Conditions: NF1 Low-grade Glioma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®) treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first 48 weeks (12 cycles) of therapy. There will also be secondary and exploratory objectives listed in the detailed description below.

Detailed description:
This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®) treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first 48 weeks (12 cycles) of therapy.

The secondary objectives are to:

1. Determine 12, 24 and 60 month progression free survival (PFS) in pediatric NF1 patients with progressive LGG treated with poly-ICLC.
2. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by best objective tumor response rate (CR+PR) within 24 cycles of therapy.
3. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by clinical benefit response rate (CR+PR+MR+SD) after 12 and 24 cycles of therapy.
4. Assess the toxicity associated with poly-ICLC treatment in pediatric NF1 patients with LGG.

Exploratory objectives are to:

1. Evaluate the visual outcome measures in children with progressive optic pathway gliomas treated with poly-ICLC. Visual response is defined as 0.2 logMAR or greater in acuity improvement.
2. Evaluate patient reported outcomes and quality of life measures.
3. Evaluate biological correlates.

Arms:
arm 1: Enrolled participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or Tuesday/Friday schedule if possible).

Interventions: intervention 1: Poly ICLC
Intervention descriptions: intervention 1: Enrolled participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or Tuesday/Friday schedule if possible).

Protocol document:
Prot_SAP_003.pdf: 
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Neurofibromatosis Clinical Trials Consortium 
 
NF111 PROTOCOL: 
A Phase II Trial of Poly-ICLC for Progressive, Previously Treated 
Low-Grade Gliomas in Children and Young Adults with 
Neurofibromatosis Type 1  
 
Sponsored by: 
 
Department of Defense 
USAMRMC 
and the 
Office of the Congressionally Directed Medical Research Programs 
(CDMRP) 
 
 
Poly-ICLC (Hiltonol®), IND # 43984 
Oncovir, Inc. 
3203 Cleveland Avenue NW 
Washington DC, 20008 
 
Protocol Chairs 
Dolly Aguilera, MD, Chair 
David Wolf, MD, PhD, Co-Chair 
Miriam Bornhorst MD, Co-Chair 
 
Research Monitor 
Nicholas Foreman, MD 
 
 
 
 


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Protocol Roster 
 
Study Chair: 
Dolly Aguilera, MD 
Assistant Professor of Pediatrics 
Aflac Cancer and Blood Disorders Center 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
Phone: 404-785-3515  
Fax: 404-785-3511  
Email: dolly.aguilera@choa.org  
 
Study Co-Chairs: 
David Wolf, MD 
Assistant Professor of Pediatrics 
Department of Neurology 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
Phone: 404-785-3515  
Fax: 404-785-3511  
Email: david.wolf@choa.org 
 
Miriam Bornhorst MD 
Clinical Director, Gilbert NF1 Institute 
Department of Hematology/Oncology and 
Neurology 
Children’s National Hospital 
Phone: 202-476-5068 
Fax: 202-476-4304 
Email: mbornhorst@cnmc.org 
 
Research Compliance Manager – NFCTC 
Operations Center: 
Juliette Southworth, BS, CCRP 
University of Alabama at Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
Email: jsouthworth@uab.edu 
 
 
 
 
 
 
 
 
 
 
Clinical Research Manager – NFCTC Operations 
Center: 
Lauren Ashley Baldwin. BS 
University of Alabama at Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
Email: lahaynes@uabmc.edu   
 
Program Director – NFCTC Operations Center: 
Karen A. Cole-Plourde, BS, Prog. Dir. II 
University of Alabama at Birmingham – Kaul 230 
Birmingham, AL 35294-0024 
Email: Kcole@uab.edu 
 
Biostatisticians: 
Courtney McCracken, PhD 
Director, Research Projects 
Emory University 
1760 Haygood Drive 
Atlanta, GA 30322 
Phone: 404-727-4113 
Email: courtney.mccracken@emory.edu 
 
Research Monitor: 
Nicholas Foreman, MD 
Professor of Pediatrics 
Children's Hospital Colorado  
Anschutz Medical Campus 
13123 East 16th Ave 
Aurora, CO 80045 
Phone: 720-777-1234 
Email: nicholas.foreman@cuanschutz.edu 
 
Department of Defense: 
Anna E. Tschiffely, PhD 
Science Officer (General Dynamics IT) 
Congressionally Directed Medical Research 
Programs 
1053 Patchel Street 
Frederick, MD 21702 
Phone: 301-619-4006 
Fax: 301-619-7796 
anna.e.tschiffely.ctr@mail.mil    
 
 


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Central - Quality of Life: 
Lisa M. Ingerski, PhD, ABPP 
Associate Professor, Department of Pediatrics 
Emory University School of Medicine 
Pediatric Psychologist 
Aflac Cancer & Blood Disorders Center 
Children’s Healthcare of Atlanta 
Phone: 404-727-9635  
Email: Lisa.Ingerski@emory.edu 
 
Neuroimaging Center: 
Nadja Kadom, MD   
Children's Healthcare of Atlanta  
Emory University  
Department of Radiology-Egleston 
1405 Clifton Rd NE 
Atlanta, GA 30322 
Cell/text: 703.585.6554 
Fax: 404-785-1216 
Email: nkadom@emory.edu  
 
Kartik Reddy, MD 
Children's Healthcare of Atlanta  
Emory University  
Department of Radiology 
1405 Clifton Rd NE 
Atlanta, GA 30322 
Fax: 404-785-1216 
Email: kartik.mahasamudram.reddy@emory.edu 
 
 
 
Biological Correlates Laboratory: 
Kavita Dhodapkar, MD  
Associate Professor of Pediatrics 
Emory University 
Children’s Healthcare of Atlanta 
Health Science Research Building, E326 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-785-1112 
Fax: 404- 727-4455 
Email: kavita.dhodapkar@emory.edu 
 
Lead Ophthalmologist: 
Jason H. Peragallo, MD 
Assistant Professor of Ophthalmology and 
Pediatrics 
Emory University 
Atlanta, GA 30322 
Phone: 404-778-5360 
Fax: 404-778-4417 
Email: jason.peragallo@emory.edu 
 
Translation Studies Lead: 
Kavita Dhodapkar, MD  
Associate Professor, Neuro-Oncology 
Emory + Pediatric Institute 
Health Science Research Building, E384 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-785-1112  
Fax:     404- 727-4455  
Email: kavita.dhodapkar@emory.edu 
 
 


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Study Committee Members 
 
Jason Fangusaro, MD 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
1405 Clifton Road NE 
ECC Bridge, Office W-354 
Atlanta, GA 30322 
Phone: 404-727-5012 
Fax: 404- 727-4455 
Email: jfangus@emory.edu 
 
Claire Mazewski, MD 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
5461 Meridian Mark Road 4th Floor 
Atlanta, GA 30342 
Phone: 404-785-3721 
Fax: 404-785-3511 
Email: claire.mazewski@@choa.org 
 
Donald Durden MD, PhD 
Professor of Pediatrics 
University of Nebraska 
111 N 84th Street 
Omaha, NE 68114 
Phone: 402-955-3950 
donald.durden@unmc.edu 
 
Tobey MacDonald, MD 
Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
1405 Clifton Road NE 
ECC Bridge, Office W-354 
Atlanta, GA 30322 
Phone: 404-727-5012 
Fax: 404-727-4455 
Email: Tobey.macdonald@emory.edu  
 
Anna Janss, MD 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University School of Medicine 
5461 Meridian Mark Road 4th Floor 
Atlanta, GA 30342 
Phone: 404-785-3721 
Fax: 404-785-3511 
Email: anna.janss@@choa.org 
 
 
 
 
 
 
 
 
Robert Craig Castellino, MD 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University 
Health Science Research Building, E394 
1760 Haygood Drive NE 
Atlanta, GA 30322 
Phone: 404-727-2078 
Fax: 404- 727-4455 
Email: rccaste@emory.edu 
 
Nathan Robison, MD 
Assistant Professor of Clinical Pediatrics  
Keck School of Medicine of USC 
Children's Hospital Los Angeles 
4650 W Sunset Blvd 
Los Angeles, CA 90027 
Phone: 323-361-8147 
Fax: 323-361-8165 
Email: nrobison@chla.usc.edu 
 
Laura Katie Metrock, MD 
Assistant Professor of Pediatrics 
University of Alabama Birmingham 
Children’s of Alabama 
1600 7th Ave South, Lowder 512 
Birmingham, AL 35233 
Phone: (205)638-6945 
Email: kmetrock@peds.uab.edu 
 
Oncovir Pharmaceutical Support: 
Andres Salazar, MD 
CEO & CSO, Oncovir, Inc. 
3203 Cleveland Ave NW 
Washington, DC, 20008 
Phone: 202-342-1726 
Email: asalazar@oncovir.com 
 


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Participating Sites 
Bruce Korf, MD, PhD 
University of Alabama at Birmingham 
1720 2nd Ave South -  KAUL 230 
Birmingham, Alabama  35294-0024 
Phone:  205-934-9411/Fax: 205-934-9488 
Email: bkorf@uabmc.edu 
James Tonsgard, MD 
University of Chicago 
5841 South Maryland Avenue, MC 3055 
Chicago, IL  60637 
Phone:  773-702-6488 
Email: tonsgard@midway.uchicago.edu 
Michael Fisher, MD 
Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard 
Philadelphia, PA 19096 
Phone:  215-590-2800 
Email: fisherm@email.chop.edu 
Amy Armstrong, MD 
Washington University School of Medicine 
660 South Euclid Avenue – Box 811 
St. Louis, MO  63110 
Phone: 314-454-6018  
Email: armstrongae@wustl.edu  
Roger Packer, MD 
Children’s National Medical Center 
111 Michigan Avenue, NW 
Washington, DC  20010 
Phone: 202-476-5997 
Email: RPacker@childrensnational.org  
Kaleb Yohay, MD 
New York Univ. Pediatrics 
222 East 41st St., 14th Floor 
NYU Langone Health 
New York, NY 10016 
Phone: 212-263-7744 
Email:  kaleb.yohay@nyumc.org  
Steven Rhodes, MD, PhD 
Indiana University  
1044 West Walnut Street  
Cancer Center, Room 325 
Indianapolis, IN  46202 
Phone: 317-944-4034 
Email: sdrhodes@iupui.edu 
Nicole Ullrich, MD, PhD 
Dana Farber/ Boston Children’s Hospital Cancer 
and Blood Disorders Center–  
300 Longwood Avenue  
Boston, MA  02115 
Phone: 617-632-2680 
Email: Nicole.Ullrich@childrens.harvard.edu 
Tena Rosser, MD 
Children’s Hospital Los Angeles 
300 Medical Plaza Box 696824 
Los Angeles, CA  90095 
Phone: 323-361-2471 
Email: trosser@chla.usc.edu 
 
Brigitte Widemann, MD 
National Institutes of Health – NCI  
10 Center Dr; Building 10-CRC: Room 1-5750 MSC 
Bethesda, MD  20892 
Phone: 301-496-7387 
Email: widemanb@mail.nih.gov  
Peter de Blank, MD  
Cincinnati Children’s Hospital Medical Center 
240 Albert Sabin Way, T6 Suite 505 
Cincinnati, OH  45229 
Phone:  513-517-2068 
Email: Peter.deBlank@cchmc.org 
 
Dusica Babovic-Vuksanovic, M.D 
The Mayo Clinic 
200 First St. SW 
Rochester, MN 55905 
Phone: 507-284-3215 
Email: DBabovic@Mayo.edu 
Laura Klesse, MD, PhD 
Children’s Medical Center of Dallas 
University of Texas Southwestern Medical Center 
5323 Harry Hines Blvd. 
Dallas, Texas 75390-9063 
Phone:  214-456-2382 
Email: Laura.Klesse@utsouthwestern.edu 
 
 
 


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Affiliate Sites  
 
Massachusetts General Hospital (Ullrich; Plotkin) 
Dana-Farber (Ullrich;) 
UCLA (Rosser; Silva; Robison) 
Johns Hopkins (Blakeley) 
Ann & Robert H. Lurie Children’s Hospital of Chicago (Waanders)   
Memorial Sloan Kettering Cancer Center (Karajannis; Piotrowski; Sait) 
Children's Healthcare of Atlanta (Wolf) 
 
 
 
 


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Schema 
 
 


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Table of Contents 
 
Protocol Roster ..............................................................................................................................2 
Study Committee Members .........................................................................................................4 
Participating Sites..........................................................................................................................5 
Schema ...........................................................................................................................................7 
List of Abbreviations ...................................................................................................................11 
Glossary of Terms .......................................................................................................................12 
Protocol Summary .......................................................................................................................13 
1. 
STUDY OBJECTIVES ........................................................................................................15 
2. 
SIGNIFICANCE ...................................................................................................................16 
2.1 
Background .................................................................................................................. 16 
2.2 
Pre-clinical Studies ...................................................................................................... 16 
2.3 
Previous Clinical Trials of Poly-ICLC for Brain Tumors ......................................... 18 
2.4 
Pediatric Phase II Trial of Poly-ICLC for Progressive LGG .................................. 20 
2.5 
Rationale for the Biological Correlates ..................................................................... 23 
3. 
PATIENT ELIGIBILITY AND ENTRY CRITERIA ...........................................................24 
3.1 
Inclusion Criteria .......................................................................................................... 24 
3.2 
Exclusion Criteria ......................................................................................................... 27 
3.3  Screening and Study Enrollment Procedures ............................................................ 28 
3.3.1     Informed Consent/Assent ................................................................................... 28 
3.3.2 
Screening Procedures ......................................................................................... 28 
3.3.3 
Study Enrollment .................................................................................................. 28 
3.4 
Requirements to Initiate Protocol Therapy .............................................................. 28 
3.5 
Criteria for Removal from Protocol Therapy and Off Study Criteria .................... 29 
4. 
TREATMENT PLAN............................................................ Error! Bookmark not defined. 
4.1 
Study Treatment .......................................................................................................... 30 
4.2. Treatment Dosing Options ......................................................................................... 30 
4.2.1 Criteria to Start Next Cycle ..................................................................................... 31 
4.3 
Surgery .......................................................................................................................... 31 
5. 
REQUIRED OBSERVATIONS ..........................................................................................31 
5.1 
Pre-treatment Evaluation ............................................................................................ 31 
5.2. Evaluation During Treatment ..................................................................................... 32 
5.3. Evaluation at Completion of Therapy or Relapsed Disease ................................. 33 


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5.4. Evaluations Off Therapy ............................................................................................. 34 
6. 
DRUG INFORMATION .......................................................................................................34 
6.1. Poly-ICLC ...................................................................................................................... 34 
6.2. Ordering ........................................................................................................................ 35 
6.3. Drug Accountability ..................................................................................................... 35 
6.4. Dose Modifications for Toxicity .................................................................................. 36 
6.5. Concomitant Medications ........................................................................................... 38 
6.6. Toxicity .......................................................................................................................... 38 
7. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..........................................40 
8. 
QUALITY OF LIFE (QOL) STUDIES AND NEURO-COGNITIVE BATTERY ...........41 
8.1. Patient Reported Outcome Battery ........................................................................... 42 
9. 
OPHTHALMOLOGIC STUDIES .......................................................................................44 
9.1. Visual Acuity (best corrected) .................................................................................... 44 
9.2. VA Norms ...................................................................................................................... 45 
9.3. Visual Fields ................................................................................................................. 45 
9.4. Optic Disc Appearance ............................................................................................... 46 
9.5. Visual Response .......................................................................................................... 46 
10. 
IMAGING PARAMETERS AND RESPONSE CRITERIA ..........................................46 
10.1. 
General Considerations .......................................................................................... 46 
10.2. 
Measurement of Effect ............................................................................................ 47 
10.3. 
Imaging Sequences ................................................................................................. 48 
10.4. 
Imaging Response Assessment ............................................................................ 50 
10.5. 
Duration of Response.............................................................................................. 51 
10.6. 
Central Review ......................................................................................................... 51 
10.7. 
Ophthalmologic (Visual Acuity) Response Criteria ............................................. 52 
11. 
ADVERSE REPORTING REQUIREMENTS ...............................................................52 
11.1. 
Definitions.................................................................................................................. 52 
11.2. 
Grading of Adverse Events using Common Terminology Criteria (CTCAE) .. 53 
11.3. 
Attribution .................................................................................................................. 53 
11.4. 
Reporting Procedures for All Adverse Events ..................................................... 53 
11.5. 
Expedited Reporting Guidelines ............................................................................ 54 
11.6. 
Reporting of Protocol Violations/Deviations and Unanticipated Problems ..... 55 
12. 
RESEARCH MONITORING AND DATA SAFETY MONITORING PLAN...............55 
13. 
REGULATORY CONSIDERATIONS ............................................................................57 


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13.1. 
Protocol Review and Amendments ....................................................................... 57 
13.2. 
Informed Consent .................................................................................................... 57 
13.3. 
Ethics and Good Clinical Practice (GCP) ............................................................. 58 
13.4. 
Data Collection ......................................................................................................... 58 
13.5. 
Study Documentation .............................................................................................. 59 
13.6. 
Records Retention ................................................................................................... 59 
13.7. 
Multi-Center Guidelines .......................................................................................... 59 
13.8. 
Publication of Data and Protection of Trade Secrets ......................................... 60 
14. 
STATISTICAL CONSIDERATIONS ..............................................................................60 
14.1. 
Participant Accrual ................................................................................................... 61 
14.2. 
Sample Size .............................................................................................................. 62 
14.3. 
Statistical Analysis Plan .......................................................................................... 62 
15. 
REFERENCES .................................................................................................................64 
APPENDIX 1: NIH Consensus Conference Criteria for NF1 ...............................................68 
APPENDIX 2: Karnofsky and Lansky Performance Status Criteria ....................................69 
APPENDIX 3: Study Calendar and Required Observations (through end of therapy) ....70 
APPENDIX 4: Off Therapy Observations ................................................................................71 
APPENDIX 5: List of Enzyme Inducing Anticonvulsants ......................................................72 
APPENDIX 6: Mandatory Biological Specimens ....................................................................73 
APPENDIX 7: Optional Tumor Tissue with Concurrent Blood Sample ..............................74 
APPENDIX 8: Poly-ICLC Diaries ..............................................................................................76 
A. 
Cycle 1: Monday/Thursday Dosing ..................................................................................76 
B. 
Cycle 1: Tuesday/Friday Dosing .......................................................................................76 
C. 
Cycle __:  Monday/Thursday Dosing ...............................................................................76 
D. 
Cycle __: Tuesday/Friday Dosing .....................................................................................76 
APPENDIX 9: Poly-ICLC Roadmap for Cycle 1 .....................................................................81 
APPENDIX 10: Poly-ICLC Roadmap for Cycles 2 – 24 ........................................................82 
APPENDIX 11: Poly-ICLC Ophthalmology Worksheet .........................................................83 
 
 
 
 


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List of Abbreviations 
 
AE  
Adverse event  
ALT  
Alanine aminotransferase/serum glutamic pyruvic transaminase/SGPT  
AST  
Aspartate aminotransferase/serum glutamic oxaloacetic transaminase/SGOT  
BID  
bis in diem/twice a day  
CNS  
Central nervous system  
CR 
Complete response 
CRO  
Contract Research Organization  
CSF  
Cerebral spinal fluid  
CTO  
Clinical Trials Office  
CV 
Carboplatin-vincristine 
DOD 
Department of Defense 
DLT  
Dose limiting toxicity  
DSMC  
Data and Safety Monitoring Committee  
IB 
Investigator’s Brochure 
IHC  
Immunohistochemical  
IRB  
Institutional Review Board  
JPA 
Juvenile Pilocytic Astrocytoma 
LGG  
Low-grade glioma  
MR 
Minor response  
MRI  
Magnetic resonance imaging  
MRS  
Magnetic resonance spectroscopy  
NF1  
Neurofibromatosis type 1  
OPG 
Optic pathway glioma 
PD 
Progressive disease 
PCP 
Pneumocystis Carinii Prophalaxis  
PJP 
Pneumocystis Jeroveci Prophalaxis 
PK  
Pharmacokinetics  
Poly-ICLC 
Polyinosinic-Polycytidylic acid – poly-L-lysine carboxymethylcellulose 
PR 
Partial response 
PRO 
Patient reported outcomes 
RANO 
Response Assessment in Neuro-Oncology 
RAPNO 
Response Assessment in Pediatric Neuro-Oncology 
RSI 
Reference Safety Information 
RTC 
Return to clinic 
SAE  
Serious Adverse Event  
SD 
Stable disease 
TMZ 
Temozolomide 
ULN 
Upper limit of institutional normal  
  
 


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Glossary of Terms 
 
Assessment  
A procedure used to generate data required by the study. 
Cycle  
Number and timing or recommended repetitions of therapy are 
usually expressed as number of days (e.g.: q28 days). 
Enrollment/Enrolled  
Point/time of patient entry into the study; the point at which all 
eligibility assessments have been completed and approval to 
enroll has been confirmed by study chairs. 
Investigational Drug  
The study treatment whose properties are being tested in the 
study; this definition is consistent with US CFR 21 Section 
312.3 and is synonymous with “investigational new drug.”  
Investigational Treatment  
Drug whose properties are being tested in the study as well as 
its associated placebo and active treatment controls (when 
applicable). This also includes approved drugs used outside of 
their indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment generally does not 
include other study treatments administered as concomitant 
background therapy required or allowed by the protocol when 
used in approved indication/dosage. 
Other Study Treatment  
Any drug administered to the patient as part of the required 
study procedures that was not included in the investigational 
treatment.  
PID1 (Screening ID) 
 
A unique participant identifying number generated when initially 
entered into the electronic Data Collection System (eDCS). 
PID2 (Enrollment ID) 
A second unique participant identifying number generated when 
entered into the electronic Data Collection System (eDCS) after 
enrollment has been approved by Protocol Chair. 
Phase  
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, 
washout, etc.  
Premature Patient 
Withdrawal  
Point/time when the patient exits from the study prior to the 
planned completion of all study treatment administration and/or 
assessments; at this time all study treatment administration is 
discontinued and no further assessments are planned, unless 
the patient will be followed for progression and/or survival.  
Study Treatment  
Includes any drug or combination of drugs in any study arm 
administered to the patient (participant) as part of the required 
study procedures. 
Study Treatment 
Discontinuation  
Point/time when patient permanently stops taking study 
treatment for any reason; may or may not also be the point/time 
of premature patient withdrawal.  
 
 
 


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Protocol Summary 
 
Study Design: 
This is a phase II, prospective, longitudinal, multi-center trial of poly-
ICLC (Hiltonol®) for progressive low-grade gliomas in pediatric and 
young adult patients with NF1. 
Primary Objective: 
Evaluate the efficacy of poly-ICLC in pediatric and young adult NF1 
patients with progressive LGG as measured by objective tumor 
response rate (CR+ PR) within the first 48 weeks (12 cycles) of therapy.  
Secondary 
Objectives: 
 
 
 
 
 
 
Secondary objectives are to: 
 
a) Determine progression free survival (PFS) at 12, 24 and  60 
months in pediatric NF1 patients with progressive LGG treated 
with poly-ICLC  
b) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with 
progressive LGG as measured by best objective tumor response 
rate (CR+PR) within 24 cycles of therapy 
c) Evaluate the clinical benefit rate (CR + PR + MR+ SD) of poly-
ICLC in pediatric NF1 patients with progressive LGG after 12 
and 24 cycles of therapy  
d) Assess the toxicity associated with treatment with poly-ICLC in 
pediatric patients with NF1 and LGG 
Exploratory 
Objectives: 
Exploratory objectives are to: 
 
a) Evaluate the visual outcome in children with progressive optic 
pathway gliomas (OPG) treated with poly-ICLC.  
 
b) Evaluate patient reported outcomes and quality of life measures 
c) Evaluate biological correlates 
d) Compare RANO and RAPNO response determinations in this 
population  
 
Treatment 
Description: 
Eligible patients will receive therapy with poly-ICLC at a dose of 20 
mcg/kg/dose IM injections twice a week. Protocol treatment will last 24 
cycles from the start of poly-ICLC in the absence of disease progression 
or significant toxicity. A cycle will consist of 28 days.  
 
Participants will be seen and monitored at their treating center at the start 
of each cycle.  
 
Response Assessment  
Imaging to assess response will be performed at the end of cycle 3 (+/- 
2 weeks) and after every three cycles (+/-2 weeks) until after cycle 24. 
All MRIs completed on study patients should be submitted for central 


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review. Response Assessment in Pediatric Neuro-Oncology (RAPNO) 
criteria will be used to determine radiographic response.  
 
Endpoints: 
Primary endpoint 
• 
Objective response rate (CR+PR) within the first 48 weeks (12 
cycles) of therapy, using RAPNO criteria 
 
Secondary endpoints: 
• 
PFS at 12, 24 and 60 months 
• 
Best response rate (CR+PR) within 24 cycles of therapy 
• 
Clinical benefit response rate (CR+PR+MR+SD) after 12 and 24 
cycles of therapy 
• 
Poly-ICLC-related toxicities 
 
Exploratory endpoints 
• 
Vision response after 12 and 24 cycles of therapy defined as 0.2 
logMAR or greater in acuity improvement 
• 
Patient reported outcomes and quality of life measures  
• 
Biological correlates 
• 
Comparison of RANO and RAPNO response determinations   
 
Accrual 
Objectives: 
Up to 20 participants will be enrolled to obtain a minimum of 16 
evaluable participants on this study. 
Study Duration: 
Participants will be followed for a minimum of 5 years from treatment. 
Overall survival outcomes will continue to be measured up to 5 years 
from treatment. 
Interim Analysis:  
There will not be an interim analysis for efficacy. 
 
 


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1. STUDY OBJECTIVES 
 
This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®) treatment 
for progressive low-grade gliomas in pediatric patients with NF1. The primary objective is to 
evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma 
(LGG) as measured by objective tumor response rate (CR+PR) within the first 48 weeks (12 
cycles) of therapy. 
 
The secondary objectives are to: 
 
a) Determine 12, 24 and 60 month progression free survival (PFS) in pediatric NF1 patients 
with progressive LGG treated with poly-ICLC.   
b) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as 
measured by best objective tumor response rate (CR+PR) within 24 cycles of therapy. 
c) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as 
measured by clinical benefit response rate (CR+PR+MR+SD) after 12 and 24 cycles of 
therapy. 
d) Assess the toxicity associated with poly-ICLC treatment in pediatric NF1 patients 
with LGG. 
 
