calculations from CT densities. 
For questions about heterogeneity corrections or approved algorithms, please contact the Study 
Chairs or refer to www.QARC.org. 
10.8.5. 
Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once radiation therapy has been 
initiated, treatment will not be interrupted except for life threatening infection, severe 
hematological toxicity defined as ANC <300/μL or platelets less than 40,000/μL, or symptomatic 
pseudoprogression during the course of treatment. Blood product support should be instituted 
according to institutional/protocol guidelines. The reason for any interruptions greater than 
3 treatment days should be recorded in the patient treatment chart and submitted with the QA 
documentation. There should be no modifications in dose fractionation due to age or field size.  
10.9. 
Treatment Technique 
10.9.1. 
Beam Configuration 
Every attempt should be made to minimize dose to organs at risk without compromising coverage 
of the target volume. Three-dimensional conformal therapy (coplanar or non-coplanar) or IMRT 
are required to minimize dose to normal tissues.  
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10.9.2. 
Field Shaping 
Field shaping will be done with either customized cerrobend blocking or multileaf collimation.  
10.9.3. 
Simulation Including Patient Positioning and Immobilization 
10.9.3.1. Patient Positioning 
Reproducible setups are critical. The patient may be treated in any appropriate, stable position. 
Consideration should be given to implications for inter- and intra-fraction motion when using 
non-standard position approaches.  
10.9.3.2. Immobilization Devices 
Standard immobilization devices for the brain or head and neck are to be used. For IMRT delivery 
approaches, the methods used for localization and immobilization of both patient and tumor are 
critical. The imaging studies should provide a clear assessment of the target volume with the 
patient in the treatment position.  
10.9.3.3. Special Considerations 
Anesthesia or sedation may be required in certain patients, such as very young patients, to prevent 
movement during simulation and daily treatments.  
10.9.4. 
Motion Management and Margins to Account for Target Volume Changes 
During Treatment  
Considering motion of target volumes is important. Brain tumors susceptible to cyst expansion 
should be monitored closely. Any change in clinical condition or anatomy related to 
hydrocephalus, VP shunt placement, subdural fluid, pseudomeningocele, or steroid use should be 
monitored carefully with repeat imaging when indicated.  
10.10. 
Organs at Risk 
The organ at risk guidelines in this section are recommendations. If the recommended doses to the 
organs at risk are exceeded because of target volume coverage requirements or other conditions, 
an explanation should be included in the quality assurance documentation. In some cases, photon 
IMRT may be the preferred treatment method to meet these recommendations and the required 
target volume coverage guidelines.  
10.10.1. 
Dose Constraints 
10.10.1.1. Cochleae 
 D50% ≤3500 cGy – Goal (each cochlea)  
 D50% ≤2000 cGy – Preferred (each cochlea)  
 Comment – There is no dose maximum for the cochleae.  
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 Structure definition — Each cochlea will be contoured on the treatment planning CT 
as a circular structure within the petrous portion of the temporal bone. The contour 
should appear on at least two successive CT images.  
10.10.1.2. Optic Globes 
 D10% ≤3500 cGy – Goal  
 D10% ≤5400 cGy – Maximum  
 Comment – Effort should be made to avoid direct treatment of the anterior chamber of 
the eye and minimize dose to the entire eye without compromising target volume 
coverage. In the event that the recommended maximum dose constraints provided in 
this section would be exceeded, the treating radiation oncologist may use their 
discretion to reduce target volume coverage.  
 Structure definition — Each eye should be separately contoured on the treatment 
planning CT or MR as a circular structure from the most superior to inferior aspect.  
10.10.1.3. Right and Left Optic Nerves and Chiasm  
 Newly diagnosed DIPG and HGG cohort: 
 D10% ≤5600 cGy – Goal  
 D90% ≤5400 cGy, D50% ≤5600 cGy and D10% ≤5800 cGy – Maximum  
 Recurrent HGG cohort 
 D90% ≤1000 cGy, Dmax ≤1200 cGy – Maximum 
 Comment – These parameters apply to each of the separate three structures, not the 
combined volume of the three structures. Effort should be made to avoid direct 
treatment of the optic nerves and chiasm without compromising target volume 
coverage. In the event that the recommended maximum dose constraints provided in 
this section would be exceeded, the treating radiation oncologist may use his/her 
discretion to reduce target volume coverage.  
 Structure definitions – The optic nerves and chiasm may be contoured on CT or MR. 
The contours should appear on at least two successive CT or MR images.  
 Note: Dose constraints specified for the recurrent HGG cohort are only applicable in 
cases where a significant prior dose (Dmax<=42 Gy) was delivered to the optic nerves 
and chiasm or the prior dose to the optic nerves and chiasm is uncertain. In cases where 
a lower previous dose was administered to these structures and can be documented, a 
higher constraint will be considered on a case by case basis.  
10.10.1.4. Spinal Cord 
 Newly diagnosed DIPG cohort: 
 D10% ≤5700 cGy – Goal  
 D10% ≤5900 cGy – Maximum  
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 Newly diagnosed HGG cohort 
 Dmax = 5000 cGy — Maximum 
 Recurrent HGG cohort: 
 D90% ≤1000 cGy, Dmax ≤1200 cGy – Maximum 
 Comment – Effort should be made to minimize dose to the spinal cord without 
compromising target volume coverage.  
 Structure Definition — For the purposes of this study, the upper aspect of the spinal 
cord begins at the inferior border of the foramen magnum and should be contoured on 
the treatment planning CT. For purposes of comparison and consistency with dose 
volume data, the spinal cord should be contoured on a number of images to be 
determined by the image section thickness (CT section thickness, n=number of images; 
2 mm, n=30; 2.5 mm, n=24; 3 mm, n=20). Using these guidelines, only the superior-
most 6 cm of anatomic spinal cord is contoured.  
 Note: Dose constraints specified for the recurrent HGG cohort are only applicable in 
cases where a significant prior dose (Dmax<=33 Gy) was delivered to the spinal cord 
or the prior dose to the spinal cord is uncertain. In cases where a lower previous dose 
was administered to these structures and can be documented, a higher constraint will 
be considered on a case by case basis.  
10.10.1.5. Brainstem 
 Recurrent HGG cohort (recurrent HGG patients): 
 D90% ≤1000 cGy, Dmax ≤1200 cGy – Maximum 
 Newly diagnosed HGG cohort  
 Effort should be made to minimize the amount of brainstem, if any, receiving 
more than 5400 cGy 
 Comment – Effort should be made to minimize dose to the brainstem without 
compromising target volume coverage.  
 Structure Definition — For the purposes of this study, the lower aspect of the brainstem 
begins above the inferior border of the foramen magnum and should be contoured on 
the treatment planning CT.  
 Note: Dose constraints specified for the recurrent HGG cohort are only applicable in 
cases where a significant prior dose (Dmax≤42 Gy) was delivered to the brainstem or 
the prior dose to the brainstem is uncertain. In cases where a lower previous dose was 
administered to these structures and can be documented, a higher constraint will be 
considered on a case by case basis.  
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10.11. 
Dose Calculations and Reporting 
10.11.1. 
Prescribed Dose 
The dose prescription and fractionation shall be reported. The total dose delivered shall also be 
reported. If IMRT is used, the monitor units generated by the IMRT planning system must be 
independently checked prior to the patient’s first treatment. Measurements in a QA phantom can 
suffice for a check as long as the patient’s plan can be directly applied to a phantom geometry.  
10.11.2. 
Normal Tissue Dosimetry 
The dose to the critical organs indicated (Table 18) should be calculated whenever they are directly 
included in a radiation field. The total dose shall be calculated and reported. The appropriate dose-
volume histograms should be submitted. If IMRT is used for the primary tumor, a DVH must be 
submitted for a category of tissue called “unspecified tissue,” which is defined as tissue contained 
within the skin, but which is not otherwise identified by containment within any other structure.  
Table 18: 
Required DVH data 
Required DVH  
Total Brain  
Optic Nerves (L+R)  
Optic Chiasm  
Optic Globes (L+R) 
Brainstem  
Spinal Cord  
Cochleae (L+R)  
Unspecified Tissue 
 
