A Phase II Trial of Poly-ICLC in the Management of Recurrent Pediatric Low Grade Gliomas
Phase: PHASE2
Conditions: Brain Tumors
Sponsor: Wake Forest University Health Sciences

Title:  A Phase II Trial of Poly-ICLC in the Management of 
Recurrent or Progressive Pediatric Low Grade Gliomas 
 
Date:  5/21/2014 
NCT01188096 
 
 

Poly-ICLC 10/22/2010 
 
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A Phase II Trial of Poly-ICLC in the Management of Recurrent 
or Progressive Pediatric Low Grade Gliomas 
 
 
 
 
 
October 22, 2010 
 
 
 
 
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
     
       Amendment #1: 6/6/2011 
Amendment #2: 3/13/2012 
Amendment #3 5/21/2014 
 
 
 
 
 
 
 
 
 
 
 

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Contact Information 
 
 
 
Principal Investigator: 
Donald L. Durden, M.D., Ph.D. 
 
 
 
 
Professor and Vice Chair for Research 
 
 
 
 
UCSD Department of Pediatrics 
 
 
 
 
Rady Children’s Hospital-San Diego  
Moores Cancer Center, RM 3312 
University of California, San Diego 
3855 Health Sciences Drive #0819 
La Jolla, CA 92093-0819 
Phone: 858-534-3355 
 
 
 
 
ddurden@ucsd.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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STUDY COMMITTEE 
 
Study Chair: 
Donald L. Durden, M.D., Ph.D. 
Professor and Vice Chair for Research 
UCSD Department of Pediatrics 
Rady Children’s Hospital-San Diego  
Moores Cancer Center, RM 3312 
University of California, San Diego 
3855 Health Sciences Drive #0819 
La Jolla, CA 92093-0819 
Phone: 858-534-3355; Fax : 858-822-0022 
ddurden@ucsd.edu 
 
 
Study Committee Members: 
Dolly Aguilera, M.D. 
Assistant Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University 
5455 Meridian Mark Road 4th Floor 
Atlanta, GA 30342 
Phone: 404-785-3721; Fax: 404-785-3511 
dolly.aguilera@@choa.org 
 
John Crawford, M.D., M.S. 
Assistant Adjunct Professor of Neurosciences and Pediatrics 
Rady Children’s Hospital-San Diego 
University of California, San Diego 
8010 Frost St Suite 400 Neurology 
San Diego CA 92123 
Phone: 858-966-5811; Fax: 858-966-8035 
jrcrawford@rchsd.org 
 
Anna Janss, M.D., Ph.D. 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University 
2015 Uppergate Drive 4th Floor 
Atlanta, GA 30322 
Phone: 404-785-0854; Fax: 404-785-6288 
anna.janss@choa.org 
 

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Howard Katzenstein, M.D. 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University 
2015 Uppergate Drive 4th floor  
Atlanta, GA 30322 
Phone: 404-785-0853; Fax: 404-727-4455 
howard.katzenstein@choa.org 
 
Tobey  MacDonald, M.D. 
Associate Professor of Pediatrics 
Children’s Healthcare of Atlanta 
Emory University 
2015 Uppergate Drive 4th Floor 
Atlanta, GA 30322 
Phone: 404-727-1447; Fax: 404-727-4455 
Tobey.macdonald@emory.edu 
 
Scott R. VandenBerg, M.D., Ph.D. 
Professor of Pathology, Director of Neuropathology 
University of California, San Diego 
9500 Gilman Drive, MC 0612 
La Jolla, CA 92093-0612 
Phone: 858-822-2808 
srvandenberg@ucsd.edu 
 
 
Research Study Coordinator: 
Mehrzad Milburn, RN, BSN, CCRC 
Oncology Research Data Center 
UCSD/Rady Children’s Hospital 
3020 Children’s Way MC 5128 
San Diego, CA 92123 
 
Phone: (858) 966-8155; Fax: (858) 966-8966 
mmilburn@rchsd.org 
Biostatistics Support: 
Karen Messer, Ph.D.  
Professor, Division of Biostatistics 
Director, Biostatistics/Bioinformatics Shared Resource  
Moores UCSD Cancer Center   
University of California, San Diego 
3855 Health Sciences Drive #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4334 