Exploratory objectives are to: 
 
a) Evaluate the visual outcome measures in children with progressive optic pathway gliomas 
treated with poly-ICLC. Visual response is defined as 0.2 logMAR or greater in acuity 
improvement. 
b) Evaluate patient reported outcomes and quality of life measures.  
c) Evaluate biological correlates. 
d) Compare RANO and RAPNO response determinations in this population. 


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2. SIGNIFICANCE 
2.1. Background 
Low-grade gliomas are the most common brain tumor of childhood (36% of childhood brain tumors). 
These tumors encompass a heterogeneous assortment of histological subtypes; the most common 
is pilocytic astrocytoma. 
 
Neurofibromatosis type 1 (NF1) is a common neurocutaneous disorder (incidence 1:3,000 births). 
Pilocytic astrocytomas can be seen in up to 20% of children with NF1, commonly localized in the 
optic pathway. Most are diagnosed before age 7 years.1 These tumors are most often diagnosed 
based on radiologic findings alone; biopsy is uncommon. Most of these tumors are indolent and do 
not require treatment. Factors deciding treatment initiation include imaging progression, decline in 
visual acuity or other functional impact. 
 
Surgical resection is not always a possibility due to the location of the tumor. Radiation therapy is 
avoided in patients with NF1 given the increased risk of treatment-induced secondary neoplasm. 
Chemotherapy is the mainstay of treatment for NF1 patients with progressive or symptomatic 
tumors.   
 
One commonly accepted chemotherapy regimen for NF1 LGG is carboplatin and vincristine. As 
reported by the Children’s Oncology Group CCG9952, the 5-year EFS rate was 69% ± 4% for the 
NF1 group. Forty-two NF1 patients (33%) had adverse events, and 6 (4.7%) died. 2 
 
Alternative regimens have also shown efficacy in treating NF1 LGG. Patients with NF1 treated 
with vinblastine at a dose of 6 mg/m2 IV x 70 weeks had a higher 5-year EFS than patients without 
NF1 (75.0%+/-15% vs 35.7%+/-7.6%, respectively). While quality of life was not affected, 
treatment was associated with a high incidence of bone marrow suppression, and the majority of 
patients required dose reductions.3 Bevacizumab and irinotecan have activity based on imaging 
responses and improvement of visual acuity in patients with progressive LGG, though limited data 
is available for NF1 patients as compared to non-NF1 patients.4 Initial data for MEK inhibition in 
NF1-associated pediatric low-grade glioma are promising: selumetinib 25 mg/m2 twice daily 
resulted in 2-year PFS of 96%. Sixty-four percent completed 26 courses and had stable or 
responsive disease. Eighty-nine percent of evaluable patients had stability in visual acuity.5 Other 
MEK inhibitors such as binimetinib (MEK162) and trametinib (MEK116540) are currently 
undergoing evaluation in clinical trials. Although the preliminary data are promising, the toxicities 
associated with MEK inhibitor therapy (rash, nailbed infection, decreased ejection fraction, among 
others) are not negligible and have significant quality of life implications in some cases. Newer 
forms of effective treatments with minimal side effects are much needed in children with NF1 and 
low-grade gliomas.  
 
Preliminary results from a pilot study suggest that poly-ICLC may be effective in NF1 LGG, 
including evidence of functional improvement. We propose to study the efficacy and toxicity of 
poly-ICLC, a biological response modifier in children with NF1 LGG. 
 
2.2. Pre-clinical Studies 
Polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) is a 
double stranded RNA (dsRNA) that was used as an interferon inducer at high doses (up to 300 
mcg/kg IV) in short-term cancer trials some years ago.6 These trials gave mixed results with 


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moderate toxicity, and the use of poly-ICLC was generally abandoned when recombinant interferons 
became available.7-13 However, lower dose (10 to 50 mcg/kg) poly-ICLC results in a broader host 
defense stimulation, including T-cell and natural killer cell activation and cytokine release (interferons 
alpha, beta, and gamma, interleukins, corticosteroids, and TNF). Levels of serum interferon induced 
by these doses of poly-ICLC are relatively low and have not been associated with anti-tumor action. 
Preliminary laboratory results of a pilot study showed no clear relationship between tumor response 
and measurable serum interferon, TNF, IL-2, IL-6, or neopterin; this agrees with prior animal 
studies.14 Low dose poly-ICLC also has a direct immune enhancing action independent of interferon, 
including increased antibody response to antigen, and NK cell, T-cell, macrophage and cytokine 
activation.  Recent evidence suggests that poly-ICLC is a ligand for the Toll receptor 3 (TLR3), an 
important component of innate immunity.  
 
Another action of poly-ICLC is a more direct antiviral and perhaps antineoplastic effect mediated by 
at least two interferon inducible nuclear enzyme systems, the 2'5'oligoadenylate synthetase (OAS) 
and the P1/eIF2a kinase, also known as the dsRNA dependent P68 protein kinase (PKR).15-18 Double-
stranded-RNA-dependent protein kinase PKR is a serine/threonine kinase which is activated by 
autophosphorylation upon binding to dsRNA. Activated PKR then phosphorylates the α-subunit 
of the translation initiation factor eIF-2, a modification that causes inhibition of protein synthesis. 
dsRNA induces an antiviral state in cells by functioning as an obligatory cofactor for OAS, which 
activates ribonuclease L; as well as for the PKR, which inhibits initiation of protein synthesis.19-23 Both 
OAS and PKR are very sensitive to dsRNA dose and structure.24 For example, simple, long chain 
dsRNA (as in poly-ICLC) is the most potent stimulator of OAS and PKR, while mismatched or 
irregular dsRNA can be inhibitory. Clinically, the OAS response is maximal at a dose of about 30 
mcg/kg of poly-ICLC and is much diminished above a dose of 100 mcg/kg.25 The clinical half-life of 
the OAS response to IM poly-ICLC is about 2.5 days, suggesting an optimum dose schedule of two 
or three times per week.25  
 
Previously treated patients showed up to a 40-fold increase in serum OAS product in response to 
treatment at 10 to 20 mcg/kg, and a significant association of serum OAS with tumor response (P= 
.03).26 Similarly, PKR has both high and low affinity binding sites and is inhibited by too high a dose 
of dsRNA.27 Koromilas, et al, have demonstrated that expression of a functionally defective mutant 
of PKR results in malignant transformation in vitro, suggesting an important role for this enzyme in 
suppression of tumorigenesis as well.28  They also suggest a possible relation to the p53 tumor 
suppressor associated with multiple malignancies (Li-Fraumeni syndrome), which includes 
astrocytomas, sarcomas, lung, and breast cancers.29 Recently, the role of PKR has been implicated 
in signaling pathways leading to transcriptional activation of the tumor suppressor p53, possibly 
through the PI-3 kinase pathway.30,31 Folkman, et al, reported that the interferons exert 
antiangiogenic activity against the tumor vasculature supporting a potential antiangiogenic effect of 
poly-ICLC.32  Importantly, the length of therapy with interferon alpha is limited whereas the use of 
poly-ICLC has been extended for up to 12 years without untoward effects. This capacity for extended 
use further supports our clinical trial of poly-ICLC in low-grade gliomas where a more extended length 
of treatment (2-3 years) may be required to establish a response to therapy. These multiple effects 
on cellular metabolism, if sustained, may mediate a broad-spectrum antitumor effect on a wide range 
of tumor cell types (Fig.1). If further studies confirm the hypothesis that OAS and/or PKR may 
mediate the possible antitumor action of poly-ICLC, this might help explain why the high doses of 
poly-ICLC used in early cancer trials were relatively ineffective. 
 
 
 
 
 


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Figure 1. Poly-ICLC Action 
       
                                                              
 
Furthermore, there is recent evidence of a novel biological effect of poly-ICLC in dendritic cells. 
In vivo studies have shown cytoplasmic activation of MDA5 and lysosomal activation of TLR3 in 
dendritic cells to peptide antigens. This response is associated with augmented production of 
immune-stimulatory cytokines by the dendritic cells, e.g. IL15, type 1 interferon and increased 
activation of CD8+ CTL.33  
 
More recently, an evaluation of poly-ICLC in healthy adult volunteers provided additional 
information on its mechanism of action. Profiling of whole blood samples was completed in 
participants exposed to poly-ICLC vs placebo. Compared to placebo, there was an upregulation 
of the interferon regulated genes (including TLR associated genes (TLR4 and TLG7), DDX58 and 
IFIH1) involved both in viral recognition and upregulation of the transcription factor genes IRF7, 
IRF-5 and IRF1. The upregulation of these genes leads to activation of transcription factors such 
as STAT1, STAT2 and STAT3. Additionally, there was upregulation of dendritic cell maturation, 
antigen presentation and NF-KB signaling. Another contributing mechanism of poly-ICLC is the 
upregulation of the complement system components including C1QB, C3AR1, SER P-ING1, and 
EIF2AK2. Other inflammasome associated genes that were found to be upregulated include IL-
1B, IL1RN, CASP1 and CASP5.34 This information provided clarification on the mechanism of 
action for poly-ICLC, however additional knowledge on the exact mechanism of action on NF-1 
associated tumors is still under investigation and the completion of this trial will  provide extremely 
valuable information. 
 
Taken together, these data suggest that immunological profiling of serum, tumor tissue and PBMC 
may identify a poly-ICLC induced immune response signature associated with augmented 
activation of immune response against pediatric NF1 LGG.  
 
2.3. Previous Clinical Trials of Poly-ICLC for Brain Tumors 
A pilot trial in adults suggested a possible beneficial effect of poly-ICLC in newly diagnosed and 
recurrent brain tumors.34 Thirty-eight patients with glioblastoma multiforme (GBM), anaplastic 
astrocytoma (AA), or recurrent GBM/AA were treated with varying doses of poly-ICLC 10-50 mcg/kg 
IM, 1 to 3 times per week for approximately 56 months.  The drug was well-tolerated, with little or no 
toxicity and quality of life was preserved in most patients. The most common side effect was mild 
temporary discomfort at the injection site, and transient fever or malaise. Twenty of thirty patients 
receiving at least twice weekly poly-ICLC showed regression or stabilization of tumor on MRI.  All 
but one patient with AA, who received poly-ICLC without interruption, remain alive, with PFS of 54 
months from diagnosis. This small study demonstrated the safety and tolerability of long-term, low 
dose intramuscularly administered poly-ICLC at a potentially beneficial dose range of 20 mcg/kg 2-
3 times weekly in patients with malignant gliomas. 
 
polyICLC
PKR
↓Protein synthesis
↓proliferation
p53
Anti-angiogenesis
TLR3
Innate immunity
Figure 1. This schematic shows the 
molecular basis for polyICLC action on 
signaling pathways in glioma or stromal 
cells, the inhibition of protein synthesis, 
angiogenesis 
and 
growth 
arrest. 
PolyICLC via TLR3 also induces innate 
immunity. 


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Most malignant gliomas actually represent a mixture of highly malignant tumor cells and lower 
grade cells that eventually become malignant themselves. Chemotherapy and radiation therapy 
are generally more effective against rapidly dividing malignant cells but are less so against the 
lower grade tumor elements. Based on information available to date, agents such as poly-ICLC 
may be more effective in stabilizing certain of these lower grade tumor elements and could thus 
be useful in treatment of low-grade tumors. In one study, the patients with lower grade tumors 
had a much greater response to poly-ICLC than standard chemotherapy regimens, with a longer 
median survival in months (119 versus 59) in WHO class 1 tumors (see Table 1). One hundred 
percent of patients who received the poly-ICLC regimen were alive at 2 years versus only 76% 
who received standard chemotherapy.34 This supports the effectiveness and less likely 
complications of poly-ICLC over chemotherapy. 
 
 
Table 1: Median Survival Poly-ICLC Trials 
 
 
 
 
 
Table 1. This table demonstrates median survival (months) of patients with prognostic class I-VI 
tumors treated in three large chemotherapy trials versus treatment with poly-ICLC. † Represents N= 
only one P-ICLC patient in groups II and IV. 
 
 
Two adult phase II clinical trials conducted by the NIH’s North American Brain Tumor Consortium 
(NABTC) have been completed. The first trial evaluated long-term poly-ICLC monotherapy in 55 
patients with recurrent glioblastoma, 11% had radiographic response, 6-month PFS was 24% and 
median survival was 43 weeks. Poly-ICLC was well tolerated but did not show improvement in 6-
month PFS. The second trial included 30 patients newly diagnosed with glioblastoma. The treatment 
schema included a combination of radiation with poly-ICLC. The 6-month PFS was 30% and the 
estimated 1-year PFS was 5%. Median time to progression was 18 weeks. The 1-year OS was 
69% and the median OS was 65 weeks. The combination therapy was well tolerated. This study 
suggests a survival advantage compared to historical studies using radiation therapy (RT) without 
chemotherapy but no survival advantage compared to RT with adjuvant nitrosourea or non-
temozolomide chemotherapy. A trial of poly-ICLC in combination with temozolomide was  
conducted by the NIH’s NABTT consortium.35 
 
A Phase I/II study of poly-ICLC was conducted in children with multiple types of newly diagnosed or 
recurrent brain tumors. Four children with progressive LGG treated on this pilot study were evaluated 
for response. These 4 children had stable disease after documented progression for 10, 12, 22 and 
24 months while receiving poly-ICLC. One of these children had leukopenia (grade 3) that resolved 
despite continued therapy, and another developed respiratory distress at the time of tumor 


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progression. Long-term responses were seen in 2 of 4 patients with LGG (unpublished data). The 
other cohorts of recurrent high-grade gliomas and newly diagnosed brain stem gliomas showed 
minimal to no response and all 8 children enrolled due to growing diffuse intrinsic pontine gliomas 
had progression of disease in < 8 months of therapy. Of the 11 children enrolled on the study with 
progressive high-grade gliomas (anaplastic astrocytoma or glioblastoma multiforme), 10 
demonstrated disease progression within 1-10 months of treatment initiation. However, 1 child had 
radiographic and clinical stability on therapy for over 2 years. The other cohorts of recurrent high-
grade gliomas and newly diagnosed brain stem gliomas showed minimal to no response. Patients 
with NF1 associated brain tumors, appeared to be very sensitive to poly-ICLC but demonstrated 
more side effects, particularly fever and erythema. Thus, it appears that poly-ICLC may have a 
beneficial role in children with LGG.36 
 
2.4. Pediatric Phase II Trial of Poly-ICLC for Progressive LGG  
Published as abstract.  
 
A Phase II trial for progressive and refractory LGG in children was initiated in 2011 (NCT01188096). 
Patients were enrolled at Children’s Healthcare of Atlanta and Rady Children’s San Diego.37 
Preliminary results were presented at the 2018 Society for Neuro-Oncology meeting. Twenty-three 
patients, including 6 with refractory NF1 LGG, were enrolled and treated with poly-ICLC. In 6 patients 
with NF1 LGG, poly-ICLC was administered IM at 20mcg/kg/dose twice a week for 12 to 24 cycles. 
Each cycle was 28 days. Patients’ demographic characteristics are in Table 2. All were pre-
treated (1-7 prior regimens, including 1 patient who was previously irradiated). There were 4 
patients with optic pathway gliomas, 1 with thalamic glioma and 1 with cervico-medullary junction 
glioma. Age ranged from 1-14 years. 
 
Table 2. NF1 LGG Patient Demographics 
 
N 
Age 
years 
Gender Pathology Molecular 
Location 
Prior 
therapies 
Radiation 
1 
9 
M 
JPA 
N/A 
Thalamic 
CV 
vinblastine 
No 
2 
1 
F 
N/A 
N/A 
OPG 
CV 
No 
3 
14 
M 
JPA 
N/A 
Cervico-
Medullary 
CV, 
vinblastine 
Yes 
4 
9 
F 
N/A 
N/A 
OPG 
CV, 
vinblastine 
No 
5 
10 
M 
JPA 
N/A 
OPG 
temporal 
CV, erlotinib, 
avastin 
No 
6 
10 
F 
JPA 
V600E+ 
OPG 
CV, TMZ, 
bevacizumab, 
vinblastine, 
everolimus, 
sorafenib 
No 
 
 
NF1 LGG responses at 12 months: 1 PD, 2 SD, 2 PR (PR+SD = 80%).  
Unpublished data.  Manuscript in preparation.  
Five of the 6 NF1 LGG patients are evaluable. As of September 2019, there have been 2 partial 
responses (PR) with a demonstrated decrease in tumor size by 67% and 68% by MRI (Fig. 2, 


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Fig. 3, and Table 3), 2 with prolonged stable disease (SD) with a decrease in tumor size by 15% 
and 7% respectively. One patient had progressive disease (PD) after 3 months on therapy. One 
of the patients with prolonged SD had significant improvement in visual fields after 3 months on 
therapy and continues to improve (Fig. 4). Three patients completed 24 cycles of protocol therapy 
All the patients with PR and SD have remained progression-free for 27+, 27+, 46+ and 102+ 
months. 
 
 
Table 3. NF1 LGG Patient Responses 
N 
Response 
at 6 
months 
% 
shrinkage 
Response 
at 12 
months  
Therapy 
duration 
months 
Time off 
therapy 
months 
PFS 
Progression 
Molecular 
Last 
follow
- up 
1 
PR 
-67 
PR 
24 
22+ 
46+ 
No 
n/a 
Alive 
2 
PR 
-68 
PR 
24 
3+ 
27+ 
No 
n/a 
Alive 
3 
SD 
-15 
SD 
12 
90+ 
102
+ 
No 
n/a 
Alive 
4 
SD 
-7 
SD 
24 
3+ 
27+ 
No 
n/a 
Alive 
5 
PD 
 
 
 
 
 
Yes 
n/a 
Alive 
6 
NE 
NE 
NE 
N/A 
N/A 
 
 
V600E+ 
Alive 
 
 
 
 
Figure 2. Patient 1 (Tables 2 & 3) Objective Response   
 
 
 
 
 
 
 
 
 
 
 


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Figure 3. Patient 2 (Tables 2 & 3) Objective Response   
 
 
 
 
 
Figure 4. Patient 4 (Tables 1 & 2) Objective Visual Response 
 
 
 
 
Toxicities 
With one exception, only infrequent and mild low-grade toxicities were observed: erythema and pain 
at site of injection, fever, myalgias and ALT elevation. There was one patient with a small 
asymptomatic intratumoral hemorrhage likely due to tumor evolution vs response to treatment.  


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Platelet count and coagulation tests were normal, and this patient spontaneously recovered without 
further bleeding. No other risk factors were identified for bleeding. No other LGG patients (NF1 and 
non-NF1) had bleeding episodes and there were no Grade 3 or 4 toxicities.  
 
Overall, in the NF1 group, compliance was greater than 90%, as verified by patient diaries. 
 
Although the population was small, 4 of 5 evaluable NF1 patients treated with poly-ICLC had clinical 
responses and clinical benefit (radiographically and/or improved vision) as well as evidence of 
prolonged stabilization of disease after discontinuation of therapy (for up to several years) without 
untoward long-term effects or secondary malignancies/transformation to higher grade. Together, 
these pilot data support initiating a phase II clinical trial of poly-ICLC in NF1 LGG. 
 
2.5. Rationale for the Biological Correlates 
Current diagnostic and therapeutic monitoring for children with NF1-associated low grade gliomas 
are significantly hindered due to limited understanding of brain tumor biology and markers that can  
predict response to therapy. If available, such markers would be highly desirable and could be used 
to: 
 
• 
Predict response to poly-ICLC therapy in children with NF-1 associated LGG. 
• 
Predict or anticipate tumor progression in children with NF-1 associated LGG. 
• 
Evaluate the immune profile for children with NF-1 associated low-grade glioma before 
and after the therapy with poly-ICLC.  
 
Functional assays. We will perform Tcell proliferation as well as characterize cytokines secreted 
by Tcells before and after Poly-ICLC therapy. We are particularly interested in understanding the 
changes in antigen-specific T cell responses after exposure to poly-ICLC.  
 
Multiplex Luminex ELISA: We will assess changes in plasma cytokine milieu, including 
circulating cytokines IL6 and TNFα at multiple time points. 
 
Surrogate marker for Poly-ICLC activity: In addition, our evaluation will seek to provide a 
surrogate marker for sensitivity of the patient’s cells to known capacity of the poly-ICLC to activate 
3 pathways: TLR3, MDA5 and PKR signaling. Recent evidence from our group identified a novel 
biological effect of poly-ICLC not seen with poly-IC, the cytoplasmic activation of MDA5 and 
lysosomal activation of TLR3 in dendritic cells (DCs), a response associated with augmented 
production of immune-stimulatory cytokines by DCs (e.g. IL15, type 1 interferon) and increased 
activation of CD8+ CTL response to peptide antigens in vivo.33  These data suggest 
immunological profiling of serum, tumor tissue and PBMC may identify a poly-ICLC induced 
immune response signature associated with augmented activation of immune response against 
pediatric LGG in NF1.  
 
Leftover samples of blood and optional tissue will be banked for future studies through the NF 
Clinical Trials Consortium. See Appendix 7. 
 
 


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Figure 5: Single Cell Mass Cytometry (CyTOF) 
 
 
3. PATIENT ELIGIBILITY AND ENTRY CRITERIA 
 
IMPORTANT NOTE:  The eligibility criteria listed below are interpreted literally and cannot be 
waived. All clinical and laboratory data required for determining eligibility of a patient enrolled on 
this trial must be available in patient’s medical/research records which will serve as a source for 
verification at the time of the audit. 
 
This protocol is open to both males and females of all races and ethnicities. Participants must 
meet the following criteria on screening examination to be eligible to participate in the study. See 
Inclusion Criteria regarding specific eligibility requirements for female and male patients of 
childbearing or child-fathering potential, respectively. 
 
All clinical and laboratory studies to determine eligibility must be performed within 14 days 
prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility 
must be no older than 14 days at the start of therapy. Laboratory tests do not need to be 
repeated if therapy starts within 14 days of obtaining labs to assess eligibility, with the 
exception of the pregnancy test, which must be performed within 7 days of starting 
treatment. Imaging studies must be obtained within 4 weeks (28 days) prior to enrollment 
and starting treatment. For OPG patients, functional ophthalmology assessments must be 
performed within 4 weeks (28 days) prior to enrollment and starting treatment.  
 
3.1. Inclusion Criteria  
1) Age: Patients must be less than 22 years at the time of enrollment; there is no lower age 
limit.  
 
2) All participants must have an identified pathogenetic constitutional NF1 mutation OR the 
clinical diagnosis of NF1 using the NIH Consensus Conference criteria (See Appendix 
1). 
 
Fig 5. Single cell mass cytometry (CyTOF) to study the immune environment of glial tumors. CyTOF 
was used to examine paired blood and tumor samples from children undergoing resection of their 
glioma. Figure on the left shows that glioma tumor tissue is enriched for myeloid cells when compared 
to the peripheral blood (n=4). ViSNE analysis of the tumor tissue from a representative patient shows 
increased myeloid (CD14+ CD33+) cells within the tumor.   
CD4
CD8
T cells
CD14
CD33
Myeloid cells
 
Fig 5. Single cell mass cytometry (CyTOF) to study the immune environment of glial tumors. CyTOF 
was used to examine paired blood and tumor samples from children undergoing resection of their 
glioma. Figure on the left shows that glioma tumor tissue is enriched for myeloid cells when compared 
to the peripheral blood (n=4). ViSNE analysis of the tumor tissue from a representative patient shows 
increased myeloid (CD14+ CD33+) cells within the tumor.   
CD4
CD8
T cells
CD14
CD33
Myeloid cells


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3) Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible. Histologic 
confirmation of tumor is not necessary in the presence of consistent clinical and 
radiographic findings. Biopsy for histologic diagnosis is required if there is clinical 
suspicion for a high-grade tumor; special attention is recommended in older adolescents 
or young adults to the potential for malignant transformation.  Patients with metastatic 
disease are eligible.  
 
4) Patients must meet at least one of the following criteria for progression or recurrence of a 
previously treated target tumor:  
 
a. 
Progression or recurrence on MRI. 
b. 
New or worsening neurologic symptoms attributable to the target tumor. 
c. 
For patients with OPG:  visual worsening, defined as worsening of visual acuity 
(VA) or visual fields (VF) documented within the past year by examination or 
history, attributable to tumor. 
5) Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2.  
6) Prior Therapy: Patients must have had at least one prior medical treatment for the target 
LGG. 
7) Performance Level: Patients must have a performance status of equal or > than 50 using 
Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years of 
age. See Appendix 2 for scale.  
8) Patients must have recovered to grade ≤1 from any acute toxicities from all prior treatments. 
to enroll on this study and meet time restrictions from end of prior therapy as defined below:  
a. Myelosuppressive chemotherapy: must have received the last dose of myelosuppressive 
therapy at least 4 weeks prior to study registration, or at least 6 weeks if nitrosourea. 
 
b. Investigational/biological agent: Patient must have received the last dose of other 
investigational, immunotherapy, or biological agent > 14 days prior to study registration 
or at least 5 half-lives, whichever is greater.  Bevacizumab last dose > 36 days prior to 
enrollment.  
 
c. Radiation therapy: Patients SHOULD NOT have received prior irradiation.  
 
d. Study specific limitations on prior therapy: There is no limit on the number of prior 
treatment regimens. 
 
e. Growth factor(s): Must not have received any hematopoietic growth factors within 7 days 
of study entry or > 14 days if pegylated GCSF is used. 
 
f. Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major surgery such 
as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from minor surgery 


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and completely recovered. Port or central line placement is not considered a major 
surgery. 
 
9) Organ Function Requirements: 
 
All patients must have adequate organ function defined as:  
 
 
9.1 Hematologic Function:  
a. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs) 
 
b. ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14 days 
since last dose of pegylated GCSF 
 
c. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last transfusion) 
 
 
9.2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per the 
table below) or GFR > 70 ml/min/1.73m2 
 
 
 
 
 
 
 
 
Table 3: Renal Function Normal for Age 
 
Age 
 
Maximum Serum 
Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 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 
 
 
 
9.3 Liver Function:  
a. Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert’s Syndrome will be allowed 
on the study regardless of their total  and indirect bilirubin levels as long as the direct 
bilirubin is less than 3.1 mg/dL.) 
b. SGPT (ALT) ≤ 5 x ULN 
c. SGOT (AST) ≤ 5 x ULN 
 
9.4 Pulmonary Function: 
No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%. 
 
 
9.5   Reproductive Function: 
Female patients of childbearing potential must have a negative serum or urine pregnancy 
test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant or 
breast-feeding. Patients of childbearing or child-fathering potential must be willing to use 
a medically acceptable form of birth control, including abstinence, while being treated on 
this study and for 90 days following cessation of treatment. 
 


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10) Patient is able to start treatment within 7 days after enrollment. 
 
11) Patients with neurological deficits must be stable for a minimum of 1 week prior to enrollment.  
 