10.12. 
Quality Assurance Documentation 
On-treatment review is NOT required for this study. Within 1 week of the completion of radiation 
therapy, detailed treatment data shall be submitted.  
10.12.1. 
External Beam Treatment Planning System 
 Digitally reconstructed radiographs (DRR) or simulator films for each treatment field 
and orthogonal (anterior/posterior and lateral) images for isocenter localization for each 
group of concurrently treated beams. When using IMRT, orthogonal isocenter images 
are sufficient.  
 Isodose distributions for the treatment plan in the axial, sagittal and coronal planes at 
the center of the treatment or planning target volume. The planning target volume, 
isocenter and the normalization method must be clearly indicated.  
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 DVH for all target volumes and required organs at risk. A DVH shall be submitted for 
the organs at risk specified in Section 10.10. When using IMRT, a DVH shall be 
submitted for a category of tissue called “unspecified tissue.” This is defined as tissue 
contained within the skin, but which is not otherwise identified by containment within 
any other structure.  
 Treatment planning system summary report that includes the monitor unit calculations, 
beam parameters, calculation algorithm, and volume of interest dose statistics.  
 Beams-eye-view (BEV) of portals showing collimator, beam aperture, target volume 
and critical structures are required when not using IMRT.  
10.12.2. 
Digital Data 
Submission of the treatment plan and all data in DICOM format is required. The information 
should be transferred via a secure Partners Healthcare Interface (transfer.partners.org). 
Participating centers will be invited to create an account within this system by study staff. If there 
are any problems with digital data submission, please contact the Study Chairs. 
10.12.3. 
Supportive Data 
A complete digital representation of the radiotherapy treatment plan, sufficient to fully reconstruct 
the plan in our system, must be uploaded in DICOM/DICOM RT format. This includes all 
diagnostic imaging (CT or MR PRIOR to surgical resection or primary tumor) and DICOM RT 
formatted files for the RT PLAN, RT STRUCTURE SET, and RT DOSE. If image registration 
was used to link CT to MR images, the image data may be uploaded either as reformatted images 
co-registered to the same frame of reference OR by providing the spatial registration in DICOM 
format. The RT Dose file should contain the dose matrix representing the total dose for all fields 
in the treatment plan in absolute dose. Radiotherapy record (treatment chart) including prescription 
and daily and cumulative doses to all required areas and organs at risk.  
If the recommended doses to the organs at risk are exceeded, an explanation should be included 
for review by the radiation oncology reviewers.  
If a PTV margin of 3 mm is used, written documentation that IGRT methods are used on a daily 
basis or alternatively that a head fixation system or verification system was used with weekly or 
more frequent imaging will be provided. See Section 10.12.  
11. 
EVALUATION CRITERIA 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria.  
11.1. 
Definitions 
11.1.1. 
Evaluable for Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with REGN2810. 
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11.1.2. 
Evaluable for Objective Response 
Only those patients who have measurable disease present at baseline, have received at least 1 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.) 
11.1.3. 
Immunotherapy Response Assessment in Neuro-Oncology (iRANO) Criteria 
Immunotherapeutic approaches for children with gliomas are a relatively new era and therefore 
we have limited experience on how to monitor response. Recently the Immunotherapy Response 
Assessment in Neuro-Oncology (iRANO) working group has proposed guidelines on how to 
monitor and assess efficacy in adult brain tumor patients treated with immunotherapy as a 
development of the iRANO criteria that were established to better account for the phenomenon of 
pseudo-progression in adult patients58,59. The pediatric neuro-oncology (RAPNO) working group 
is currently working on their guidelines for response criteria for pediatric neuro-oncology 
patients60. Our limited experience with immunotherapies have shown that early radiological 
changes could be misinterpreted as progression due to therapy-induced inflammation, and long-
term benefit can still be seen even after initial progression or even after the appearance of new 
lesions61,62.  
11.2. 
Disease Parameters 
11.2.1. 
Solid Tumors 
The parameters below are adopted directly from published Response Evaluation Criteria in Solid 
Tumors (RECIST) guidelines.63 
11.2.1.1. Measurable Disease 
Measurable lesions are defined as those that can be accurately measured in at least 1 dimension 
(longest diameter to be recorded) as ≥20 mm by chest x-ray, as ≥10 mm with computed 
tomography (CT) scan, or ≥10 mm with calipers by clinical exam. All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters).  
11.2.1.2. Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥15 mm in short 
axis when assessed by CT scan (CT scan slice thickness no greater than 5 mm). At baseline and in 
follow-up, only the short axis will be measured and followed.  
11.2.1.3. Non-Measurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter <10 mm or 
pathological lymph nodes with ≥10 to <15 mm short axis), are considered non-measurable disease. 
This includes bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed 
by CT or MRI).  
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Cystic lesions that meet the criteria for radiographically-defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target lesions.  
11.2.2. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions total, representative 
of all involved organs, should be identified as target lesions and recorded and measured at baseline. 
Target lesions should a) be selected based on the largest measurable lesions, b) appropriately 
represent involved organs, and c) be reproducibly measurable. The longest diameter of target 
lesions should be measured in the plane from which the images were taken. The longest measured 
diameters for each lesion should be recorded as the baseline sum diameters and used to objectively 
measure treatment response.  
11.2.3. 
Non-Target Lesions 
All other lesions (or sites of disease) including measurable lesions over and above the 5 target 
lesions should be identified as non-target lesions and should also be recorded at baseline. 
Measurements of these lesions is not required. These lesions will be followed as “present,” 
“absent,” or “unequivocal progression.”  
11.3. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers. All 
baseline assessments should be done as close as possible to treatment start and per study 
requirements.  
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam.  
Clinical lesions will only be considered measurable when they are superficial (eg, skin nodules 
and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers (eg, skin nodules). In 
the case of skin lesions, documentation by color photography, including a ruler to estimate the size 
of the lesion, is recommended.  
11.3.1. 
Chest X-Ray 
Chest computed tomography (CT) is the preferred method of assessment for lesions in the chest, 
specifically when assessing treatment response. Lesions on chest x-ray can be considered 
measurable if they are clearly defined and surrounded by aerated lung.  
11.3.2. 
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption that CT 
slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 mm, the minimum 
size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
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situations (e.g. for body scans). Ideally, the same acquisition protocol should be followed as 
closely as possible to comparison scans.  
11.3.3. 
Ultrasound 
Ultrasound is not considered a useful modality to assess lesion size and should not be used for 
target lesion measurement. 
11.3.4. 
Positron Emission Tomography-Computed Tomography 
At present, the low dose or attenuation correction CT portion of a combined Positron Emission 
Tomography-CT (PET-CT) scan is limited in its use for diagnostic and treatment effect evaluations 
and should not substituted for a complete diagnostic CT. However, if the site can document that 
the CT performed as part of a PET-CT is of identical diagnostic quality to a diagnostic CT (with 
IV and oral contrast), then the CT portion of the PET-CT can be used for RECIST measurements. 
The PET portion of the CT introduces additional data, which may bias an investigator if it is not 
routinely or serially performed.  
11.3.5. 
Tumor Markers 
Tumor markers alone cannot be used to assess objective response. If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response.  
11.3.6. 
Cytology and Histology 
These techniques can be used to differentiate between partial responses (PR) and complete 
responses (CR) in rare cases such as residual lesions in tumor types, i.e. germ cell tumors, where 
known residual benign tumors can remain.  
Cytology should be obtained if an effusion appears or worsens during treatment when the 
measurable tumor has met criteria for response or stable disease.  
11.3.7. 
FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions based on FDG-PET imaging can be 
identified according to the following algorithm:  
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
progressive disease (PD) based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this is 
PD. If the positive FDG-PET at follow-up is not confirmed as a new site of disease on 
CT, additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing based on the anatomic images, this is not 
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PD. A ‘positive’ FDG-PET scan lesion means one that is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
11.4. 
Response Criteria 
11.4.1. 
Response Criteria for Patients with Solid Tumors and Measurable Disease: 
Evaluation of Target Lesions 
Response criteria for primary tumors outside the CNS will be evaluated per RECIST1.1. Immune-
related RECIST (irRECIST) will also be considered.  
Complete Response 
Disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target 
or non-target) must have reduction in short axis to <10 mm. If immunocytology is available, no 
disease must be detected by that methodology.  
Partial Response 
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive Disease 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition 
to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  
NOTE: The appearance of 1 or more new lesions is also considered progression. See 
Section 11.4.5.4 for exceptions.  
NOTE: In the presence of stable disease (SD) or PR in target disease but “unequivocal 
progression” in non-target lesions, the patient has PD if there is an overall level of substantial 
worsening in non-target disease such that the overall tumor burden has increased sufficiently to 
merit discontinuation of therapy.  
Stable Disease 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum of diameters while on study.  
11.4.2. 
Response Criteria for Patients with Solid Tumors and Evaluable Disease  
Evaluable Disease 
The presence of at least 1 lesion, with no lesion that can be accurately measured in at least 
1 dimension. 
Such 
lesions 
may 
be 
evaluable 
by 
nuclear 
medicine 
techniques, 
immunocytochemistry techniques, tumor markers or other reliable measures.  
Complete Response 
Disappearance of all evaluable disease and normalization of tumor markers, as appropriate. All 
lymph nodes must be non-pathological in size (<10mm short axis).  
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Non-complete Response and Non-progressive Disease  
Persistence of >1 non-target lesion and/or maintenance of tumor markers above normal limits. 
Progressive Disease 
Unequivocal progression of non-target lesions and/or the appearance of 1 or more new lesions 
and/or elevation in tumor markers. 
11.4.3. 
Response Criteria for Neuroblastoma Patients with Metaiodobenzylguanidine-
Positive Lesions  
11.4.3.1. Metaiodobenzylguanidine-Positive Lesions 
Per the International Neuroblastoma Response Criteria, assessment of disease response will 
incorporate response in the primary tumor as well as soft tissue and bone metastases, the following 
assessments are adopted directly from these recommendations.64 Primary and metastatic soft tissue 
sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-
123 [123I]–metaiodobenzylguanidine (MIBG) scans or [18F]fluorodeoxyglucose–positron emission 
tomography scans if the tumor is MIBG nonavid. 123I-MIBG scans, or [18F]fluorodeoxyglucose–
positron emission tomography scans for MIBG-nonavid disease should be done instead of 
technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment.  
Bone marrow will be assessed by histology or immunohistochemistry and cytology or 
immunocytology. Bone marrow with ≤5% tumor involvement will be classified as minimal 
disease.  
Urinary catecholamine levels will not be included in response assessment.  
Overall response will be defined as complete response, partial response, minor response, stable 
disease, or progressive disease. 
11.4.3.2. Primary Soft Tissue Disease 
Complete Response 
<10 mm residual soft tissue at primary site AND complete response of MIBG or FDG-PET uptake 
(for MIBG-nonavid tumors) at primary site 
Partial Response 
≥30% decrease in longest diameter of primary site AND MIBG or FDG-PET uptake at primary 
site stable, improved, or resolved 
Stable Disease 
Neither sufficient shrinkage for partial response nor sufficient increase for progressive disease at 
the primary site 
Progressive Disease 
>20% increase in longest diameter taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study) AND minimum absolute increase of 5 mm in longest 
diameter 
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11.4.3.3. Metastatic Soft Tissue and Bone Disease 
Complete Response 
Non-primary target and nontarget lesions measure <10 mm AND lymph nodes identified as target 
lesions decrease to a short axis <10 mm AND complete response of MIBG or FDG-PET uptake 
(for MIBG-nonavid tumors) at non-primary lesions 
Partial Response 
≥30% decrease sum of diameters of nonprimary target lesions compared with baseline AND 
nontarget lesions may be stable or smaller in size AND no new lesions AND ≥50% reduction in 
MIBG absolute bone score or ≥50% reduction in number of FDG-PET-avid bone lesions 
Stable Disease 
Neither sufficient shrinkage for partial response nor sufficient increase for progressive disease at 
the nonprimary lesions 
Progressive Disease 
Any new soft tissue lesion detected by CT/MRI that is also MIBG- or FDG-PET-avid OR any new 
soft tissue lesion seen on anatomic imaging that is biopsied and confirmed to be neuroblastoma or 
ganglioneuroblastoma OR any new bone site that is MIBG-avid OR a new bone site that is FDG-
PET-avid (for non-MIBG-avid tumors) and also has CT/MRI findings consistent with tumor or if 
confirmed by histology OR ≥20% increase in the longest diameter taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study) and minimum absolute 
increase of 5 mm in sum of diameters of target soft tissue lesions OR relative MIBG score ≥1.2 
11.4.3.4. Bone Marrow Disease 
Complete Response 
Bone marrow with no tumor involvement on reassessment, independent of baseline tumor 
involvement 
Minimal Disease 
Bone marrow with ≤5% tumor involvement and remains >0 to ≤5% tumor involvement on 
reassessment OR bone marrow with >20% tumor involvement that has >0 to ≤5% tumor 
involvement on reassessment 
Stable Disease 
Bone marrow with tumor infiltration that remains positive with >5% tumor involvement on 
reassessment that does not meet other disease criteria 
Progressive Disease 
Bone marrow without tumor infiltration that becomes >5% tumor involvement on reassessment 
OR bone marrow with tumor involvement that increases by >2-fold and has >20% tumor 
involvement on reassessment 
11.4.3.5. Overall Response 
 Complete Response: All components that meet the criteria for complete response 
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 Partial Response: Partial response in at least one component and all other 
components are either complete response, minimal disease (bone marrow), partial 
response (soft tissue or bone), or no involvement; no component of progressive 
disease 
 Minor Response: Partial response or complete response in at least one component 
but at least one other component with stable disease; no component of progressive 
disease 
 Stable Disease: Stable disease in one component with no better than stable disease or 
no involvement in any other component; no component of progressive disease 
 Progressive Disease: Any component with progressive disease 
11.4.3.6. Scoring Based on Relative Curie Score 
Relative score is calculated by dividing the absolute score at each time point by the corresponding 
pre-treatment absolute score. The relative score of each patient is calculated at each response 
assessment compared to baseline and classified as below:  
 Complete Response: all areas of uptake on MIBG scan completely resolved. If 
morphological evidence of tumor cells in bone marrow biopsy or aspiration is present 
at enrollment, no tumor cells can be detected by routine morphology on two 
subsequent bilateral bone marrow aspirates and biopsies done at least 21 days apart to 
be considered a CR.  
 Partial Response: Relative score ≤0.2 (lesions almost disappeared) to ≤0.5 (lesions 
strongly reduced).  
 Stable Disease: Relative score >0.5 (lesions weakly but significantly reduced) to 1.0 
(lesions not reduced).  
 Progressive Disease: New lesions on MIBG scan.  
11.4.4. 
Response Criteria for Solid Tumor Patients with Bone Marrow Involvement  
Bone marrow involvement is defined as bone marrow obtained within 28 days prior to study 
enrollment with tumor cells seen on routine morphology (not by immunohistochemical staining 
only) of bilateral aspirate or biopsy on 1 bone marrow sample.  
Bone marrow responses are determined by H&E staining of bilateral bone marrow biopsies and 
aspirates.  
Complete Response 
No tumor cells detectable by routine morphology on 2 consecutive bilateral bone marrow aspirates 
and biopsies performed at least 21 days apart. Normalization of urinary catecholamines or other 
tumor markers if elevated at study enrollment. 
Progressive Disease 
Patients who enroll with neuroblastoma in bone marrow by morphology have progressive disease 
if there is a doubling in the amount of tumor in the marrow AND a minimum of 25% tumor in 
bone marrow by morphology. (For example, a patient entering with 5% tumor in marrow by 
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morphology must increase to ≥25% tumor to have progressive disease; a patient entering with 30% 
tumor must increase to >60%.) Patients who enroll without evidence of neuroblastoma in bone 
marrow will be defined as having progressive disease if tumor is detected in 2 consecutive bone 
marrow biopsies or aspirations done at least 21 days apart.  
Stable Disease 
Persistence of tumor in bone marrow that does not meet the criteria for either complete response 
or progressive disease.  
11.4.5. 
Response Criteria for Central Nervous System Tumors 
Response criteria for CNS tumors will be evaluated per RANO criteria with the addition of iRANO 
criteria as a supplement to evaluation, as appropriate.65,66 Patients will have their response 
classified according to the definitions stated below.  
11.4.5.1. Measurable Disease 
Measurable disease is defined as the lesions (or lesions) that can be accurately measured in at least 
2 dimensions by MRI (no less than double the slice thickness). All tumor measurements will be 
recorded in millimeters or decimal fractions of centimeters. Tumor response criteria for this study 
are to be determined by changes in size using the maximal 2-dimensional cross-sectional tumor 
measurements, T x W (product of the longest diameter of the tumor [width (W)] and its longest 
perpendicular diameter [transverse (T)]), using either T1 or T2 weighted images (which ever gives 
the best estimate of tumor size).  
The following section describes the methodology: 
1. For MRI imaging, the longest diameter can be measured from the axial plane or the plane 
in which the tumor is best seen or measured, provided the same plane is used in follow-
ups. 
2. The longest measurement of the tumor (or width, W) should be determined.  
3. The 2 perpendicular measurements should be determined (transverse [T]) measurement-
perpendicular to the width (W) in the selected plane 
Target Lesions 
All measurable lesions up to a maximum of 5 lesions total, representative of all involved areas, 
should be identified as target lesions and recorded and measured at baseline. Target lesions will 
be selected on the basis of their size (largest) and their suitability for accurate repeated 
measurements.  
11.4.5.2. Non-Measurable Disease  
Non-measurable disease is all other lesions (or sites of disease), including leptomeningeal disease. 
11.4.5.3. Methods for Evaluation of Measurable Disease 
All measurements will be taken and recorded in metric notation using a ruler or calipers. All 
baseline evaluations will be performed as closely as possible to the beginning of treatment.  
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The same method of assessment and the same technique will be used to characterize each identified 
and reported lesion at baseline and during follow-up.  
11.4.5.4. Response Criteria, per RANO Criteria and Allowing for Integration of iRANO 
Criteria to Supplement RANO Criteria as Appropriate 
Complete Response 
Disappearance of all enhancing lesions, determined by two separate observations conducted not 
less than 4 weeks apart. Stable or improved T2/FLAIR non-enhancing lesions. There can be no 
appearance of new lesions. 
Partial Response 
At least a 50% decrease in the size of enhancing target lesions, taking as reference to the baseline 
MRI and determined by two separate observations conducted not less than 4 weeks apart. Stable 
or improved T2/FLAIR non-enhancing lesions. There can be no appearance of new lesions. 
Stable Disease 
Neither sufficient shrinkage to qualify for complete response or partial response nor sufficient 
increase to qualify for progressive disease, taking as reference the smallest target size since the 
treatment started. Stable or improved T2/FLAIR non—enhancing lesions. There can be no 
appearance of new lesions. 
Progressive Disease 
At least a 25% increase in the sum of the size of enhancing target lesions, taking as reference the 
smallest target size since the treatment started that is confirmed on a 3-month follow-up scan as 
long as the patient is NOT experiencing significant neurological decline (defined as CTCAE grade 
3 or higher). The confirmatory scan requirement will assure that patients are not prematurely 
assigned to have progressive disease while receiving immune-based therapy. In addition, the 
appearance of new lesions might be part of an immune response and if the patient is clinically 
stable, these should be confirmed on a 3-month follow-up scan to assess for true progressive 
disease versus pseudoprogression. This will apply to patients that demonstrate worsening of the 
MRI within 6 months of start of therapy. Patients who develop worsening radiographic findings 
>6 months from start of immunotherapy are expected to have a low likelihood of ultimately 
deriving benefit from the therapy and should be considered PD based on imaging if they have a 
50% increase in size of the target lesion or if new lesions appear.  
Patients who experience significant clinical decline or those who have radiographic progression 
on the 3-month follow-up scan should be classified as progressive disease and the date of 
progression should be entered as the first MRI that showed progressive disease. 
If the follow-up 3-month scan shows stabilization or reduction of tumor size in the setting of stable 
clinical examination and absence of increased use of steroid treatment, the patient will be classified 
as having pseudoprogression and will continue on study therapy.  
If feasible, we recommend to obtain tissue if imaging is concerning for progression as tissue 
evaluation remains the gold standard to differentiate between pseudoprogression versus true 
progression. If pathology mainly consists of recurrent tumor, the patient should be considered to 
have true tumor progression and be taken off study. If the tissue mainly consists of gliosis and 
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inflammation (consistent with treatment effect) the patient should be classified has having 
pseudoprogression and should remain on study. Patients that have tissue available will be centrally 
reviewed at UCSF.  
In cases for which it remains difficult to differentiate between progression versus 
pseudo-progression, the PI should discuss with the study chair the possibility of continuation of 
therapy. Images will also be centrally reviewed at UCSF. Continuation of therapy might be 
considered if the patient derives clinical benefit with acceptable toxicity.  
This is applicable for imaging findings within the first 6 months since start of immunotherapy.  
11.5. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment to the end 
of the study. The reference for progressive disease is the smallest measurements recorded since 
the treatment started. The patient’s best response assignment will depend on the achievement of 
both measurement and confirmation criteria.  
11.6. 
Duration of Response 
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. 
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.  
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11.7. 
Additional Guidelines for Response Criteria for CNS Tumors 
Figure 7: 
Additional Guidelines for Response Criteria for CNS Tumors 
 