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kmesser@ucsd.edu 
 
Hongying Li, Ph.D 
Senior Statistician 
Biostatistics/Bioinformatics Shared Resource 
Moores UCSD Cancer Center  
University of California, San Diego 
3855 Health Sciences Drive #0901 
La Jolla, CA 92093-0901 
Phone: 858-822-4818 
hol031@ucsd.edu 
  
Minya Pu, M.A. 
Senior Statistician 
Biostatistics/Bioinformatics Shared Resource 
Moores UCSD Cancer Center  
University of California, San Diego 
3855 Health Sciences Drive #0901 
La Jolla, CA 92093-0901 
Phone: 858-534-2368  
mpu@ucsd.edu 
 
 
 
 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
SECTION 
 
 
 
 
 
 
 
 
 
 
PAGE  
1.0 
OBJECTIVES  
 
                               
 
 
 
 
7 
           1.1 Primary Objectives                                                                                    
7 
           1.2 Secondary Objectives                                                                               
7 
 
2.0 
BACKGROUND AND RATIONALE  
 
 
                  
 
7-14 
 
3.0 
PATIENT ELIGIBILITY AND STUDY ENTRY 
 
 
 
       
14-19 
 
3.1 
Patient Registration 
 
 
 
 
 
 
 
14-15 

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3.2 
Inclusion Criteria 
 
 
 
 
 
 
       
15-18 
 
3.3 
Exclusion Criteria 
 
 
 
 
 
 
       
18-19 
 
3.4 
Regulatory 
 
 
 
 
 
 
 
       
19 
 
4.0 
STUDY TREATMENT 
 
 
 
 
 
 
       
19-20 
 
4.1 
Treatment Schedule  
 
 
 
 
 
       
19 
 
4.2 
Dose Modifications Based on Toxicity 
 
 
 
       
20 
 
4.3 
Concomitant Therapy  
 
 
 
 
 
       
20 
 
5.0 
REQUIRED OBSERVATIONS 
 
 
 
 
 
       
21-26 
 
5.1 
Pretreatment evaluation 
 
 
 
 
 
       
22 
 
5.2 
Evaluation during treatment  
 
 
 
 
       
22 
 
5.3 
Evaluation at end of therapy or relapsed disease 
 
 
 
23 
 
 
5.4 
Special Laboratory Specimens 
 
 
 
                   
23-25 
            5.5 
Pathology Specimens  
 
 
 
 
 
 
25-26 
 
6.0 
DRUG INFORMATION 
 
 
 
 
 
 
       
26-27 
 
7.0 
RESPONSE CRITERIA 
 
 
 
 
 
 
       
27-29 
 
7.1  
Evaluation Criteria 
 
 
 
 
 
 
 
27-29 
 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY 
 
       
29-30 
 
8.1 
Criteria for Removal from Protocol Therapy  
 
 
 
29-30 
 
8.2 
Off Study Criteria 
 
 
 
 
 
 
 
30 
 
9.0 
STATISTICAL CONSIDERATONS  
 
 
 
 
       
30-33 
 
9.1 
Study Design and Justification of Sample Size 
 
                   
31-32 
 
9.2 
Analysis of Results 
 
 
 
 
 
 
       
32-33 
 
10.0 
ADVERSE REACTION REPORTING AND TOXICITY CRITERIA  
        
33-35 
 
10.1 
Reporting Adverse Drug Reactions Occurring with Investigational Agents 34 
 
10.2 
Toxicity Criteria  
 
 
 
 
 
 
 
34 
 
10.3 
Data Safety Monitoring  
 
 
 
 
                
35 
 
10.4 
FDA Annual Reporting 
 
 
 
 
 
 
35 
 
11.0 
REFERENCES 
 
 
 
 
 
 
 
        
36-39 
APPENDIX I-IV 
 
 
 
 
 
 
 
 
40-43 
 
 
1.0 
Objectives: 
 
1.1 
Primary Objectives 
 
1.1.1 
The primary endpoint will be the progression free survival rate to poly-ICLC at 6 months, in the children 
with recurrent low grade gliomas; tumor assessments are to be performed per Modified McDonald’s 
criteria. Progression free survival is defined as the time from starting study therapy to tumor progression, 
tumor recurrence, death from any cause, or occurrence of a second malignant neoplasm. 