12) Patients are only eligible if complete resection of the LGG with acceptable morbidity is not 
feasible or if a patient with a surgical option refuses surgery. 
 
13) Patients and/or parents/legal guardians must provide written informed consent and agree 
that they will comply with the study. 
 
3.2. Exclusion Criteria 
 
1. Prior radiation treatment for the low-grade glioma. 
 
2. Prior exposure to poly-ICLC. 
 
3. Patients currently receiving other anti-tumor therapy or experimental therapy (targeted agents, 
chemotherapy radiation). 
 
4. Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV). 
 
5. Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other malignancy 
requiring treatment in the last 48 months. 
 
6. Patients may not have fever (≥38.50 C) within 3 days of enrollment. 
 
7. Patients who, in the opinion of the investigator, may not be able to comply with the safety 
monitoring requirements of the study. 
 
8. Active auto-immune illness. 
 
9. Pregnant or lactating females.  
 
10. Sexually active patients of reproductive potential who have not agreed to use an effective 
contraceptive method for the duration of their study participation and for 90 days after stopping 
study therapy are not eligible. 
 
11.  Severe unresolved infection that requires systemic IV antibiotics. 
 
12. Patients with any significant medical illnesses that in the investigator’s opinion cannot   be 
adequately controlled with appropriate therapy or would compromise the patient’s ability to 
tolerate this therapy. 
 
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired 
gastrointestinal function, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
 
14. Patients requiring high doses of steroids. Patients may not be on immunosuppressive therapy, 
including corticosteroids (with the exception of physiologic replacement, defined as ≤ 0.75 


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mg/m2/day dexamethasone or equivalent) at time of enrollment. However, patients who 
require intermittent use of bronchodilators or local steroid injections will not be excluded from 
the study. 
 
3.3. Screening and Study Enrollment Procedures 
 
The NFCTC Operations Center should be contacted to ensure availability of a treatment slot for 
this research. Contact the center at nfcop@uab.edu. 
 
3.3.1. Informed Consent/Assent  
The investigational nature and objectives of the trial, the procedures and treatments involved 
and their attendant risks and discomforts, and potential alternative therapies will be carefully 
explained to the patient or the patient’s parent(s) or guardian if the patient is a child. When 
appropriate, pediatric patients will be included in all discussions. All patients and/or their 
parents or legally authorized representatives must sign a written informed consent to 
participate in this research. Assent, when appropriate, will be obtained according to 
institutional guidelines. 
 
• 
A study participant should sign the institution’s Release of Medical Information 
Waiver if applicable. 
 
3.3.2. Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility for this trial 
must only be done after obtaining written informed consent. Documentation of the informed 
consent for screening will be maintained in the participant’s research chart. Studies or 
procedures that were performed for clinical indications (not exclusively to determine 
eligibility) may be used for baseline values even if the studies were done before informed 
consent was obtained. See section 3.4. 
 
Before the patient can be enrolled, the responsible institutional investigator must sign and 
date the completed eligibility checklist. The completed eligibility checklist and redacted 
supporting source documents should be scanned and emailed to the NFCTC Operations 
Center to confirm eligibility prior to participant enrollment.  Email: nfcop@uab.edu.  
3.3.3. Study Enrollment 
Patients may be enrolled on the study once all eligibility requirements for the study have been 
met, and a treatment number for participant has been confirmed by the NFCTC Operations 
Center. All patients who give informed consent for the protocol in order to undergo screening 
for eligibility will be registered but are not considered enrolled until the screening is 
completed, they are determined to meet all eligibility criteria, and approval for enrollment has 
been confirmed by the study chair. Treatment must start within 7 days of enrollment. 
Participants must not receive any protocol therapy prior to enrollment. 
 
3.4. Requirements to Initiate Protocol Therapy  
All studies to determine eligibility must be performed within 2 weeks (14 days) prior to enrollment 
except the baseline MRI study and eye exam for OPG documenting disease status, which must 
be obtained within 4 weeks (28 days) prior to study enrollment and starting treatment. All clinical 
and laboratory data required for determining eligibility of a participant enrolled on this trial must be 


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available in the participant's medical or research record which will serve as the source document for 
verification at the time of audit/monitoring.  
3.5. Criteria for Removal from Protocol Therapy and Off Study Criteria 
Removal from Protocol Therapy  
 
The following are criteria for removal from protocol therapy: 
 
a) Confirmed progressive disease (clinical or radiographic).  
b) Completion of cycle 24. 
c) Poly-ICLC related toxicity requiring removal. 
d) Participant has not received drug (for any reason) for greater than 28 days. 
e) Refusal of further protocol therapy by participant/parent/guardian. 
f) Another tumor develops that requires non-surgical therapy (e.g. chemotherapy, radiation 
etc;). 
g) Non-compliance, that in the opinion of the investigator does not allow for on-going 
participation. 
h) Physician determines it is not in the participant’s best interest. 
i) Participant has complete resection of target lesion and there is no evidence of residual 
disease. 
j) Participant becomes pregnant. 
• 
If a participant becomes pregnant while receiving investigational therapy or within 90 
days after the last dose of study drug, the participant should be followed until the 
outcome of the pregnancy. 
 
 
Participants who are off protocol therapy are to be followed until they meet the criteria for 
OFF Study (see below). 
 
Off-Study Criteria: 
 
• Completion of their 5 year follow-up MRI scan 
• Participant starts new tumor-directed therapy 
• Death 
• Lost to follow-up 
• Withdrawal of consent for any further data submission 
 
 


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4. TREATMENT PLAN 
4.1. Study Treatment  
 
Overview: 
Enrolled participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using 
Monday/Thursday or Tuesday/Friday schedule if possible). The first dose will be administered in the 
clinic under supervision of a nurse, advance care provider or physician. It is recommended that the 
participant stay in the clinic for the 1st hour (+/- 30 min) after first dose is administered to 
evaluate for fever, rash, hives, or any other reactions. Premedication with acetaminophen, 
ibuprofen and antihistamines is strongly recommended to minimize injection related and 
drug related toxicities. Prophylaxis with acetaminophen and/or ibuprofen is recommended 
for 24 hours after injection, per treating physician discretion. 
 
4.2. Treatment Dosing Options 
Table 4: Recommended Dosing Options 
 
 
 
Option 1* 
Option 2* 
Monday 
X 
 
Tuesday  
 
X 
Wednesday 
 
 
Thursday 
X 
 
Friday  
 
X 
Saturday 
 
 
Sunday  
 
 
 
 
 
X= drug administration. Cycles are 28 days 
*If a participant misses a dose of medication on the scheduled day, a dose can be  
given up to 24 hours later. Injections must be separated by at least 48 hours.  
 
Participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or 
Tuesday/Friday schedule if possible). The first dose will be administered in the clinic under 
supervision.  To facilitate processing of biological samples, samples should not be obtained on a 
Friday. 
 
Participant will be monitored 1 hour (+/- 30 minutes) after the first dose. For all subsequent cycle 1 
doses administered at home, a log will be kept documenting the temperature of the participant before 
study drug administration and 12 hours (+/- 6 hours) after study drug administration. After cycle 1, 
temperature will only be monitored on an as needed basis, such as if the participant is not feeling 
well. Participants or their parents will be instructed to use a log to record the temperature monitored 
at home and any fever > 390 Celsius should be recorded on the log.   
 
Participant or parent will receive appropriate teaching by the medical team for intramuscular 
injections administration. After the first dose if family and medical team feel comfortable, then the 
rest of the medication will be administered at home. The study drug will be dispensed to the 
participant/parent/guardian by the institutional research pharmacy. The study drug will be dispensed 
in vials along with syringes in order to minimize errors in dosing.  Needle size/gauge to be used for 
IM injections should follow institutional guidelines and practice.   


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Total length of treatment will be 24 cycles. Each cycle will be 28 days +/- 5 days. Treatment will not 
be continued beyond 24 cycles.  
 
Participants will be seen and monitored at the start of each cycle. A medication supply for up to a 
maximum of 33 days (28 + 5 days) will be dispensed. 
 
If a participant misses a dose of medication on the scheduled day, a dose can be given up to 24 
hours later. No injections should be given closer than 48 hours.  
 
4.2.1 Criteria to Start Next Cycle 
a. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs) 
b. ANC: > 750/mm3 
c. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last transfusion)  
d. SGPT (ALT) ≤ 5 x ULN 
e. SGOT (AST) ≤ 5 x ULN 
 
4.3. Surgery 
Patients may undergo surgical tumor resection at any point during the protocol if it is clinically 
indicated per treating physician recommendation.  
 
Study drug should be held for at least 72 hours prior to surgery. Patients who undergo resection will 
require a post-operative MRI of the primary tumor site, preferably within 72 hours after resection. 
Patients who undergo gross total resection of the target lesion with no measurable disease on post-
operative imaging will permanently discontinue study drug. Patients with residual measurable tumor 
after resection may resume study drug when clinically cleared by medical team (usually 2-4 weeks 
after resection) and when they meet the criteria described in 4.2.1 to start a new cycle.  Measurable 
tumor for this purpose is defined as tumor with a maximal diameter at least twice the slice thickness 
of the MRI sequence used to define tumor dimensions. Postoperative MRI will be used as the new 
baseline for subsequent response determinations.  
 
 
5. REQUIRED OBSERVATIONS 
5.1. Pre-treatment Evaluation  
(See Appendix 3) 
The following evaluations must be performed within 14 days prior to start treatment unless 
otherwise indicated. Imaging must be obtained within 4 weeks (28 days) prior to start of 
treatment. For OPG patients, functional ophthalmology assessment must be performed 
within 4 weeks (28 days) prior to start treatment.  
  
A. History (including concomitant medication list), vital signs (RR, HR, BP, temperature and 
oxygen saturation) and physical examination, including neurologic evaluation. 
B. CBC, differential, platelet count.  
C. CMP: including sodium, potassium, CO2, chloride, total protein, glucose, AST, ALT, alkaline 
phosphatase, albumin, calcium, total bilirubin, BUN, creatinine, phosphorous.   


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D. Disease evaluation of primary tumor with MRI. MRI must be performed within 4 weeks of 
starting treatment.  
E. Serum or urine B-HCG in females of childbearing age (must be repeated if not performed 
within 7 days  of day 1 cycle 1). 
F. Lansky Play Scale assessment for patients ≤ 16 years of age; Karnofsky score for patients 
> 16 years old (see Appendix 2). 
G. QOL Assessment after signing consent prior to study drug. 
H. Ophthalmology Functional Assessments (see section 9) only for patients with optic 
pathway gliomas.  
I. 
Blood biology studies after signing consent prior to study drug (see section 7). 
 
J. Study entry form/eligibility checklist to be approved by the study chair or designee prior to 
starting treatment. 
5.2. Evaluation During Treatment 
(See Appendix 3) 
 
A. Disease evaluation with MRI brain (with orbital cuts for optic pathway tumors) or 
spine MRI depending on the primary tumor site every 3 cycles (+/-2 weeks) while on 
therapy (to be done at the end of the cycle). CSF cytology if clinically indicated. 
Tumor Evaluation forms are to be completed every 3 cycles while participant is on 
study. More frequent MRIs can be done at the treating physician discretion. Every 
MRI performed on participants on study will be submitted to the NFCTC Operations 
Center for central review at the conclusion of the study. 
B. History, vital signs, physical and neurological examination and concomitant 
medication list, on cycle 1 day 1 and cycle 1 day 15 (+/-48 hours) and on day 1 (+/-5 
days) of each subsequent cycle. 
C. Labs: 
(a) CBC/differential, platelets are to be obtained on cycle 1 day 1if not performed 
within 14 days, on cycle 1 day 8 (+/-48 hours) and cycle 1 day 15 (+/-48 hours) 
and on day 1 (+/-5 days) of each subsequent cycle.  
(b) CMP (including sodium, potassium, CO2, chloride, total protein, glucose, AST, 
ALT, alkaline phosphatase, albumin, calcium, total bilirubin, BUN, creatinine, 
phosphorous) are to be obtained on cycle 1 day 1  if not performed within 14 days  
and on day 1 (+/-5 days) of each subsequent cycle.  
 
Biological correlates SHOULD NOT be obtained on a Friday. 


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D. Pregnancy test if female patient is of childbearing age.  
E. Toxicity monitoring and review of medication diary and temperature log at every visit 
after starting study treatment. 
F. Lansky Play Scale assessment for participants < 16 years of age; Karnofsky score 
for participants ≥ 16 years old at baseline, cycle 1 day 15, and then prior to each 
cycle (see Appendix 3). 
G. Ophthalmology Functional Assessments (see section 9) only for patients with optic 
pathway gliomas at the end of cycle 3 (+/- 2 weeks) then every 3 cycles (+/-2 weeks) 
until end of treatment. 
H. QOL Assessment will be done on day 1 Cycle 6 (+/-2 weeks) and day 1 cycle 12 (+/-
2 weeks) and end of cycle 24 or end of therapy (+/- 2 weeks) (see section 8).  
I. Blood biology studies (see section 7) on day 8 cycle 1, day 15 cycle 1, day 1 cycle 3, 
6, and 12, and at the end of treatment. Biology studies should be drawn within 24 
hours prior to the next scheduled dose whenever possible. Mandatory biological 
correlates SHOULD NOT be obtained on a Friday. Samples should be at room 
temperature. Biological blood samples should not be obtained through a fingerstick. 
5.3. Evaluation at Completion of Therapy or Relapsed Disease 
 
(See Appendix 3) 
 
A. Disease evaluation: MRI brain (with orbital cuts for optic pathway tumors) with and 
without contrast or spine MRI with and without with contrast if primary spinal tumor (+/-2 
weeks). 
B. History, vital signs, physical and neurological  examination, and concomitant medication 
list (+/- 14 days). 
C. Labs (+/-14 days):  
(c) CBC/differential, platelets 
(d) CMP: including sodium, potassium, CO2, chloride, total protein, glucose, AST, 
ALT, alkaline phosphatase, albumin, calcium, total bilirubin, BUN, creatinine, 
phosphorous 
D. Toxicity monitoring and review of medication diary and temperature log 
E. Lansky Play Scale assessment for patients < 16 years of age; Karnofsky score for 
patients ≥ 16 years old (see Appendix 2). 
F. Ophthalmology Functional Assessments (see Section 9) only for patients with optic 
pathway gliomas (+/-2 weeks).  
G. QOL Assessment (+/-2 weeks) at cycle 24 (+/-2 weeks) (see Section 8). 


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H. Blood biology studies (see Section 7). 
5.4. Evaluations Off Therapy 
(See Appendix 4) 
 
A. Disease evaluation: MRI brain (with orbital cuts for optic pathway tumors) with and without 
contrast or spine MRI with and without contrast if spine is the primary tumor location every 3 
months (+/-4 weeks) for the first 12 months, then every 6 months (+/- 4 weeks) for months 
12 - 36, then every 12 months (+/-6 weeks) until month 60. 
B. Ophthalmology Functional Assessments (see section 8) only for patients with optic 
pathway gliomas every 3 months (+/-4 weeks) for the first 12 months, then every 6 months 
(+/-4 weeks) for months 12-36, then every 12 months (+/-6 weeks) until month 60. 
C. QOL Assessment at month 24 (+/- 4 weeks) (see section 8) or at time of post-treatment 
progression if applicable. 
D. Blood biology studies (see section 7) at 3-month post treatment and 12-month post treatment 
study visits, and at the time of post-treatment progression if applicable. 
     E.  See Section 7 for Optional Tumor Tissue and Concurrent Blood Sample. 
 
 
6. DRUG INFORMATION  
6.1. Poly-ICLC 
Product:  
Polyinosinic-Polycytidylic acid – poly-L-lysine carboxymethylcellulose 
 
Name:  
Poly-ICLC (Hiltonol®) 
 
Poly-ICLC is classified as an investigational new drug. It is a synthetic complex of polyinosinic and 
polycytidylic acid, stabilized with polylysine and carboxymethyl cellulose. The thermal denaturation 
point is 89.5o C, about 40o C above that of plain polyI-polyC; the resistance to hydrolysis is several 
times that of the parent compound, and it induces peak levels of about 5000 IU of interferon per ml 
of serum in monkeys given 2 mg/kg intravenously. 
 
The current study will be conducted under IND #43984, held by Oncovir. The drug to be used in this 
study is prepared and packaged in the GMP facility of Dalton Pharma Svcs, Toronto, ON, Canada, 
under the direction and under contract to Oncovir. It is then tested for identity (RNAase resistance 
and thermal denaturation) bioactivity, sterility and pyrogenicity before release for clinical 
experimental use.   
 
FORMULATION: Supplied in 1 ml vials of 1.8 mg/ml opalescent solution/suspension = 1800 mcg/ml. 
 
STORAGE:  Should be refrigerated but NOT FROZEN. Stable at room temperature for 3 days. 
 
SOLUTION PREPARATION:  Solution is injected as supplied. 
 
ADMINISTRATION:  Administered as a single intramuscular injection twice per week.  


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Up to two doses can be obtained from the same vial. Instructions will be provided to 
patient/parents/guardian on how to draw, measure and administer the study medication. 
 
SIDE EFFECTS:  Discomfort at injection site, occasional malaise, myalgias, or fever. Rare transient 
leukopenia has been reported. At higher intravenous doses, transient liver enzyme and BUN 
elevations, and leukopenia have been reported. Idiosyncratic hypercoagulopathy has been reported 
in dogs at very high doses but has not been seen in humans. See investigator brochure. 
 
MAXIMAL TOLERATED DOSE: As reported in cancer trials, 250-300 micrograms/kg. 
6.2. Ordering 
The drug will be supplied by Oncovir and shipped to the UAB Investigational Drug Service (IDS), 
which is designated as the Central Pharmacy. The UAB IDS is responsible for the transfer and 
transportation of shipment of poly-ICLC to study sites. Transport of poly-ICLC to study sites must 
be pre-approved by the sponsor and IRB before any study drug will be transported. Poly-ICLC will 
be transported in accordance with specific storage requirements. 
 
When study drug is needed at a study site, an electronic ordering system is utilized for planned 
transport of study drug, with date and time specifications included in the request. To initiate an 
order, the UAB IDS ordering form will be sent to nfcop@uab.edu.    Once received, NFCTC will 
approve the order and forward to UAB IDS. UAB IDS will arrange the transportation to the 
requesting site. Poly-ICLC will be shipped out 3-7 business days after the UAB IDS ordering form 
is received. Once the study site receives the shipped product, the form must be completed and 
sent back to nfcop@uab.edu.  
 
       Drug Distribution Center - UAB Research Pharmacy 
o According to 21 CFR 312.6, UAB IDS will label the packaging of the investigational 
drug with the following statement: "Caution: New Drug - Limited by Federal law to 
investigational use". 
o UAB IDS will maintain records showing the receipt, shipment, and other pertinent 
information of the investigational drug including:  
• Name of the investigator to whom the drug is shipped 
• Date, quantity, and batch number of each shipment 
• Return, destruction, or other appropriate disposition of unused study drug 
 
UAB Research Pharmacy 
Attention: Chris Chapleau, PharmD, PhD, MBA | Pharmacy Manager/IDS Pharmacy 
North Pavilion | Room 3470 | 1802 6th Avenue South | Birmingham, AL, 35249 
Phone: 205.934.7191 or 205.975-0376 | Fax: 205.975.6647 
        
 
 
6.3. Drug Accountability 
The research pharmacist at each participating site will maintain records of all dispensed vials of study 
drugs. All unused vials will be returned to the manufacturer (Oncovir) at the completion of the study 
as well as all the drug accountability forms.  


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6.4. Dose Modifications for Toxicity 
Dose modifications below apply to toxicities that are at least possibly related to study drug. 
Laboratory results requiring drug hold must be repeated weekly or sooner if clinically indicated 
until they meet the criteria for restarting drug.  
 
Liver Toxicity 
 
If AST/ALT > 5x ULN while on study, poly-ICLC will be held until the AST/ALT ≤ 5x ULN; if resolved 
within 21 days, maintain the dose 20 mcg/kg/dose twice weekly.  
 
If event resolves >22-28 days, hold study drug until values < 2.5x ULN then restart at the reduced 
dose of 10 mcg/kg/dose twice weekly. 
 
If AST/ALT do not decrease to ≤ 5x ULN within 28 days (despite holding the drug for 28 days and 
only if elevated AST/ALT is attributable to the drug), then the study drug will be stopped, and 
participant will be off treatment for toxicity.  
 
It is recommended to evaluate other medications that participant is taking for potential liver toxicity 
(e.g. acetaminophen, trimethoprim/sulfamethoxazole, seizure medications). It is also recommended 
to evaluate potential viral liver infection if there is persistent elevation of AST/ALT. 
Elevations of AST/ALT are expected, and repeat elevations do not require permanent drug 
discontinuation unless deemed medically necessary by the treating physician after discussion with 
the principal investigator.  
 
Hematological Toxicities: Thrombocytopenia 
 
Continue drug at 20 mcg/kg/dose unless platelet count is less than 75,000/mm3. Then refer to the 
table below for further instructions.  
 
Platelet (Plt) < 75,000/mm3 
Interrupt study drug until Plt ≥75,000/mm3. If 
the event resolves within 21 days, then study 
drug may be restarted at the same dose.  
If Plt count of <75,000/mm3 attributable to the 
study drug, and the event resolves between 
22-28 days, then study drug may be restarted 
at lower dose of 10 mcg/kg/dose. If Plt is 
<75,000/mm3 after 28 days and at least 
“possibly” attributed to study drug, the 
participant will be taken of protocol therapy. 
  
Transient and repeated thrombocytopenia is 
expected and does not require permanent 
removal from study therapy unless deemed 
medically necessary by the treating physician 
after discussion with the principal investigator 
or study team.  
 
Hematological Toxicities: Neutropenia 


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Continue drug same dose until absolute neutrophil count (ANC) is less than 750/mm3, then refer 
to the table below for further instructions. 
 
ANC < 750/mm3 
Interrupt study drug until resolution to ≥ 
750/mm3. If the event resolves within 21 
days, then study drug may be restarted at 
the same dose. If event resolves between 
days 22 and 28, restart at lower dose of 10 
mcg/kg/dose.  
 
If ANC is < 750/mm3 greater than 28 days 
after dose reduction, and and at least 
“possibly” attributed to the study drug, the 
participant will be taken off protocol 
therapy.  
 
Transient and repeated neutropenia is not 
unexpected and does not require permanent 
removal from study therapy unless deemed 
medically 
necessary 
by 
the 
treating 
physician after discussion with the principal 
investigator or study team. 
 
All other adverse events (suspected to be related to the study drug)  
 
Grade 1-2  
Grade 1 AE continue drug same dose 20 
mcg/kg/dose. Provide specific therapy to 
address symptoms.  
 
If the event is an intolerable Grade 2 AE, not 
responsive to a specific therapy, consider 
study drug interruption until resolution to 
Grade ≤1. If the event is clinically significant 
and resolves within 21 days, then study 
drug may be restarted at same dose. If 
event resolves between days 22 and 28, 
restart at a lower dose of 10 mcg/kg/dose. 
If the patient continues to have grade 2 
intolerable toxicity despite dose reduction 
and providing specific therapy to address 
symptoms, 
protocol 
therapy 
will 
be 
permanently discontinued.  
Grade 3 and Grade 4  
Interrupt study drug until resolution to 
Grade ≤1. If the event resolves within 21 
days, then study drug may be restarted at 
the same dose. If event resolves between 
days 22 and 28, or the patient has a repeat 
grade 3 or grade 4 event, restart at lower 
dose of 10 mcg/kg/dose. If toxicity returns 


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to grade 3 or 4 after drug reduction, protocol 
therapy will be permanently discontinued.  
 
6.5. Concomitant Medications 
Non-enzyme inducing anticonvulsants may be given as clinically indicated. Enzyme inducing 
anticonvulsant agents should be avoided if possible. See Appendix 5 for a list of the enzyme inducing 
anticonvulsant agents.   
 
During the trial, corticosteroids may be given as clinically indicated in the lowest possible dose per 
treating physician discretion. However, if the dose of steroids is increased while on therapy due to 
worsening of neurological symptoms, MRI of primary tumor is recommended to evaluate for disease 
status.  
 
Acetaminophen and NSAIDS (ibuprofen, naproxen) may be given as needed to control poly-ICLC 
side effects.  Use of ibuprofen or other NSAIDS during thrombocytopenia less than 50,000 /mm3 
should be avoided. Other instructions on the use of NSAIDS in this setting will be per treating 
physician discretion. 
 
Vitamins at the daily recommended dosage are allowed while on study treatment. Other 
supplements, including cannabidiol-containing compounds, are not recommended. 
 
For additional information on concomitant medications, see Investigator Brochure. 
 
Radiotherapy or other-directed tumor therapy are not allowed in the trial.  
 
Appropriate antibiotics, GCSF (Granulocyte Colony Stimulating Factor), blood products, 
antiemetics, fluids, electrolytes and general supportive care are to be used as necessary and as 
per institutional guidelines.  
 
PJP (formerly PCP) prophylaxis will be given following institutional guidelines based on absolute 
lymphocyte count.  
 
Given the risk of intratumoral hemorrhage with thrombocytopenia, a platelet transfusion should 
be considered if the platelet count is < 25,000/mm3. Higher transfusion parameters may be used 
if clinically indicated. All blood products will be leukocyte depleted and irradiated to prevent graft-
versus-host disease.  
 
Influenza vaccine administration: Inactivated Influenza vaccine can be given to patients on study, 
but it is recommended that it not be given the same day as study drug. 
 
Other vaccinations must be approved by the Protocol Chairs. 
 
6.6. Toxicity 
  
See the current Investigator’s Brochure for a complete list of expected toxicities.  
 


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1. Discomfort at IM injection site: The most common adverse effect is mild, transient discomfort 
at the site of IM injection. With subcutaneous (SC) injections, there is a transient mild to moderate 
grade 1 or 2 erythematous skin reaction.3 
 
2. Flu-like symptoms: Approximately 8 to 12 hours after doses of 10 to 50 mcg/kg IM, patients 
may develop a mild flu-like syndrome with fever of less than 39 ºC, which may last for about 12 
hours, but responds readily to acetaminophen or ibuprofen. Mild myalgia, arthralgia, sometimes 
nausea, and malaise can be present during this period. This flu-like syndrome typically diminishes 
markedly after the first few poly-ICLC treatments. On rare occasions in the course of treatment, 
patients who have been tolerating treatment uneventfully may develop an earlier, more 
pronounced fever with chills and malaise (typical of higher dose IV poly-ICLC) in response to an 
IM injection. This will typically resolve over 12 to 24 hours, responds to acetaminophen, and does 
not typically recur on subsequent dosing. 
 