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12. 
STATISTICAL CONSIDERATIONS 
12.1. 
Study Endpoints  
Study endpoints are provided below. Study objectives are provided in Section 1. Evaluation 
criteria definitions are provided in Section 11.4. 
12.1.1. 
Primary Endpoints 
Phase 1 
 Safety, as measured by the incidence and severity of treatment-emergent adverse events 
(TEAEs)/immune-related adverse events (irAEs)/adverse events of special interest 
(AESIs) / serious adverse events (SAEs), deaths, and laboratory abnormalities (grade 
3 or higher per version 4.0 of Common Terminology Criteria for Adverse Events 
(CTCAE v4.0), from initiation of study treatment until 90 days after the last study 
treatment (or until the patient receives another systemic anticancer therapy, whichever 
is earlier) 
 Tolerability, as measured by the incidence of DLTs from the first dose of REGN2810 
through the end of the DLT observation period for cemiplimab given as monotherapy 
 PK for REGN2810 given as monotherapy in pediatric patients  
Efficacy Phase 
 Incidence and severity of TEAEs, irAEs, AESIs, SAEs, deaths, and laboratory 
abnormalities (Grade 3 or higher per CTCAE v4.0) for REGN2810 given in 
combination with radiation therapy, from initiation of study treatment until 90 days 
after the last study treatment (or until the patient receives another systemic anticancer 
therapy, whichever is earlier) 
 Incidence of DLTs during the DLT observation period for REGN2810 given in 
combination with radiation therapy  
 PK for REGN2810 given as given in combination with radiation therapy in pediatric 
patients  
 Overall survival at 12 months (OS12) among newly diagnosed DIPG patients and 
recurrent HGG patients, respectively.  
OS is defined as the time from randomization to the date of death due to any cause. A 
patient who has not died will be censored at the last date that patient is documented to 
be alive.  
 Progression-free survival at 12 months (PFS12) among newly diagnosed HGG patients.  
PFS is defined as the time from randomization to the date of the first documented tumor 
progression, as determined per RANO/iRANO criteria, or death due to any cause. 
Patients will be censored according to rules listed below: 
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 Patients without a documented tumor progression or death will be censored on the 
date of their last evaluable tumor assessment. 
 Patients without a documented tumor progression or death before initiation of 
another anti-tumor therapy will be censored on the date of their last evaluable tumor 
assessment prior to or on the date of new anti-tumor therapy. 
 Patients who withdraw consent before taking any study treatment, and as a 
consequence have no post-baseline tumor assessment, will be censored at the date 
of randomization 
 Patients without any evaluable tumor assessments after randomization and did not 
die will be censored on the date of randomization  
12.1.2. 
Secondary Endpoints 
Phase 1 
 Objective response rate (ORR). ORR is defined as the percentage of patients who have 
a best overall response (BOR) of confirmed complete response (CR) or partial response 
(PR).  
BOR is defined as the best overall response, as determined per RECIST 1.1/irRECIST 
criteria for solid tumors and per RANO/iRANO criteria for CNS tumors, between the 
date of first dose of REGN2810 and the date of the first objectively documented 
progression or the date of receiving another anticancer systemic therapy, whichever 
comes first.  
 Anti-drug antibody (ADA) assessments for REGN2810 given as monotherapy 
Efficacy Phase 
 ADA assessments for REGN2810 given in combination with radiation therapy  
12.1.3. 
Exploratory Endpoints 
Phase 1 and Efficacy Phase 
 Quality of Life (QoL), as measured using Pediatric Quality of Life (PedsQL) for 
younger age group 2 to <18 years  
 QoL, as measured using the Functional Assessment of Cancer Therapy-Brain 
(FACT-Br) for older age group 18 to 25 years.  
 Circulating tumor cells, biomarker data, circulating cytokines, and peripheral blood 
mononucleated cells (PBMC), tumor expression of PD-L1 for biomarker and 
correlative studies 
12.2. 
Sample Size 
In Phase 1, a minimum of 30 patients will be enrolled. This will include at least 6 patients in the 
age 0 to <12 recurrent/refractory tumor cohort (Cohort A), at least 3 patients in the age 12 to <18 
recurrent/refractory tumor cohort (Cohort B), at least 6 patients in the age 0 to <12 CNS tumor 
cohort (Cohort C), and at least 3 patients in the age 12 to <18 CNS tumor cohort (Cohort D), as 
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well as 6 additional patients (at the corresponding identified RP2D) in each of the solid tumor 
cohorts. 
In the Efficacy Phase, a minimum of 30 patients will initially be enrolled as part of the 3+3 design 
to assess the safety of the anticipated RP2D of REGN2810 in combination with either conventional 
or hypofractionated radiation. This will include at least 6 patients in the age 3 to <12 newly 
diagnosed DIPG (Cohort E; 3 in each treatment arm), at least 6 patients in the age 12 to 25 newly 
diagnosed DIPG cohort (Cohort F; 3 in each treatment arm), at least 6 patients in the age 3 to <12 
newly diagnosed HGG cohort (Cohort G; 3 in each treatment arm), at least 6 patients in the age 12 
to 25 newly diagnosed HGG cohort (Cohort H; 3 in each treatment arm), at least 3 patients in the 
age 3 to <12 recurrent HGG cohort (Cohort I), and at least 3 patients in the age 12 to 25 recurrent 
HGG cohort (Cohort J). 
Once the RP2D of REGN2810 is confirmed for a given cohort (and treatment arm, where 
applicable), additional patients will be enrolled as part of expansion. During expansion, the total 
number of patients enrolled will be based on treatment regimen, irrespective of patient age or 
cohort. Additional patients will be enrolled until at least 20 evaluable patients are reached, based 
on a Simon two-stage design, in each of the following pooled treatment arms: 
 Newly diagnosed DIPG with conventionally fractionated radiation + REGN2810 
(DIPG Arm 1) 
 Newly diagnosed DIPG with hypofractionated radiation + REGN2810 (DIPG Arm 2) 
 Newly diagnosed HGG with conventionally fractionated radiation + REGN2810 
(Newly Diagnosed HGG Arm 1) 
 Newly diagnosed HGG with hypofractionated radiation + REGN2810 (Newly 
Diagnosed HGG Arm 2) 
 Recurrent HGG with reirradiation + REGN2810 (Recurrent HGG Arm 1) 
In total, a minimum of 100 patients (20 patients per pooled treatment arm at the respective 
confirmed RP2D) will be enrolled in the Efficacy Phase. The justification of sample size is 
described in Section 12.3.  
12.3. 
Sample Size Justification and Accrual Rate 
The most recent Children’s Oncology Group study that treated children with newly diagnosed 
DIPG with a combination of radiation therapy and temozolomide resulted in a mean OS12 rate of 
40% (Standard Deviation +/-6.5%)67. We will apply these findings as historical controls for our 
DIPG treatment arms. The null hypothesis for each DIPG treatment arm is an OS12 of 40%, with 
a target alternative hypothesis of 70% OS12. Note that although DIPG cohorts will be randomized 
equally between arms 1 and 2, evaluations will be done within each arm as this trial is not powered 
for comparisons between arms.  
Within each DIPG radiation arm, 20 eligible and evaluable DIPG patients will be randomized in 
order to achieve at least 80% power to detect the above absolute increase of 30% in OS12 within 
an arm using a one-sided 0.05 level exact binomial test. This phase of the study will follow a 
two-stage design, where initially 7 patients are entered at the first stage in each arm. If no more 
than 3 deaths occur within 12 months in the initial cohort, the study will move to the second stage. 
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In each arm, an additional 13 eligible patients will be randomized. If at the first stage, 4 or more 
patients die within 12 months in an arm, that arm will be temporarily closed and a detailed review 
performed. The study team together Regeneron and its delegates will determine if accrual will 
continue or enrollment be stopped in this arm. The arm will be considered a success (reject the 
associated null hypothesis) if at least 12 of the 20 patients survive beyond 12 months. There is a 
71% chance of stopping early under the null hypothesis under this two-stage design. To allow for 
ineligibility, we anticipate there may be an additional 1-2 patients enrolled in this cohort overall 
to achieve the target number of eligible and evaluable patients. 
It is expected that the study will not pause after the first stage accrual goals are met for each cohort, 
but that the first stage patients will be monitored with respect to the first stage futility rule above. 
However, given the requirement of 12 months of follow-up to determine the OS12 endpoint for 
each patient, should the accrual to the first stage be rapid and there is insufficient follow-up in the 
first stage cohort to obtain an OS signal before continuing to accrue to the second stage, 
consideration will be given to pausing accrual in order to gather information at the first stage. 
Furthermore, if before expansion to the second stage there is clear evidence for a need to pause 
accrual (eg, 2 or 3 deaths observed in the first cohort) then the study will halt accrual until it can 
be confirmed that it is warranted to move to the second stage. 
The most recent Children’s Oncology Group study that treated children with newly diagnosed 
HGG with a combination of radiation therapy, lomustine, and temozolomide resulted in a mean 
PFS12 rate of 49%68. We will apply these findings as historical controls for our newly diagnosed 
HGG treatment arms. The null hypothesis for each arm is a PFS12 of 50% with a target alternative 
hypothesis of 80% PFS12. Note that although HGG cohorts will be randomized equally between 
arms 1 and 2, evaluations will be done within each arm as this trial is not powered for comparisons 
between arms.  
Within each newly diagnosed HGG treatment arm, 20 eligible and evaluable newly diagnosed 
HGG patients at the RP2D level will be randomized in order to maintain 80% power to detect the 
alternative hypothesis using a one-sided 0.05 level exact binomial test. This phase of the study will 
also follow a two-stage design where initially 7 patients are entered at the first stage. If no more 
than 2 patients experience disease progression or death within 12 months in the initial cohort, the 
study will move to the second stage and an additional 13 patients will be entered. If at the first 
stage, 3 or more patients experience disease progression or death within 12 months, the arm will 
be temporarily closed and a detailed review performed. The study team together with Regeneron 
and its delegates will determine if accrual will continue or enrollment be stopped in this arm. The 
arm will be considered a success (reject the associated null hypothesis) if at least 14 of the 
20 patients do not experience disease progression or death at or beyond 12 months. There is a 77% 
chance of stopping early under the null hypothesis under this two-stage design. To allow for 
ineligibility, there may be an additional 1-2 patients enrolled in this cohort overall to achieve the 
target eligible and evaluable number of patients.  
Based on cumulative outcome data from a 20-year systematic review and meta-analysis69, the 
cumulative median overall survival over the last decade was 8.5 months for recurrent pediatric 
HGG, which translates into OS12 of 37.6% under exponential distribution. We assume the OS12 
of 40% as null hypothesis and OS12 of 70% as alternative hypothesis. The target sample size for 
all recurrent HGG patients is 20 eligible and evaluable recurrent HGG patients at the RP2D level 
in order to maintain 80% power to detect the alternative hypothesis using a one-sided 0.05 level 
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exact binomial test. This phase of the study will also follow a two-stage design where initially 
7 patients are entered at the first stage. If no more than 3 deaths occur within 12 months in the 
initial cohort, the study will move to the second stage and an additional 13 patients will be entered. 
If at the first stage, 4 or more patients die within 12 months, the arm will be temporarily closed 
and detailed review performed. The study team together with Regeneron and its delegates will 
determine if accrual will continue or enrollment be stopped in this arm. The arm will be considered 
a success (reject the associated null hypothesis) if at least 12 of the 20 patients survive beyond 12 
months. There is a 71% chance of stopping early under the null hypothesis under this two-stage 
design. To allow for ineligibility, there may be an additional 1-2 patients enrolled in this cohort 
overall to achieve the target number of eligible and evaluable patients. 
It is expected that the study will not pause after the first stage accrual goals are met for these 
cohorts, but that the first stage patients will be monitored with respect to the first stage futility rule 
above. However, given the requirement of 12 months of follow-up to determine the OS12 or PFS12 
endpoint for each patient, should the accrual to the first stage be rapid and there is insufficient 
follow-up in the first stage cohort to obtain an OS or PFS signal before continuing to accrue to the 
second stage, consideration will be given to pausing accrual in order to gather information at the 
first stage. Furthermore, if before expansion to the second stage there is clear evidence for a need 
to pause accrual (eg, 1 or 2 deaths observed in the first cohort) then the study will halt accrual until 
it can be confirmed that it is warranted to move to the second stage. 
In the event that interim pharmacokinetic analysis indicates serum concentrations below goal 
trough exposure for any cohort or age group, study investigators along with study sponsors will 
determine appropriateness of additional dose escalation or expansion cohorts in Phase 1 or the 
Efficacy Phase. 
12.4. 
Criteria to be Evaluable for Efficacy and Toxicity 
As per Intention to Treat analyses, any patient who receives at least one dose of REGN2810 will 
be evaluable for efficacy and toxicity.  
As Per Protocol analyses, there will be separate criteria to be considered evaluable for efficacy 
and DLT. Patients who receive less than 85% of the prescribed dose of REGN2810 or who receive 
less than the required percentage of radiation during the DLT period within each cohort (as per 
description and tables below), may not be evaluable for efficacy or toxicity in the Per Protocol 
analyses (and may be replaced by another enrollee as per replacement criteria). 
Due to the known role of radiation in the treatment of newly diagnosed DIPG and HGG, we will 
require patients receive at least 90% of intended radiation dosing to be evaluable for toxicity or 
efficacy in the Per Protocol analyses. This includes the following minimum fractions for each 
newly diagnosed cohort: 
Cohort 
Minimum # of radiation fractions 
for Per Protocol analyses 
Newly diagnosed DIPG 
Conventional fractionation 
27 
Hypofractionation 
12 
Newly diagnosed HGG 
Conventional fractionation 
30 
Hypofractionation 
12 
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Due to the lesser known role of radiation in the treatment of recurrent HGG, we will require 
patients received at least 80% of intended radiation dosing to be evaluable for toxicity or efficacy 
in the Per Protocol analyses. This includes the following minimum fractions for each newly 
diagnosed cohort: 
Cohort 
Minimum # of radiation 
fractions for Per Protocol 
analyses 
Recurrent HGG 
8 
12.5. 
Replacement Criteria 
Patients who come off study during the DLT period for reasons other than a DLT or progression 
and who receive less than 85% of the prescribed dose of REGN2810 or who receive less than the 
required percentage of radiation during the DLT period within each cohort may not be applied 
toward the final enrollment number and may be considered for replacement by another enrollee. 
Final decisions for replacement will be determined by the study chairs. 
The study team will review all instances of patients coming off study for reasons other than DLT 
or progression during the DLT period in order to ensure that patients are being treated with 
adequate therapy, before moving into the expansion phase of each cohort. 
12.6. 
Stratification Factors for the Efficacy Phase of the Study 
Within the efficacy phase of the study, the trial will enroll into cohorts based on disease: newly 
diagnosed DIPG cohort, newly diagnosed HGG cohort, and recurrent HGG cohort. The newly 
diagnosed DIPG and newly diagnosed HGG cohorts will include 2 radiation arms: Arm 1 will 
follow a conventionally fractionated radiation schedule; Arm 2 will follow a hypofractionated 
radiation schedule. Randomization within the 3 to <12 years age group of the newly diagnosed 
DIPG and HGG cohorts will occur once the RP2D has been confirmed for this age group in Phase 
1. Randomization within the 12 to 25 years age group will occur at the anticipated RP2D at time 
of enrollment.  
12.7. 
Analysis of Primary Endpoints 
12.7.1. 
Phase 1: RP2D and Pharmacokinetics 
 RP2D will be determined based on the MTD in each age and disease cohort, as 
applicable. It is possible more than 1 RP2D will be identified in each age cohort and 
between solid or CNS tumors. 
 PK parameters will include but will not be limited to concentrations at pre-dose, end-of 
Infusion (Ceoi) after the first dose and during treatment. AUC2w and estimated t1/2 
after the first dose will be determined by non-compartmental analysis.  
 The PK analysis set will include all enrolled patients who received any study drug 
(safety population) and who had at least 1 REGN2810 concentration following the first 
dose.  
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12.7.2. 
Efficacy Phase: RP2D and Efficacy  
 RP2D will be determined based on the MTD in each age group of each CNS tumor 
cohort and radiation arm. It is possible more than 1 RP2D will be identified in each 
CNS tumor cohort and each radiation arm. 
 For the DIPG cohort, assuming 20 eligible patients in each arm, if in each arm 12 or 
more patients are alive at 12 months, the null hypothesis for that arm will be rejected 
and efficacy as demonstrated by improving OS12 will have been demonstrated. See 
Section 12.2 and Section 12.3 for details of sample size considerations.  
 For the newly diagnosed HGG cohort, assuming 20 eligible patients in each arm, if 14 
or more patients do not experience disease progression at 12 months, the null 
hypothesis for that arm will be rejected and efficacy as demonstrated by improving 
PFS12 will have been demonstrated. See Section 12.2 and Section 12.3 for details of 
sample size considerations. 
 For the recurrent HGG cohort, assuming 20 eligible patients, if 12 or more patients are 
alive at 12 months, the null hypothesis for that arm will be rejected and efficacy as 
demonstrated by improving OS12 will have been demonstrated. See Section 12.2 and 
Section 12.3 for details of sample size consideration. 
 Safety and toxicity measurements of repeated administration of REGN2810 using 
CTCAE version 4.0 in children. 
12.7.3. 
Efficacy Phase: Pharmacokinetics 
 PK parameters will include but will not be limited to concentrations at pre-dose, Ceoi 
after the first dose and during treatment. AUC2w and estimated t1/2 after the first dose 
will be determined by non-compartmental analysis.  
 The PK analysis set will include all randomized patients who received any study drug 
(safety population) and who had at least 1 REGN2810 concentration following the first 
dose.  
12.8. 
Analysis of Secondary Endpoints 
12.8.1. 
Phase 1: Objective Response 
 Objective response will be for descriptive purposes only in the phase 1 of this study. 
No formal hypothesis testing will be performed on efficacy. Objective tumor response 
is determined according to Section 10.  
12.8.2. 
Efficacy Phase: Toxicity Profile 
 All AEs reported in this study will be listed and summarized according to CNS tumor 
type and radiation arm. 
 AEs will be collected for descriptive purposes. No formal hypothesis will be performed 
on the AEs. Results will potentially be used as reference for future clinical trials. 
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12.8.3. 
Phase 1 and Efficacy Phase: ADA 
 ADA analysis will be conducted on serum samples for anti-REGN2810 antibody at 
time points according to the Schedules of Events 
 The ADA population includes all treated patients who received any amount of study 
drug and who had at least 1 non-missing result in the ADA assay following the first 
dose of the study drug. 
Anti-drug antibody variables include ADA response status and titer as follows: 
 Total patients with preexisting immunoreactivity 
 Total patients with treatment-emergent response 
 Total patients with treatment-boosted response 
 Titer values (Titer value category)  
o Low (Titer <1000) 
o Moderate (1,000 ≤ Titer ≤10,000) 
o High (Titer >10,000) 
12.9. 
Analysis of Exploratory Endpoints 
12.9.1. 
Phase 1 and Efficacy Phase: Quality of Life 
 Quality of life will be measured using the Pediatric Quality of Life Inventory (PedsQL) 
in patients aged 2 to <18 years 
 Quality of life will be measured using the Functional Assessment of Cancer 
Therapy-Brain (FACT-Br) in patients aged 18 to 25 years 
 Quality of life will be collected for descriptive purposes. No formal hypothesis will be 
performed on the Quality of Life. Results will potentially be used as reference for future 
clinical trials. 
12.9.2. 
Phase 1 and Efficacy Phase: Biology Studies 
 Circulating tumor cells will be analyzed using standard scientific and statistical 
methods and summarized by phase, age, tumor type, and radiation arm 
 Biomarker data, circulating cytokines, and PBMC results will be analyzed using 
standard scientific and statistical methods and summarized by phase, age, tumor type, 
and radiation arm 
 Analyses of correlative scientific endpoints are largely exploratory and hypothesis 
generating. Any promising findings will be tested in future studies. All analyses will 
be descriptive in nature; however, statistical power is provided below in order to 
provide a sense of precision for the proposed analyses.  
Regarding PD-L1 expression in tumor tissue, an unpaired t-test will be used to compare % positive 
tumor cells in responders compared to non-responders. Responders will be determined using the 
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primary endpoint of the trial – overall survival at 12 months. Based on prior data obtained in adult 
gliomas it is assumed that approximately 60% of tumors will express PD-L135. 
To give a sense of power for studies to be done on paired blood samples (paired within patient 
comparing baseline and on-treatment) for analyses of T-cell subsets, myeloid-derived suppressor 
cells, immunologic cytokines and antibodies, differences will be taken for all measures and the 
hypothesis is that markers of immune response (e.g., antibody titer, levels of antigen reactive 
T-cells) should increase post-therapy. Assuming that within each cohort we will obtain the accrual 
of at least 20 patients, using a one-sided 0.10 level paired t-test, there is at least 80% power to 
detect a 0.58 standard deviation change in mean of a quantitative correlative parameter using a 
one-sided test with 5% type I error. Thus, with a modest level of consent for these studies there is 
sufficient power for meaningful analyses. Power for these tests will be further improved with 
greater numbers. 
13. 
PHARMACEUTICAL INFORMATION 
13.1. 
Agent 
13.1.1. 
Agent - REGN2810 
Product description: REGN2810 is an investigational agent supplied by Regeneron.  
REGN2810 will be supplied as a liquid in sterile, single-use vials. Each vial will contain 
REGN2810 at a concentration of 50 mg/mL. 
Instructions on dose preparation are provided in the study reference manuals. 
REGN2810 will be administered in an inpatient or outpatient setting as a 30-minute IV infusion. 
Each patient’s dose will depend on individual body weight. The dose of REGN2810 must be 
adjusted each cycle for changes in body weight of ≥10%. Dose adjustments for changes in body 
weight of <10% will be at the discretion of the investigator. REGN2810 will be administered alone 
or in combination with radiation. A pharmacist or other qualified individual will be identified at 
each site to prepare REGN2810 for administration.  
13.2. 
Treatment Logistics and Accountability 
13.2.1. 
Drug Ordering 
Study drug supply will be managed by an IWRS, which will assign treatment for each patient 
dosing visit. Member sites should refer to SharePoint about details for drug ordering.  
13.2.2. 
Packaging, Labeling and Storage 
Open-label study drug will display the product lot number on the label. Study drug will be stored 
at the site at a temperature of 2°C to 8°C; storage instructions will be provided in the pharmacy 
manual. 
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13.2.3. 
Supply and Disposition 
Study drug will be shipped at a temperature of 2o to 8oC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be destroyed or returned to the 
sponsor or designee. 
13.2.4. 
Solution Preparation 
Detailed preparation and administration instructions will be provided to the sites in the study 
reference manuals.  
13.2.5. 
Storage Requirements 
Open-label REGN2810 will be supplied as a liquid in sterile, single-use vials that will display the 
product lot number on the label. Each vial will contain REGN2810 at a concentration of 50 mg/mL. 
REGN2810 will be refrigerated at the site at a temperature of 2° to 8°C, and refrigerator 
temperature will be logged daily. Further storage instructions will be provided in the study 
reference manual.  
13.2.6. 
Stability 
Details regarding RENG2810 infusion bag stability are provided in the pharmacy manual. 
13.2.7. 
Route of Administration 
REGN2810 will be administered in an outpatient setting as a 30-minute IV infusion every 14 days. 
Each patient’s dose will depend on individual body weight. The dose of REGN2810 must be 
adjusted each cycle for changes in body weight of ≥10%. Dose adjustments for changes in body 
weight of <10% will be at the discretion of the investigator.  
13.2.8. 
Accountability 
The investigator, or a responsible party designated by the investigator, will be responsible for drug 
accountability and this should be managed per each PNOC institutions’ guidelines.  
All drug accountability records must be kept current.  
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study medication dispensed to each patient, returned from 
each patient (if applicable), and disposed of at the site or returned to the sponsor or designee.  
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study.  
13.2.9. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
 