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1.2 
  Secondary Objectives 
 
1.2.1 
To determine the overall response rate to poly-ICLC in the treatment of children with recurrent low grade 
gliomas; tumor assessments are to be performed per 3D measurements. 
 
1.2.2 
 Progression free survival  over the course of the study. 
 
1.2.3 
Overall survival at 6 months – the time from starting study therapy to death from any cause. 
 
1.2.4 
To assess the toxicity associated with treatment with poly-ICLC in pediatric patients with recurrent low 
grade gliomas.  
            
1.2.5 
To study the effect of treatment with poly-ICLC on the signaling pathways controlling apoptosis in low 
grade glioma tumor cells.  
 
1.2. 6   To determine if surrogate markers of tumor response and progression can be identified in the serum,    
      PBMC and/or cerebrospinal fluid of patients with recurrent low grade gliomas treated with poly-ICLC.    
      Proteomics analysis will be performed to obtain protein levels of these markers such as OAS, interferon ,     
     , , PKR kinase, phosphorylation state of eIF2a, and induction of p21waf-1.   
 
 
2.0 
Background/Rationale 
 
 
The incidence of primary pediatric brain tumors in the United States is about 1500 per year.  Brain tumors 
are the most common solid tumor diagnosed in childhood and thus account for significant childhood mortality in 
the United States. Low-grade astrocytomas and gliomas are the most common type of brain tumor of childhood 
(36% of childhood brain tumors). These tumors encompass a heterogeneous assortment of histological subtypes 
including: fibrillary, protoplasmic, gemistocytic, and mixed variants. Pilocytic astrocytomas, pleomorphic 
xanthroastrocytomas and subependymal giant cell astrocytomas are also included. Furthermore, in young children 
there are some unique rare entities that behave like low-grade tumors, including infantile desmoplastic 
gangliogliomas, pilomyxoid variant, and desmoplastic astrocytomas. 
 
  
Although children with low-grade astrocytomas often survive many years after conventional treatment with 
surgery and sometimes radiotherapy, there can be tremendous morbidity depending on the location of tumor and 
the effects of therapy. These tumors constitute a heterogeneous group because of differing locations within the 
brain and varying biological behavior of different subtypes. For those where total excision is possible, such as 
cerebellar astrocytomas, prognosis is excellent with over 90% ten-year survival rates with surgical excision alone. 
In contrast, survival rates in children with cerebral or diencephalic tumors are 40-70% at five years with irradiation, 
but decline to 11-50% at 10 years (Mundigers, 1990). Some tumors however may be unresectable/partially 
resectable, and radiation can have undesirable side effects in young children. While the most significant 
intellectual deficits occur in young children less than 5 years treated with cranial irradiation, the deficits recognized 
even in young adults warrant extending the age to 10 years for avoiding radiation. Chemotherapy regimens are 
used for high-risk patients (progressive tumor, residual tumor) as a means to avoid or delay radiation in young 
patients, but side effects of chemotherapy are frequently reported. Newer forms of effective treatment that will 
have lesser side effects are much needed in childhood brain tumors especially low-grade gliomas. We propose to 
study the efficacy and toxicity of poly-ICLC, a biological response modifier in children with low-grade gliomas. 
PROTEOMICS 

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Current diagnostic and therapeutic monitoring of brain tumor patients are significantly hindered due to 
limited understanding of brain tumor biology and response to therapy. The majority of CNS tumors cannot be 
identified or followed by expression of serum or CSF markers. However, if available, such markers would be 
highly desirable and could be used to: 
 
• 
Detect minimal residual disease 
• 
Predict response to specific targeted therapies 
• 
Predict or anticipate tumor progression 
• 
Distinguish tumor recurrence from post surgical changes or post-radiation changes on neuro-imaging 
• 
Augment current histopathologic classification systems 
• 
Improve current clinical and pathological treatment stratification schemata 
• 
Assess efficacy of and tumor response to specific biologic targeted therapies that may not impact tumor 
size as a primary tumor endpoint (e.g., small molecule inhibitors or anti-angiogenic strategies) 
 
 
While such markers would be useful to prognosticate, monitor and treat all CNS tumors, its use in glial 
tumors including recurrent low grade astrocytomas is critical since these tumors are often biopsied at 
presentation, but not at recurrence. Often these tumors are not amenable complete resection or biopsy due to 
the eloquence of brain tissue they infiltrate (e.g., optic pathway, brainstem or hypothalamic gliomas), or the blood 
vessels that they encase.   
 