3. Hematologic abnormalities: Several cases of transient leukopenia have been reported at 
higher doses. High dose Poly-ICLC has been associated with a coagulopathy in dogs, but not in 
other species including primates. There has been no change in the expected incidence of deep 
venous thrombosis, pulmonary embolus, or coagulopathy in multiple sclerosis, AIDS or malignant 
glioma patients on low dose IM poly-ICLC. One paralyzed multiple sclerosis patient treated with 
100 mcg/kg IV suffered a fatal pulmonary embolus, which was not judged to be due to the drug. 
 
4. Hepatic enzyme elevation: Mild and typically transient hepatic enzyme elevation has been 
described in poly-ICLC when given intravenously at doses from 20 to 100 mcg/kg. Preclinical 
studies have shown increased hepatic NK cells, as well as suppression of the P450 hepatic 
enzyme system by poly-ICLC, but the clinical implications of this finding are not clear. 
 
5. Seizures: Seizures during high febrile episodes have been reported with glioma and known 
seizure disorder.   
 
6. Diarrhea: Grade 1-2 diarrhea has been reported in brain tumor patients receiving IM Poly-ICLC 
two to three times weekly for months. 
 
7. Tuberculosis (TB) in Mice: Mouse studies have reported a risk of worsening of TB in mice 
already infected with TB that are treated with Interferon or with poly-ICLC. Temporary worsening 
of TB has also rarely been reported in patients treated with high doses of interferon.  
 
8. Transient anaphylactic reaction: There have been reports of transient anaphylactic reaction 
to the combination of a personalized glioma vaccine, GM-CSF, and poly-ICLC in glioblastoma 
patients. GM-CSF is known to cause anaphylaxis, but there have been no previous such reports 
in patients receiving poly-ICLC alone or with other vaccines. 


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9. Transient peritumoral edema: In a pilot brain tumor trial, a few patients showed an increase 
in gadolinium enhancing lesions after 3 - 6 months of IM poly-ICLC, followed by an apparent tumor 
response at 6 - 12 months and prolonged survival on continued treatment. Dexamethasone was 
used as needed in the first few months of treatment on that study. In a more recent follow-up open 
study in patients with advanced recurrent gliomas, several patients have shown increased 
peritumoral edema after several weeks of poly-ICLC therapy. This has resolved in all cases on 
continued poly-ICLC, with or without concomitant steroids. Biopsy data in at least two patients 
treated with poly-ICLC also showed a peritumoral inflammatory response. Likewise, in a dendritic 
cell vaccination trial in recurrent glioma patients with twice-weekly application of poly-ICLC IM, 
remarkable post-vaccination immune cell infiltration into the tumor was seen. These findings are 
commonly reported with other immunotherapies, and they raise the possibility that poly-ICLC may 
at times be facilitating a relatively early immunologic response to the tumor, perhaps manifested 
by transient increased edema or gadolinium enhancement. In line with this, one case of post-
vaccination brain edema (Grade 3) possibly related to poly-ICLC adjuvant vaccination of a multi-
peptide vaccine was reported from a Phase I trial in glioblastoma. 
 
7. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
This protocol involves extensive correlative studies to gain fundamental insights into the effects 
of poly-ICLC on the circulating immune cells and whenever possible tumor infiltrating immune 
cells. The proposed studies may help understand correlates of response in NF1 patients with 
LGG who are treated with poly-ICLC. 
 
Specimens: 
Both blood and tissue specimens (if available) will be analyzed. 
 
Time-points for mandatory biological studies: 
Baseline; cycle 1 day 8 and day 15; day 1 of cycles 3, 6 and 12; and at end of therapy or 
progression. Additional samples will be collected at 3 time points when participant is off therapy:  
3 months, 12 months and at the time of progression. See Appendix 6. We will collect 5-10ml of 
blood per sample in sodium heparin tubes for patients < 8 years of age. For patients that weigh 
less than 10 kg, collect 2 ml on cycle 1 day 8. For patients ≥ 8 years, we will collect 10-15 ml. 
Biological samples should be drawn within 24 hours prior to the next study dose (when applicable) 
whenever possible. No biological samples should be drawn on a Friday. Samples should be 
shipped at room temperature.  Biological samples should not be obtained through a finger 
stick. These samples will be processed at Emory University.   
 
 
 


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Figure 6: Research Sample Collection Schedule 
 
Mandatory Biological Specimens 
Single cell mass cytometry or CyTOF will be used for phenotypic characterization of circulating 
as well as tumor infiltrating immune cell populations, using a 36-marker panel that we have 
developed. Fig 5 shows enrichment of myeloid cells within glioma tumor tissue using multi-
parameter analytic platforms such as ViSNE, which can be utilized to analyze mass cytometry 
data.  
 
Functional assays: We will perform T cell proliferation as well as characterize cytokine secreted 
by T cells before and after poly-ICLC therapy. We are particularly interested in understanding the 
changes in antigen specific Tcell responses which has been shown to be important for glioma 
initiating/stem cells. 
 
Multiplex Luminex ELISA: We will assess changes in plasma cytokine milieu, including 
circulating cytokines IL6 and TNFα.  
 
Optional Pre and post treatment tissue and blood samples: 
When available, fresh frozen and/or FFPE tumor sample is requested (either from surgical 
resection within 6 months prior to enrollment, during study therapy and/or progression). Blood 
sample will be collected at the time of surgical resection. These samples will be stored in a tissue 
bank located at Children’s Hospital of Philadelphia for future use studies. See Appendix 7. 
 
Tumor and Blood samples left over from the biological correlates drawn at any of the above 
time points may be banked for future research. 
 
 
 
8. QUALITY OF LIFE (QOL) STUDIES AND NEURO-COGNITIVE BATTERY 
Brief Background: Mounting literature suggests that pediatric cancer survivors are negatively 
affected by persisting and clinically significant late-effects due to cancer and its treatment. 
Compared to other diagnoses, CNS-tumor survivors are at highest risk for neurocognitive, 
psychological, cardiopulmonary, endocrine, and musculoskeletal complications and second 
malignancies. Only limited data describe pediatric LGG and/or NF outcomes, despite their 


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prevalence.38-41 Extant research describes HRQOL impairments for adults with a LGG39,40 and, 
while not methodologically robust (i.e., small sample size, retrospective design, lack of validated 
PROs), preliminary research in PLGG survivors provides evidence of cognitive decline, learning 
disability, and adjustment difficulties following treatment.41-45 For youth with refractory or 
progressive pediatric brain tumors especially, longer life may come at significant cost in morbidity 
and health-related quality of life (HRQOL). Use of both patient-reported outcomes (PROs), data 
collected “directly from the patient, without interpretation of the patient’s response by a clinician46 
and objective performance-based measures to monitor potential neuro-toxicity are critical to 
understanding the impact of new treatments on a child’s general functioning. Novel treatments 
that increase survival while also maintaining HRQOL are highly desirable.47-50 
 
Diagnosis and subsequent treatment may result in impaired neurobehavioral functioning or, given 
its relatively encouraging prognosis, may not result in adverse outcomes directly. Rather, as 
suggested by the Human Evolutionary Response to Trauma/Stress (HEART) model,51 insult to 
the child’s developing nervous system (i.e. as measured by the parent proxy reported executive 
functioning measure)  may moderate the relationship between diagnosis/treatment and long-term 
functioning (Figure 7). Guided by the HEART theoretical model, a complementary battery of 
measures was selected whereby the patient is embedded within the family and larger social 
systems.52 Given a growing literature suggesting a cancer diagnosis may also result in 
growth/positive adjustment, measures of both negative and positive psychological functioning 
were selected. Factors have broad support in previous literature and are highly salient to existing 
interventions.53-55 In the event the cognitive battery or self-report PRO battery cannot be 
completed due to intellectual disability (i.e., known IQ ≤ 70 by medical record review), informant 
PRO measures will still be completed. Measured constructs and their corresponding measure are 
briefly described in Table 6. All measures are psychometrically sound; appropriate validity, 
reliability, and normative data is available for all ages proposed.  
8.1. Patient Reported Outcome Battery 
Children and adolescents will complete a PRO 
measurement battery (by patient age; Table 7) prior to first 
dose at treatment initiation. cycle 6, cycle 12, end of 
treatment (cycle 24) or progression and when applicable, at 
24 months post completion of therapy (+/-5 days). Of note, 
safety and suicidal ideation will not be assessed; however, 
negative affect items will be reviewed, and each site notified 
of elevated scores. A trained study team member 
(supervised by a licensed clinical psychologist) will be 
available to assist younger children with PRO questionnaire completion as needed.  
 
Time to complete the complete the PRO battery (treatment initiation, cycle 6, cycle 12, cycle 24 
or time of progression, 24 months post completion of treatment) varies by age: Young Child (3-
7y) = 0 minutes; Child (8-17y) = 27-37 minutes; Adult (≥18y) = 32-42 minutes, Parent/Informant 
= 35 minutes. The demographic questionnaire (5 minutes) will be completed at baseline only by 
adult patients and parents/informants.  
 
PROs will be administered via paper form, iPad using the NIH Toolbox App and the eDCS, a 
secure, web-based application designed to support data capture for research studies. Similar to 
other data collection programs, both eDCS and the NIH Toolbox App provide a questionnaire 
response system designed to collect sensitive information to reduce social desirability.58 
Figure 7: HEART Model, Adapted 


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Participant responses are entered directly into the computer program, minimizing data entry errors 
and/or multiple responses to items. This method of measure administration has been used 
successfully in other pediatric research protocols at pediatric institutions.   
 
Table 6. Patient-Reported Outcome Battery by Age (years) 
CONSTRUCT CHILD: 8-17 
YOUNG ADULT: ≥ 18  
PARENT/INFORMANT (of all patients) 
HRQOL 
Pediatric Quality of Life Inventory (PedsQL 4.0): physical, emotional, social, and school/work 
HRQOL; self- and proxy report  
Executive 
functioning 
— 
— 
Behavior Rating Inventory of Executive 
Function (BRIEF-2): inhibit, plan/organize, 
emotional control, working memory, 
organization, etc.  
Negative 
Affect 
PROMIS  Depression, Anxiety, Anger:  fear, sadness, anger; self- and parent proxy report (CAT)  
Psychological 
Well-Being 
PROMIS  Positive Affect, Life Satisfaction:  positive affect, life satisfaction; self- and parent proxy 
report (CAT)  
Stress & Self-
Efficacy 
PROMIS Stress Experiences/Psychosocial Impact and Self-Efficacy perceived stress, self-efficacy; 
self- and parent proxy report (CAT)  
Social 
Relationships 
PROMIS Peer and Family Relationships/Companionship and Emotional Supportsocial support, 
companionship, social distress; self- and parent proxy report (CAT)  
Fatigue 
PedsQL Multidimensional Fatigue Scale: general fatigue, sleep and rest fatigue, cognitive fatigue; 
self- and proxy report  
Adverse 
Symptoms 
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE™): NCI patient-reported outcome measure of adverse events in patients on clinical 
trials  
Social 
Attainment  
— 
Demographic Questionnaire: will collect information re. socio-
demographic status, education/vocational attainment, independent 
living, Supplemental Security Income (SSI), supportive services, etc. 
Baseline only 
Note. Items for PROMIS scales will vary; computer adaptive testing (CAT) will be utilized to minimize the number 
of items required to be completed. 
 
*IMPORTANT ADMINISTRATION GUIDELINES: English and Spanish translations of all 
measures below will be utilized. There are different PRO forms based on patient age as 
described below. The participant will complete the questionnaire according to the age they are 
on the date of survey completion.   
 
PedsQL 4.0 Core Scale and PedsQL Multidimensional Fatigue Scale. For this study, patients 8-
25 years old will complete the PedsQL self-report measures. Parents or informants of patients 
2-25 years of age will complete the PedsQL parent proxy report measures. Parents/informants 
will complete proxy forms by the following patient age: toddler: 2 – 4 years; young child: 5 – 7 
years; child: 8 – 12 years; adolescent: 13 – 17 years; young adult: 18 - 25 years. Patients will 
complete parallel self-report forms by patient’s age: child: 8 – 12 years; adolescent: 13 – 17 
years; young adult: 18 – 25 years.   
 
NIH Toolbox PROMIS Measures. Patients 8-25 years old will complete the PROMIS self-report 
measures. Parents or informants of patients 2-12 years of age will complete the PROMIS parent 
proxy report measures. Parents/informants will complete proxy forms by the following patient 
age: young child: 3–7 years (Anger, Fear Sadness, Positive Affect, General Life Satisfaction, 
Positive Peer Interaction), child: 8-12 years (Anger, Fear Sadness, Positive Affect, General Life 
Satisfaction, Perceived Stress, Self-Efficacy, Positive Peer Interaction). Patients will complete 
parallel self-report forms by patient’s age: child 8-17 years (Anger, Fear Sadness, Positive 
Affect, General Life Satisfaction, Perceived Stress, Self-Efficacy, Emotional Support, 


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Friendship) and adult 18-25 years (Anger (Affect), Fear (Affect), Sadness, Positive Affect, 
General Life Satisfaction, Perceived Stress, Self-Efficacy, Emotional Support, Friendship).  
 
Behavior Rating Inventory of Executive Function. Parents or informants of patients 5-25 years 
will complete the BRIEF by patient age: 5-18 BRIEF2 Parent Report, 19-25 BRIEFA Adult 
Informant Report. 
  
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE). Patients will complete the following forms by patient age: Peds PRO-CTCAE: 8-
17 years, PRO-CTCAE: 18-25 years. Parents or informants of patients 3-7 years of age will 
complete the Peds PRO-CTCAE Caregiver parent proxy report measure. 
 
 
 
9. OPHTHALMOLOGIC STUDIES 
For patients with tumors involving the optic pathway (including suprasellar/hypothalamic tumors) 
all of the assessments in this section are mandatory. For patients with tumors not involving the 
optic pathway, ophthalmologic examinations are at the discretion of the treating physician.   
 
For patients with optic pathway gliomas, the study examinations should occur at baseline, after 
cycle 3 (+/-2 weeks) then every 3 months while on therapy (+/- 2 weeks), and every 3 months for 
the first year off therapy (+/-4 weeks), and every 6 months (+/-4 weeks) thereafter for the following 
2 years, then yearly (+/-6 weeks) for years 4 and 5.   
  
The following functional assessments should be performed (see Appendix 11): 
· Teller Acuity Cards (TAC, all participants) 
· HOTV (in participants developmentally able to perform) 
· Visual fields to confrontation 
· Optic disc appearance 
9.1. Visual Acuity (best corrected) 
IMPORTANT NOTE: if the VA data at a particular visit is felt to be unreliable due to poor 
cooperation, testing should be repeated within 4 weeks. Only the visit believed to have yielded the 
most reliable data should be reported.  
  
Teller acuity testing using TAC II cards will be attempted on all participants at all visits. All VA 
testing will be performed by study personnel who have undergone TAC teaching by the study team. 
VA testing will be performed in each eye separately at a distance of 55 cm in all participants. The 
tester will utilize the “Two down, one up” protocol to achieve the best visual acuity. Acuity will be 
reported in cycles/cm by the site and converted by the operations center to logMAR. Reasons for 
VA testing not being completed will be recorded. 
  
Table 8: Visual acuity in feet and logMAR equivalents for acuity in cycles/cm 
Card @ 55 cm 
(Cycles/cm) 
VA 
equivalent 
logMAR 
26 
20/24 
0.06 
19 
20/32 
0.20 
13 
20/47 
0.36 
9.8 
20/63 
0.49 


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6.5 
20/94 
0.66 
4.8 
20/130 
0.80 
3.2 
20/190 
0.97 
2.4 
20/260 
1.10 
1.6 
20/380 
1.27 
1.3 
20/470 
1.36 
0.86 
20/710 
1.54 
0.64 
20/960 
1.67 
0.43 
20/1400 
1.84 
0.32 
20/1900 
1.97 
 
HOTV will be attempted on participants who are old enough. HOTV will be performed using the 
PEDIG ATS-HOTV computerized protocol in each eye separately at a recommended testing 
distance of 3 meters in all participants. Acuity will be reported in logMAR. Reasons for VA testing 
not being completed will be recorded. 
  
For primary analysis, the VA endpoint will be the difference between best-corrected VA at 
baseline and at approximately 1 year (i.e., at the post-cycle 12 assessment). 
  
9.2. VA Norms  
Note: The rate of visual development varies across patients. The table is presented as a reference 
only. 
  
Table 9: VA Norms 
Age 
Grating acuity by TACII 
Recognition Acuity 
  
Normal VA 
(cy/cm)  
logMAR 
  
Snellen 
Equivalent § 
Normal VA 
(feet) 
logMAR 
6m 
2.4 
1.097 
20/260 
  
  
12m 
3.2 
0.972 
20/190 
  
  
18m 
4.8 
0.796 
20/130 
  
  
24m 
4.8 
0.796 
20/130 
  
  
30m 
6.5 
0.664 
20/94 
  
  
36m 
9.8 
0.486 
20/63 
  
  
42m 
13.0 
0.363 
20/47 
  
  
48m 
  
  
  
20/32 
0.2 
5yo 
  
  
  
20/25 
0.10 
≥6yo 
  
  
  
20/20 
0.00 
 
¶ Normal VA with TAC [low limit of normal at 95% CI]  
§ Conversion of grating acuity to Snellen equivalents is not recommended and is only provided 
for purposes of communication. 
 
9.3. Visual Fields 
Visual field testing will be performed by confrontation and reported as the number of quadrants 
(0, 1, 2, 3, or 4) with VF deficits.  
  


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9.4. Optic Disc Appearance 
Optic discs will be assessed for the presence or absence of pallor and edema.   
 
9.5. Visual Response 
Primary functional outcome is based on visual acuity (VA) and is defined as the difference in in 
VA after approximately 12 cycles of treatment. Eyes above the visual “ceiling” (0.2 logMAR 
below normal for age or 0.2 logMAR below a previous reliably documented VA) at baseline 
cannot improve and will be excluded from the analysis of visual response. A significant 
improvement in VA will be defined as a decrease of ≥ 0.2 logMAR (corrected for age) from 
baseline (pre-treatment baseline) to end of ~12 cycles of treatment. The analysis will be based 
on per participant outcome (rather than per eye).  
 
A significant improvement in VA will be defined as a decrease of ≥ 0.2 logMAR from baseline 
(pre-treatment baseline) to end of ~12 cycles of treatment.  
 
Ophthalmologic (Visual Acuity) Response Criteria  
∙ Visual Responsive ≥ 0.2 logMAR improvement in VA compared to baseline  
∙ Stable VA = does not meet criteria for Improved or Worsening VA compared to baseline  
∙ Visual Progressive Disease ≥ 0.2 logMAR worsening compared to baseline*  
 
* 0.2 logMAR worsening (or up to a 2-card drop in Teller Acuity) will not be considered visual 
progressive disease at the first on-therapy staging evaluation (at 12 weeks), if the tumor is 
stable or smaller on MRI. In these cases, a repeat visual acuity assessment will be required 6-
12 weeks later to confirm that further visual progression is not occurring. If the repeat visual 
acuity is stable or improved (0.2 logMAR or less [or a 2 card drop in Teller Acuity or less] from 
pre-treatment baseline), the patient will remain on protocol therapy. If the visual acuity is now > 
0.2 logMAR (or > 2 card drop in Teller acuity) worse from pre-treatment confirmed by a second 
exam, then the participant will be removed from the protocol.   
 
Visual worsening ≥ 0.2 logMAR in the setting of possible pseudoprogression should be 
discussed on a case-by-case basis with the study chair.  In most cases, patient may 
continue on study until pseudoprogression vs progression is confirmed. Corticosteroids 
may be considered, and a short interval repeat eye exam is recommended. If a repeat vision 
exam shows continued deterioration of visual function, then patient will be permanently removed 
from therapy and the time of progression will be the date of the initial MRI or vision exam showing 
progression. See section 10.4 for additional information regarding possible pseudoprogression. 
 
 
10. IMAGING PARAMETERS AND RESPONSE CRITERIA 
10.1. General Considerations  
Patients with NF1-associated LGG may have multiple lesions; typically, however, decision to treat 
is based on a clinical or radiographic progression of a single lesion.  If multiple measurable lesions 
are present, ONE should be selected as the “target” lesion. The overall response assessment 
takes into account response in the target lesion only.  The target lesion should be the same as 
the target tumor identified for eligibility confirmation (section 3.1), and should be selected on the 
basis of clinical relevance, size, and suitability for accurate repeated measurements. The lower 


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size limit of the target lesion should be at least twice the thickness of the slices showing the tumor 
to decrease the partial volume effect (e.g., 8 mm lesion for a 4 mm slice). 
 
Up to 2 additional lesions may be followed as non-target lesions. Any change in size of non-target 
lesions should be noted. The response to non-target lesions will be evaluated independently of 
the response of the target lesion but will not be included in the primary response assessment. 
 
Development of new lesions is not considered progressive disease for this study.   
 
10.2. Measurement of Effect  
Methods for Evaluation of Measurable Disease: Whole Brain MRI With and Without Contrast. 
For patients with optic pathway gliomas, orbital cuts are necessary. For target tumors outside the 
brain (i.e. spinal cord), clinically appropriate imaging modalities may be added or substituted.  
 
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-up. This 
longest measurement of the tumor is referred to as the width (W).  
 
2. The perpendicular measurements should be determined − transverse (T) measurement, 
perpendicular to the width in the selected plane.  
 
3. The cystic components of a tumor are considered in tumor measurements.  
 
4. Leptomeningeal tumor spread is usually not a target lesion, and usually cannot be measured 
accurately. Presence and location of leptomeningeal tumor spread should be noted and change 
in extent/thickness assessed on follow up studies.  
 
Imaging Response Criteria for Target Lesion  
 
Response criteria are assessed in 2 dimensions – the product of W x T.  
Baseline measurements should include the longest diameter and the longest perpendicular 
diameter. These same 2 measurements should then be followed throughout therapy.  
 
For example, if anterior-posterior (AP) is the longest diameter and cranio-caudal (CC) is the 
longest perpendicular diameter, and then AP and CC should be followed throughout therapy for 
that lesion. 
 
To assess response/progression/relapse, the ratio is calculated:  
 
W x T (current scan) /  W x T (reference scan) 
 
Imaging: Standard MRI evaluation is required for disease evaluation as per institutional imaging 
parameters. Both 1.5T and 3.0 T magnets are acceptable.  
 
Additional Imaging Studies: MR diffusion-weighted imaging (DWI), dynamic contrast-enhanced 
(DCE), and T1 permeability perfusion MRI, and MR spectroscopy (MRS) are recommended as 


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part of standard of care at each evaluation period. The data obtained from these studies will be 
correlated with patient response and outcome.  
 
The following sequences incorporate the standard CNS imaging protocol. Institutional brain tumor 
or solid tumor imaging protocols can be substituted as long as similar disease evaluation is 
possible.   
 
10.3. Imaging Sequences 
Table 10: Imaging Sequences 1.5 T 
 
Sequence 
Slice 
Thickness 
TR 
(ms) 
TE (ms) 
TI 
(ms) 
Directions 
B0 
 
FOV 
(cm) 
Matrix 
Sagittal T1 
5 mm skip 1 
400 
9 
 
 
 
22 
256 x 256 
Axial FSE T2 
2 mm skip 0 
3800 
102 
 
 
 
20 
256 x 256 
Axial T2 FLAIR 
4 mm skip 0 
10000 
160 
2200 
 
 
20 
256 x 224 
Axial diffusion 
2.5 mm skip 
0 
 
 
 
12-30 
1000 
26 
128 x 128 
single shot 
Sagittal T2 
3 mm skip 1 
3800 
102 
 
 
 
22 
256 x 256 
Axial MPGR 
4 mm skip 0 
 
 
 
 
 
 
 
 
Axial T1 
4 mm skip 0 
 
500 
min 
 
 
 
 
20 
320 x 224 
Axial T1 with 
Contrast 
4 mm skip 0 
 
500 
min 
 
 
 
 
20 
320 x 224 
Sagittal T1 
FSPGR with 
contrast 
1.5 mm skip 
0 
 
 
min, flip 
angle 
15  
 
 
 
 
24 
256 x 256 
T1 permeability 
perfusion 
sequence 
5 mm skip 0 
(See below) 
 
 
 
 
 
 
 
 
Single-voxel MR 
Spectroscopy 
PRESS 
Volume: 
15x15x15 
mm3 
 
1500
ms  
 
35ms  
 
 
 
 
 
 
 
 
Table 11: Imaging Sequences 3.0 T 
Sequence  
Slice Thickness  
TR (ms)  TE (ms)  
Directions  
Sagittal T1 MPRAGE  
1.0 mm skip 0  
2530 
 
 
Sagittal T2  
3.0 mm skip 1.0 mm  
 
 
 
Axial T2  
2.5 mm no skip  
11730 
91 
 
Axial T2 FLAIR  
4 mm, no skip  
9000 
137 
 
Axial diffusion  
2 skip 0  
9100 
88 
30 
Sagittal MPRAGE  
1.0 mm no skip  
 
 
 
Axial T1 post contrast  
4.0 mm skip 0  
650 
9.7 
 
Axial SWI  
1.25 mm no skip  
 
 
 


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T1 permeability perfusion 
sequence  
5 mm skip 0 (See 
Below)  
 
 
 
Single-voxel MR 
Spectroscopy PRESS  
Volume: 15x15x15 
mm3  
2000 
ms  
35ms  
 
 
T1 Permeability Imaging  
T1 permeability should begin with a set of T1 maps with flip angles of 2, 5, 10, and 15 followed 
by the T1 permeability sequence. After the T1 map sequence with 15-degree flip angle, start 
the T1 permeability series and 20 seconds into it inject 0.1 mmol/kg of intravenous contrast. 
See below. 
 