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14. 
REPORTING AND EXCLUSIONS 
14.1. 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with REGN2810. 
14.2. 
Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible. Each patient will be assigned 1 of the 
following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because 
of other cause, or 9) unknown (not assessable, insufficient data). (Note: By arbitrary convention, 
category 9 usually designates the “unknown” status of any type of data in a clinical database.) 
All of the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) should be included in the main analysis of the response rate. Patients 
in response categories 4-9 should be considered to have a treatment failure (disease progression). 
Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the 
analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific.  
All conclusions should be based on all eligible patients. Subanalyses may then be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have been 
identified (e.g., early death due to other reasons, early discontinuation of treatment, major protocol 
violations, etc.). However, these subanalyses may not serve as the basis for drawing conclusions 
concerning treatment efficacy, and the reasons for excluding patients from the analysis should be 
clearly reported. The 95% confidence intervals should also be provided.  
 
 
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15. 
REGISTRATION PROCEDURES 
15.1. 
General Guidelines 
Patients must meet all inclusion criteria and cannot meet any exclusion criteria. The patient or 
LAR must have signed and dated an approved, current version of all applicable consent forms. To 
allow non-English speaking patients to participate in this study, bilingual health services will be 
provided in the appropriate language when feasible. 
Registration materials will be submitted to the PNOC Operations Office as described below. The 
PNOC Operations Office will check the registration materials for completeness and contact the 
site with any discrepancies.  
The PNOC Operations Office will forward the eligibility checklist, including source 
documentation to the Study Chair or Co-Chair as well as the Project Leader or Co-Project Leader 
of PNOC for review of eligibility and signoff.  
Patient eligibility will be reviewed in OnCore®. Once eligibility is confirmed via email from the 
PNOC Operations Office to the registering site, the site will enroll the patient via the Interactive 
Web Response System (IWRS). Enrollment into the IWRS and treatment initiation on protocol 
therapy cannot occur unless eligibility has been reviewed and confirmed with receipt of the 
registration confirmation email from the PNOC Operations Office.  
15.2. 
Reservation and Registration Process 
The wait-list for study slots will be maintained by the PNOC Operations Office. Investigators can 
view updated information about slot availability and registration process updates on the PNOC 
Member’s SharePoint homepage using their secure login and password, or by emailing a request 
to PNOC_Registration@ucsf.edu. 
To place a patient on the waitlist, please complete the Qualtrics survey (link available on 
SharePoint). An automatic screening ID will be generated, and emailed to both the Operations 
Office and the person submitting the form. This screening ID will be used for registration and 
patient tracking purposes. 
To register a patient for the study, limited patient information (confirmation of screening ID, 
gender, ethnicity, race, month & year of birth, ZIP or country code, disease site, histology, 
diagnosis date, name of treating physician and study specific information) along with a signed 
consent form and HIPAA authorization (if applicable to your institutional regulatory guidelines) 
should be emailed to the PNOC Operations Office at PNOC_Registration@ucsf.edu. All subject 
PHI must be redacted, and the screening ID included on each source document or consent form 
page. The patient will be given the status of consented in OnCore®. 
When the eligibility checklist has been completed, the member institution PI and/or Coordinator 
will upload the completed eligibility checklist (along with copies of any supporting documents) 
into the patient’s OnCore® record.  
Once the necessary documents have been received and patient eligibility has been confirmed, the 
PNOC Operations Office will send a confirmation e-mail to the institutional PI(s) and Research 
Coordinator(s) to proceed with enrollment via IWRS.  
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The ICON Clinical Trial Manager will maintain the Master Enrollment Tracker.  
16. 
DATA REPORTING / REGULATORY REQUIREMENTS 
16.1. 
Data Reporting 
16.1.1. 
Method 
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Study specific 
Case Report Forms (CRFs; throughout this protocol, CRF refers to either a paper CRF or an 
electronic CRF) will document safety and treatment outcomes for safety monitoring and data 
analysis. All study data will be entered into eCRFs using single data entry with a secure access 
account. The electronic data capture (EDC) system used for this study is Medidata Rave. The 
Clinical Research Coordinator (CRC) will complete the CRFs as soon as possible upon completion 
of the study visit; the Investigator will review and approve the completed CRFs.  
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained at each 
PNOC site. For participating sites, source documents will be maintained per institutional 
guidelines. All source documentation should be kept in separate research folders for each patient. 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. This 
signed declaration will accompany each set of patient CRFs that will be provided to Regeneron. 
All source documentation and Clinical Trial Management System data will be available for 
review/monitoring by Regeneron and delegates, and regulatory agencies.  
The Principal Investigator will be responsible for ensuring the accurate capture of study data. At 
study completion, when the CRFs have been declared to be complete and accurate, the database 
will be locked. Any changes to the data entered into the CRFs after that time can only be made by 
joint written agreement among the Study Chair, the Trial Statistician, Regeneron, and the PNOC 
Project Leader. 
16.1.2. 
Responsibility for Data Submission 
Please refer to Appendix 3 for data submission timelines. 
16.2. 
Oversight and Monitoring Plan 
This is a multicenter trial. Regeneron and delegates will be responsible for overall safety and data 
monitoring on this study.  
The study monitor and/or designee (e.g., CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study. 
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16.2.1. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file. Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities.  
16.2.2. 
Multicenter Communication 
The PNOC Operations Office provides administration and organizational support for the 
participating sites in the conduct of the clinical trial. The PNOC Operations Office will coordinate, 
at minimum, quarterly conference calls with the PNOC member institutions to discuss risk 
assessment. The following items will be discussed, as appropriate: 
 Enrollment information  
 Cohort updates (i.e., DLTs) 
 Adverse events (i.e., new AEs and updates on unresolved AEs and new safety 
information) 
 Protocol violations 
 Other issues affecting the conduct of the study 
16.2.3. 
Record Keeping and Record Retention 
The Principal Investigator for each PNOC institution is required to maintain adequate records of 
the disposition of the drug, including dates, quantity, and use by patients, as well as written records 
of the disposition of the drug when the study ends per institutional guidelines. 
The site Principal Investigator is required to prepare and maintain adequate and accurate case 
histories that record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (eg, 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, each PNOC member institution must retain records and all 
essential study documents, including Informed Consent Forms (ICFs), source documents, 
investigator copies of CRFs, and drug accountability records for at least 15 years following the 
completion or discontinuation of the study, or longer, if a longer period is required by relevant 
regulatory authorities. The PNOC member institution must consult with Regeneron before 
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discarding or destroying any essential study documents following study completion or 
discontinuation. Records must be destroyed in a manner that ensures confidentiality. 
If the PNOC member institution’s situation is such that archiving can no longer be ensured, the 
PNOC member institution must inform Regeneron and/or its delegates and the relevant records 
will be transferred to a mutually agreed-upon destination. 
16.2.4. 
Regulatory Documentation  
Prior to implementing the protocol at each PNOC institution, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be first approved 
by Regeneron and/or its delegates. Prior to implementing this protocol at the participating sites, 
approval for the protocol must be obtained from the participating site’s IRB.  
It is the responsibility of the investigator to obtain written informed consent from each patient (or 
LAR, if patient is a minor) prior to the patient’s participation in the study and after the aims, 
methods, objectives, and potential hazards of the study have been explained in language that the 
patient or LAR can understand. The ICF should be signed and dated by the patient or LAR and the 
same investigator or designee who explained the ICF.  
If the patient is a minor, local law must be observed in deciding whether 1 or both parents or LAR 
consent is required. The patient may also be required to sign and date the ICF, as determined by 
the IRB/EC and in accordance with the local regulations and requirements. 
 Patients (and/or LARs) who can write but cannot read will have the assent form read 
to them before writing their name on the form. 
 Patients (and/or LARs) who can understand but who can neither write nor read will 
have the ICF read to them in presence of an impartial witness, who will sign and date 
the ICF to confirm that informed consent was given. 
The original ICF must be retained by the investigator as part of the patient's study record, and a 
copy of the signed ICF must be given to the patient’s LAR. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF must 
be reviewed and updated appropriately. All study patients (and their LARs, for patients who are 
minors) must be informed of the new information, and patients who wish to continue in the study 
must provide their written consent. The original signed revised ICF must be maintained in the 
patient’s study record and a copy must be given to the patient. For patients who are minors, an 
LAR must provide written consent for a patient to continue in the study. The original signed 
revised ICF must be maintained in the patient’s study record and a copy must be given to the 
patient’s LAR. 
The investigator may not implement a change in the design of the protocol or ICF without an 
IRB/EC-approved amendment and approval of Regeneron. 
Appendix 4 lists the documents which must be provided to Regeneron and/or its delegates before 
the participating site can be initiated and begin enrolling participants. 
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17. 
DEFINITIONS OF DEVIATIONS IN PROTOCOL 
PERFORMANCE 
DEVIATION  
Minor  
Major  
Prescription Dose  
Difference in prescribed or computed dose is 
6-10% of protocol specified dose  
Difference in prescribed or computed dose is 
>10% of protocol specified dose  
Dose Uniformity and Coverage  
>10% PTV received >110% 
of the protocol dose or 
95% isodose covers <100% of CTV  
>20% of PTV received >110% of the protocol 
dose or 
90% isodose covers <100% of CTV  
Volume  
CTV or PTV margins are less than the protocol 
specified margins in the absence of anatomic 
barriers to tumor invasion (CTV) or without 
written justification (PTV)  
GTV does not encompass MR-visible residual 
tumor  
Organs at Risk  
Dose to any OAR exceeds the goal dose stated 
in Section 10.6.1  
Dose to any OAR exceeds the maximum dose 
stated in Section 10.6.1 
 
 
 
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APPENDIX 1. PERFORMANCE STATUS CRITERIA 
Karnofsky 
Lansky 
Score Description 
Score Description 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
90 
Able to carry on normal activity, 
minor signs or symptoms of 
disease. 
90 
Minor restrictions in physically strenuous 
activity. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
80 
Active, but tires more quickly 
70 
Cares for self, unable to carry on 
normal activity or do active work. 
70 
Both greater restriction of and less time 
spent in play activity. 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
50 
Requires considerable assistance 
and frequent medical care. 
50 
Gets dressed, but lies around much of the 
day; no active play, able to participate in 
all quiet play and activities. 
40 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed; participates in quiet 
activities. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
30 
In bed; needs assistance even for quiet 
play. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
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Clinical Study Protocol 
 
 
PNOC 013, R2810-ONC-1690: Amendment 3 
 
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CONFIDENTIAL 
 
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Clinical Study Protocol 
 
PNOC 013, R2810-ONC-1690: Amendment 3 
 
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CONFIDENTIAL 
APPENDIX 3. REQUIRED DATA AND TIME TABLE FOR 
SUBMISSION 
The submission timelines listed below represent target timelines; however, timing may vary 
according to individual site. 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration 
On Study Forms 
Within 14 days of registration 
Baseline Assessment Forms 
Within 14 days of registration 
Treatment Forms 
Within 10 days of the last day of the cycle 
Adverse Event Report Forms 
All AEs are due within 10 business days of the date of 
assessment. 
Serious Adverse Event 
Reporting 
Within 1 business day of first PI awareness  
Response Assessment Forms 
Within 10 days of the completion of the cycle required for 
response evaluation 
Off Treatment/Off Study 
Forms 
Within 14 days of completing treatment or being taken off 
study for any reason 
Follow-up/Survival Forms 
Within 14 days of the protocol defined follow-up visit date 
 
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CONFIDENTIAL 
APPENDIX 4. PNOC INSTITUTIONS, REQUIRED REGULATORY 
DOCUMENTS 
Prior to opening a study at any member institution, the following regulatory documents 
must be submitted to Regeneron or its delegates:  
 Participating Site IRB approval(s) for the protocol, appendices, informed consent form 
and HIPAA authorization  
 Participating Site IRB approved consent form  
 Participating Site IRB membership list  
 Participating Site IRB’s Federal Wide Assurance number and OHRP Registration 
number  
 Curriculum vitae and medical license for each investigator and consenting professional  
 Documentation of Human Subject Research Certification training for investigators and 
key staff members at the Participating Site  
 Participating site laboratory certifications and normals  
 Signed copy of the completed delegation of authority log 
 Signed copy of the protocol signature page 
 Signed copy of the final contract 
 Completed Form 1572 
 
Upon receipt of the required documents, Regeneron or its delegates will formally contact the site 
and grant permission to proceed with enrollment.  
Sites will upload new or revised documents as applicable to reflect any changes, including changes 
in staff and approved/expired documents. 
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Page 160 of 161 
CONFIDENTIAL 
APPENDIX 5. INFORMATION SHEET ON POSSIBLE DRUG 
INTERACTIONS 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers and Non-
Study Healthcare Team 
 
[Note to investigators: This appendix consists of an “information sheet” to be handed to the patient 
at the time of enrollment. Use or modify the text as appropriate for the study agent, so that the 
patient is aware of the risks and can communicate with their regular prescriber(s) and pharmacist. 
A convenient wallet-sized information card is also included for the patient to clip out and retain at 
all times.] 
 