CNS biologic material in CSF 
 
Glial tumors tend to disseminate locally along white matter tracts rather than through sub-arachnoid 
seeding. Dissemination of low grade gliomas along the sub-arachnoid space has been reported in children with 
low grade gliomas.  Even focal tumors are frequently adjacent to CSF pathways (e.g., intrapeduncular fossa, 
third and fourth ventricles) resulting in direct contact between tumor tissue and spinal fluid.  Yet examination of 
CSF cytology for these tumors is not standard. Given limitations of identifying tumor cells in the CSF, 
methodologies that could improve our understanding of CNS tumors of all types are needed. This would provide 
a significant improvement in currently available knowledge about the biology of these tumors, and could elucidate 
potential therapeutic avenues.  
 
 
Proteomics, a relatively new area of research whereby total protein complement of a tissue compartment 
is analyzed, has successfully been used to identify novel biomarkers in solid tumors (Zheng, 2003; Khwaja, 
2007). Because proteins are effectors of all cellular functions, their measurement should represent the most 
direct means of cellular characterization and hence tumor biology. Because cells and their environment exist in 
an integrated state, it has been possible to interrogate the proteins of extra-cellular compartments to assess the 
presence and impact of tumor cells. This has been done primarily using serum or plasma to establish a method 
of screening for the presence of low stage tumors. 
 
 
An analogous extra-cellular compartment for use in brain tumors would be cerebrospinal fluid (CSF). It 
circulates throughout the CNS and exchanges proteins with the extra-cellular fluid of the brain and spinal cord. 
CSF is continuously created and reabsorbed, providing a real time steady state proteome. Unlike serum, which 
contains a highly complex protein mixture ranging from very low abundance proteins in the 10-30 pg/mL range to 
very abundant proteins in the 35-55 mg/mL range, CSF contains a less complex protein mixture (Omenn, 2005). 
Therefore, the CSF is more likely to contain higher relative concentrations of tumor-specific proteins (higher 
signal to noise ratio) than serum. Taken together this makes CSF and attractive alternative to serum for detection 
of brain tumor related biomarkers. 

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Unlike leukemia and many solid tumors outside the CNS, where serial biopsies are readily performed, 
tumors of the CNS are not easily accessible other than at the time of initial or repeat resection or biopsy. While 
studies on these samples provide important findings regarding tumor biology, serial analyses during treatment 
are not reasonable. By contrast, the CSF of tumor patients can be more readily sampled in most pediatric 
patients. With the development of proteomic technology, investigation of tumor related signals at the time of 
diagnosis through treatment, and then in remission and/or at the time of recurrence or progression is possible. 
 
 
While CSF for seeding tumors is readily available and routinely obtained for cytology, the systematic 
evaluation of the proteins within these samples could be of considerable scientific importance. In addition to 
identifying potential makers of disease or response to therapy, the glycosylation and phosphorylation status of 
many proteins can also be evaluated. Studies in tumor tissue have show that such information reveals activity of 
different enzymes that correlate with either treatment response (Mellinghoff, 2005; Helgi, 2005) or progression of 
leptomeningeal metastases (Brandsma, 2006).  
 