Table 12: 3D T1W Specifications for T1 Maps and Dynamic Series 
 
Table 13: T1 Maps/DCE 
Series Name 
Sequence 
Flip Angle 
Notes 
T1 map15  
3D fast GRE  
15 degrees  
Axial, 2 NEX  
T1 map10  
3D fast GRE  
10 degrees  
Axial, 2 NEX  
T1 map05  
3D fast GRE  
5 degrees  
Axial, 2 NEX  
T1 map02  
3D fast GRE  
2 degrees  
Axial, 2 NEX  
T1 DCE  
Dynamic Series, 
3D fast GRE  
15 degrees  
Axial, 1 NEX,  
inject 20 sec into this  
 
Sequence Type 
Spoiled Gradient Echo 
Imaging mode  
3D  
Slice orientation  
Axial  
Frequency direction  
A/P  
Phase direction  
R/L  
FOV - frequency  
220 mm  
FOV - phase  
220 mm  
Matrix - frequency  
256  
Matrix - phase  
160-192  
In-plane resolution  
≤ 1 mm  
Fat-suppression  
No Fat Sat  
TR  
~4 msec  
TE  
Less than 2 msec or min full  
TI (STIR sequence)  
N/A  
Flip Angle  
DCE -15 degrees; T1 maps - 2, 5, 10 and 15  
Slice thickness (acquired, not 
interpolated)  
5mm, maximum 6mm  
Number of slices  
Minimum 10 prior to zero fill  
Slice Gap  
No gap  
Parallel imaging factor  
≤ 2  
Number of averages  
1 for DCE, 2 for T1 maps  
k-space ordering  
standard, non-centric  
Temporal Resolution of “T1 DCE”: 
(seconds per phase/measurement)  
≤ 6 seconds  
“T1 DCE” imaging duration  
≥ 5 minutes  


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10.4. Imaging Response Assessment    
The overall response assessment takes into account response in the target lesion ONLY. 
The response in the non-target lesions will be evaluated independently from the response for the 
TARGET lesion.  
 
Note: Participants with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as "symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment.  
 
Evaluation of Target Lesion  
 
• Complete Response (CR) Complete disappearance of the target lesion on T2 weighted and T2 
weighted fluid attenuated inversion recovery (FLAIR) imaging and contrast imaging using baseline 
MRI or best recorded response for comparison. Overall, the patient must be clinically stable or 
have improved on physical examination and functional or neurological assessment. 
 
• Partial Response (PR): a 50% or greater reduction in the target lesion on T2 weighted and T2 
weighted-FLAIR imaging using the baseline MRI for comparison. Overall, the patient must be 
clinically stable or have improved on physical examination and functional or neurological 
assessment.   
 
• Minor Response (MR): a 25-49% reduction in the target lesion on T2-weighted and T2-
weighted-fluid-attenuated inversion recovery imaging using the baseline MRI or best recorded 
response for comparison. Overall, the patient must be clinically stable or have improved on 
physical examination and functional or neurological assessment.   
 
• Stable Disease (SD):  An increase or a decrease in the target lesion that is not sufficient to 
qualify as progressive disease or responsive disease (partial response or minor response), 
respectively. Overall, the patient must be clinically stable or have improved on physical 
examination and functional or neurological assessment.   
 
• Progressive Disease (PD):  A greater than 25% increase in the target lesion, usually assessed 
on T2-weighted and T2-weighted FLAIR using the baseline MRI or best recorded response for 
comparison. A determination of PD may be deferred if pseudoprogression is suspected (see 
“Consideration for possible pseudoprogression / treatment-related effect” below). Given the 
possibility of pseudoprogression with immunotherapy, a short interval MRI at the discretion of the 
treating physician is recommended for participants with PD.    
Note that the appearance of new discrete lesions should be noted, but is not considered 
progressive disease. See section 3.5 regarding off therapy and off study criteria for patients 
requiring therapy for new or progressive non-target lesions.  
 
See section 9.5 for definition of visual progressive disease. For progressive disease by clinical 
criteria, confirmatory imaging studies should be obtained when feasible.  
 
• Unevaluable (UN): Assessment of target lesion cannot be made due to insufficient or 
unevaluable data. In this case, a concise explanation must be given.  
 
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Immunotherapy may be associated with transient inflammatory-mediated increase in tumor size, 
or “pseudoprogression.” In many cases, it may not be initially possible to distinguish true 
progression from pseudoprogression. 
 
Where pseudoprogression is suspected in a patient who meets criteria for PD, the patient may 
continue on study therapy. A shorter interval repeat MRI may be performed if clinically indicated 
but is not required. Corticosteroids may be considered for symptomatic patients. See section 9.5 
for additional information regarding visual symptoms due to suspected pseudoprogression. 
  
If the tumor size is stable or smaller on repeat imaging, and any signs and symptoms related to 
progression vs pseudoprogression are stable or have improved, patient may remain on study and 
continue protocol therapy. If the repeat MRI shows continued disease progression, then patient 
will be permanently removed from therapy and the time of progression will be the date of the initial 
MRI showing progression.  
 
10.5. 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 
recurrence or PD is objectively documented, taking as reference for PD the smallest 
measurements recorded since the treatment started.  
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that recurrent 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.  
 
Progression-Free and Overall Survival: Progression-Free Survival (PFS) is defined as the 
duration of time from patient enrollment to time of objective disease progression or death from 
any cause.  
 
Overall Survival (OS): Overall survival is defined as the duration of time from patient enrollment 
to time of death from any cause. 
 
10.6. Central Review  
Central imaging review for response evaluation will be performed at the conclusion of the trial. 
Optional imaging studies will also be reviewed.  Real time response determination will be made 
by the site investigator based on the local MRI read.  For assistance with response 
determinations, a real-time MRI review may be requested in consultation with the study chair. In 
addition to the primary RAPNO response determinations, response assessments will also be 
made using RANO criteria. RANO response assessments will be used to satisfy the exploratory 
response comparison objective only, and will not be used for the primary response determination. 
RANO criteria are as described by Wen et al. 56 
  


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10.7. Ophthalmologic (Visual Acuity) Response Criteria 
See section 9.5 regarding visual response criteria.   
See “Consideration for possible pseudoprogress/treatment-related effect” in section 10.4 
regarding management of pseudoprogression.   
 
11. ADVERSE REPORTING REQUIREMENTS 
11.1. Definitions 
Adverse Events: An adverse event is any new, undesirable medical occurrence or change 
(worsening) of an existing condition in a participant that occurs from study enrollment until 30 
days after drug discontinuation, whether or not considered to be product related. Therefore, 
adverse events are treatment emergent signs or symptoms. Elective hospitalizations for 
pretreatment conditions (e.g., elective cosmetic procedures) are not adverse events. Non-
clinically significant abnormal laboratory values should not be reported as adverse events; 
however, any clinical consequences of the abnormality should be reported as adverse events.  
All adverse events must be noted on the electronic case report forms and submitted via eDCS 
within 2 weeks of completion of every treatment cycle. 
 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification (within 24 hours) to 
the site PI and clinical coordinator, as well as the NFCTC Operations Center. Follow-up of the 
adverse event, even after the date of therapy discontinuation, is required if the adverse event 
or its sequelae persist. Follow-up is required until the event or its sequelae resolve or stabilize 
at a level acceptable to the investigator and sponsor. 
 
Serious Adverse Events: A serious adverse event is defined by regulatory agencies as one 
that suggests a significant hazard or side effect, regardless of the investigator’s or sponsor’s 
opinion on the relationship to investigational product. 
 
This includes, but may not be limited to, any event that (at any dose): 
is FATAL; 
is LIFE THREATENING (places the participant at immediate risk of death); 
requires HOSPITALIZATION or prolongation of existing hospitalization; 
is a persistent or significant DISABILITY/INCAPACITY; or 
is a CONGENITAL ANOMALY/BIRTH DEFECT 
 
Important medical events that may not be immediately life threatening or result in death or 
hospitalization but may jeopardize the participant or require intervention to prevent one of the 
outcomes listed above, or result in urgent investigation, may be considered serious. Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias.  


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11.2. Grading of Adverse Events using Common Terminology Criteria (CTCAE) 
Adverse events (toxicities) will be graded according to the National Cancer Institute CTCAE 
version 5.0 for reporting of adverse events.  A copy of the current version of the CTCAE 
version 5.0 can be downloaded from the CTEP home page: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
11.3. Attribution  
Definitions of relationship to study medication are as follows: 
 
• UNRELATED: bears no relation to timing of medication, similar to symptoms or signs expected 
in the disease process, does not recur on rechallenge. 
• UNLIKELY: does not have temporal relationship to intervention, could readily have been 
produced by the participant’s clinical state, environmental, or other interventions, does not 
reappear or worsen with reintroduction of intervention. 
• POSSIBLY: bears relation to timing of medication, similar to symptoms or signs expected in the 
disease process, does not recur on rechallenge. 
• PROBABLY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, does not recur on rechallenge. 
• DEFINITELY: bears clear relation to timing of medication, distinct from symptoms or signs 
expected in the disease process, occurs on rechallenge. 
 
Adverse events can be “Expected” or “Unexpected”. 
 
Expected adverse event 
Expected adverse events are those that have been previously identified as resulting 
from administration of the agent. For the purposes of this study, expected adverse 
events are those adverse events that are listed or characterized in the Package Insert 
or current Investigator’s Brochure (IB). 
Unexpected adverse event 
For the purposes of this study, unexpected adverse events are those not listed in the 
current Investigator Brochure or not identified. This includes adverse events for which 
the specificity or severity is not consistent with the description in the package insert or 
IB.  
 
11.4. Reporting Procedures for All Adverse Events 
All observed or volunteered adverse events, regardless of suspected causal relationship to study 
drug, will be recorded as Adverse Events in the electronic case report forms and submitted via 
eDCS within 14 days of completion of each treatment cycle. Events involving adverse drug 
reactions, illnesses with onset during the study, or exacerbation of pre-existing illnesses should 
be recorded. Objective test findings (e.g. abnormal laboratory test results) should also be 
recorded if considered to be clinically significant by the treating investigator. 
 
It will be left to the investigator’s clinical judgment whether or not an adverse event is of sufficient 
severity to require that the participant should be removed from treatment. A participant may also 
voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse 


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event. If either of these occurs, the participant will be given appropriate care under medical 
supervision until symptoms cease or until the condition becomes stable. 
 
The severity of toxicities will be graded in accordance with the Common Terminology Criteria for 
Adverse Event (CTCAE) version 5.0 (CTCAE_v5_Quick_Reference). 
 
The relationship of adverse events to the study medications will be assessed by means of the 
question: “Is there a reasonable possibility that the event may have been caused by the study 
medication?”, Please answer Yes or No.  
 
11.5. Expedited Reporting Guidelines 
The following adverse events require expedited reporting: 
• 
All adverse events that are both serious and unexpected regardless of grade 
• 
Adverse events that might influence the benefit-risk assessment of administration of poly-
ICLC as outlined in the protocol 
• 
All grade 5 adverse events 
• 
A serious adverse event that occurs within 30 days of the last dose of the investigational agent 
• 
Pregnancy 
If a participant or a participant’s partner becomes pregnant while receiving 
investigational therapy or within 30 days after the last dose of study drug, a report 
should be completed and expeditiously submitted as an SAE. Follow-up to obtain the 
outcome of the pregnancy should also occur. Abortion, whether accidental, 
therapeutic, or spontaneous, should always be classified as serious, and 
expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a 
child born to a female participant exposed to the poly-ICLC should be reported as an 
SAE. 
• 
Expedited AE reporting timelines defined: 
“24 hours; 3 business days” – The investigator must initially report the AE within 24 hours (or 
immediately if the event is fatal or life-threatening) of learning of the event to the Study Chair 
(dolly.aguilera@choa.org) and NF Operations Center, followed by a complete written report 
within 3 business days of the initial 24-hour report. 
 
Adverse events requiring expedited reporting will be reported and documented on Form FDA 
3500A MedWatch Form http://www.fda.gov/medwatch/getforms.htm) and forwarded to: 
 
NFCTC Operations Center 
Clinical Research Manager: Lauren Ashley Baldwin, BS  
Program Director: Karen Cole – Plourde, BS                              
Research Compliance Manager: Juliette Southworth, BS, CCRP          
Direct Email:  nfcop@uab.edu  
 
 
The clinical research manager from the NFCTC Operations Center will forward all related adverse 
events that are both serious and unexpected to the FDA on Form FDA 3500A MedWatch Form 
https://www.fda.gov/media/69876/download: 


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MedWatch 
Fax: 1-800-FDA-0178 
 
The final MedWatch Form or CIOMS-1 form will be submitted by the  Clinical Research Manager 
to Oncovir within one to two business days of submission to the FDA or applicable regulatory 
agency (including confirmation of date that the report was submitted) to allow Oncovir time to 
cross-report to Oncovir’s IND. E-mail: asalazar@oncovir.com; Fax 202-248-2324.  
11.6. Reporting of Protocol Violations/Deviations and Unanticipated Problems 
Site reporting to NFCTC Operations Center 
Sites will report unanticipated problems and/or protocol deviations that impact participant safety 
or the scientific integrity of the study to the Operations Center promptly to nfcop@uab.edu and 
entered into eDCS.  Other protocol violations and deviations should be reported to the NF 
Operations Center in eDCS within 14 days of the visit. 
 
NFCTC Operations Center reporting requirements 
The Operations Center will report unanticipated problems that impact participant safety or the 
scientific integrity of the study to the USAMRMC Office of Human and Animal Research Oversight 
(OHARO) OHRO promptly.  Unanticipated problems will also be reported to the protocol team, 
Research Monitor, and DSMB. 
 
All unanticipated problems involving risk to participants or others must be promptly reported by 
the NFCTC Operations Center via phone (301-619-2165), email (usarmy.detrick.medcom-
usamrmc.other.hrpo@health.mil), or facsimile (301-619-7803) to the OHRO.  A complete written 
report will follow the initial notification.  In addition to the methods above, the complete report can 
be sent to the US Army Medical Research and Materiel Command, ATTN: MCMR-RP, 810 
Schreider Street, Fort Detrick, Maryland 21702-5000.   
 
Suspensions, clinical holds (voluntary or involuntary), or terminations of this research by the IRB, 
the institution, the Sponsor, or regulatory agencies will be promptly reported to the USAMRMC 
OHARO OHRO. 
 
Other protocol violations and deviations that do not impact participant safety or affect scientific 
integrity of the study will be provided annually to the Sponsor. 
 
 
12. RESEARCH MONITORING AND DATA SAFETY MONITORING PLAN 
 
The trial PI and clinical coordinator will review the study progress regularly. Participants entered 
on the trial and adverse events will be reviewed to ensure that the study is implemented as 
outlined in the protocol. Monthly reports will be generated by the NFCTC to assess completeness 
of data. There will be monthly phone conferences between the NFCTC and the Principal 
Investigator to address QA issues.  A Data Safety Monitoring Board has been established for the 
purpose of ensuring data compliance and regular monitoring of this trial.  
 


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Additionally, there will be a designated research monitor for this study. This person is a qualified 
physician and is not associated with this particular protocol. The designated research monitor will 
work closely with the Principal Investigator to monitor the participants’ treatment while on this 
study. 
  
The research monitor’s duties should be based on specific risks or concerns about the research. 
The research monitor may perform oversight functions and report their observations and findings 
to the IRB or a designated official.  The research monitor may be identified from within or outside 
the PI’s institution. 
  
Research monitor functions may include: 
• 
observing recruitment and enrollment procedures and the consent process for individuals, 
groups or units,  
• 
overseeing study interventions and interactions,  
• 
reviewing monitoring plans and UPIRTSO reports;  
• 
overseeing data matching, data collection, and analysis 
  
There may be more than one research monitor (e.g., if different skills or experiences are 
necessary). The monitor may be an ombudsman or a member of the data safety monitoring board. 
 
At a minimum, the research monitor: 
• 
may discuss the research protocol with the investigators, interview human participants, 
and consult with others outside of the study about the research;  
• 
shall have authority to stop a research protocol in progress, remove individual human 
participants from a research protocol, and take whatever steps are necessary to protect 
the safety and well-being of human participants until the IRB can assess the monitor’s 
report; 
• 
shall have the responsibility to promptly report their observations and findings to the IRB 
or other designated official and the OHRO.  
 
In addition, on this study, the research monitor is specifically required to review all unanticipated 
problems involving risk to participants or others, serious adverse events and all participant deaths 
associated with the protocol and provide an unbiased written report of the event.  At a minimum, 
the research monitor should comment on the outcomes of the event or problem, and in the case 
of a serious adverse event or death, comment on the relationship to participation in the study.  
The research monitor should also indicate whether he/she concurs with the details of the report 
provided by the study investigator.   
 
Safety Monitoring Criteria  
Table 14 below defines the maximum allowed number of Grade 4 adverse events that are at 
least possibly attributable to the study drug. 
 
If the number of events exceeds the number in the second column, accrual to the study should 
be placed on hold for safety evaluation, pending review of toxicities by the study committee in 
consultation with the DSMB and the research monitor, to determine whether the study should 
continue, be amended, or be terminated. For example, if 2 or more patients experience an event 
before the sixth patient begins therapy, the trial will be on hold. 
 
 
 


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Table 14. Safety Rules for Grade 4  Adverse Events 
 
Number of Patients 
Maximum  
Number Permitted 
Probability to  
Stop 
Cumulative 
Probability to Stop 
5 
1 
0.081 
0.081 
10 
2 
0.070 
0.151 
16 
3 
0.068 
0.219 
 
Statistical Justification: The trial should hold enrollment and have a DSMB evaluation for safety 
if the probability that a Grade 4 adverse event (defined above) exceeds 10% is equal to or higher 
than 0.95, i.e., stop if Pr{ϴ>0.10|data}≥0.95. The table above gives the safety rule for each set of 
5 participants that enrolls in the study, with column 2 indicating the maximum number of cases of 
events that are permitted. The third column gives the probability of holding enrollment on the trial 
when in fact, the true ϴ = 0.10. Safety rules were generated using a binomial distribution.  
 
 
 
13. REGULATORY CONSIDERATIONS  
13.1. Protocol Review and Amendments  
This protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) and any other necessary documents 
must be submitted, reviewed, and approved by a properly constituted IRB. All decisions of the 
IRB concerning the conduct of the study must be made in writing. 
 
Any changes made to the protocol must be submitted as amendments and must be approved by 
the IRB prior to implementation. Any changes in study conduct must be reported to the IRB.  
 
Additionally, the DoD (Department of Defense)/OHRO (Office of Human Research Oversight) 
must approve ALL substantive modifications to the protocol and any modifications that could 
potentially increase risk to participants prior to implementation. OHRO defines a substantive 
modification as a change in Principal Investigator, change or addition of an institution, elimination 
or alteration of the consent process, change in the IRB of Record, change to the study population 
that has regulatory implications (e.g. adding children, adding active duty population, etc.), 
significant change in study design (i.e. would prompt additional scientific review), or a change that 
could potentially increase risks to participants.   
 
The NF Clinical Trials Consortium (NFCTC) Operation Center will disseminate protocol 
amendment information to all participating investigators.  
 
13.2. Informed Consent  
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study.  
 
The formal consent of a participant, using the IRB-approved consent form, must be obtained 
before the participant is involved in any study-related procedure. The consent form must be 
signed and dated by the participant or the participant’s legally authorized representative, and by 


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the person obtaining the consent. The participant must be given a copy of the signed and dated 
consent document. The original signed copy of the consent document must be retained in the 
medical record or research file.  
 
13.3. Ethics and Good Clinical Practice (GCP) 
This study is to be conducted according to the following considerations, which represent good 
and sound research practice:  
• 
E6 Good Clinical Practice: Consolidated Guidance 
https://www.fda.gov/media/93884/download 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and 
ethical principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch
.cfm?CFRPart=11 
o Title 21 Part 50 – Protection of Human Subjects 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch
.cfm?CFRPart=50  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch
.cfm?CFRPart=56 
o Title 21 Part 312 – Investigational New Drug Application 
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.
cfm?CFRPart=312 
 
• 
State laws  
 
• 
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such 
case, the deviation must be reported to the IRB according to the local reporting 
policy.  
13.4. Data Collection 
The trial is being conducted by the NFCT Consortium.  Case report forms developed by the 
NFCTC Operations Center and Protocol Chair will be used for submitting clinical data to the 
Operations Center.  Data must be submitted to the Operations Center within two weeks of 
completing each required evaluation while the subject is on study via eDCS. Delinquent data 
delays will be reported to the NFCT Consortium’s Site Evaluation Committee and the NFCTC 
Operations Center.  
 


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Completed QOL and pain evaluations will be submitted in real-time via an iPad and NIH Toolbox 
to the NFCTC Data Coordinating Center.  
 
Blood and tissue samples for banking will be handled and stored in the biorepository located in 
the Colket Translational Research Building at the Children’s Hospital of Philadelphia (CHOP), 
Philadelphia, PA.  The specimens will be under the management of the Center for Data Driven 
Discovery in Biomedicine (D3b) and the Biorepository Core (BioRC), according to their standard 
operating procedures (SOPs).  Samples will be stored at -80°C.  Biological specimens will be 
coded with a randomly generated study number prior to shipping to the biorepository in order to 
prevent identification of subjects and protect confidentiality.  The study number will not be derived 
from or related to information about the subject and will not contain any elements of PHI.  The 
specimen number will be entered into the NFCTC Operations Center eDCS, thus providing a link 
between the specimen and the study data.  Specimens may be shared with outside 
investigators/laboratories, who may analyze (and store, if applicable) the samples. Shared 
specimens will be labeled only with a study number.  Requests for samples will be reviewed by 
the NF111 Study Chairs and the NFCTC Biology Committee.  If a subject withdraws consent to 
store samples after collection, existing samples in the biorepository will be destroyed; however, 
any samples already shared to an outside laboratory or other entity will not be destroyed and any 
data generated already from the samples will not be destroyed. 
13.5. Study Documentation  
The investigator must prepare and maintain adequate and accurate case histories designed to 
record all observations and other data pertinent to the study for each research participant. This 
information enables the study to be fully documented and the study data to be subsequently 
verified.  
 
Original source documents supporting entries in the case report forms include but are not limited 
to hospital records, clinical charts, laboratory and pharmacy records, recorded data from 
automated instruments, microfiches, photographic negatives, microfilm or magnetic media, and/or 
x-rays.  
13.6. Records Retention  
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. Study-related documents will be stored 
in a secured location accessible only to the investigators and formally designated study personnel.  
13.7. Multi-Center Guidelines 
This protocol will adhere to the policies and requirements of NFCTC IRB, DoD and the Sponsor. 
The specific responsibilities of the Protocol Chair, NFCTC Operations Center, and Participating 
Institutions are presented in the Multi-Center Data and Safety Monitoring Plan. 
 
• 
The Protocol Chair and NFCTC Operations Center are responsible for distributing all 
IND Action Letters or Safety Reports to all participating institutions for submission to 
their individual IRBs for action as required. 
• 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site.  


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13.8. Publication of Data and Protection of Trade Secrets 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide any such publication to Oncovir, Inc. for review at 
least sixty (60) days prior to submission and also comply with any provisions regarding publication 
as are agreed to between the Neurofibromatosis Clinical Trials Consortium and Oncovir, Inc. in 
the Clinical Trial Agreement related to this study. The results will be made public within 13 months 
of the end of data collection.  
However, if a report is planned to be published in a peer-reviewed journal, then that initial release 
may be an abstract that meets the requirements of the International Committee of Medical Journal 
Editors. In any event, a full report of the outcomes should be made public no later than three (3) 
years after the end of data collection. Authorship for abstracts and manuscripts resulting from this 
study will be determined according to guidelines established by the International Committee of 
Medical Journal Editors. 
 
14. STATISTICAL CONSIDERATIONS  
 
Primary Endpoints  
 
The primary endpoint of the study is objective response rate (defined as CR or PR) during the 
first 12 months of treatment. Response will be assessed through the time of the post-12th cycle 
tumor assessment, or through the last tumor assessment time during this nominal period for 
patients in follow-up but who have withdrawn from protocol therapy, or through the last available 
tumor assessment for patients who are lost to follow-up during this time.  
 
The percent change in tumor sizes compared to baseline will be recorded at each evaluation time 
and will be used to define the categorical response as described below, per the definition of CR, 
PR, MR, SD, and PD in section 10.4.  
 
• For tumors that regress compared to baseline during the assessment period without first 
satisfying the criteria for progressive disease (PD), response will be defined at the nadir of the 
tumor size compared to baseline provided that the percent reduction at the nadir satisfies the 
definition of CR, PR, or MR per section 10, with the response value of CR, PR, or MR determined 
by the percent reduction at this time.  
 
The associated time of response will also be recorded.  
 
• For tumors that progress compared to baseline and satisfy the definition of PD without first 
satisfying the criterion at least for minor response (MR), response will be defined at the first time 
at which the percent increase in tumor size compared to baseline satisfies the criterion for PD. 
The response value will be PD. The associated time of response will also be recorded.  
Progressive disease could be confirmed with a short follow-up MRI (+/- 6 weeks)  per treating 
physician decision, otherwise continue with MRI interval per protocol. 
 
• For tumors that neither regress sufficiently to satisfy the criterion for MR nor progress sufficiently 
to satisfy the criterion for PD during the assessment period, the response value will be determined 
to be SD.  
 


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Patients will be considered evaluable for response if they have received at least one dose of 
treatment and have at least one post-baseline tumor assessment.  
 
Patients who undergo gross total resection while on study will be excluded from further response 
at the time of surgery. Patients who have measurable residual disease (at least twice the thickness 
of the MRI slide) after resection will be able to continue study drug and the post-op MRI will be used 
as the new baseline. 
 
Secondary Endpoints  
 
• Progression free survival (PFS), defined as the time from start of treatment to the first occurrence 
of tumor recurrence, tumor progression, occurrence of a second malignancy, or death from any 
cause. Patients event-free at last follow-up will be censored in analysis. PFS will be determined 
at 12, 24 and 60 months. 
 
• Objective response rate (defined as CR or PR) after 24 cycles of treatment. Response will be 
assessed through the time of the post-24th cycle tumor assessment, or through the last tumor 
assessment time during this nominal period for patients in follow-up, but who have withdrawn 
from protocol therapy, or through the last available tumor assessment for patients who are lost to 
follow-up during this time. 
 
• Clinical benefit defined as (CR+PR+MR+SD). Clinical benefit will be assessed through the time 
of the post-12 and 24th cycle tumor assessment, or through the last tumor assessment time during 
this nominal period for patients in follow-up but who have withdrawn from protocol therapy, or 
through the last available tumor assessment for patients who are lost to follow-up during this time. 
 
• The grade and duration of CTCAE toxicities observed during treatment using CTAE version 5.0. 
 
• Evaluation for visual acuity for patients with optic pathways gliomas will be assessed at 12 
months and 24 months from starting therapy. Patient visual outcome will be assessed through 
the time of the post-12th and 24th cycle visual assessment, or through the last visual assessment 
time during this nominal period for patients in follow-up but who have withdrawn from protocol 
therapy, or through the last available tumor assessment for patients who are lost to follow-up 
during this time. 
 