The patient ____________________________ is enrolled on a clinical trial using the experimental 
agent REGN2810. This clinical trial is sponsored by the Pacific Pediatric Neuro-Oncology 
Consortium and Regeneron. This form is addressed to the patient but includes important 
information for others who care for this patient.  
 
REGN2810 has no known drug interactions. 
 
Many health care prescribers can write prescriptions. You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
Bring this paper with you and keep the attached information card in your wallet. These are the 
things that you and they need to know:  
 
Other medicines can be a problem with your study drugs.  
 
You should check with your doctor or pharmacist whenever you need to use an over-the-counter 
medicine or herbal supplement.  
 
Your regular prescriber should check a medical reference or call your study doctor before 
prescribing any new medicine for you. Your study doctor’s name is 
_____________________________________ and he or she can be contacted at  
 
_____________________________________.  
 
 
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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the conduct of the study. 
Study Title: A Safety and Pharmacokinetic Study of Single Agent REGN2810 in Pediatric Patients 
with Relapsed or Refractory Solid or Central Nervous System (CNS) Tumors and a Safety and 
Efficacy Trial of REGN2810 in Combination with Radiotherapy in Pediatric Patients with Newly 
Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed High-Grade Glioma, or Recurrent 
High-Grade Glioma 
Protocol Number: 
R2810-ONC-1690  
Protocol Version: 
Amendment 3 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
 
                                        VV-RIM-00102228-1.0 Approved - 19 Mar 2020 GMT-5:00


Signature Page for VV-RIM-00102228 v1.0
Signature Page for VV-RIM-00102228 v1.0 Approved
ESig Approval
16-Mar-2020 21:30:59 GMT+0000
ESig Approval
16-Mar-2020 21:37:27 GMT+0000
ESig Approval
17-Mar-2020 13:54:29 GMT+0000
ESig Approval
20-Mar-2020 01:13:17 GMT+0000
                                        VV-RIM-00102228-1.0 Approved - 19 Mar 2020 GMT-5:00

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
 
 
Biostatistics and Data Management 
REGENERON CONFIDENTIAL 
Page 1 of 37 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2023 
 
STATISTICAL ANALYSIS PLAN 
VERSION: 1 
 
Clinical Study Protocol Title:  A Safety and Pharmacokinetic Study of Single Agent REGN2810 
in Pediatric Patients with Relapsed or Refractory Solid or Central Nervous System (CNS) 
Tumors and a Safety and Efficacy Trial of REGN2810 in Combination with Radiotherapy in 
Pediatric Patients with Newly Diagnosed Diffuse Intrinsic Pontine Glioma, Newly Diagnosed 
High-Grade Glioma, or Recurrent High-Grade Glioma 
 
Compound: 
 
 
REGN2810 
Protocol Number: 
 
PNOC 013/ R2810-ONC-1690 
Clinical Phase:  
 
Phase 1 & 2 
Sponsor: 
 
 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician:  
  
Clinical Study Team Leader: 
 
Study Medical Director: 
 
Version: 
 
 
1 
Date:  
 
 
Jun 19, 2023 
 
 
  
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 2 of 37 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
 
Biostatistics    
See appended electronic signature page 
 
 
 
Clinical Sciences 
 
See appended electronic signature page 
 
 
 
Clinical Pharmacology 
  
See appended electronic signature page 
 
 
 
Bioanalytical Sciences  
See appended electronic signature page 
 
 
 
Precision Medicine 
See appended electronic signature page 
 
   
 
Biostatistics and Data Management  
See appended electronic signature page 
 
 
 
                                        VV-RIM-00305225-1.0 Approved - 21 Jun 2023 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 3 of 37 
TABLE OF CONTENTS 
ABBREVIATIONS AND DEFINITIONS ......................................................................................6 
1. 
OVERVIEW .................................................................................................................8 
1.1. 
Study Objectives ...........................................................................................................8 
1.1.1. 
Primary Objectives .......................................................................................................8 
1.1.2. 
Secondary Objectives ...................................................................................................9 
1.1.3. 
Exploratory Objectives ...............................................................................................10 
1.1.4. 
Modifications from the Statistical Section in the Final Protocol ................................10 
1.1.5. 
Modifications from the Approved Statistical Analysis Plan ......................................10 
2. 
INVESTIGATION PLAN ..........................................................................................11 
2.1. 
Study Design and Randomization ..............................................................................11 
2.2. 
Sample Size and Power Considerations .....................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................15 
3.1. 
The Dose Limiting Toxicity Set .................................................................................15 
3.2. 
The Full Analysis Set (FAS) .......................................................................................15 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................15 
3.4. 
The Pharmacokinetics Analysis Set (PKS).................................................................15 
3.5. 
The Immunogenicity Analysis Set..............................................................................16 
4. 
ANALYSIS VARIABLES .........................................................................................17 
4.1. 
Disposition of Patients ................................................................................................17 
4.2. 
Demographic and Baseline Characteristics ................................................................17 
4.3. 
Medical History ..........................................................................................................18 
4.4. 
Pre-Treatment / Concomitant Medication ..................................................................18 
4.5. 
Treatment Exposure ....................................................................................................18 
4.6. 
Efficacy Variable ........................................................................................................18 
4.6.1. 
Primary Efficacy Variable(s) (Efficacy Phase Only) .................................................18 
4.6.2. 
Secondary Efficacy Variables .....................................................................................19 
4.7. 
Safety Variables ..........................................................................................................20 
4.7.1. 
Adverse Events and Serious Adverse Events .............................................................20 
4.7.2. 
Special Safety Variables of Interest ............................................................................21 
4.7.2.1. 
Adverse Events of Special Interest .............................................................................21 
4.7.2.2. 
Dose Limiting Toxicity ...............................................................................................22 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 4 of 37 
4.7.3. 
Laboratory Safety Variables .......................................................................................23 
4.8. 
Pharmacokinetic Variables .........................................................................................23 
4.9. 
Anti Drug Antibody Variables(ADA) ........................................................................23 
4.10. 
Variables for Correlative Studies................................................................................23 
5. 
STATISTICAL METHODS .......................................................................................24 
5.1. 
Demographics and Baseline Characteristics ...............................................................24 
5.2. 
Medical History ..........................................................................................................24 
5.3. 
Protocol Deviations ....................................................................................................25 
5.4. 
Prior/Concomitant Medications and Procedures ........................................................25 
5.5. 
Patient Disposition ......................................................................................................25 
5.6. 
Extent of Study Treatment Exposure and Compliance ...............................................26 
5.6.1. 
Measurement of Compliance ......................................................................................26 
5.6.2. 
Exposure to Investigational Product ...........................................................................26 
5.7. 
Analyses of Efficacy Variables ..................................................................................26 
5.7.1. 
Analysis of Primary Efficacy Variable(s) ...................................................................27 
5.7.2. 
Analysis of Secondary Efficacy Variables .................................................................27 
5.8. 
Analysis of Safety Data ..............................................................................................27 
5.8.1. 
RP2D...........................................................................................................................27 
5.8.2. 
Adverse Events ...........................................................................................................27 
5.8.3. 
Analysis of Adverse Events of Special Interest ..........................................................29 
5.8.4. 
Clinical Laboratory Measurements.............................................................................29 
5.9. 
Analysis of Pharmacokinetic and Antibody Data .......................................................29 
5.9.1. 
Analysis of the Pharmacokinetic Variables ................................................................29 
5.9.2. 
Analysis of ADA Data ................................................................................................30 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................31 
5.10.1. 
Immunogenicity and Exposure ...................................................................................31 
5.10.2. 
Immunogenicity and Safety and Efficacy ...................................................................31 
5.10.3. 
Analysis of Exploratory Biomarker Data ...................................................................31 
6. 
DATA CONVENTIONS ............................................................................................33 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................33 
6.2. 
Data Handling Convention for Efficacy Variables .....................................................33 
6.3. 
Data Handling Convention for Missing Data .............................................................33 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 5 of 37 
6.4. 
Unscheduled Assessments ..........................................................................................34 
7. 
SOFTWARE ...............................................................................................................36 
8. 
REFERENCES ...........................................................................................................37 
 
LIST OF TABLES 
Table 1: 
Patient Cohorts in Phase 1 ............................................................................................8 
Table 2: 
Patient Cohorts in the Efficacy Phase ...........................................................................8 
 
 
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 6 of 37 
ABBREVIATIONS AND DEFINITIONS 
ADA  
Anti-drug antibody 
AE 
 
Adverse event 
AESI  
Adverse event of special interest 
BMI 
 
Body mass index 
BOR  
Best overall response 
CNS  
Central nervous system 
CR 
 
Complete response 
CRF 
 
Case report form (electronic or paper) 
CSR 
 
Clinical Study Report 
CT 
 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DIPG  
Diffuse intrinsic pontine glioma 
DLT 
 
Dose-limiting toxicity 
DOR  
Duration of response 
ECOG  
Eastern Cooperative Oncology Group 
FAS 
 
Full analysis set 
FDA  
Food and drug administration 
HGG  
High-grade glioma 
ICF 
 
Informed consent form 
ICH 
 
International Council for Harmonization 
irRC 
 
Immune-related response criteria 
imAE  
Immune-mediated adverse event 
iRANO 
Immunotherapy Response Assessment in Neuro-Oncology 
IRR 
 
Infusion related reaction 
IV 
 
Intravenous 
IWRS  
Interactive web response system 
KM 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
 
Magnetic resonance imaging 
MTD  
Maximum tolerated dose 
NE 
 
Not evaluable 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 7 of 37 
ORR  
Objective response rate 
OS 
 
Overall survival 
PBMC  
Peripheral blood mononucleated cell 
PDDD  
Protocol deviation definition document 
PD-1  
Programmed death-1 (receptor) 
PD-L1  
Programmed death ligand 1 
PD-L2  
Programmed death ligand 2 
PET 
 
Positron-emission tomography 
PFS 
 
Progression-free survival 
PK 
 
Pharmacokinetic 
PR 
 
Partial response 
PT 
 
Preferred term 
QOL  
Quality of life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D  
Recommended phase 2 dose 
SAE 
 
Serious adverse event 
SAF 
 
Safety analysis set 
SAP 
 
Statistical analysis plan 
SAS 
 
Statistical Analysis Systems (software) 
SD 
 
Stable disease 
SOC  
System organ class 
TEAE  
Treatment-emergent adverse event 
  
 
 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 8 of 37 
1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the analysis of data for R2810-ONC-1690 study for a clinical study report. 
This plan may be revised during the study to accommodate protocol amendments and/or to make 
changes to adapt to unexpected issues in study execution and/or data that affect planned 
analyses. These revisions will be based on review of the study and data, and a final plan will be 
issued prior to data lock. 
R2810-ONC-1690 is a multicenter, phase 1 and early efficacy study conducted through the 
Pacific Pediatric Neuro-oncology Consortium (PNOC).  Phase 1 will consist of 4 cohorts (Cohort 
A through Cohort D) as specified in Table 1 below. 
Table 1: 
Patient Cohorts in Phase 1 
Recurrent or refractory solid tumors 
Recurrent or refractory CNS tumors 
Cohort A: Age 0 to <12 years 
Cohort B: Age 12 to <18 years 
Cohort C: Age 0 to <12 years 
Cohort D: Age 12 to <18 years 
The Efficacy Phase will consist of 6 cohorts (Cohort E through Cohort J) of pediatric patients 
with either newly diagnosed DIPG, newly diagnosed HGG, or recurrent HGG, and defined 
according to patient age as specified in Table 2 below.   
Table 2: 
Patient Cohorts in the Efficacy Phase 
Newly diagnosed DIPG 
Newly diagnosed HGG 
Recurrent HGG 
Cohort E: Age 3 to <12 years 
Cohort F: Age 12 to 25 years 
Cohort G: Age 3 to <12 years 
Cohort H: Age 12 to 25 years 
Cohort I: Age 3 to <12 years 
Cohort J: Age 12 to 25 years 
In this phase of the study, REGN2810 will be given in combination with radiation therapy: 
REGN2810 + conventionally fractionated radiation) and REGN2810 + hypofractionated radiation.  
1.1. 
Study Objectives  
1.1.1. 
Primary Objectives 
Phase 1 
• To confirm the safety and anticipated recommended phase 2 dose (RP2D) of 
REGN2810 (cemiplimab) for children with recurrent or refractory solid or CNS 
tumors 
• To characterize the pharmacokinetics (PK) of REGN2810 given in children with 
recurrent or refractory solid or CNS tumors 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 9 of 37 
Efficacy Phase 
• To confirm the safety and anticipated RP2D of REGN2810 to be given concomitantly 
with conventionally fractionated or hypofractionated radiation among patients with 
newly diagnosed diffuse intrinsic pontine glioma (DIPG) 
• To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed high-grade glioma (HGG) 
• To confirm the safety and anticipated RP2D of REGN2810 given concomitantly with 
re-irradiation in patients with recurrent HGG  
• To assess PK of REGN2810 in pediatric patients with newly diagnosed DIPG, newly 
diagnosed HGG, or recurrent HGG when given in combination with radiation 
• To assess anti-tumor activity of REGN2810 in combination with radiation in 
improving overall survival at 12 months (OS12) among patients with newly 
diagnosed DIPG 
• To assess anti-tumor activity of REGN2810 in combination with radiation in 
improving progression-free survival at 12 months (PFS12) among patients with newly 
diagnosed HGG 
• To assess anti-tumor activity of REGN2810 in combination with radiation in 
improving overall survival at OS12 among patients with recurrent HGG  
1.1.2. 
Secondary Objectives 
Phase 1 
• To assess anti-tumor activity of REGN2810 monotherapy as identified by objective 
response in children with recurrent or refractory solid or CNS tumors 
• To assess immunogenicity 
Efficacy Phase 
• To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed DIPG 
• To assess safety and tolerability profiles of REGN2810 given in combination with 
conventionally fractionated or hypofractionated radiation among patients with newly 
diagnosed HGG 
• To assess safety and tolerability profiles of REGN2810 given in combination with 
re-irradiation among patients with recurrent HGG 
• To assess immunogenicity 
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 10 of 37 
1.1.3. 
Exploratory Objectives 
Phase 1 and Efficacy Phase 
• To assess Quality of Life (QoL) in patients with solid or CNS tumors treated with 
REGN2810 as monotherapy or given concurrently with radiation followed by 
adjuvant monotherapy  
• To investigate the biologic activity of REGN2810 and potentially identify biomarkers 
predictive of drug response using DNA, serum, plasma, and tumor biopsy samples 
1.1.4. 
Modifications from the Statistical Section in the Final Protocol 
Revision to this plan may be made if deemed necessary to the furtherance of the trial objectives. 
Such revision, if necessary, will be completed prior to the final data base lock.        
1.1.5. 
Modifications from the Approved Statistical Analysis Plan 
This is the first version of the SAP, based on the study protocol PNOC 013/ R2810-ONC-1690 
Amendment 3.  
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Regeneron Pharmaceuticals, Inc. 
Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 11 of 37 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a multi-center safety and efficacy study conducted through the PNOC.  This study will 
consist of Phase 1 and Efficacy Phase conducted in parallel.  
Phase 1  
A 3+3 design will be used to confirm the anticipated RP2Ds of cemiplimab as monotherapy in 
patients age 0 to <18 years with recurrent/refractory solid or recurrent/refractory CNS tumors in 
Phase 1 of this study. The recurrent/refractory solid tumor and recurrent/refractory CNS tumor 
cohorts will each be sub-grouped by age (0 to <12 years and 12 to <18 years), due to concern 
that exposure may vary between lower body weight younger and higher body weight older 
patients. Based on the 3+3 design, for each age group of a tumor cohort, a minimum of 3 DLT 
evaluable patients who have completed the 28-day DLT period at a dose level will be required to 
derive DLT at that dose level. Refer the protocol for dose escalation/de-escalation rules.  
Efficacy Phase  
The Efficacy Phase will enroll patients aged 3 to 25 years with either newly-diagnosed DIPG, 
newly-diagnosed HGG, or recurrent HGG. Each of the three disease cohorts will be sub-grouped 
by age (3 to <12 years, 12 to 25 years). In this phase of study, cemiplimab will be given in 
combination with radiation therapy and continue cemiplimab monotherapy once radiation 
therapy is complete. All the patients in the recurrent HGG cohort will undergo re-irradiation 
(referred to as “rRT” hereinafter). Within each age group of newly diagnosed DIPG cohort and 
newly diagnosed HGG cohort, patients will be randomized 1:1 to either conventionally 
fractionated radiation (referred to as “RT” hereinafter) or hypofractionated radiation (referred to 
as “HfRT” hereinafter). There will be 5 treatment arms in the Efficacy Phase as follows:   
Simon’s two-stage design will be utilized in this phase.  Up to 20 patients will be enrolled for 
each treatment arm at two stages. Enrollment and randomization within the younger age groups 
of 3 to <12 years occur once the RP2D for this age group from Phase 1 is confirmed. Enrollment 
and randomization within the age groups of 12 to <25 years will take place immediately in 
parallel with the Phase 1 since this age cohort will be enrolled at the anticipated RP2D (DL1).  
To assess safety of cemiplimab combined with radiation, a 3+3 safety run-in will be initiated in 
this phase to confirm the RP2D of cemiplimab in combination with radiation for each age group 
of each disease cohort and radiation arm. The DLT period for the Efficacy Phase includes the 
length of radiation therapy (details are given in Section 2.3.1) plus 4 weeks after completion of 
radiation therapy. The same dose decision rules for Phase 1 patients will be followed.  Once 
safety of the combination therapy is confirmed in 3-6 DLT-evaluable patients in each age group, 
the newly diagnosed DIPG cohort, newly diagnosed HGG cohort and recurrent HGG cohort will 
be fully opened for enrollment. Once PK, tolerability, and preliminary efficacy of the 
combination of cemiplimab and radiation are established in patients >3 years of age, patients ≤3 
years of age will also be enrolled, if appropriate, in the Efficacy Phase at the determined RP2D 
for their age group.  
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Protocol: PNOC 013/ R2810-ONC-1690 
Statistical Analysis Plan 
Date: June 19, 2023 
 