 
Proteomics 
 
CSF proteomics has been applied to many neurological disorders including Alzheimer’s disease, 
amyotrophic lateral sclerosis, multiple sclerosis, acute brain injury and Creutzfeldt-Jakob disease (Rohlff, 2001). 
Reports of its use in neuro-oncology are limited, but demonstrate the potential of this technology to effectively 
identify tumor biomarkers. One study used two dimensional polyacrylamide (2-D) gel electrophoresis to measure 
the relative quantities of two pre-selected markers, N-Myc and l-CaD, in the CSF of brain tumor patients (Zheng, 
2003). Another used ELISA of CSF to identify Osteopontin as predictive of AT/RT and correlated with response 
to therapy (Kao, 2005). CSF proteomics using 2-D gel electrophoresis in combination with mass spectroscopy 
and cleavable isotope Coded Affinity Tag (cICAT) was used to evaluate 60 samples of CSF and tumor cyst fluid 
taken from adults with brain tumors and non-neoplastic controls. These techniques were used to find a panel of 
proteins differentially expressed in lower vs. higher-grade gliomas. Findings were confirmed using Western Blot 
analysis probing for eight selected proteins based on implied role in gliomagenesis and availability of antibodies. 
This report, which has been accepted for publication pending revisions, identified 21 potential CSF biomarkers 
for astrocytoma. 
 
 
As mentioned above, there is evidence that gliomas disseminate through the subarachnoid space. The 
presence of leptomeningeal dissemination of glial tumors is significant because it demonstrates that glial tumor 
cells have access to the CSF space, and thus, proteins secreted from these tumors have the ability to access the 
CSF space and may be detected by CSF proteomics.  Currently there are several consortia actively studying 
protein expression in the spinal fluid of children with malignant glial and embryonal tumors (Pediatric Brain Tumor 
Consortium and Pediatric Oncology Experimental Therapeutics Consortium).  Proteins interrogated in these 
protocols include those involved with angiogenesis and neovascularity (EGF, VEGF and bFGF), those involved in 
tumor growth and migration (secreted protein with acidic and cysteine rich domains (SPARC), attractin).  There is 
no consortium actively collecting spinal fluid sample in children with lower grade tumors.  A secondary goal of this 
study is to examine these proteins in the CSF of children with low grade gliomas who have tumor progression.  
Comparison of CSF protein expression of high grade and low grade tumors is likely to help identify biological 
markers specific for tumor progression, or for tumor pathology. 
 
 
 
2.1       Pre-clinical studies: 
 

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Polyinosinic-Polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly-ICLC) (Levy, 
1985) 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.  These trials gave mixed results with moderate toxicity, and the use 
of poly-ICLC was generally abandoned when recombinant interferons became available (Levy, 1987); 
(Rettenmaier, 1986); (Krown, 1985); (Theriault, 1986); (Droller, 1987); (Hawkins, 1985); (Nakamura, et al 1982).  
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 in the past 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 (Black, 1992).  Low dose poly-ICLC also has a direct immune enhancing action 
independent of IFN, including increased antibody response to antigen, and NK cell, T-cell, macrophage and 
cytokine activation.  While discussion of the complex immunostimulatory effects of poly-ICLC and the interferons is 
beyond the scope of this protocol, their role in the potential anti-neoplastic effect that has been seen needs further 
investigation. 
  
 
Recent evidence suggests that polyIC 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) (Chebath, 1992), (Samuel, 
1992), (Katze, 1992) (Williams, 1999). 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  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 RibonucleaseL; as well as for the PKR, which inhibits initiation of protein synthesis (Levy, 1992); 
(Talmadge, 1985); (Levy, 1988); (Ewel, 1992); (Black, 1992).  Both, OAS and PKR are very sensitive to dsRNA 
dose and structure (Minks, West et al, 1979).  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 (M. Kende, unpublished). 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 (Maluish, 1985) (M. Kende, unpublished).  
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) (Salazar, 1996). Similarly, 
the PKR has both high and low affinity binding sites and is inhibited by too high a dose of dsRNA (Galabru, 1989). 
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 
(Koromilas, 1992).  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 (Malkin, 
1990). 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 (Cuddihy, 1999); (Williams, 1999). 
Folkman et al reported that the interferons exert antiangiogenic activity against the tumor vasculature supporting a 
potential antiangiogenic effect of poly-ICLC (Folkman, 1992).  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 the PKR may mediate the 

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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. 
 