Exploratory Endpoint 
 
The RANO criteria for response assessment will be determined and descriptively compared to 
the primary response using RAPNO. 
14.1. Participant Accrual 
Participants of both genders, from all racial and ethnic groups are eligible for this trial if they meet 
the criteria outlined in Section 3.0. To date, there is no information that suggests differences in 
drug metabolism or disease response among racial or ethnic groups or between the genders, 
indicating that results of the trial will be applicable to all groups. Efforts will be made to extend the 
accrual to a representative population, but in a phase II study with limited accrual, a balance must 
be struck between patient safety considerations and limitations on the number of individuals 
exposed to potentially toxic or ineffective treatments on the one hand, and the need to explore 
gender, racial, and ethnic aspects of clinical research on the other. If differences in outcome that 


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correlate to gender, age, racial, or ethnic identity are noted, accrual may be expanded, or 
additional studies may be performed to investigate those differences more fully. 
 
14.2. Sample Size 
Target is 20 patients for 16 evaluable participants.  
 
To allow for 25% unevaluable participants, a maximum of up to 20 participants will be enrolled.  
We anticipate enrollment to be completed in 36 months with primary outcome measure defined 
in 12 months. The sample size for this trial is based on 3 primary factors:  safety based on risk 
versus benefit. Sample size estimates were based on a single stage phase II clinical trial with the 
goal of demonstrating that the objective response rate of poly-ICLC is better than an objective 
response rate of a poor drug. For the sample size calculation, we assumed that the response rate 
of a poor drug (P0) was 5% (i.e., P0 = 5%) and that the objective response rate poly-ICLC (P) 
would be at least 25% (i.e., P = 25%).  
 
In addition, the type I error rate (alpha) was set to 0.05 (5%) and the type II error rate (beta = 1 – 
power) was set to 0.20 (20%). Using a single stage design, a sample size of 16 participants 
achieves at least 80% power to demonstrate that the objective response rate of poly-ICLC is 
better than a poor objective response rate of 5% and at least 25%. If the number of responders 
is 3 or more, the hypothesis that P ≤ 5% is rejected with an actual error rate of 0.043. If the number 
of responses is 2 or less, the hypothesis that P ≥ 25% is rejected with an actual error rate of 0.197. 
Sample size estimates were determined using PASS v. 19.0.2 (NCSS, LLC, Kaysville, UT).  
 
 
Table 15: PASS Output Single-Stage Phase II Clinical Trials Analysis 
 
 
Design for Testing H0: P ≤ P0 versus H1: P ≥ P1 
 
 
 
 
 
Cut-Off 
 
Actual 
Actual 
P0 
P1 
Alpha 
Beta 
R + 1 
N 
Alpha 
Beta 
 
0.05 
0.25 
0.050 
0.2 
3 
16 
0.04 
0.197 
 
Report Definitions 
• 
P0 is the maximum response proportion of a poor drug. 
• 
P1 is the minimum response proportion of a good drug. 
• 
N is the sample size. 
• 
If the number of responses ≥ R+1, P0 is rejected. 
• 
If the number of responses ≤ R, P1 is rejected. 
• 
Alpha is the probability of rejecting that P ≤ P0 when this is true. 
• 
Beta is the probability of rejecting that P ≥ P1 when this is true. 
14.3. Statistical Analysis Plan 
The primary goal of the study is to evaluate the effectiveness of the poly-ICLC. Based on the 
single stage design, response of the drug will be determined after 16 participants are evaluable 
for the primary endpoint assessment. Participants will be classified based on response (CR/PR 
vs. MR/SD/PD). If at least 3 of 16 participants respond to treatment, the hypothesis that P ≤ 5% 
is rejected at alpha = 0.05 and accept that the higher rate of P greater or equal to 25% is more 
likely; otherwise, the drug will be deemed ineffective based on having an objective response rate 


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not significantly different than the objective response rate of a poor drug. Comparison between 
RANO and RAPNO response criteria will be descriptive only.  
 
Key secondary outcomes will be examined at baseline including clinical, quality of life and visual 
function. Following complete accrual, study enrollment and completion will be summarized as per 
a Consort Diagram with reasons for withdrawal or unable to complete the study. Appropriate data 
analysis sets will be defined as follows. The full-analysis set will include data from all participants 
who receive ≥ 1 dose of therapy on this study; a safety analysis set will comprise data from 
participants in the full-analysis set with any treatment doses. Other data sets (responding, 
evaluable) will be defined and will include data from participants who have the necessary baseline 
and on-study measurements to provide interpretable results for specific parameters of interest. 
 
Descriptive summaries will be prepared to show sample size, mean, standard deviation, 95% 
confidence intervals (CIs) median, minimum, and maximum for continuous variables and counts, 
percentages, and 95% CIs for categorical variables.  
 
For endpoints relating to tumor control, participant well-being, and biomarkers, analyses will be 
done based on the full analysis, responding, evaluable data sets, as appropriate. Time-to-event 
analyses will be performed with reference to the date of first treatment on this study. Analyses will 
focus on evaluation of outcomes and will be largely descriptive. Changes in tumor volumes will 
be summarized by medians, ranges, and the corresponding 95% CI.   
 
Based on the safety analysis set, information regarding study treatment administration, drug 
dosing and cycle compliance, safety variables, will be described and summarized. Data from the 
biological analysis will also be described and summarized. Safety will be assessed via tabulations 
of AEs and SAEs as well as Diary recordings following treatment dose/cycle of therapy. 
 
All analyses for outcome results will be based on evaluable participants, as defined in section 14. 
 
At the end of the trial, we will report poor performance if the treatment is rejected when not meeting 
the criteria of at least 3 responders’ cases. If there is no success, we will report a failure to reject 
the null hypothesis. If the null hypothesis is rejected, the probability of the estimated success rate 
will be reported and 95% confidence intervals as well as the distribution of changes in tumor size. 
 
Dose-limiting toxicity (DLT) is not an objective in this trial. Toxicity will be continuously monitored.   
 
 
15. PUBLICATION PLAN  
Timely publication will be the responsibility of the principal investigator. No data should be 
submitted for presentation at public meetings or in abstract form without approval of the Principal 
Investigator and the NF Clinical Trials Consortium. Guidelines will follow the rules for publication 
for the NF Clinical Trials Consortium. 
 
The results should be made public within 13 months of the end of data collection, sooner if 
possible. If a report is planned to be published in a peer-reviewed journal, then that initial release 
may be an abstract that meets the requirements of the International Committee of Medical Journal 
Editors. A full report of the outcomes should be made public no later than three (3) years after the 
end of data collection. 
 
 
 


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16. REFERENCES 
 
1. Campen, C. J., & Gutmann, D. H. (2018). Optic Pathway Gliomas in Neurofibromatosis 
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2. Ater, J., Xia, C., Mazewski, C., Booth, T., Freyer, D., Packer, R., Sposto, R., Vezina, G., 
& Pollack, I. (2016). Nonrandomized comparison of neurofibromatosis type 1 and non-
neurofibromatosis type 1 children who received carboplatin and vincristine for 
progressive low-grade glioma: A report from the Children's Oncology Group.. Cancer, 
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3. J Clin Oncol. 2012 Apr 20;30(12):1358-63. doi: 10.1200/JCO.2011.34.5843. Epub 2012 
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Baruchel S. 
4. Gururangan S, Fangusaro J, Poussaint TY, et al. Efficacy of bevacizumab plus 
irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor 
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5. Fangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients 
with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or 
progressive low-grade glioma: a multicentre, 
phase 2 trial. 
Lancet Oncol. 
2019;20(7):1011-1022. doi:10.1016/S1470-2045(19)30277-3 
6. Levy H, F Riley (1985).  Utilization of stabilized forms of polynucleotides.  Interferons and 
their applications.  S Baron, D Copenhaver, F Dianzani et al, Galveston, U. Texas Medical 
Branch, 65-76. 
7. Levy H (1987). Clinical studies with polynucleotides. The interferon system, a current review 
to 1987.  S Baron, F Dianzani, G Stanton, W Fleishman.  Austin, University of Texas Press:  
469-475. 
8. Rettenmaier MA, Berman ML, DiSaia PJ (1986). Treatment of advanced ovarian cancer 
with poly-ICLC.  Gynecol Oncol 24:359-361. 
9. Krown S, D Kerr et al  (1985).  Phase I trials of Poly-ICLC in advanced cancer.  J Biol 
Response Mod 4(6): 640-649. 
10. Theriault R, G Hortobagye et al (1986). Evaluation of Poly-ICLC in metastatic breast 
cancer.  Cancer Treat Rep 70(11): 1341-1342. 
11. Droller M (1987). Immunotherapy of metastatic renal cell carcinoma with polyinosinic-
polycytidylic acid.  J Urol 137(2): 202-206. 
12. Hawkins M., M Levin et al (1985).  An ECOG phase I-II pilot study of Poly-ICLC in patients 
with metastatic malignant melanoma.  J. Biol Response Mod 4(6): 664-668. 
13. Nakamura O, N Shitara et al. (1982). Phase I-II trials of Poly-ICLC in malignant brain tumor 
patients.  J. Interferon Res. 2(1): 1-4. 
14. Black K, K. Chen, et al. (1992). Inflammatory leukocytes associated with increased 
immunosuppression by glioblastoma.  Journal of Neurosurgery 77:120-126. 
15. Chebath J, M Revel (1992). The 2-5 A System: 2-5 A synthetases, isospecies and functions.  
Interferons: Principles and Medical Applications. S. Baron, D. Copenhaver, F. Dianzani, et 
al, Galveston, & U. Texas Medical Branch, Galveston: 225-236. 
16. Samuel C (1992). The RNA-dependent P1/Eif-2a protein kinase.  Interferon: Principles 
and Medical Applications.  S Baron, D Copenhaver, F Dianzani et al, Galveston, U. Texas 
Medical Branch, Galveston: 237-249. 
17. Katze MG (1992).  The war against the interferon-induced dsRNA-activated protein kinase, 
can viruses win?  Journal of Interferon Research 12: 241-248. 


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18. Williams, Bryan RG (1999).  PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112-
6120. 
19. Levy H, Salazar AM: Interferon inducers, in Baron S, Copenhaver DH, Dianzani F, Fleishman 
WR, Hughs TK, Klimpel GR, Neisesel DW, Stanton GJ, Tyring SK (eds): Interferon: 
Principles and Medical Applications.  Galveston, University of Texas Medical Branch, 1992, 
pp65-76. 
20. Talmadge J, R Herberman et al (1985). Hypo responsiveness to augmentation of murine 
natural killer cell activity in different anatomical compartments by multiple injections of 
various immunomodulators including recombinant interferons and interleukin 2. J Immunol 
135(4): 2483-2491. 
21. Levy H, C Bever (1988). Immune modulating effects of poly-ICLC in mice, monkeys, and 
man.  Applied Bioactive Polymers.  C Carraher, V Foster, New York, Plenum. 
22. Ewel C, W Urba, et al (1992). Polyinosinic-Polycytidylic acid complexed with poly-L lysine 
and carboxymethylcellulose in combination with interleukin 2 in patients with cancer: clinical 
and immunological effects.  Cancer Research 52: 3005-3010. 
23. Black K, K. Chen, et al. (1992). Inflammatory leukocytes associated with increased 
immunosuppression by glioblastoma.  Journal of Neurosurgery 77:120-126. 
24. Minks M, D West et al (1979). Structural requirements of dsRNA for the activation of the 
2’5’ oligoA polymerase and protein kinase of interferon treated HeLa cells. J Biol Chem 
254(20):  10180-10183. 
25. Maluish AE, Reid JW, Crisp EA, Overton WR, Levy H, Foon KA, Herberman RB (1985): 
Immunomodulatory effect of poly-ICLC in cancer patients. J Biol Resp Modif 4:656-663. 
26. Salazar A, H Levy et al (1996). Long-term treatment of malignant gliomas with 
intramuscular administered polyinosinic-polycytidylic acid stabilized with polylysine and 
carboxymethylcellulose:  an open pilot study.  Neurosurgery 38: 1096-1104. 
27. Galabru J, M Katze et al (1989). The binding of dsRNA an adenovirus VA1 RNA to the 
interferon induced protein kinase.  European Journal of Biochemistry 178: 581-589. 
28. Koromilas A, S Roy et al (1992). Malignant transformation by a mutant of the IFN-inducible 
dsRNA dependent protein kinase.  Science 257: 1685-1689. 
29. Malkin D, F Li et al (1990). Germ line P53 mutations in a familial syndrome of breast 
cancer, sarcomas, and other neoplasms.  Science 250: 1233-1238. 
30. Mol Cell Biol. 1999 Apr;19(4):2475-84.  
31. Williams, Bryan RG (1999).  PKR; a sentinel kinase for cellular stress. Oncogene 18, 6112-
6120. 
32. Folkman J, Ingber D  (1992) Inhibition of angiogenesis.  Semin. Cancer Biol.  3: 89-96. 
33. Celis et al, Cancer Immunology and Immuno-oncology, 67: 1091, 2018 
34. Butowski N, Lamborn KR, Lee BL, et al. A North American brain tumor consortium phase 
II study of poly-ICLC for adult patients with recurrent anaplastic gliomas. J Neurooncol. 
2009;91(2):183-189. doi:10.1007/s11060-008-9705-3 
35. Butowski N, Chang SM, Junck L, et al. A phase II clinical trial of poly-ICLC with radiation 
for adult patients with newly diagnosed supratentorial glioblastoma: a North American 
Brain Tumor Consortium (NABTC01-05). Journal of Neuro-oncology. 2009 Jan;91(2):175-
182. DOI: 10.1007/s11060-008-9693-3. 
36. Hartman LL, Crawford JR, Makale MT, et al. Pediatric phase II trials of poly-ICLC in the 
management of newly diagnosed and recurrent brain tumors. J Pediatr Hematol Oncol. 
2014;36(6):451-457. doi:10.1097/MPH.0000000000000047J Exp Med. 2011 Nov 
21;208(12):2357-66. doi: 10.1084/jem.20111171. Epub 2011 Nov 7.  
37. Aguilera D, MacDonald T, Crawford J, et al. LGG-58. A PHASE II TRIAL OF POLY-ICLC 
IN THE MANAGEMENT OF RECURRENT OR PROGRESSIVE PEDIATRIC LOW 
GRADE 
GLIOMAS 
(NCT01188096): 
PRELIMINARY 
ANALYSIS. Neuro 
Oncol. 


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2018;20(Suppl 2):i116-i117. doi:10.1093/neuonc/noy059.398J Immunol. 1994 Jul 
1;153(1):333-42.  
38. Bowers DC, Adhikari S, El-Khashab YM, Gargan L, Oeffinger KC. Survey of long-term 
follow-up programs in the United States for survivors of childhood brain tumors. Pediatric 
Blood & Cancer 2009;53:1295-301. 
39. Freyer DR. Transition of care for young adult survivors of childhood and adolescent 
cancer: rationale and approaches. Journal of Clinical Oncology 2010;28:4810-8. 
40. Vinchon M, Baroncini M, Leblond P, Delestret I. Morbidity and tumor-related mortality 
among adult survivors of pediatric brain tumors: a review. Childs Nerv Syst 2011;27:697-
704. 
41. Benesch M, Lackner H, Sovinz P, et al. Late sequela after treatment of childhood low-
grade gliomas: a retrospective analysis of 69 long-term survivors treated between 1983 
and 2003. Journal of Neuro Oncology 2006;78:199-205. 
42. Bhat SR, Goodwin TL, Burwinkle TM, et al. Profile of daily life in children with brain 
tumors: an assessment of health-related quality of life. Journal of Clinical Oncology 
2005;23:5493-500. 
43. Meyer EA, Kieran MW. Psychological adjustment of ‘surgery-only’ pediatric neuro-
oncology patients: a retrospective analysis. Psycho-Oncology 2002;11:74-9. 
44. Nwachukwu CR, Youland RS, Chioreso C, et al. Health related quality of life (HRQOL) in 
long-term survivors of pediatric low grade gliomas (LGGs). Journal of Neuro-Oncology 
2015;121:599-607. 
45. Lundar T, Due-Tønnessen BJ, Egge A, Scheie D, Stensvold E, Brandal P. 
Neurosurgical treatment of oligodendroglial tumors in children and adolescents: a 
single-institution series of 35 consecutive patients. Journal of Neurosurgery: 
Pediatrics 2013;12:241-6. 
46. Eiser C, Morse R. Can parents rate their child's health-related quality of life? 
Results of a systematic review. Qual Life Res 2001;10:347-57. 
47. Zebrack BJ, Stuber ML, Meeske KA, et al. Perceived positive impact of cancer among 
long-term survivors of childhood cancer: a report from the childhood cancer survivor 
study. Psycho-Oncology 2012;21:630-9. 
48. Phipps S. Adaptive style in children with cancer: implications for a positive psychology 
approach. Journal of Pediatric Psychology 2007;32:1055-66. 
49. Tillery R, Howard Sharp KM, Okado Y, Long A, Phipps S. Profiles of resilience and 
growth in youth with cancer and healthy comparisons. Journal of Pediatric Psychology 
2016;41:290-7. 
50. Alderfer MA, Navsaria N, Kazak AE. Family functioning and posttraumatic stress 
disorder in adolescent survivors of childhood cancer. Journal of Family Psychology 
2009;23:717-25. 
51. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the Pediatric Quality 
of Life Inventory. Medical Care 1999;37:126-39. 
52. McCarthy MC, DeGraves S, Wakefield CE, Bowden MJ, Marks LV, Williams LK. The 
association of psychosocial screening and service provision in pediatric oncology: the 
Psychosocial Assessment Tool (PAT2.0) into clinical practice. Supportive Care in 
Cancer 2016;24(7):2945-52. 
53. Varni JW, Limbers C, Burwinkle TM. Literature review: health-related quality of life 
measurement in pediatric oncology: hearing the voices of the children. Journal of 
Pediatric Psychology 2007;32:1151-63. 
54. Salsman JM, Butt Z, Pilkonis PA, et al. Emotion assessment using the NIH Toolbox. 
Neurology 2013;80:S76-S86. 
55. Palmer SN, Meeske KA, Katz ER, Burwinkle TM, Varni JW. The PedsQL™ brain tumor 
module: Initial reliability and validity. Pediatric Blood & Cancer 2007;49:287-93. 


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56. Wen P, Chang SM, VanDenBent M, Vogelbaum MA, McDonald Dr, Lee EQ. Response 
Assessment in Neuro-Oncology Clinical Trials. J Clin Oncol 2017;35(21):2439-2449. 
 
 


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APPENDIX 1: NIH Consensus Conference Criteria for NF1 
 
• Six or more café-au-lait spots (≥ 0.5 cm in prepubertal participants or ≥ 1.5 cm in post pubertal 
participants)  
• Two or more neurofibromas of any type or one plexiform neurofibroma  
• Freckling in the axilla or groin  
• Optic glioma  
• Two or more Lisch nodules  
• A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of long bone 
cortex)  
• A first-degree relative with NF1 
 


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APPENDIX 2: Karnofsky and Lansky Performance Status Criteria 
 
 
 
 
 
 


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APPENDIX 3: Study Calendar and Required Observations (through end of therapy)  
Observation 
Pre-
Study 
Day 1 
Cycle 1 
Day 8 
Cycle 1 
Day 15 
Cycle 1 
Prior to 
subsequent 
cycles 2-24 
End of 
Therapy/Off 
Study 
History, VS: BP,HR, 
temperature, oxygen 
saturation, RR,  height, 
weight, Physical and 
neurological exam1 
x 
x 
 
x 
x 
x 
Performance Status1 
x 
x 
 
x 
x 
x 
Toxicity Evaluation 
 
x 
x 
x 
x 
x 
Review Medication 
diary/temperature log 
 
 
x 
x 
x 
x 
Concomitant Meds 
x 
x 
 
x 
x 
x 
CBC Diff7 
x 
x 
x 
x 
x 
x 
CMP/ Phosphorous6 
x 
x 
 
 
x 
x 
Serum or Urine Pregnancy2 
x 
Prior to initiation of each cycle 
 
MRI-Brain with and without 
contrast3 
(with orbital cuts for optic 
pathway tumors) 
x 
 
 
 
Every 3 cycles 
starting with end 
of Cycle 3 
x 
MRI Spine with/without 
contrast3 
x 
 
 
 
Every 3 cycles 
starting with end 
of Cycle 3 
x 
Ophthalmology Functional 
Assessments4 
x 
 
 
 
Every 3 cycles 
starting with end 
of Cycle 3 
x 
Biology-sodium heparin green 
top blood samples 
x 
 
x8 
x 
Day1 cycle 3 
Day 1 cycle 6 
Day 1 cycle 12 
x 
Quality of Life Studies 
x 
 
 
 
Cycle 6 day 1 
Cycle 12 day 1 
x 
Tissue (with concurrent blood 
sample) submission if available5 
 
x 
At the time surgery is performed 
 
1: Performance Status = Karnofsky if ≥ 16 y/o or Lansky if < 16 y/o; All evaluations for Day 8 and Day 15 of Cycle 1 must be done 
+/-48 hours, then +/-5 days for subsequent cycles.  
2: Required for female patients of childbearing potential; urine or serum pregnancy test must be negative within 7 days of starting 
each cycle  
3: Brain and/or spine MRI should be obtained depending on tumor location. MRI will be obtained at the end of cycle 3(+/-2 weeks), 
then every 3 cycles (+/-2 weeks), at the end of therapy/off study or at progression.    
4: Ophthalmology evaluation only for patients with optic pathway gliomas at the end of cycle 3 (+/-2 weeks), then every 3 
cycles (+/-2 weeks) 
5: Tissue submission with concurrent blood sample if available 6 months prior to enrollment and at any point during protocol 
treatment (optional). 
6: CMP: including sodium, potassium, CO2, chloride, total protein, glucose, AST, ALT, alkaline phosphatase, albumin, calcium, total 
bilirubin, BUN, Creatinine including phosphorous. Labs must be completed within 14 days of cycle 1 day 1 and on day 1 +/-5 days of 
subsequent cycles. 
7.  CBC/Differential/Platelet Count:  Labs must be completed within 14 days of cycle 1 day 1, +/- 48 hours of cycle 1 day 8 and day 15, 
and +/-5 days of subsequent cycles. 
8. Collect 5-10ml of blood per sample in sodium heparin tubes for patients < 8 years of age. For patients that weigh less than 10 kg, 
collect 2 ml on cycle 1 day 8. For patients ≥ 8 years, collect 10-15 ml. 
 
Note: MRI Brain/Spine should be obtained with and without gadolinium including pre T1, post T1, T2 and flair sequences. Both axial 
and either coronal or sagittal pre-post gadolinium images should be obtained. A copy of the MRI de-identified images will be submitted 
to the coordinating site.  
 


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APPENDIX 4: Off Therapy Observations 
 
 
Observation 
1-12 Months 
Off Therapy   
13-36 Months 
Off Therapy  
37-60  
Months Off 
Therapy 
MRI-Brain with and 
without contrast1,2 
(with orbital cuts for 
optic pathway tumors) 
Every 3 months 
Every 6 months 
Every 12 months 
MRI Spine with and 
without contrast1,2 
Every 3 months 
Every 6 months 
Every 12 months 
Ophthalmology 
Functional 
Assessments3 
Every 3 months 
Every 6 months 
Every 12 months 
Quality of Life Studies 
 
At month 246 
 
Biology-sodium heparin 
green top blood samples 
3 month and 12 
month off 
therapy visit5 
 
X5 
Tissue (with concurrent 
blood sample) 
submission if available4 
X 
X 
 
X 
 
1: MRI should be done +/-4 weeks for 1-12 months, +/-4 weeks for 12-36 months, +/-6 weeks for 36-60 months 
2: Brain and/or spine MRI should be obtained depending on tumor location.     
3: Ophthalmology evaluation only for patients with optic pathway gliomas (+/- 4 weeks for 1-12 months, +/-4 weeks for 
12-36 months, +/-6 weeks for 36-60 months) 
4: Tissue submission with concurrent blood sample if available at the time of progression if surgery performed (optional) 
5: Biology samples should be drawn at the 3 months off therapy visit, 12 months off therapy visit and if MRI shows 
progression. Collect 5-10ml of blood per sample in sodium heparin tubes for patients < 8 years of age. For 
patients ≥ 8 years, collect 10-15 ml. 
6: QOL assessment to be done at 24 months post therapy +/- 4 weeks or at progression if sooner. 
 
Clinical evaluations including laboratory evaluations should be performed as per 
standard of care. 
 
 
 


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APPENDIX 5: List of Enzyme Inducing Anticonvulsants 
 
 
Enzyme inducing anticonvulsants 
 
-Carbamazepine 
-Phenytoin 
-Phenobarbital 
-Primidone 
-Oxcarbazepine 
-Topiramate 
-Fosphenytoin 
 


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APPENDIX 6: Mandatory Biological Specimens  
The following type of bio-specimens will be collected for the performance of correlative studies.  
The samples obtained will be processed in the receiving lab. Aliquots of mononuclear cells will 
be utilized for the performance of several correlative studies (depending on sample availability 
and quality) as described. Plasma will be used for detection of circulating cytokines and 
chemokines. 
Sample Type 
Collection Times 
Peripheral Blood 
• 
Baseline (prior to Cycle 1 Day 1)  
• 
Cycle 1 Day 8 
• 
Cycle 1 Day 15  
• 
Cycle 3 Day 1  
• 
Cycle 6 Day 1  
• 
Cycle 12 Day 1  
• 
End of treatment/time of progression  
• 
3 months post treatment 
• 
12 months post treatment 
• 
Post treatment progression  
 
Procedure: 
• 
For children age 8 or less, obtain 5- 10 ml of peripheral blood. For patients that weigh 
less than 10 kg, collect 2 ml on cycle 1 day 8. 
• 
For children older than 8 years of age, obtain 10-15 mlof peripheral blood. 
• 
Draw in sodium heparin green top tubes and shipped at room temperature the same day 
the sample is drawn. Do not draw from a finger stick. 
• 
No processing is required prior to shipping blood. DO NOT REFRIGERATE OR 
FREEZE THE SAMPLE. Label each specimen with participant’s research identifier, date 
drawn, and sample collection time point (Cycle 1 Day 8, etc.). 
Shipping and Handling:  
Blood samples must be shipped  at room temperature  the same day they are collected 
(Monday-Thursday only). They should be shipped first priority if possible, otherwise by priority 
overnight, taking care to avoid Friday collection and shipping. Shipping of samples on Fridays is 
not allowed. Accordingly, in the event that a sample collection date falls on a Friday, sample 
may be collected a day earlier.  
Please notify the receiving laboratory by emailing: Ava Horvat (ava.alyse.horvat@emory.edu 
and Mahesh Shrestha (mahesh.shrestha@emory.edu when samples are shipped. 
 