REGENERON CONFIDENTIAL 
Page 12 of 37 
2.2. 
Sample Size and Power Considerations 
In Phase 1, a minimum of 30 patients will be enrolled. This will include at least 6 patients in the 
age 0 to <12 recurrent/refractory tumor cohort (Cohort A), at least 3 patients in the age 12 to <18 
recurrent/refractory tumor cohort (Cohort B), at least 6 patients in the age 0 to <12 CNS tumor 
cohort (Cohort C), and at least 3 patients in the age 12 to <18 CNS tumor cohort (Cohort D), as 
well as 6 additional patients (at the corresponding identified RP2D) in each of the solid tumor 
cohorts. 
In the Efficacy Phase, a minimum of 30 patients will initially be enrolled as part of the 3+3 
design to assess the safety of the anticipated RP2D of REGN2810 in combination with either 
conventional or hypofractionated radiation. This will include at least 6 patients in the age 3 to 
<12 newly diagnosed DIPG (Cohort E; 3 in each treatment arm), at least 6 patients in the age 12 
to 25 newly diagnosed DIPG cohort (Cohort F; 3 in each treatment arm), at least 6 patients in the 
age 3 to <12 newly diagnosed HGG cohort (Cohort G; 3 in each treatment arm), at least 6 
patients in the age 12 to 25 newly diagnosed HGG cohort (Cohort H; 3 in each treatment arm), at 
least 3 patients in the age 3 to <12 recurrent HGG cohort (Cohort I), and at least 3 patients in the 
age 12 to 25 recurrent HGG cohort (Cohort J). 
Once the RP2D of REGN2810 is confirmed for a given cohort (and treatment arm, where 
applicable), additional patients will be enrolled as part of expansion. During expansion, the total 
number of patients enrolled will be based on treatment regimen, irrespective of patient age or 
cohort. Additional patients will be enrolled until at least 20 evaluable patients are reached, based 
on a Simon two-stage design, in each of the following pooled treatment arms: 
• Newly diagnosed DIPG with conventionally fractionated radiation + REGN2810 
(DIPG Arm 1) 
• Newly diagnosed DIPG with hypofractionated radiation + REGN2810 (DIPG Arm 2) 
• Newly diagnosed HGG with conventionally fractionated radiation + REGN2810 
(Newly Diagnosed HGG Arm 1) 
• Newly diagnosed HGG with hypofractionated radiation + REGN2810 (Newly 
Diagnosed HGG Arm 2) 
• Recurrent HGG with reirradiation + REGN2810 (Recurrent HGG Arm 1) 
Sample size justification and accrual rate 
The most recent Children’s Oncology Group study that treated children with newly diagnosed 
DIPG with a combination of radiation therapy and temozolomide resulted in a mean OS12 rate 
of 40% (Standard Deviation +/-6.5%). We will apply these findings as historical controls for our 
DIPG treatment arms. The null hypothesis for each DIPG treatment arm is an OS12 of 40%, with 
a target alternative hypothesis of 70% OS12. Note that although DIPG cohorts will be 
randomized equally between arms 1 and 2, evaluations will be done within each arm as this trial 
is not powered for comparisons between arms.  
Within each DIPG radiation arm, 20 eligible and evaluable DIPG patients will be randomized in 
order to achieve at least 80% power to detect the above absolute increase of 30% in OS12 within 
an arm using a one-sided 0.05 level exact binomial test. This phase of the study will follow a 
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two-stage design, where initially 7 patients are entered at the first stage in each arm. If no more 
than 3 deaths occur within 12 months in the initial cohort, the study will move to the second 
stage. In each arm, an additional 13 eligible patients will be randomized. If at the first stage, 4 or 
more patients die within 12 months in an arm, that arm will be temporarily closed and a detailed 
review performed. The study team together Regeneron and its delegates will determine if accrual 
will continue or enrollment be stopped in this arm. The arm will be considered a success (reject 
the associated null hypothesis) if at least 12 of the 20 patients survive beyond 12 months. There 
is a 71% chance of stopping early under the null hypothesis under this two-stage design. To 
allow for ineligibility, we anticipate there may be an additional 1-2 patients enrolled in this 
cohort overall to achieve the target number of eligible and evaluable patients. 
It is expected that the study will not pause after the first stage accrual goals are met for each 
cohort, but that the first stage patients will be monitored with respect to the first stage futility rule 
above. However, given the requirement of 12 months of follow-up to determine the OS12 
endpoint for each patient, should the accrual to the first stage be rapid and there is insufficient 
follow-up in the first stage cohort to obtain an OS signal before continuing to accrue to the 
second stage, consideration will be given to pausing accrual in order to gather information at the 
first stage. Furthermore, if before expansion to the second stage there is clear evidence for a need 
to pause accrual (eg, 2 or 3 deaths observed in the first cohort) then the study will halt accrual 
until it can be confirmed that it is warranted to move to the second stage. 
The most recent Children’s Oncology Group study that treated children with newly diagnosed 
HGG with a combination of radiation therapy, lomustine, and temozolomide resulted in a mean 
PFS12 rate of 49%. We will apply these findings as historical controls for our newly diagnosed 
HGG treatment arms. The null hypothesis for each arm is a PFS12 of 50% with a target 
alternative hypothesis of 80% PFS12. Note that although HGG cohorts will be randomized 
equally between arms 1 and 2, evaluations will be done within each arm as this trial is not 
powered for comparisons between arms.  
Within each newly diagnosed HGG treatment arm, 20 eligible and evaluable newly diagnosed 
HGG patients at the RP2D level will be randomized in order to maintain 80% power to detect the 
alternative hypothesis using a one-sided 0.05 level exact binomial test. This phase of the study 
will also follow a two-stage design where initially 7 patients are entered at the first stage. If no 
more than 2 patients experience disease progression or death within 12 months in the initial 
cohort, the study will move to the second stage and an additional 13 patients will be entered. If at 
the first stage, 3 or more patients experience disease progression or death within 12 months, the 
arm will be temporarily closed and a detailed review performed. The study team together with 
Regeneron and its delegates will determine if accrual will continue or enrollment be stopped in 
this arm. The arm will be considered a success (reject the associated null hypothesis) if at least 
14 of the 20 patients do not experience disease progression or death at or beyond 12 months. 
There is a 77% chance of stopping early under the null hypothesis under this two-stage design. 
To allow for ineligibility, there may be an additional 1-2 patients enrolled in this cohort overall 
to achieve the target eligible and evaluable number of patients.  
Based on cumulative outcome data from a 20-year systematic review and meta-analysis69, the 
cumulative median overall survival over the last decade was 8.5 months for recurrent pediatric 
HGG, which translates into OS12 of 37.6% under exponential distribution. We assume the OS12 
of 40% as null hypothesis and OS12 of 70% as alternative hypothesis. The target sample size for 
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all recurrent HGG patients is 20 eligible and evaluable recurrent HGG patients at the RP2D level 
in order to maintain 80% power to detect the alternative hypothesis using a one-sided 0.05 level 
exact binomial test. This phase of the study will also follow a two-stage design where initially 
7 patients are entered at the first stage. If no more than 3 deaths occur within 12 months in the 
initial cohort, the study will move to the second stage and an additional 13 patients will be 
entered. If at the first stage, 4 or more patients die within 12 months, the arm will be temporarily 
closed and detailed review performed. The study team together with Regeneron and its delegates 
will determine if accrual will continue or enrollment be stopped in this arm. The arm will be 
considered a success (reject the associated null hypothesis) if at least 12 of the 20 patients 
survive beyond 12 months. There is a 71% chance of stopping early under the null hypothesis 
under this two-stage design. To allow for ineligibility, there may be an additional 1-2 patients 
enrolled in this cohort overall to achieve the target number of eligible and evaluable patients. 
It is expected that the study will not pause after the first stage accrual goals are met for these 
cohorts, but that the first stage patients will be monitored with respect to the first stage futility 
rule above. However, given the requirement of 12 months of follow-up to determine the OS12 or 
PFS12 endpoint for each patient, should the accrual to the first stage be rapid and there is 
insufficient follow-up in the first stage cohort to obtain an OS or PFS signal before continuing to 
accrue to the second stage, consideration will be given to pausing accrual in order to gather 
information at the first stage. Furthermore, if before expansion to the second stage there is clear 
evidence for a need to pause accrual (eg, 1 or 2 deaths observed in the first cohort) then the study 
will halt accrual until it can be confirmed that it is warranted to move to the second stage. 
In the event that interim pharmacokinetic analysis indicates serum concentrations below goal 
trough exposure for any cohort or age group, study investigators along with study sponsors will 
determine appropriateness of additional dose escalation or expansion cohorts in Phase 1 or the 
Efficacy Phase.  
• There are also two arms of nEach cohort in the Efficacy Phase will aso enroll 
minimum number of children in certain age groups defined as follows: 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998) the following population of analysis will be 
used for all statistical analysis.  
3.1. 
The Dose Limiting Toxicity Set  
The DLT analysis set includes  
• Phase 1: All DLT-evaluable patients treated with monotherapy cemiplimab1 
• Efficacy Phase: The first 6 DLT-evaluable patients of each disease cohort by age 
group who are treated with cemiplimab + radiotherapy during 3+3 safety run-in 
DLT evaluable patients are defined as those patients who have completed the corresponding 
DLT observation period and those patients who discontinued early due to the development of a 
DLT. This population will be used for the assessment of DLTs. 
3.2. 
The Full Analysis Set (FAS) 
In Phase 1, the FAS includes all enrolled patients who have passed screening and are deemed to 
be eligible for this study.  
In Efficacy Phase, the FAS includes two parts:  
• All newly diagnosed DIPG and newly diagnosed HGG patients to whom the radiation 
treatment has been assigned by the IWRS at randomization. This is the intent to treat 
(ITT) population for these two disease cohorts. Per ITT principle, these patients will 
be analyzed according to the treatment they have been assigned to during the 
randomization.  
• All recurrent HGG patients who have pass screening and are deemed to be eligible for 
this study.    
FAS will be used for all baseline, demographic, and efficacy endpoints.    
3.3. 
The Safety Analysis Set (SAF) 
The SAF includes all enrolled patients who have received any study treatment (at least one dose 
of any component of study treatment in a combination therapy) in each study phase. Patients will 
be analyzed according to the study treatment received (as treated). Treatment administration and 
all clinical safety variables will be analyzed using the SAF.  
3.4. 
The Pharmacokinetics Analysis Set (PKS) 
The pharmacokinetic analysis set (PKS) includes all treated patients who received any amount of 
study drug cemiplimab (safety analysis set) and has at least one non-missing cemiplimab 
concentration following the first dose of cemiplimab up to the end of the study.  
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3.5. 
The Immunogenicity Analysis Set 
The Anti-drug Antibody (ADA) analysis set includes all treated patients who received any 
amount of study drug cemiplimab and had at least 1 non-missing ADA result following the first 
dose of cemiplimab. The ADA analysis set is based on the actual treatment received.  
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4. 
ANALYSIS VARIABLES 
4.1. 
Disposition of Patients  
The following summaries regarding patient enrollment, randomization, discontinuation and 
completion will be provided to assess the patient disposition: 
• Summary of analysis populations, patients screened.  
• Number of patients randomized in Efficacy Phase 
• Number of patients discontinued treatment and the reasons for treatment 
discontinuation 
• Number of patients discontinued study participation and the reasons for study 
discontinuation.  
4.2. 
Demographic and Baseline Characteristics 
Patient demographic variables include: 
• Age at screening in years (quantitative and qualitative variable:  Phase 1: 0 to <12, 12 
to <18 years; Efficacy Phase: 3 to 12 years, 12 to 25 years) 
• Sex (Male, Female)  
• Race (American Indian/Alaskan Native, Asian, Black/African American, Native 
Hawaiian/Other Pacific Islander, White, and Other) 
• Ethnicity (Hispanic/Latino, Not Hispanic/Latino, Not reported) 
• Baseline weight (kg) 
• Baseline height (cm) 
• Performance status by Karnofsky score (quantitative variable) 
• Performance status by Lansky score (quantitative variable)  
Baseline disease characteristics variables include: 
• Tumor type (Solid, CNS)  
• Primary diagnosis 
• Primary site of tumor   
• Histological/cytologic type of tumor 
• WHO grade at initial diagnosis and screening 
• TNM stage at initial diagnosis and screening 
• Time from initial diagnosis to first dose/randomization in months 
• Time from most recent relapse/recurrence to first dose/randomization in months 
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4.3. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class (SOC) according to the latest available version of Medical Dictionary for Regulatory 
Activities (MedDRA®). 
4.4. 
Pre-Treatment / Concomitant Medication 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded to the ATC level 2 (therapeutic main group) and ATC 
level 4 (chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD). Patients will be counted once in all ATC categories linked to the 
medication. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the study drug, particularly, prior cancer related surgery, prior cancer related 
radiotherapy, and prior cancer related systemic therapy: chemotherapy, targeted therapy, 
immunotherapy and others.  
Concomitant medications/procedures: any treatment administered from the time of informed 
consent until 90 days after the last study treatment will be considered concomitant treatment. 
This includes medications and other therapies for which administration started before the study 
and are ongoing during the study, as well as any therapies started in the follow-up period to treat 
a study drug-related AE. All concomitant treatments will be recorded in the study case report 
form (CRF) with the generic name, dose, dose unit, frequency, indication, and start/stop date, 
appropriate. 
4.5. 
Treatment Exposure 
Cemiplimab 
Duration of treatment exposure to cemiplimab (in weeks) is calculated as the minimum of  
• [date of last dose – date of first dose + 14] / 7  
The actual dose intensity = total dose received / duration of treatment exposure (week)  
The relative dose intensity = actual dose intensity / planned dose intensity, where planned dose 
intensity (in week) = planned dose / 2.  
Duration of exposure to radiotherapy (RT, HfRT, rRT) will not be calculated for the combination 
therapy in Efficacy Phase. 
4.6. 
Efficacy Variable 
4.6.1. 
Primary Efficacy Variable(s) (Efficacy Phase Only) 
OS is defined as the time from randomization (for newly diagnosed DIPG patients) or time from 
the first dose of study treatment (for recurrent HGG patients) to the date of death due to any 
cause. OS12 is defined as the K-M estimated probability of patients who survived at 12 months 
after randomization (for newly diagnosed DIPG patients) or after the first dose of study treatment 
(for recurrent HGG patients). All deaths due to any cause occurring on or before cut-off date in 
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the FAS will be used in the OS analysis. A patient who has not died or is lost to follow up at the 
time of analysis cut-off date will be censored at the last date that patient is documented to be 
alive.  
PFS is defined for newly diagnosed HGG patients as the time from randomization to the date of 
the first documented tumor progression, as determined per Response Assessment in 
Neuro-Oncology (RANO) criteria with integration of Immunotherapy Response Assessment in 
Neuro-Oncology (iRANO) criteria, or death due to any cause, whichever is earlier. In PFS 
analysis, patients will be censored according to rules listed below: 
• Patients without a documented tumor progression or death will be censored on the 
date of their last evaluable tumor assessment. 
• Patients without a documented tumor progression or death before initiation of another 
anti-tumor therapy will be censored on the date of their last evaluable tumor 
assessment prior to or on the date of new anti-tumor therapy. 
• Patients who withdraw consent before taking any study treatment, and as a 
consequence have no post-baseline tumor assessment, will be censored at the date of 
randomization 
• Patients without any evaluable tumor assessments after randomization and did not die 
will be censored on the date of randomization.  
PFS12 is defined as the K-M estimated probability of patients who are progression-free at 