 
       
                                      
   
                                                                   
2.2    Previous clinical trials: 
 
 
A pilot trial in adults suggested a possible beneficial effect of poly-ICLC in newly diagnosed and recurrent 
brain tumors (Salazar et al, 1996).  Thirty-eight patients with glioblastoma multiforme (GBM), anaplastic 
astrocytoma (AA), or recurrent GBM/AA were treated with varying doses of poly-ICLC of 10-50 mcg/kg IM, one to 
three times per week for approximately 56 months.  The drug was exceptionally 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 median progression-free survival 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. 
 
 
Most malignant gliomas actually represent a mixture of highly malignant tumor cells and lower grade 
cells that nevertheless 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 Figure 2). One hundred percent of patients who received the poly-ICLC regimen were alive at 2 
years versus only 76% who received standard chemotherapy (Salazar et al, 1996). This supports the 
effectiveness and likely less complications of poly-ICLC over chemotherapy.  
 
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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Figure 2. 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 patients with recurrent 
glioblastoma. This study included 55 patients, where 11% had radiographic response, 6 month progression-free 
survival (PFS) was 24% and median survival was 43 weeks. Poly-ICLC was well tolerated but did not show 
improvement on 6 month PFS. The second trial included patients newly diagnosed with glioblastoma. The 
treatment schema included a combination of radiation with poly-ICLC. 30 patients were enrolled in the trial. The 
6-month progression-free survival was 30% and the estimated 1-year progression-free survival was 5%. 
Median time to progression was 18 weeks. The 1-year survival was 69% and the median survival 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 third trial is a combination study of poly-
ICLC with temodar chemotherapy, and is being conducted by the NIH’s NABTT consortium. 
 
 
A Phase I/II study of poly-ICLC was conducted by the Principal investigator (Donald L. Durden), in children 
with multiple types of newly diagnosed or recurrent brain tumors. Long-term responses were seen in 2 of 4 
patients with low-grade gliomas (unpublished data). Four children with progressive low grade gliomas treated on 
this pilot study were evaluated for response. These four children had stable disease after documented progression 
for 10, 12, 22 and 24 months while receiving poly-ICLC. One of these children suffered from reduced white count 
(grade 3) that resolved despite continued therapy, and another developed respiratory distress at the time of tumor 
progression. The other cohorts of recurrent high-grade gliomas and newly diagnosed brain stem gliomas showed 
minimal to no response.  All eight children enrolled due to growing diffuse intrinsic pontine gliomas had 
progression of disease in <8 months of therapy.  Eleven children enrolled on the study had progressive high grade 
gliomas (anaplastic astrocytoma or glioblastoma multiforme).  Ten demonstrated disease progression within 1-10 
months of initiation treatment, however, one child on therapy 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 neurofibromatosis 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 low-grade gliomas. However more children with low-grade gliomas 
need to be studied to confirm this impression.  
 

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Phase I/II data for use of poly-ICLC has also been reported in patients with renal cell carcinoma, refractory 
lymphomas, melanomas, and colorectal cancers (Giantonio et al, 2001, Ewel et al, 1992). Varying doses of poly-
ICLC from 0.01 mg/m2 up to 1 mg/m2 were used either IV or IM 2 times a week. In all of these studies, poly-ICLC 
was well tolerated. Grade 1 or 2 fatigue, fever, nausea, vomiting and pain at injection site were seen in some 
patients and usually resolved by 24 hours after the injection (Ewel, 1992). In another study fever was a common 
side effect in 25.6% of patients, and chills in 23.1% (Giantonio, 2001). In both studies stable disease and a partial 
response was seen in some patients: however no complete remissions were observed. Thus it appears that poly-
ICLC has been used in several types of cancers in varying doses and varying modes of administration, and is well 
tolerated: however best results were seen in patients with brain tumors, at doses of 20-30 micrograms/kg given 2-
3 times a week as IM injections. 
 
 
 Based on preliminary data showing efficacy and tolerability of poly-ICLC in brain tumors, we propose to 
study this drug further, in children with progressive or recurrent low-grade gliomas, for clinical efficacy and 
tolerability. We would also simultaneously like to conduct laboratory experiments to determine the patient’s cellular 
response to poly-ICLC, by evaluating the induction of PKR, the phosphorylation of eIF2, and the activation of p53 
specific target gene, p21waf-1 in an attempt to better understand the anti-tumor effects of this drug.   
 