Emory University - Winship Cancer Institute 
Dhodapkar’ s Lab 
Attn.:  Ava Horvat (ava.alyse.horvat@emory.edu 
Mahesh Shrestha (mahesh.shrestha@emory.edu) 
HSRB, Room E369 
1760 Haygood Drive, Atlanta, GA 30322 
Work phone: 404-778-4724 
 


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APPENDIX 7: Optional Tumor Tissue with Concurrent Blood Sample 
If a patient has surgery 6 months prior to enrollment or surgery is indicated during therapy or at 
the time of progession, tissue and concurrent blood sample may be obtained for banking to 
store in the biorepository located at the Children’s Hospital of Philadelphia (CHOP), 
Philadelphia, PA. 
 
 
1) Blood  
Prior to the day of blood draw, the site will have arranged for a sample collection kit supplied by 
the biorepository to be shipped to the site.  The Center for Data Driven Discovery in 
Biomedicine (D3b) at CHOP will be providing kits and labels. The kit will contain tubes and bar-
coded labels (which include a specimen number) for blood collection.  It will also contain 
shipping materials and instructions for sending collected blood samples to the biorepository, as 
well as a pre-paid shipping label. 
 
Samples 
• 
Streck tube (for plasma):  ~ 2 mL.   
• 
EDTA tube (for DNA):  ~ 5 mL.   
• 
PAXGene tube (for RNA) ~ 2.5 mL. 
 
Tubes should be inverted at least 10 times after being drawn. 
 
The samples will only be obtained if the total blood volume does not exceed 5 mL/kg.  If not 
enough blood can be drawn for all tubes, the priority order for obtaining the specimens is: 1) 
Streck tube, 2) EDTA tube, 3) PAXGene tube. 
 
Label the specimens with the specimen labels provided with the specimen kit. 
 
Blood samples must be shipped (unprocessed) same day at ambient temperature to the 
biorepository by overnight delivery using shipping container provided by the biorepository.  
Samples must be shipped Monday through Thursday. 
 
Enter the specimen numbers into the NFCTC Data Coordinating Center eDCS. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to 
sending samples, please contact:  Catherine Sullivan (sullivanca@email.chop.edu) and BioRc 
(biorc@email.chop.edu). 
 
2) Tumor Tissue 
Prior to the day of surgery, the site will have arranged for a tissue sample collection kit supplied 
by the biorepository to be shipped to the site.  The Center for Data Driven Discovery in 
Biomedicine (D3b) at CHOP will be providing kits and labels. The kit will contain bar-coded 
cryovials (which include a specimen number) for tissue collection.  It will also contain shipping 
materials and instructions for sending collected tissue samples to the biorepository, as well as a 
pre-paid shipping label. 
 
Samples 
• 
Fresh frozen tissue:  1-2 pea sized aliquots (~ 0.3 cm3, equivalent to 0.8 cm in diameter) 
of excess (left over) tumor tissue.  Place each aliquot in a separate cryovial and label the 
specimen with subject’s study number. Snap freeze the aliquots in liquid nitrogen 


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(preferred) or dry ice and then store in a freezer at -80°C or below until they can be sent 
to the biorepository. 
• 
1 H&E stained slide cut from each submitted piece to confirm tumor is present.  
• 
If fresh frozen tissue is unavailable, please submit processed DNA (at least 3 
micrograms) and RNA (at least 400 nanograms with optimal RIN > 7) if available.  
 
Label the specimen manifest with the subject’s study number. 
Fresh frozen tissue or DNA/RNA must be shipped on dry ice via overnight delivery using 
shipping materials provided by the biorepository. The H&E slide should be shipped at ambient 
temperature.  Samples must be shipped Monday through Thursday. 
 
Enter the specimen numbers into the NFCTC Data Coordinating Center eDCS. 
 
For questions about shipping, kits, tubes, etc., and to confirm the shipping address prior to 
sending samples, please contact:  Catherine Sullivan (sullivanca@email.chop.edu) and BioRc 
(biorc@email.chop.edu). 
 


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APPENDIX 8: Poly-ICLC Diaries 
Cycle 1: Monday/Thursday Dosing 
Cycle 1: Tuesday/Friday Dosing 
Cycle __:  Monday/Thursday Dosing 
Cycle __: Tuesday/Friday Dosing 
 


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A: NF Protocol 111 Medication Diary Cycle 1 
 
 
 
 
 
 
 
 
 
Patient Initials________ 
Monday/Thursday Dosing 
 
 
 
 
 
 
 
 
 
 
 
PID#________________ 
Administer Poly-ICLC as an intramuscular injection two days a week on Mondays and Thursdays.  Each dose must be given at least 2 days apart.  If a dose is missed, it may be 
given within 24 hours of when the initial dose is due.  After 8 doses, do not administer any more doses until you return to clinic. 
 
Write down the date, time, and site of administration of Poly-ICLC.  For Cycle 1 record the temperature prior to each dose and 12 hours (+/- 6 hours) after each dose.  After Cycle 
1 temperature is only monitored on an as needed basis (if patient is not feeling well), and should be recorded if greater than 102.2° Fahrenheit (39.0° Celsius). 
 
 
Date 
Time 
Site of 
Administration 
Temperature 
Other Problems 
Week 1 Dose 1 
(Monday) 
 
 
 
Pre-Dose Temp_________ Time_________    
12 Hour Temp _________  Time_________ 
 
 
Week 1 Dose 2 
(Thursday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 2 Dose 1 
(Monday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 2 Dose 2 
(Thursday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 3 Dose 1 
(Monday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 3 Dose 2 
(Thursday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 4 Dose 1 
(Monday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 4 Dose 2 
(Thursday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
 
 


NF 111 Protocol Version 1.4 
2-28-2024 
 
 
  
Page 78 of 84 
B: NF Protocol 111 Medication Diary Cycle 1 
 
 
 
 
 
 
 
 
 
Patient Initials________ 
Tuesday/Friday Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
PID#________________ 
Administer Poly-ICLC as an intramuscular injection two days a week on Mondays and Thursdays.  Each dose must be given at least 2 days apart.  If a dose is missed, it may be 
given within 24 hours of when the initial dose is due.  After 8 doses, do not administer any more doses until you return to clinic. 
 
Write down the date, time, and site of administration of Poly-ICLC.  For Cycle 1 record the temperature prior to each dose and 12 hours (+/- 6 hours) after each dose.  After Cycle 
1 temperature is only monitored on an as needed basis (if patient is not feeling well), and should be recorded if greater than 102.2° Fahrenheit (39.0° Celsius). 
 
 
Date 
Time 
Site of 
Administration 
Temperature 
Other Problems 
Week 1 Dose 1 
(Tuesday) 
 
 
 
Pre-Dose Temp_________ Time_________    
12 Hour Temp _________  Time_________ 
 
 
Week 1 Dose 2 
(Friday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 2 Dose 1 
(Tuesday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 2 Dose 2 
(Friday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 3 Dose 1 
(Tuesday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 3 Dose 2 
(Friday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 4 Dose 1 
(Tuesday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
Week 4 Dose 2 
(Friday) 
 
 
 
Pre-Dose Temp_________ Time_________ 
12 Hour Temp _________  Time_________ 
 
 
 


NF 111 Protocol Version 1.4 
2-28-2024 
 
 
  
Page 79 of 84 
C: NF Protocol 111 Medication Diary Cycle ____ 
 
 
 
 
 
 
 
 
 
Patient Initials________ 
Monday/Thursday Dosing 
 
 
 
 
 
 
 
 
 
 
 
PID#________________ 
Administer Poly-ICLC as an intramuscular injection two days a week on Mondays and Thursdays.  Each dose must be given at least 2 days apart.  If a dose is missed, it may be 
given within 24 hours of when the initial dose is due.  After 8 doses, do not administer any more doses until you return to clinic. 
 
Write down the date, time, and site of administration of Poly-ICLC.  For Cycle 1 record the temperature prior to each dose and 12 hours (+/- 6 hours) after each dose.  After Cycle 
1 temperature is only monitored on an as needed basis (if patient is not feeling well), and should be recorded if greater than 102.2° Fahrenheit (39.0° Celsius). 
 
 
Date 
Time 
Site of 
Administration 
Temperature (after Cycle 1 
only required if patient 
not feeling well) 
Other Problems 
Week 1 Dose 1 
(Monday) 
 
 
 
 
 
Week 1 Dose 2 
(Thursday) 
 
 
 
 
 
Week 2 Dose 1 
(Monday) 
 
 
 
 
 
Week 2 Dose 2 
(Thursday) 
 
 
 
 
 
Week 3 Dose 1 
(Monday) 
 
 
 
 
 
Week 3 Dose 2 
(Thursday) 
 
 
 
 
 
Week 4 Dose 1 
(Monday) 
 
 
 
 
 
Week 4 Dose 2 
(Thursday) 
 
 
 
 
 
 


NF 111 Protocol Version 1.4 
2-28-2024 
 
 
  
Page 80 of 84 
D: NF Protocol 111 Medication Diary Cycle ____ 
 
 
 
 
 
 
 
 
 
Patient Initials________ 
Tuesday/Friday Dosing 
 
 
 
 
 
 
 
 
 
 
 
 
PID#________________ 
Administer Poly-ICLC as an intramuscular injection two days a week on Mondays and Thursdays.  Each dose must be given at least 2 days apart.  If a dose is missed, it may be 
given within 24 hours of when the initial dose is due.  After 8 doses, do not administer any more doses until you return to clinic. 
 
Write down the date, time, and site of administration of Poly-ICLC.  For Cycle 1 record the temperature prior to each dose and 12 hours (+/- 6 hours) after each dose.  After Cycle 
1 temperature is only monitored on an as needed basis (if patient is not feeling well), and should be recorded if greater than 102.2° Fahrenheit (39.0° Celsius). 
 
 
Date 
Time 
Site of 
Administration 
Temperature (after Cycle 1 
only required if patient 
not feeling well) 
Other Problems 
Week 1 Dose 1 
(Tuesday) 
 
 
 
 
 
Week 1 Dose 2 
(Friday) 
 
 
 
 
 
Week 2 Dose 1 
(Tuesday) 
 
 
 
 
 
Week 2 Dose 2 
(Friday) 
 
 
 
 
 
Week 3 Dose 1 
(Tuesday) 
 
 
 
 
 
Week 3 Dose 2 
(Friday) 
 
 
 
 
 
Week 4 Dose 1 
(Tuesday) 
 
 
 
 
 
Week 4 Dose 2 
(Friday) 
 
 
 
 
 
 


NF 111 Protocol Version 1.4 
2-28-2024 
 
 
  
Page 81 of 84 
APPENDIX 9: Poly-ICLC Roadmap for Cycle 1 
Start cycle when:  
• 
ANC ≥ 750/mm3 
• 
Hgb ≥ 8gm/dL (may transfuse PRBCs) 
• 
Platelets ≥ 75,000 (transfusion independent; > 7 days from last transfusion) 
• 
SGPT (ALT) and SGOT (AST)= or  < 5x ULN 
Drug 
Route Dose 
Days 
Comments 
Poly-
ICLC 
IM 
20mcg/kg/dose Twice weekly 
on  
Mon/Thurs OR 
Tues/Friday 
Injections must be given at least 48 hrs apart; 
a missed dose can be made up within 24 hrs 
Premedication with acetaminophen or 
ibubrofen and continued dosing every 6 hrs 
for 24 hrs is recommended 
Cycle: __1__  
Height: ________ cm Weight: ________kg BSA: _______m2 
Date 
Due 
Date 
Given 
Day Poly-ICLC 
Site Given 
Observations 
 
 
1 
_________mcg 
 
A, B, C, D, E, F 
 
 
4 
_________mcg 
 
 
 
 
8 
_________mcg 
 
B, D 
 
 
11 
_________mcg 
 
 
 
 
15 
_________mcg 
 
A, B, D, E 
 
 
18 
_________mcg 
 
 
 
 
22 
_________mcg 
 
 
 
 
25 
_________mcg 
 
 
 
 
28 
 
 
 
A. 
History, VS,  Height, weight, PE with neuro evaluation and Performance Status 
B. 
CBCD 
C. 
CMP, Phos 
D. 
Biology Blood Samples:. Collect 5-10ml of blood per sample in sodium heparin tubes for patients < 8 years of age. For patients that 
weigh less than 10 kg, collect 2 ml on cycle 1 day 8. For patients ≥ 8 years, collect 10-15 ml. 
E. 
Pregnancy Test (urine or serum BHCG) – only in females of childbearing potential (all menstruating females and any female ≥ 12 
years of age) 
F. 
QOL 
G. 
MRI brain with and without contrast – at the end of Cycles 3, 6, 9, 12, 15, 18, 21 and 24 (end of treatment). MRI  orbits with  and 
without contrast only for OPG. 
H. 
MRI spine with contrast – only if primary tumor is on  the spine or clinically indicated 
I. 
Ophthalmology Exam – for any tumor involving the optic pathway ophthalmology exams are required at the end of Cycles 3, 6, 9, 12, 
15, 18, 21, and 24 (end of treatment)  
 
 
MD Signature/Date: ___________________________________________________________ 
 
PID1/PID2:________________________ 
 


NF 111 Protocol Version 1.4 
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Page 82 of 84 
APPENDIX 10: Poly-ICLC Roadmap for Cycles 2 – 24  
Start each cycle when:  
• 
ANC ≥ 750/mm3, Hgb ≥ 8gm/dL (may transfuse PRBCs), Platelets ≥ 75,000 (transfusion 
independent; > 7 days from last transfusion) 
• 
SGPT (ALT) and SGOT (AST)   = or < 5x ULN 
Drug 
Route Dose 
Days 
Comments 
Poly-
ICLC 
IM 
20mcg/kg/dose 
Twice weekly 
on 
Mon/Thurs 
OR 
Tues/Friday 
Injections must be given at least 48 hrs apart; 
a missed dose can be made up within 24 hrs 
Premedication with acetaminophen or 
ibubrofen and continued dosing every 6 hrs 
for 24 hrs is recommended 
Cycle: ________ 
Height: ________ cm Weight: ________kg BSA: _______m2 
Date 
Due 
Date 
Given 
Day Poly-ICLC 
Site Given 
Observations 
 
 
1 
_________mcg 
 
A, B, C, D, E, F 
 
 
4 
_________mcg 
 
 
 
 
8 
_________mcg 
 
 
 
 
11 
_________mcg 
 
 
 
 
15 
_________mcg 
 
 
 
 
18 
_________mcg 
 
 
 
 
22 
_________mcg 
 
 
 
 
25 
_________mcg 
 
 
 
 
28 
 
 
G, H, I 
A. 
History, VS, height, weight,  PE with neuro evaluation and Performance Status 
B. 
CBCD 
C. 
CMP, Phos 
D. 
Biology Blood Samples required at C3D1, C6D1, and C12 D1.  5 -10 ml of blood per sample in sodium heparin tubes for patients < 8 
years of age. For patients ≥ 8 years, we will collect 15 ml of blood.   
E. 
Pregnancy Test (urine or serum BHCG) – only in females of childbearing potential (all menstruating females and any female ≥ 12 
years of age) 
F. 
QOL – required at beginning of Cycle 6 and 12 and end of therapy 
G. 
MRI brain with and without contrast – at the end of Cycles 3, 6, 9, 12, 15, 18, 21 and 24 (end of treatment) 
H. 
MRI spine with contrast – only if primary tumor is on the spine or clinically indicated 
I. 
Ophthalmology Exam – for any tumor involving the optic pathway ophthalmology exams are required at the end of Cycles 3, 6, 9, 12, 
15, 18, 21, and 24 (end of treatment) 
 
MD Signature/Date: ____________________________________ 
 
PID1/PID2:________________________ 


NF 111 Protocol Version 1.4 
2-28-2024 
 
 
  
Page 83 of 84 
APPENDIX 11: Poly-ICLC Ophthalmology Worksheet 
 
 


NF 111 Protocol Version 1.4 
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Page 84 of 84 
 

ICF_002.pdf: 
Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 1 of 22 
NF111 ICF Version Date: 2/28/2024 
 
Site Name 
 
Protocol Title:   
A Phase II Trial of Poly-ICLC for Progressive, Previously Treated Low-Grade 
Gliomas in Children and Young Adults with Neurofibromatosis Type 1   
IND Number:  
43984 
IRB Protocol #:  
IRB-300005076 
Sponsor:   
 
Department of Defense, U.S. Army 
Sponsor Protocol #: NF111 
Support from: 
Oncovir, Inc. 
Principal Investigator:  
Site PI 
 
 
 
 
For Children (persons under 18 years of age) participating in this study, the term “You” addresses 
both the participant ("you") and the parent or legally authorized representative ("your child"). 
 
General Information 
You are being asked to take part in a research study. This research study is 
voluntary, meaning you do not have to take part in it. The procedures, 
risks, and benefits are fully described further in the consent form. 
Purpose 
The purpose of the study is to find out if a tumor fighting drug called 
Poly-ICLC will work on decreasing the size of low-grade gliomas in 
pediatric patients with Neurofibromatosis Type 1 (NF1). 
Duration & Visits 
You will receive drug for up to 2 years of treatment and up to 5 additional 
years for follow up. You will come to clinic once a month for up to 28 
visits the first two years. Then you will come to clinic every 3-12 months 
for follow-up for approximately 10 visits over the 5 additional years. You 
will be involved in the study for up to 7 years. Each visit should last 
between 1-3 hours.  
Overview of 
Procedures 
Over the course of the study, you will get Poly-ICLC intramuscular 
injections twice a week for 24 cycles. Each cycle is approximately 28 
days. The dose of Poly-ICLC will be calculated by your weight. Every 4 
weeks, you will be evaluated in clinic or any reactions to Poly-ICLC.  
Every 12 weeks you will have an MRI to see if your tumor is shrinking. If 
your tumor is on the optic pathway you will have eye exams every 12 
weeks. If the tumor is growing, you will be taken off the study.  
Risks 
The most common risks include muscle soreness and redness where the 
drug is injected. A complete listing of the risks is included in the “Risks 
and Discomforts” section later in this form. 
Benefits 
The potential benefit is to stop the growth and/or decrease the symptoms 
you feel from your progressive low-grade glioma. It is possible that you 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 2 of 22 
NF111 ICF Version Date: 2/28/2024 
will not respond to the treatment. The study doctors hope to be able to use 
the information to determine the effectiveness of this medication on this 
tumor type. We also hope that information learned from this study will 
help other patients with NF1 and low-grade gliomas in the future.   
Alternatives 
Other possible alternatives are surgery, treatment with other experimental 
therapies or commercially available drugs, or receive no antitumor 
therapy and only receive treatment for your symptoms.  
 
Before you can make your decision, you will need to know what the study is about, the possible risks 
and benefits of being in this study, and what you will have to do in this study. You may also decide to 
discuss this study and this form with your family, friends, or doctor. If you have any questions about 
the study or about this form, please ask us. If you decide to take part in this study, you must sign this 
form. We will give you a copy of this form signed by you for you to keep. 
 
Purpose of the Research Study 
This is a clinical trial, a type of research study. Your study doctor, Site PI, and his associates from the 
Site Name will explain the clinical trial to you. 
 
We are asking you to take part in a research study because you have been diagnosed with 
Neurofibromatosis Type 1 (NF1) and have progressive low-grade gliomas. 
 
The purpose of this research study is to test how well a new drug called Poly-ICLC works in treating 
children with NF1 and progressive low-grade gliomas. The new drug, Poly-ICLC, is investigational 
and not yet approved by the Food and Drug Administration (FDA). Poly-ICLC has been used in 
children and adults with different types of brain tumors in other research studies like this one. Earlier 
studies showed that this drug worked better for children and young adults with low-grade gliomas than 
for children with more aggressive brain tumors.  
 
In this study, investigators will use Poly-ICLC treatment in a larger number of patients with NF1 and 
previously treated low-grade gliomas to see how well it works and how many side effects occur in 
these patients. This is a Phase II study. A Phase II study is a research study that tests the effectiveness 
of the drug and monitors side effects of a drug. 
 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 20 participants will take part in this study at multiple sites across the United States, and about 
XXX people will participate at Site Name. 
 
 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 3 of 22 
NF111 ICF Version Date: 2/28/2024 
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY? 
Study Participation & Procedures 
Your participation in this research study will involve up to 28 scheduled visits for 2 years while you 
are receiving drug, with an additional 28 visits for follow-up that will last an additional 5 years. You 
will be part of this study for up to 7 years. To monitor if there has been a response to treatment, you 
will have an MRI (Magnetic Resonance Imaging test) and an eye exam (if your tumor is on the 
pathway that affects your vision) every 12 weeks. Your participation in this research study will last 
until the study drug stops working and your tumors grow. Each of these visits will take between 1 – 5  
hours, depending on what tests are needed. 
 
You are not allowed to take certain medications during the research study. Before taking medications 
other than the study drug (such as a prescribed drugs, over-the-counter drugs like allergy medications, 
cough and cold remedies, pain relievers, vitamins, herbs and minerals), you must first ask the study 
doctor. If you need to have surgery while on this study, please contact the study doctor. 
 
If you agree to participate in this research study and you sign this informed consent form, you will be 
asked to participate in screening tests and procedures (described below) to determine if you are eligible 
for participation in this study. 
 
Before you begin the main part of the study... 
 
Screening/Baseline Study Visit (will last about 4 - 5 hours) 
The following tests and procedures will be performed: 
• 
You will have a physical examination, neurological exam and your vital signs will be 
measured (pulse, blood pressure, oxygen saturation, breathing rate and temperature) 
• 
You will be asked about your medical history and about any medications you have 
taken in the past or are currently taken.  
• 
The study doctor will check your performance status to monitor your ability to function 
and perform activities of daily living. 
• 
About 1-2 teaspoon (5-10ml) of blood will be drawn from a vein in your arm for 
laboratory testing including testing to see how well your bone marrow, kidneys and 
liver are working. 
• 
If you are a female who is able to have children, you will have a pregnancy test (either 
with some of the blood drawn or with urine). If the results of this pregnancy test are 
positive, you will not be able to participate in this study. 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 4 of 22 
NF111 ICF Version Date: 2/28/2024 
• 
An eye exam with an Ophthalmologist (doctor that specializes in eye and vision care) 
for patients with optic nerve tumors. 
• 
You will have an MRI of your brain and spine to find out the location and size of 
tumors. An MRI is a body scanning technique that uses magnetic waves to look at 
organs and soft tissues in the body. This will be done to identify the tumors before 
starting therapy. You will be asked to lie down on the MRI table. The table will move 
into a long chamber inside the MRI machine. The space is open at both ends. You will 
hear loud tapping or knocking for which you may wear earplugs. An MRI lasts about 45 
minutes to 1 hour and you will need to lie still for the entire time. A small amount of 
contrast agent is usually injected into your vein before an MRI. The contrast agent helps 
make the pictures clear. 
You will have a spine MRI only if your tumor is in the spine or your doctor feels this is 
necessary based on your symptoms. 
• 
You and/or your parent/guardian will be asked to complete a questionnaire about how 
your disease affects your activities in daily life. 
 
During the main part of the study... 
If the results of these screening tests and procedures show you can participate in this study, you will be 
asked to return to the study clinic for the study drug portion of this study. All study participants will 
get Poly-ICLC.  
 
Several required tests such as the MRI and eye exam (for patients with optic nerve tumors) may not be 
scheduled on the same day for a study visit due to your availability and/or available appointments. This 
could require you to come in up to 3 separate days. 
 
 
Study Treatment with Poly-ICLC: 
• You will get injections of Poly-ICLC into muscle two times weekly. The first treatment will be 
given in the clinic so nurses and doctors can make sure you do not have any (allergic) reaction 
to the injection. They will also teach you or a caregiver how to safely give the injections. If you 
tolerate the injections and do not have a severe reaction, then the rest of the injections will be 
given at home. 
 
• The medicine will be supplied in vials and you will be taught how to pull the medicine out of 
the vials safely. You will also be given syringes that have a line on the syringe showing the 
amount of medicine to put into the syringe. The vials should be kept in the refrigerator, but not 
frozen. They can be left at room temperature for up to 3 days without losing effectiveness. 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 5 of 22 
NF111 ICF Version Date: 2/28/2024 
• If you forget to administer the medication, you need to contact your physician to get instructions 
of when to give the medication again, but no closer than 48 hours between doses. 
 
• While you are receiving Poly-ICLC, you will be asked to keep a temperature log, noting your 
temperature before you receive the Poly-ICLC, and again at 12 hours after you get the drug for 
the first 28 days or cycle one. After the first 28 days, your temperature will be monitored if 
needed. Temperature may be taken orally, under the arm, skin or in the ear. Your doctor will 
review the log with you. You will need to bring this log with you each time you come to the 
clinic.  
 
• You will also be asked to keep a medication diary, noting the date, time, place of the injection 
and any problems you had when taking the Poly-ICLC. This will be done with every dose of 
Poly-ICLC and you will need to bring this diary with you each time you come to the clinic.  
 
• While you are on this study, information about how you are doing will also be collected. This 
will include what medications you are taking, any side effects from the treatment that happen 
and the status of your disease.  
 
Recommended days to receive Poly-ICLC injections: 
 
 
 
Option 1* 
Option 2* 
Monday 
X 
 
Tuesday  
 
X 
Wednesday 
 
 
Thursday 
X 
 
Friday  
 
X 
Saturday 
 
 
Sunday  
 
 
*If you miss a dose of medication on the scheduled day, a dose can be  
given up to 24 hours later. Injections must be separated by at least 48 hours.  
 
 
Day 1 (will last about 2 hours): 
• 
You will have a physical examination, neurological exam and your vital signs will be 
measured. 
• 
You will be asked about any medications you have taken or are currently taking. 
• 
The study doctor will check your performance status to monitor your ability to function 
and perform activities of daily living. 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 6 of 22 
NF111 ICF Version Date: 2/28/2024 
• 
About 1-2 teaspoons (5-10 ml) of blood will be drawn from a vein in your arm for a 
baseline to compare to future tests to see how well the drug is working.  
• 
If you are a female who is able to have children, you will have a pregnancy test (either 
with some of the blood drawn or with urine). 
• 
You will get your first injection of Poly-ICLC into your muscle. The nurses and doctors 
will make sure you do not have any (allergic) reaction to the injection. They will also 
teach you or a caregiver how to safely give the injections. If you tolerate the injections 
and do not have a severe reaction, then the rest of the injections will be given at home. 
 