12 months after randomization.  
For OS variables, the time to event (day) is defined as the date of event/censor - the date of 
randomization + 1. For PFS variables, the time to event (day) is defined as the date of 
event/censor - the date of first study treatment +1.  
4.6.2. 
Secondary Efficacy Variables 
The secondary efficacy variables in Phase 1 includes the objective response rate (ORR), best 
overall response (BOR), duration of response (DOR).   
ORR is defined as the percentage of patients who have a confirmed complete response (CR) or 
partial response (PR), as determined per standard criteria between the date of first study 
treatment and the date of the first objectively documented progression or the date of receiving 
another anti-cancer systemic therapy, whichever comes first. 
BOR is defined as the best overall response, as determined per standard criteria between the date 
of first study treatment and the date of the first objectively documented progression or the date of 
receiving another anti-cancer systemic therapy, whichever comes first. For solid tumor, RECIST 
1.1 will be used as the standard response criteria while also taking into consideration of immune-
related RECIST (irRECIST) criteria. For CNS tumor, RANO with the integration of iRANO will 
be used as the standard response criteria.  
• Best overall response of CR or PR needs to be confirmed by subsequent evaluations 
of overall response of CR or PR at time points at least 4 weeks apart.  
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• Best overall response of SD must have met the response SD criteria at least once 
>=39 days after start of study treatment.  
• For solid tumor, best overall response of early PD does not require confirmation using 
RECIST 1.1.  For CNS tumor, best overall response of PD should be confirmed on a 
3-month follow-up scan to assess for true progressive disease versus pseudo 
progression as long as the patient is NOT experiencing significant neurological 
decline (defined as CTCAE grade 3 or higher) 
• Best overall response for patients who do not have any post-baseline tumor 
assessment will not be evaluable (NE). 
Duration of overall response (DOR) is defined for a patient whose BOR is CR or PR as the time 
from the time the criteria are met for a confirmed CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented, or death, whichever 
occurs first. The same censoring rules as PFS will be applied to DOR.   
4.7. 
Safety Variables 
Beside the evaluations used to address the primary endpoint of the DLT evaluation period (the 
incidence of DLTs), safety endpoints include deaths due to adverse events, serious adverse 
events and adverse events, treatment-emergent adverse events, immune-related adverse events, 
and other events of special interest, laboratory evaluations, electrocardiograms (ECGs), and 
reasons off treatment. 
4.7.1. 
Adverse Events and Serious Adverse Events 
An Adverse Event (AE) is any untoward medical occurrence in a patient administered a study 
drug and which does not necessarily have to have a causal relationship with the study drug.  A 
Serious Adverse Event (SAE) is an AE that is classified as “serious” according to the criteria 
specified in the protocol. 
The investigator (or designee) will seek information on AEs at each patient contact. All AEs 
after initiation of study treatment and until 90 days after the last dose of study drug, or until the 
patient commences another anticancer systemic therapy, whichever is earlier, will be recorded on 
AE eCRF.  After signing the informed consent but prior to initiation of study treatment, only the 
SAE and Non-SAEs associated with a protocol-mandated intervention (e.g., AEs related to an 
invasive procedure such as a biopsy) will be reported on the AE eCRF. Additionally, any SAE or 
other AE of concern that the investigator believes may be related to study treatment and that 
occurs later than 90 days after last study treatment will be reported. Information for any non-
SAE that starts during the treatment period or within 90 days after last study treatment will be 
collected from the time of the event until resolution of the event, or until the patient’s last study 
visit, whichever comes first.  
The relationship of AEs to study drug will be assessed by the investigator and be determined 
based on protocol specified criteria. 
All adverse events are to be coded to a “Preferred Term (PT)” and associated primary “System 
Organ Class (SOC)” according to the Medical Dictionary for Regulatory Activities (MedDRA, 
the Version 26.0 or the latest current available version). The revised National Cancer Institute 
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(NCI) CTCAE version 4.0 will be utilized for adverse events grading of severity.  When specific 
AEs are not listed in the CTCAE they will be graded by the Investigator according to the 
following grades and definitions:  
1. Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2. Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)*.  
3. Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL **.  
4. Grade 4:  Life-threatening consequences; urgent intervention indicated. 
5. Grade 5:  Death related to AE 
* Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc. 
** Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.  
Laboratory results, vital signs, or ECG abnormalities are to be recorded as AEs if they are 
medically relevant: symptomatic, requiring corrective therapy, leading to treatment 
discontinuation and/or fulfilling a seriousness criterion.  
4.7.2. 
Special Safety Variables of Interest 
4.7.2.1. 
Adverse Events of Special Interest 
An AE of special interest (AESI) are AEs (serious or non-serious) required to be monitored, 
documented, and managed in a pre-specified manner as described in the protocol. All AESIs 
must be reported within 24 hours of identification using the same reporting process as for SAE 
reporting. In this study, AESI are listed below (as provided in the protocol), along with each 
AESI detailed definition: 
• Any AE that meets DLT criteria 
• Grade 2 or greater infusion-related reactions 
• Grade 2 or greater allergic/hypersensitivity reactions 
• Grade 3 or greater immune-related AE (imAE) (or Grade 2 or greater Uveitis).  
Note: An imAE can occur shortly after the first dose, several months after the last dose of 
treatment, or any time in-between. All AEs of unknown etiology associated with drug exposure 
should be evaluated to determine possible immune etiology. If an imAE is suspected, efforts 
should be made to rule out neoplastic, infectious, metabolic, toxin or other etiologic causes prior 
to labeling an AE as an imAE. 
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4.7.2.2. 
Dose Limiting Toxicity 
Dose-limiting toxicities (DLTs) are generally defined as any of the following study drug related 
toxicities observed during the DLT evaluation period (only for cohorts that include a DLT 
evaluation period).  
For all Phase 1 and Efficacy Phase patients: 
Non-Hematologic Dose-Limiting Toxicity: 
• Any Grade ≥3 non-hematologic toxicity considered related to cemiplimab. 
• Any cemiplimab-related AE during the first cycle of therapy that leads to a dose 
reduction or results in delay of treatment ≥7 days or which results in the permanent 
cessation of therapy will be considered dose limiting. 
Hematologic Dose-Limiting Toxicity:  
• Any grade 4 hematologic toxicity with the exception of lymphopenia and anemia 
considered related to cemiplimab 
• Grade 3 neutropenia with fever considered related to cemiplimab 
• Grade 3 thrombocytopenia considered related to cemiplimab 
Immune-related Dose-Limiting Toxicity:  
• Grade 3 immune-related AE considered related to cemiplimab. Examples include, but 
are not limited to, neurological toxicities, uveitis, endocrine toxicity, and colitis.  
For Efficacy Phase patients only: 
Interruption of Planned Radiation: 
• Newly diagnosed DIPG and HGG Arm 1 (conventionally fractionated radiation): 5 
consecutive fractions or 10 fractions total due to cemiplimab attributable toxicity (and 
not due to technical issues) 
• Newly diagnosed DIPG and HGG Arm 2 (hypofractionated radiation): 2 consecutive 
fractions or 4 factions total due to REGN2810 attributable toxicity (and not due to 
technical issues) 
• Recurrent HGG with reirradiation: 2 consecutive fractions or 3 fractions total due to 
REGN2810 attributable toxicity (and not due to technical issues)  
The frequency, time to onset, and severity of toxicities, as well as the success of standard 
medical management and dosing interruptions/delays, will be analyzed to determine if a given 
toxicity should be considered a DLT for dose escalation purposes.  
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4.7.3. 
Laboratory Safety Variables 
The clinical laboratory data consists of hematology, serum chemistry, serum or urine pregnancy 
test, and other. Clinical laboratory values will be converted to standard international (SI) units 
and grouped by function in summary tables. Conventional unit may be provided. Functions are 
defined as follows: 
• Complete blood count (CBC) with differential and platelet count 
• Serum chemistry, including alkaline phosphatase, ALT, AST, total bilirubin, calcium, 
phosphorus, blood urea nitrogen (BUN/urea), creatinie, total protein, albumin, 
glucose, potassium, sodium, chloride, bicarbonate, and magnesium 
• Urinalysis including glucose, pH, ketones, blood, specific gravity, spot urine protein 
• Serum or urine pregnancy test for females of childbrearing age 
• Serum thyroid stimulating hormone (TSH) 
• Serum free Thyroxine T4 
• Serum amylase 
• Serum lipase 
• Serum C-reactive protein (CRP) 
4.8. 
Pharmacokinetic Variables  
Pharmacokinetic variables are cemiplimab concentrations in serum over time.   
4.9. 
Anti Drug Antibody Variables(ADA)  
The immunogenicity variables include ADA status and titer at nominal sampling time/visit.  
4.10. 
Variables for Correlative Studies 
For both Phase 1 and Efficacy Phase, correlative variables include the summary of PD-L1 
expression level (%Tumor cell, %TC), and efficacy (OS, ORR and DOR) in subsets according to 
PD-L1 expression (>=1%TC, <1%TC). 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, standard deviation, minimum, and maximum.  In 
addition, 25th percentile and 75th percentile will be provided. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category.  
The denominator will be determined by the analysis population used for the summary.  
For time-to-event variables, median time-to-event (and the survival rate at a fixed time point) 
and its 95% confidence intervals will be summarized by the Kaplan-Meier method. 
Summary analyses will be presented as follows unless otherwise specified:  
• For study population  
− For Phase 1 by solid and CNS tumors, 
− For efficacy phase by newly diagnosed DIPG (ndDIPG) crossed over with 
conventional radiation therapy (CRT) and hypofractionated radiation therapy 
(HYRT), newly diagnosed HGG (ndHGG) by CRT and HYRT, recurrent HGG 
(rHGG), and  
− Overall. 
• For efficacy:  
− Phase 1: by solid and CNS tumors on ORR, 
− Efficacy Phase: by ndDIPG crossed over with CRT and HYRT, and by rHGG; by 
ndHGG crossed over with CRT and HYRT, for other efficacy parameters 
• For safety: the same as the study population  
• PK: by Cohort (see Table 1 and Table 2) and by dose, and overall 
• ADA: by Cohort (see Table 1 and Table 2) and by dose, and overall 
5.1. 
Demographics and Baseline Characteristics 
Patient demographics and baseline characteristics variables listed in Section 4.2 will be listed and 
summarized by cohort and/or treatment arm based on the study phase specific FAS population.  
Assessments made before the first dose of study treatment will be used as baseline measurements 
for the purposes of statistical analysis and reporting unless otherwise specified. 
5.2. 
Medical History 
Medical history will be listed and summarized based on the FAS population.  Listing of medical 
history will include SOC, PT, investigator verbatim, start date, and end date. The summaries will 
be presented by primary system organ class and preferred term in descending of frequency of 
SOC followed by PT. 
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5.3. 
Protocol Deviations 
Protocol deviations will be defined in a separate protocol deviation definition document 
(PDDD).  Listing of all patients with protocol deviations and the description of deviation will be 
provided.  The major protocol deviation, such as violation of inclusion/exclusion criteria, post-
enrollment deviations which may impact assessment of efficacy, or safety endpoints will be 
determined before database lock and be summarized for Phase 1 and Efficacy Phase, 
respectively.   
5.4. 
Prior/Concomitant Medications and Procedures 
Prior medications and procedures will be summarized and listed based on the FAS. Listing of 
prior cancer related medications will include generic name and ATC Levels 2 and 4, indication, 
start and end dates.  Listing of prior cancer related radiotherapy will include type of radiation 
therapy, site of radiation, intent of treatment, start and end dates, and total dose. Listing of prior 
cancer related surgery will include type of procedure, date of surgery, and surgery location. The 
number and percentage of patients who received any prior cancer related medications, prior 
cancer related radiotherapy, or prior cancer related surgery will be summarized. 
Concomitant medications and procedures will be listed and summarized by cohort based on the 
SAF. Listing of concomitant medications will include generic name, ATC levels 2 and 4, 
indication, start and end dates, dose, route, frequency, and ongoing status and summarized by 
ATC level 2 and ATC level 4. The number and proportion of patients taking concomitant 
medications will be summarized, sorted by decreasing frequency of ATC Level 2 and ATC 
Level 4. Patients will be counted once in all ATC categories linked to the medication.  
New anti-tumor treatment received after disease progression will be listed and summarized by 
cohort and/or treatment arm based on the SAF. 
5.5. 
Patient Disposition 
The following summaries by table will be provided for patient disposition: 
• Number of screened patients: met the inclusion criteria regarding the target indication 
and signed the ICF 
• Number of randomized patients (Efficacy Phase only) 
• Number of patients in SAF 
• Number of patients who discontinued the study treatment and the reasons for the 
treatment discontinuation 
• Number of patients who discontinued the study, and the reasons for the study 
discontinuation 
Listing of patient disposition will include dates of the first and the last cemiplimab 
administration, date of the end of treatment and end of study visits, and reasons for treatment and 
study discontinuation. 
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5.6. 
Extent of Study Treatment Exposure and Compliance 
5.6.1. 
Measurement of Compliance 
Compliance with study treatment cemiplimab will be calculated as follows: 
• Treatment Compliance = (Number of doses of cemiplimab administered during 
treatment period) / (Number of doses of cemiplimab planned to be administered 
during treatment period) × 100%,  
where temporary dose discontinuation is ignored. 
Treatment compliance will be summarized and listed by study part specific FAS. The following 
will be summarized by solid and CNS tumors for Phase 1 patients, by cohort and radiation type 
for Efficacy Phase patients:  
• Number of doses administered 
• Number and percentage of patients who have <60%, >=60 to <80%, >=80 to 
<=100%, and >100% compliance will be summarized for each treatment arm, or by 
study drugs 
• Wrong dose table (if applicable). 
5.6.2. 
Exposure to Investigational Product 
Exposure to Investigational Product will be summarized and listed based on SAF by study phase.  
Duration of exposure will be summarized by dose level/cohort for Phase 1 patients and by cohort 
/treatment arm for patients in Efficacy Phase. For cemiplimab, the following will be 
summarized:  
• Duration of exposure  
• Number of doses administered  
• Cumulative dose administered  
• Actual dose intensity  
• Relative dose intensity  
Cemiplimab dose delays and dose interruptions will be summarized by dose level/cohort for 
Phase 1 patients and by cohort /treatment arm for patients in Efficacy Phase.     
Listing of treatment exposure will include duration of exposure, number of doses administered, 
cumulative dose administered, actual dose intensity, and relative dose intensity. A listing of dose 
administration will be provided and will include date of administration, actual dose, dose delay, 
infusion interruption, and dose modification.  
5.7. 
Analyses of Efficacy Variables 
All efficacy analyses will be based on FAS according to the assigned treatment group and 
stratification factors used to randomize patients (from the IVR data).   
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5.7.1. 
Analysis of Primary Efficacy Variable(s) 
Newly diagnosed DIPG cohort and recurrent HGG cohort: 
The primary analysis of OS is the estimate of OS12 rate.  
OS will also be summarized by median and displayed by Kaplan-Meier approach.  
Newly diagnosed HGG cohort: 
The primary analysis of PFS is the estimate of PFS12 rate. PFS will also be summarized by 
median and displayed by Kaplan-Meier approach.  
5.7.2. 
Analysis of Secondary Efficacy Variables 
The overall response rate, and the response of CR, PR, SD, PD, NE will be summarized for 
groups as specified for study population and efficacy population.  
5.8. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. The 
safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations, vital signs etc.).  The analysis will comprise the basis upon which 
conclusions will be drawn regarding cemiplimab.  