 
Day 8 (will last about 0.5 hour) 
• 
About ½ -2 teaspoon (2-10ml) of blood will be drawn from a vein in your arm for 
laboratory testing including testing to see how well your bone marrow is working.  
• 
An additional 1-3 teaspoons (5-15ml) of blood will be collected at the same time the 2-
10ml is collected (as described above). This will not require another needle prick. This 
blood will be tested to look at how well the drug works, as part of this study.  
 
Day 15 (will last about 1 hour): 
• 
You will have a physical examination, neurological exam and your vital signs will be 
measured. 
• 
You will be asked about your medical history and about any medications you have 
taken in the past or are currently taken.  
• 
Review of any side effects you may be experiencing. 
• 
Review of drug/temperature diary. 
• 
The study doctor will check your performance status to monitor your ability to function 
and perform activities of daily living. 
• 
About ½ -2 teaspoon (2-10ml) of blood will be drawn from a vein in your arm for 
laboratory testing including testing to see how well your bone marrow is working. 
• 
An additional 1-3 teaspoons (5-15ml) of blood will be collected at the same time the 2-
10ml is collected (as described above). This will not require another needle prick. This 
blood will be tested to look at how well the drug works, as part of this study.  
 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 7 of 22 
NF111 ICF Version Date: 2/28/2024 
Study Visits for Beginning of Cycles 2-24 and Off-Study (will last about 1 - 4 hours depending on 
when you have your MRI and ophthalmology exam): 
The following tests and procedures will be performed every 28 days (once every 4 weeks): 
• 
You will have a physical examination, neurological exam and your vital signs will be 
measured. 
• 
You will be asked about any medications you have taken or are currently taking. 
• 
Review of any side effects you may be experiencing. 
• 
Review of drug/temperature diary. 
• 
The study doctor will check your performance status to monitor your ability to function 
and perform activities of daily living. 
• 
About 1-2 teaspoon (5-10ml) of blood will be drawn from a vein in your arm for 
laboratory testing including testing to see how well your bone marrow, kidneys and 
liver are working.  
• 
If you are a female who is able to have children, you will have a pregnancy test (either 
with some of the blood drawn or with urine). If the results of this pregnancy test are 
positive, you will not be able to continue participating in this study, and your 
participation will end. 
• 
At the beginning of cycles 3, 6 and 12 and 30 days after receiving the last dose of drug, 
an additional 1-3 teaspoons (5-15 ml) of blood will be collected at the same time the 5-
10 ml is collected (as described above). This will not require another needle prick. This 
blood will be tested to look at how well the drug works, as part of this study.  
• 
You and/or your parent/guardian will be asked to complete a questionnaire about how 
your disease affects your activities in daily life at the end of Cycle 6 and 12 and after 30 
days receiving the last dose of drug.  
• 
In addition to your monthly physical and laboratory examinations, you will have an 
MRI to see whether your tumors are responding to therapy and an eye exam with an 
Ophthalmologist (for patients with optic pathway gliomas) beginning of Cycles 4, 7, 10, 
13, 16, 19, 22, and 30 days after receiving the last dose of drug. 
 
The study doctor will discuss with you your responsibilities as a participant. 
 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 8 of 22 
NF111 ICF Version Date: 2/28/2024 
After you have stopped the study drug…… 
You will have the off treatment follow up visit about 30 days from the last dose of the study drug for a 
physical exam, vital signs, blood test and to make sure you don’t have any residual side effects from 
the study drug if you come off treatment due to side effects or progression.  
 
After all the study drug is stopped, you will have periodic physical exams as part of your regular care 
to see if the tumors are growing or have come back. We would like to learn about how patients are 
doing after stopping the study drug.   
 
Study Visits for the first 12 months after you have stopped taking drug – Year 3 of study (will 
last about 1.5 - 3 hours depending on when you have your MRI and ophthalmology exam): 
The following tests and procedures will be performed: 
• 
At the end of the 3rd month and 12 month, an additional 1-3 teaspoons (5-15 ml) of 
blood will be collected. This blood will be tested to look at how well the drug works, as 
part of this study. 
• 
Every 3 months, you will have an MRI to see whether your tumors are responding to 
therapy and an eye exam with an Ophthalmologist (for patients with optic pathway 
gliomas). 
 
Study Visits for the 13 to 36 months after you have stopped taking drug – Year 4 and 5 of study 
(will last about 1.5 - 3 hours depending on when you have your MRI and ophthalmology exam): 
The following tests and procedures will be performed: 
• 
After the 24th month after you have stopped taking drug, you and/or your 
parent/guardian will be asked to complete a questionnaire about how your disease 
affects your activities in daily life.  
• 
Every 6 months, you will have an MRI to see whether your tumors are responding to 
therapy and an eye exam with an Ophthalmologist (for patients with optic pathway 
gliomas). 
 
Study Visits for the 37 – 60 months after you have stopped taking drug – Year 6 and 7 of study 
(will last about 1 - 2 hours depending on when you have your MRI and ophthalmology exam): 
The following tests and procedures will be performed every 12 months: 
• 
You will have an MRI to see whether your tumors are responding to therapy and an eye 
exam with an Ophthalmologist (for patients with optic pathway gliomas). 
 


Research Consent Form 
NF Clinical Trials Consortium 
NF111: Poly-ICLC Protocol Version 1.4 
Page 9 of 22 
NF111 ICF Version Date: 2/28/2024 
Study Visit if you have PROGRESSION between 1 to 60 months after you have stopped taking 
drug – Year 3 through Year 7 of study (will last about 45 minutes): 
• 
You will have 1-3 teaspoons (5-15 ml) of blood collected. This blood will be tested to 
help understand how the drug worked, as part of this study. 
• 
You and/or your parent/guardian will be asked to complete a questionnaire about how 
your disease affects your activities in daily life if you have tumor progression before 24 
months post-therapy. 
 
Risks and Discomforts 
You may have some side effects from taking the study drug. All medications have side effects. Poly-
ICLC has been used safely in children and adults at this dose and at higher doses in other research 
studies. Frequently seen side effects include irritation of the skin where the injection is made and mild 
flu-like symptoms. These are usually relieved or avoided by use of over-the-counter medicines like 
acetaminophen (Tylenol) or ibuprofen (Advil, Motrin). 
 
Side Effects of Poly-ICLC Include: 
 
Common 
(21-100 patients per 
100) 
Occasional 
(5 to 20 patients per 
100)  
Rare 
(1 to 4 patients per 100) 
Immediate 
(within 1 to 2 days of 
receiving the drug) 
Muscle soreness and 
redness where the drug 
is injected.  
Diarrhea 
 
Prompt 
(within 2 to 3 weeks) 
 
Fatigue 
Muscle aches 
Joint aches 
Fever 
Chills 
Decreased number of 
white blood cells  
Delayed 
(anytime later during 
therapy) 
 
 
Increased liver enzymes 
levels in the blood 
 
Many side effects go away shortly after the medications are stopped, but in some cases side effects can 
be serious, long lasting or permanent. Your doctor will be checking closely to see if any of these side 
effects are occurring. Routine physical examinations, eye exams and blood tests will be performed 
once a month or more frequently to look for side effects of the drug.  
 


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Tell the study team right away if you have any new or worsening symptoms, so that the cause can be 
determined and adequate treatment can be provided. All problems need to be reported to the study 
doctors or study nurses looking after you either by phone or at the next visit.  
 
Some drugs or supplements may interact with your treatment plan. Talk to your doctor, pharmacist, or 
study team before starting any new prescription or over-the-counter drugs, herbals, or supplements and 
before making a significant change in your diet. Supplements may come in many forms, such as teas, 
drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms should be avoided. 
For more information about risks and side effects, you should feel free to ask your study doctor. If you 
are concerned about your health between visits due to participating in this trial, please call the 
emergency telephone numbers provided. 
 
There may be additional side effects related to Poly-ICLC that your treating team still does not know. 
It is very important to tell them if you have any bad experiences while on this study. 
 
Other risks: 
Blood Draw Risks: Risks associate with needle sticks for drawing blood are slight, but some possible 
risks include excessive bleeding, fainting or feeling lightheaded, bruising, infection (a slight risk any 
time the skin is broken), and multiple punctures to locate veins. 
 
Quality of Life Questionnaire: Some of the questions in the interview are about anxiety and 
depression and may make you feel uncomfortable. You do not have to answer any questions you do 
not want to answer. All answers you do give will be kept private. Although your answers are private, 
there is a slight chance that your information might be seen by someone who is not supposed to see it.   
 
MRI Risks: Because the MRI machine acts like a large magnet, it could move iron-containing objects 
in the MRI room during your examination, which in the process could possibly harm you. Precautions 
have been taken to prevent such an event from happening; loose metal objects, like pocketknives or 
key chains, are not allowed in the MRI room. If you have a piece of metal in your body, such as a 
fragment in your eye, aneurysm clips, ear implants, spinal nerve stimulators, or a pacemaker, you will 
not be allowed into the MRI room and cannot have an MRI. 
 
Having an MRI may mean some added discomfort for you. In particular, you may be bothered by 
feelings of claustrophobia and by the loud banging noise during the study. Temporary hearing loss has 
been reported from this loud noise. This is why you will be asked to wear earplugs. At times during the 
test, you may be asked to not swallow for a while, which can be uncomfortable. 
 
Because the risks to a fetus from MRI are unknown, pregnant women must not participate in this 
study.  


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Contrast agent (gadolinium) risks: A few side effects of gadolinium injection such as mild headache, 
nausea, and local pain may occur. Rarely (less than 1% of the time) low blood pressure and 
lightheadedness occurs. This can be treated immediately with intravenous fluids. Very rarely (less than 
one in one thousand), participants are allergic to gadolinium. These effects are most commonly hives 
and itchy eyes, but more severe reactions have been seen which result in shortness of breath. 
 
Participants with severe kidney disease sometimes have a bad reaction to gadolinium contrast. The 
condition is called nephrogenic systemic fibrosis (NSF). It can cause skin to tighten or scar and can 
damage internal organs. Sometimes it can be life-threatening. There are no reports of NSF in 
participants with normal kidney function. Before you have an MRI scan requiring an injection of 
gadolinium contrast, you will have a blood test in order to check the function of your kidneys. Based 
on your medical history and the results of the test, a doctor will decide whether it is safe for you to 
undergo the MRI scans. 
 
Confidentiality risks: There is a risk someone could get access to the personal information in your 
medical records or other information researchers have kept about you. Someone might be able to trace 
this information back to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of tracing information. 
In some cases, this information could be used to make it harder for you to get or keep a job. There are 
laws against misuse of genetic information, but they may not give full protection. The researcher 
believes the chance these things will happen is very small but cannot promise that they will not occur.  
 
Sedation Risks: 
If you need sedation for any procedure, you will get a separate consent form that explains the risks of 
sedation.  
 
Information for Women of Childbearing Potential, Nursing Mothers, and/or Men Capable of 
Fathering a Child 
Patients who are pregnant or breast-feeding cannot take part in this study. Poly-ICLC may hurt an 
embryo, fetus or nursing child. Women capable of becoming pregnant must have a negative pregnancy 
test before entering the study. For females who are able to become pregnant and sexually active, you 
must practice an effective method of birth control during the treatment and for 3 months after stopping 
the treatment.   
 
Recommended methods of birth control are:  
• 
the consistent use of an approved oral contraceptive (birth control pill) 
• 
an intrauterine device (IUD) 
• 
hormone implants (Norplant) 


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• 
contraceptive injection (Depo-Provera) 
• 
double barrier methods (diaphragm with spermicidal gel or condoms with contraceptive 
foam) 
• 
sexual abstinence (no sexual intercourse)  
• 
sterilization 
Oral contraceptives, hormone implants, and injections are only considered effective if used properly 
and started at least one month before beginning the study, continuing throughout the study, and for 3 
months after the study.  
 
A pregnancy test will be given to females of childbearing potential before therapy begins. Because the 
drug in this study can affect an unborn baby, you should not become pregnant or father a baby 
while on this study. You should not nurse a baby while on this study. If a female caregiver is 
pregnant or suspects she is pregnant, she should not handle Poly-ICLC. If you become pregnant 
during the study, you will need to inform your doctor immediately and stop taking Poly-ICLC. The 
principal investigator may ask you to provide information about the outcome of your pregnancy and 
the health of your baby. Ask about counseling and more information about preventing pregnancy. 
 
Note to Men  
Because the effects of participating in this study on sperm are unknown, male patients, whose sexual 
partner(s) are women of childbearing potential, are required to use adequate contraception during the 
study and for 3 months after the end of treatment, using one of the methods described above. If your 
partner becomes or thinks she may have become pregnant during the time you are in the study or 
within one month after stopping the study drug, you must tell the principal investigator right away. The 
principal investigator may ask for your partner’s permission to collect information about the outcome 
of her pregnancy and the health of her baby. The principal investigator will discuss with you whether 
you have to stop taking part in the study if your partner becomes pregnant for safety reasons. 
 
What Will Be Done to Minimize the Risks? 
The doctor and/or staff will be checking you closely to see if any of the side effects are occurring. 
Most side effects go away after the treatment is stopped. The doctor may prescribe drugs to lessen or 
control side effects. Treatment will be modified, whenever necessary, to prevent permanent damage.  
The doctor will do everything possible to prevent any serious complications. If they do occur, your 
doctor will provide appropriate measures (blood transfusions, antibiotics, anti-vomiting medications, 
etc.). 
 
Although you will be treated according to a specific plan (protocol), individual circumstances may arise. In 
such cases, your health will always be considered more important than strictly following the protocol.  
Changes will be discussed before they are made whenever possible. 
 


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Benefits 
It is hoped that the use of Poly-ICLC will control your disease, but this cannot be guaranteed. We also 
hope that information learned from this study will help improve treatment for other patients who have 
NF1 progressive low-grade gliomas in the future. There may be no direct benefit from participating in 
this study. 
 
Alternatives 
You may decide not to take part in this research study without any penalty. The choice is totally up to 
you. You do not have to participate in this study to receive ongoing care for your condition. The study 
doctor will discuss with you the alternatives to participation and their risks and benefits. 
Alternatives to this therapy include: 
• use of drugs or other therapies that have been previously tried in the treatment of this disease 
• surgery 
• no anti-tumor therapy at this time 
• palliative care, which treats the symptoms and quality of life, rather than the disease. 
 
PLEASE TALK TO YOUR DOCTOR AS WELL AS OTHER TRUSTED PROFESSIONALS AND 
FAMILY ABOUT THESE AND ANY OTHER OPTIONS. 
 
Confidentiality and Authorization to Use and Disclose Information for Research Purposes 
 
Insert site HIPAA language 
 
A Data and Safety Monitoring Board (DSMB), the National Cancer Institute, a research monitor, 
Department of Defense, Oncovir Inc., members of the Neurofibromatosis Consortium and a site 
monitor will be reviewing the data from this research throughout the study.  
 
A description of this clinical trial will be available on www.ClinicalTrials.gov, as required by U.S. 
Law. This website will not include information that can identify you. At most, the website will include 
a summary of the results. You can search this website at any time. 
 
Voluntary Participation and Withdrawal 
If you decide to take part in the study, you may withdraw from participation at any time without 
penalty or loss of benefits to which you would otherwise be entitled. However, if you are thinking of 
leaving the study, we ask that you speak with a study team member about this decision. Leaving this 
study early will not affect your regular medical care.  
 
If you do decide to withdraw your consent, we ask that you contact Site PI and let him know that you 
are withdrawing from the study. The mailing address is Site Mailing Address. If you wish to withdraw 


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your Authorization as well as your consent to be in the study, you must contact the study doctor in 
writing. 
 
This study is expected to end after all participants have completed all visits, and all information has 
been collected. This study may also be stopped, or your participation ended at any time by your 
physician, or the study sponsor, without your consent because: 
• The principal investigator feels it is necessary for your health or safety. Such an action would 
not require your consent, but you will be informed if such a decision is made and the reason for 
this decision. 
• You have not followed study instructions.  
• The study sponsor, the principal investigator, the Food and Drug Administration (FDA) or 
other body responsible for monitoring the safety of the study has decided to stop the study. 
 
Cost of Participation 
Oncovir, Inc., the makers of Poly-ICLC, is supplying the drug at no cost to you, and providing support 
to conduct this study. 
 
Taking part in this study may lead to added costs to you or your insurance company. You or your 
insurance company will be charged for all of the costs associated with your standard clinical care, such 
as the laboratory tests, MRIs, eye exams, and clinic visits described in this consent form. These are 
considered part of standard care for someone with your illness. However, you will not be responsible 
for the cost of the study drug. Oncovir, Inc. will provide the Poly-ICLC free of charge to participating 
research participants.  
 
Your individual insurance or government health insurance program may not cover certain services, 
items or procedures. You may want to discuss this with your insurance carrier in advance. You will be 
responsible for any co-payments and/or deductibles for standard clinical care services rendered. If you 
believe you have received a bill for a research related procedure contact the study team at Site 
Telephone Number or the billing office that sent the bill. 
 
The costs of your standard medical care will be billed to you and/or your insurance company in the 
usual manner. 
 
If you have any questions, your doctor and the study team will be able to provide you with answers. 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print 
a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. 
 


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Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to 
send you a free copy. 
 
Payment for Participation in Research: 
You will not be paid for taking part in this study. 
 
Treatment and Compensation for Injury:   
 
Insert Site Injury Language 
 
The Department of Defense, Oncovir Inc., and the Neurofibromatosis Consortium have made no 
provision for monetary compensation in the event of injury from the research, and in the event of such 
injury, treatment will be provided, but is not free of charge. 
 
 
WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY? 
Taking part in this study is your choice. You may choose either to take part or not to take part in the 
study. If you decide to take part in this study, you may leave the study at any time. No matter what 
decision you make, there will be no penalty to you, and you will not lose any of your regular benefits.  
 
Leaving the study will not affect your medical care. You can still get your medical care from our 
institution.  
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
You are not waiving any of your legal rights by signing this consent form. 
 
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY? 
You can talk to your study doctor about any questions, concerns, or complaints about the research, or a 
research-related injury, including available treatments. Contact your study doctor, Site PI or his/her 
associates at Site Telephone Number. 
 
Site IRB/HRPP contact information 
 
If you have questions about your rights as a research participant, or concerns or complaints about the 
research, you may contact the UAB Office of the IRB (OIRB) at (205) 934-3789 or toll free at 1-855-
860-3789. Regular hours for the OIRB are 8:00 a.m. to 5:00 p.m. CT, Monday through Friday.   
 


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Significant New Findings 
During the course of this study we may find more information that could be important to you. This 
includes information that might cause you to change your mind about being in the study. We will 
notify you as soon as possible if such information becomes available. The investigator will tell you 
about new information from this or other studies that may affect your health, welfare, or willingness to 
stay in this study. 
 


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Optional Consent 
Consent for Use of Study Data for Future Research: 
If you agree, we would like to keep your data containing personal information such as your medical 
history, eye exam and imaging results, and adverse events for future research about NF, treatments for 
these conditions, and ways to prevent these conditions.   
 
The data will be labeled with a unique study identification number, instead of your name. The data will 
be used for research purposes only and will not benefit you. It is also possible that the stored data may 
never be used. Results of research done on your data will not be available to you or your doctor. Your 
data will be stored indefinitely. We may give this data about you to other researchers or companies not 
at Site Name. The results might help people who have NF in the future. 
 
Your information may be put in controlled-access databases. This means only researchers who apply 
for and get permission to use the information for a specific research project will be able to access the 
information. Your information stored in these databases will not include any identifying information. 
We will replace identifying information with a code number. We will keep a master list that links your 
code number to your identifying information at Site Name. Only certain study personnel for this study 
at Site Name will have access to this master list. Researchers approved to access information in the 
controlled-access database will agree not to attempt to identify you. 
 
Consent for Use of Leftover Blood for Future Research: 
Donating your blood for future research is completely voluntary.  
 
You will have blood collected as part of your participation in this clinical trial at baseline, day 8 and 
day 15 of cycle 1, day 1 cycles 3, 6 and 12, at the end of therapy or at the time of progression during 
treatment, 3 months post treatment, 1-year post treatment, and at time of progression when off treatment if 
applicable. After the study has been completed, instead of discarding your leftover specimens, with 
your permission, we will save (bank) them for possible future research to learn more about cancer and 
other diseases. Any leftover blood samples will be coded and stored indefinitely at the Dhodapkar 
Laboratory at Emory University in Atlanta, Georgia. 
 
The research that may be done with your blood specimens are not designed specifically to help you. It 
might help people who have NF and other diseases in the future. 
 
Reports about research done with your blood will not be given to you or your doctor. These reports 
will not be put in your health record. The research will not have an effect on your care. If the research 
is published or presented at scientific meetings, your name and other personal information will not be 
used. 
 


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Consent to Collect Tumor Tissue and blood sample: 
You might have had surgery to determine the type of tumor you have before beginning this study. As 
part of this study, we would like to use any left-over tissue from that surgery for this study. The tissue 
will be banked at the Children’s Hospital of Philadelphia for possible future research.  
 
If you have tumor surgery while on this study, we would like your permission to use any left-over 
tissue from that surgery as well. Surgeries will not be done solely for the study. This is a request to use 
any left-over tissue that has been stored by the hospital that was not used for evaluation of your 
disease. We would also like to collect 10 mL (2 teaspoons) of blood. 
 
Things to Think About 
If you decide now that your study data and/or left over blood and/or tumor tissue with blood samples 
can be used for future research, you can change your mind at any time. Just contact the study doctor, 
Site PI, at Site Name at Site Address and let us know that you do not want us to use your blood or 
study data.  
 
Then any samples that remain or stored study data that has not already been shared will no longer be 
used for research. We will destroy any remaining identifiable specimens and information if they are no 
longer needed for your care. However, if any research has already been done using portions of your 
specimens or study data, the data will be kept and analyzed as part of those research studies. 
 
Your blood and study data will be used only for research and will not be sold. The research done with 
your blood specimen and study data may help to develop new products in the future. You will not 
receive any payment or financial benefit from any products, tests, or discoveries derived from these 
samples. 
 
Confidentiality risks: There is a risk someone could get access to the personal information in your 
medical records or other information researchers have kept about you. Someone might be able to trace 
this information back to you. The researchers believe the chance that someone will identify you is very 
small, but the risk may change in the future as people come up with new ways of tracing information. 
In some cases, this information could be used to make it harder for you to get or keep a job. There are 
laws against misuse of genetic information, but they may not give full protection. The researchers 
believe the chance these things will happen is very small, but cannot promise that they will not occur. 
 
Research use of your private information and biospecimens will be conducted in compliance with 
applicable regulatory requirements. 
 
Risks associated with genetic testing: 
If you agree to allow blood to be banked for future research, the research studies on your samples may 
involve genetic analyses, and these data may be shared with other researchers. The risks related to 


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genetic analyses can be to individuals or to groups. These harms include stigmatization and 
insurability. To reduce this risk, only coded samples will be stored and used for research. Information 
about this study will not be recorded in your medical record. 
 
A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it 
illegal for health insurance companies, group health plans, and some employers to discriminate against 
you based on your genetic information. This law generally will protect you in the following ways: 
• 
Health insurance companies and group health plans may not request your genetic information that 
we get from this research. 
• 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. 
• 
Employers with 15 or more employees may not use your genetic information that we get from this 
research when making a decision to hire, promote, or fire you or when setting the terms of your 
employment. 
 
Be aware that this federal law does not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance, nor does it protect you against 
genetic discrimination by all employers. 
 
 
Making Your Choice 
 
Please think about your choice. After reading, put your initials next to the "Yes" or "No" statement.  
If you have any questions, please talk to your doctor or nurse. 
 
If the subject/parent does not speak English, the person obtaining consent should initial the 
subject’s/parent’s choice below.  
 
 
The choice to let us use your study data for future research is optional and is up to you. No matter 
what you decide to do, it will not affect your care. 
 
_________ Yes, I will allow my study data to be kept for use in future research about NF and other 
diseases. 
 
_________ No, I will NOT allow my study data to be kept for use in future research about NF and 
other diseases. 
 
 


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The choice to let us keep any leftover blood for future research is optional and is up to you. No matter 
what you decide to do, it will not affect your care. 
 
 
_________ Yes, I will allow my leftover blood to be kept for use in future research about NF and 
other diseases. 
 
_________ No, I will NOT allow my leftover blood to be kept for use in future research about NF and 
other diseases. 
 
The choice to let us collect any tumor sample and blood sample for future research is optional and is 
up to you. No matter what you decide to do, it will not affect your care. 
 
___________ Yes, I agree to allow for tumor tissue and blood sample (from pre-study surgery and 
surgeries during study) to be used for use in future research about NF and other diseases. 
 
___________No, I do NOT agree to allow for tumor tissue and blood sample (from pre-study 
surgery and surgeries during study) to be used for use in future research about NF and 
other diseases. 
 
 
 
 


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DOCUMENT OF CONSENT: 
 
PARTICIPATION IN RESEARCH IS VOLUNTARY.  
 
You have the right to decline to participate or to withdraw at any point in this study without penalty or 
loss of benefits to which you are otherwise entitled.   
My signature below indicates that I agree to participate in this study. I am aware that I will receive a 
copy of this signed agreement: 
 
• I have had enough time to read the consent or have the consent form read to me and think 
about participating in this study; 
• I am willing to participate in this study; 
• I have been told that my participation is voluntary, and I can withdraw at any time 
 
 
PARTICIPANT NAME:   _____________________________________________________  
(Print Name) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Participant's Signature for Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
__ 
Date 
 
 
Signature of Participant 14 Years of Age and Older 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Signature of Parent or Guardian 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Legally Authorized Representative (if applicable) / Relationship of Legally Authorized 
Representative to Participant 
 
 
 
 
 
 
 
 
 
 
 
 
 
__ 
Date 
 
 
Signature of Legally Authorized Representative (if applicable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date 
 
 
Witness Signature  
(Only required if the participant is a non-English speaker) 
 
 


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Waiver of Assent 
 
The assent of ______________________________ (name of child/minor) was waived because of: 
 
 
Age _________ 
 
 
To be completed by person obtaining consent: 
 
For Adult Participants: 
 The participant is an adult and provided consent to participate.  
 The participant is an adult who lacks capacity to provide consent and his/her legally authorized 
representative: 
 gave permission for the adult participant to participate  
 did not give permission for the adult participant to participate  
 
 
For Minor Participant: 
 
 The parent or legally authorized representative gave permission for the minor to participate. 
  Parent or legally authorized representative is illiterate. 
 
The consent form was read to the parent or legally authorized representative who was given the 
opportunity to ask questions. 
 The parent or legally authorized representative did not give permission for the minor to 
Participate. 
 
 
Signature of Individual obtaining consent:  
 
 
 
Printed name of above: 
 
 
 
Date: ____________________________