5.8.1. 
RP2D 
For both Phase 1 and Efficacy Phase, a minimum of 3 patients at each dose level will be required 
to be evaluable for DLT. Tolerability of a dose level will only be determined when all potentially 
DLT-evaluable patients complete the 28-day DLT period. Number and proportion of patients 
with DLTs will be summarized using the Dose Limiting Toxicity Set. 
In Phase 1, RP2D will be determined based on the MTD after DLT evaluation in A, B, C, and D 
cohort, as applicable.  
In Efficacy Phase, RP2D will be determined based on the MTD after DLT evaluation in each E, 
F, G, and H cohort by radiation type; and in each I and J group by age (3 to <12, and 12 to 25), 
respectively.   
5.8.2. 
Adverse Events  
Period of observation:  
For safety variables, 3 observation periods are defined as follows: 
• The pre-treatment period is defined as the time from signing the informed consent 
form to before the first dose the study drug 
• The on-treatment period is defined as the time from the day of first dose of study drug 
to the day of the last dose of study drug of original treatment plus 90 days, or to 1 day 
before patients receive another anticancer systemic therapy, whichever is earlier 
• The post-treatment period is defined as the time starting 1 day after the end of on-
treatment period 
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Day 1 is the first day of patient receiving study treatment, Day-1 is the day before, and there is 
no Day 0.  
• Pre-treatment AEs are defined as AEs that developed during the pre-treatment 
period. 
• Treatment-emergent AEs (TEAEs) are defined as AEs that developed or worsened 
during the on-treatment period and any treatment-related AEs that occur during the 
post-treatment period but prior to initiation of other anticancer therapy. 
• Post-treatment AEs are defined as AEs that developed or worsened during the post-
treatment period and are not considered drug related by the investigator. 
• Infusion-related reaction (IRR) is any AE that occurs during administration of the 
study drug or within 2 hours after the infusion of the study drug is completed. All 
IRR will be reported as AEs and graded using CTCAE. 
• Immune-mediated AE (imAE) is any AE with unknown etiology associated with 
drug exposure and consistent with an immune phenomenon. imAEs are identified for 
the study drug by investigator assessment.  
The focus of adverse event reporting will be on TEAEs. For details on handling missing data and 
partial dates, see Section 6.   Summaries of adverse events will include: TEAEs, Treatment 
related TEAEs, Serious TEAEs, Treatment-related Serious TEAEs, AESI, immune-related AEs 
(imAE), and infusion related reaction (IRR).  For AEs (TEAEs, AESIs, imAEs and IRRs), the 
following will be summarized: 
• The number and proportions of patients reporting at least 1 AE, presented by SOC 
and PT 
• AEs by severity (CTCAE, latest available version), presented by SOC and PT 
• AEs by relationship to treatment (related, not related), presented by SOC and PT 
• AEs occurring in > x% patients, presented by SOC and PT 
• AEs leading to permanent treatment discontinuation, presented by SOC and PT 
• AEs leading to death, presented by SOC and PT 
For each AE summary presented by SOC and PT, the summary table will be sorted by 
decreasing frequency of SOC and PT.  For AE summary presented by PT, the summary table 
will be sorted by decreasing frequency of PT. 
The imAEs reported by investigator will be summarized.  Additionally, imAEs identified by the 
sponsor will be summarized.  The sponsor-defined imAEs are listed in a separate document.  The 
list may be updated to include all possible imAEs.  All imAEs occurred during the on-treatment 
and post-treatment periods will be included.  
For AE listings, the following variables will be displayed:  
• Age/gender 
• Verbatim Term  
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• PT 
• SOC  
• AE start date and end date/ongoing (and corresponding study day) 
• AE duration 
• Relationship to study drug: unrelated or related 
• Seriousness (Serious AE or not) 
• NCI CTCAE grade: mild, moderate, severe, life-threatening or fatal 
• Action taken: none, dose decreased, dose temporarily stopped or discontinued 
• Treatment for AE: none, medication, surgery or others 
• Outcome: recovered/resolved, recovered/resolved with residual effects, recovering/ 
resolving, not recovered/not resolved, fatal, or unknown 
Counts will be provided for each PT within each SOC.  Percentages will be calculated using the 
number of patients from the safety set. 
5.8.3. 
Analysis of Adverse Events of Special Interest 
Treatment emergent adverse events of special interest as defined in Section 4.7.2.1 will be 
presented by SOC and PT. The summaries will be sorted by decreasing incidence of PT within 
each SOC in the total. 
5.8.4. 
Clinical Laboratory Measurements  
Listings of laboratory values, normal ranges, grade, date, and visit/cycle will be provided.  For 
numeric lab variables, values and change from baseline to each visit/cycle will be summarized.  
Listings of abnormal lab values by patient and visit/cycle will also be constructed.  
Summary tables for new or worsened laboratory values with all grade and NCI CTCAE grade 
≥ 3 will be generated.  
Summary of Shift tables from baseline to post-treatment worst NCI CTCAE grade will be 
generated. The shift tables include the overall and individual Hematologic Test (Hemoglobin, 
Platelet counts, Red blood cells, White Blood cells, and differential of Neutrophils, Lymphocytes 
and Monocytes).  
Baseline clinical laboratory analytes and change from baseline in selected clinical laboratory 
analytes to each scheduled assessment time will be summarized with descriptive statistics.  
Summary statistics will include the number of patients, mean, median, standard deviation, 
quartiles, minimum, and maximum. 
5.9. 
Analysis of Pharmacokinetic and Antibody Data  
5.9.1. 
Analysis of the Pharmacokinetic Variables  
Cemiplimab concentrations in serum over time will be reported at nominal timepoints as 
individual values (together with patients' baseline body weight) and with descriptive statistics, by 
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age group and dose. PK parameters after the first dose will be determined by non-compartmental 
analysis. The PK parameters will include but will not be limited to concentrations at pre-dose 
and Ceoi after the first dose and during treatment. Additional PK parameters after the first dose 
include AUC2w and estimated t1/2, estimated over the 2-week dosing interval.   
5.9.2. 
Analysis of ADA Data 
The immunogenicity variables described in Section 1.9 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category, and maximum 
titer observed in patients in the ADA analysis set. For samples confirmed as drug specific ADA 
positive, but found negative at the lowest titer dilution, the lowest dilution in the titer assay is 
imputed.   
The ADA status of each patient may be classified as one of the following: 
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 9-fold the baseline titer value  
• Negative - If all samples are found to be negative in the ADA assay.   
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥9-fold the baseline titer value 
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients/Subjects/Participants that are 
treatment-emergent will be further categorized as follows: 
Treatment-emergent is further sub-categorized as: 
• Persistent - A positive result in the ADA assay detected in at least 2 consecutive post 
baseline samples separated by at least a 12/16-week post baseline period [based on 
nominal sampling time], with no ADA-negative results in-between, regardless of any 
missing samples 
• Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
• Transient - Not persistent or indeterminate, regardless of any missing samples 
The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000≤ titer ≤10,000) 
• High (titer >10,000) 
The following will be summarized by treatment group and ADA titer level:  
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of pre-existing patients 
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• Number (n) and percent (%) of treatment-emergent ADA positive patients 
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients  
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients  
− Number (n) and percent (%) of transient treatment-emergent ADA positive 
patients  
• Number (n) and percent (%) of treatment-boosted ADA positive patients 
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent 
and treatment-boosted ADA response. 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
5.10.1. 
Immunogenicity and Exposure 
Potential association between immunogenicity and systemic exposure to cemiplimab will be 
explored by treatment groups.  Plots of individual cemiplimab concentration time profiles may 
be provided to examine the potential impact of ADA category and maximum titer category on 
these profiles.  
5.10.2. 
Immunogenicity and Safety and Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period: 
• Infusion reactions 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow])  
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
The safety analyses mentioned above will be conducted using the following categories:  
• ADA Positive  
− Treatment-emergent  
− Treatment-boosted  
• Maximum post-baseline titer category in ADA positive patients 
5.10.3. 
Analysis of Exploratory Biomarker Data  
The tumor expression of PD-L1 will be reported as % Tumor cell staining in individual patients 
with available PD-L1 IHC result. The efficacy variables (OS, ORR and DOR) will be 
summarized according to PD-L1 expression in following subsets of patients: 
- 
All patients with available PD-L1 result (PD-L1 biomarker subset) 
- 
Patients with PD-L1 expression score >=1%TC (PD-L1 positive biomarker subset) 
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- 
Patients with PD-L1 expression score <1%TC (PD-L1 negative biomarker subset) 
All other biomarker endpoints are exploratory, and the analysis plan will be described in a 
separate Biomarker analysis plan (BAP) document. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product.  
6.2. 
Data Handling Convention for Efficacy Variables  
Incomplete date of death in OS analysis 
• If the day of death is missing, it will be imputed to the first day of the month except if 
the date of patient’s last contact is the same month as the death date.  In this case, the 
death date will be imputed to the date of the last contact + 1 day.  
• If the day and month of death are missing, date of death will be imputed to the 1st of 
January of the year, except if date of patients’ last contact is the same year as death 
date.  In this case, the death date will be imputed to the date of the last contact + 1 
day.  
Last contact date 
Last contact date will be used for censoring patients in the OS analysis.  The last contact date 
will be derived for patients alive at the analysis cut off using the latest complete date among the 
following: 
• ‘Last known date alive’ recorded on the ‘Survival status’ eCRF page.  
• Assessments with non-missing values corresponding to actual patient contact 
(including: retreatment screening, vital signs assessments, performance status 
assessments, physical examinations, tumor imaging, brain MRI, chest X-ray, scans, 
laboratory, ECG, pregnancy test, immunoglobulin, HIV testing, sample collection 
dates, AE start date, AE resolution date, and other dates on AE CRF, concomitant 
medication, procedures, post treatment anti-cancer procedure, study drug 
administration, cyclophosphamide administration, chemotherapy administration, 
radiation therapy administration, GM-CSF administration, inform consent tracking) 
Non-evaluable response in ORR analysis 
Patients who are deemed NE according to RECIST version 1.1. or unevaluable by the other 
response criteria will be considered as not reaching CR/PR in calculating ORR, i.e. they are not 
considered as responders in the numerator of ORR, but they are counted in the denominator of 
ORR.  
6.3. 
Data Handling Convention for Missing Data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
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Medication missing/partial dates 
To determine whether a medication is prior, concomitant or post-treatment medication, the 
missing medication start date is estimated as early as possible up to date of the first study 
treatment, and the missing medication end date is estimated as late as possible.  If the medication 
start date is missing, the onset day will not be imputed in medication listings.  
Missing AE severity and relationship with treatment 
If the intensity of a TEAE is missing, it will be classified as “Grade 3” in the frequency tables by 
intensity of TEAEs.  If the assessment of relationship of a TEAE to the investigational product is 
missing, it will be classified as related to the investigational product. 
Missing AE and concomitant medication dates 
• Imputation of AE and concomitant medication missing/partial start dates: 
Every effort will be made to collect the start dates of all AEs and concomitant medications.  
However, in the case the start date of an AE or concomitant medication is incomplete or missing, 
it will be assumed to have occurred on or after the first dose of study medication, except if an 
incomplete date (e.g., month and year) clearly indicates that the event started prior to treatment.  
If the partial date indicates the same month or year of the first dose of study medication date, 
then the start date of the first dose will be imputed. Otherwise, the missing day or month by the 
first day or the first month will be imputed.  However, if the imputed start date is after the non-
missing end date, the start date will be imputed to the end date. 
• Imputation of AE and concomitant medication missing/partial end dates: 
When only year is present, missing AE/concomitant medication end day and month will be 
imputed to the earlier of (study end date, 31DECYYYY).  When both month and year present, 
missing AE/concomitant medication end day will be imputed to the last day of the month.  There 
will be no attempt to impute completely missing AE or concomitant medication end dates.  
This represents the most conservative approach in the handling of missing or partial 
AE/concomitant medication start and end dates as well as missing AE severity.  
• Date of first / last infusion  
The date of first administration of study drug is derived as the first date when a non-zero dose of 
any component of study treatment was administered on the eCRF.  The date of last 
administration of study treatment is derived as the last date when a non-zero dose of any 
component of study drug was administered and recorded on the eCRF. If a patient’s date of the 
last dose is totally missing or unknown, his/her last visit date will be substituted. 
6.4. 
Unscheduled Assessments 
Unscheduled visit measurements may be used to provide a measurement for a baseline or 
endpoint value if appropriate according to their definition.  The measurements may also be used 
to determine abnormal laboratory values. 
The determination of baselines and values at the end of treatment for both efficacy and safety 
variables will be based on scheduled available assessments and unscheduled available 
assessments.  
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Extra assessments (laboratory data or vital signs associated with non-protocol clinical visits or 
obtained in the course of investigating or managing adverse events) will be included in listings, 
but not summaries except for the endpoint determination.  If more than one laboratory value is 
available for a given visit, the first observation will be used in summaries and all observations 
will be presented in listings. 
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7. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
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8. 
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Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
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Jakacki RI, Cohen KJ, Buxton A, et al. Phase 2 study of concurrent radiotherapy and 
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grade glioma: a report of the Children's Oncology Group ACNS0423 study. Neurooncology. 
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Klimo P, Jr., Nesvick CL, Broniscer A, Orr BA, Choudhri AF. Malignant brainstem tumors in 
children, excluding diffuse intrinsic pontine gliomas. Journal of neurosurgery. Pediatrics. 
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Kline C, Felton E, Allen IE, Tahir P, Mueller S. Survival outcomes in pediatric recurrent high-
grade glioma: results of a 20-year systematic review and meta-analysis. Journal of neuro-
oncology. 2018; 137(1):103-110. 
Lam S, Lin Y, Auffinger B, Melkonian S. Analysis of survival in pediatric high-grade brainstem 
gliomas: A population-based study. J Pediatr Neurosci. 2015; 10(3):199-206. 
Papadopoulos KP, Crittenden MR, Johnson ML, et al. A first-in-human study of REGN2810, a 
monoclonal, fully human antibody to programmed death-1 (PD-1), in combination with 
immunomodulators including hypofractionated radiotherapy (hfRT). Journal of Clinical 
Oncology. 2016; 34(15_suppl):3024-3024. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 
antibody in cancer. The New England journal of medicine. 2012; 366(26):2443-2454. 
Vanan MI, Eisenstat DD. DIPG in Children - What Can We Learn from the Past? Frontiers in 
oncology. 2015; 5:237. 
Vanan MI, Eisenstat DD. Management of high-grade gliomas in the pediatric patient: Past, 
present, and future. Neuro-oncology practice. 2014; 1(4):145-157. 
 
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