 
2.3     Drug Information and Toxicity: 
 
Drug Information: 
 
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 eight times that of the parent 
compound, and it induces peak levels of about 1000-2000 IU of interferon per ml of serum in monkeys given 1 
mg/kg intravenously. 
 
 
The current study will be done under IND #43984, held by Oncovir.  The drug to be used in this study is 
prepared and packaged in the GMP facility of Bioserv, Inc, San Diego, under the direction and under contract to 
Oncovir.  It is then tested for identity (RNAase resistance and thermal denaturation) bioactivity in primates, sterility 
and pyrogenicity before release for clinical experimental use.   
 
Toxicity: 
  
 
The degree of adverse effects of poly-ICLC is dependent on three factors: (1) dose, (2) route of injection, 
and (3) health status of the patient.  Early Phase I studies were done to determine the maximum tolerated dose 
(MTD) under the assumption that this was also the most effective dose.  In these studies of cancer patients, it was 
found that the MTD was 12 mg/m2 IV in 25 adult and pediatric patients (Levine and Levy, 1978).  Patients typically 
showed fevers of 40oC, myalgia, arthralgia, malaise, nausea and vomiting, and mild elevations of liver enzymes.  
Fever was the primary dose-limiting factor.  At this dose, the mean serum interferon level was 2000 IU/ml.  While 
this level is rarely attained by giving exogenous interferon, levels of 100 IU/ml in response to exogenous interferon 
are associated with the same types and degree of adverse effects as seen with high dose poly-ICLC.  Children 
who were terminally ill with leukemia could not tolerate 12 mg/m2 IV, although healthier children could (Leventhal 
et al, 1981).  In most of the early cancer trials, however, about 6 mg/m2 poly-ICLC IV was generally used.  Mild 
(grade 1), transient (7 days) hepatic enzyme elevations were described in a trial of 100 mcg/kg poly-ICLC given 
intravenously in multiple sclerosis patients.  In three patients this was prolonged >7 days, but in all patients the 
enzymes returned to normal values after temporary discontinuation of the poly-ICLC.  One paralyzed multiple 
sclerosis patient in this group suffered a fatal pulmonary embolus which was not judged to be due to the drug.  
Poly-ICLC has been associated with coagulopathy in dogs, but not in other species (including primates); and there 

Poly-ICLC 10/22/2010 
 
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15
has been no increase 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. 
 
Low dose poly-ICLC:   
 
It was subsequently shown that low doses were better than higher ones for enhancing immune effects, 
and that the higher dose actually inhibited a number of cell-associated immune functions.  It was also found that 
intramuscular injection brought about a much milder set of side effects.  The most common complaint is a mild, 
transient discomfort at the injection site.  On occasion, 8-12 hours after doses of 10 to 50 mcg/kg IM, patients may 
also develop a mild flu like syndrome with fever of less than 38oC which may last for another 12 hours, but 
responds readily to acetaminophen or aspirin.  Mild myalgia, arthralgia, sometimes nausea, and malaise are 
present during this period of time.  This flu-like syndrome typically diminishes markedly after the first little poly-
ICLC treatment.  Hepatic enzyme elevations are not typically seen at these dosages.  Several multiple sclerosis or 
malignant glioma patients at Walter Reed Army Medical Center (WRAMC) have been maintained on regular 
intramuscular poly-ICLC for as long as 12 years without significant adverse effects.  On very rare occasions in the 
course of treatment patients who have been tolerating treatments uneventfully may develop a more pronounced 
fever with chills and malaise (typical of higher dose IV poly-ICLC) in response to a single IM injection on 
subsequent dosing.  This will typically respond to aspirin or acetaminophen and does not recur on repeated 
dosing.  Whether it represented inadvertent IV injection on those occasions is uncertain. In a previous pediatric 
study conducted by the Principal Investigator, there was no dose limiting toxicity seen over 3 years in 45 children 
at doses of 20-30 micrograms/kg given 2 times a week as intra-muscular injection. 
 
Summary of Poly-ICLC Toxicity data reported to FDA, 2005: 
 
In the two recent, ongoing multi-center NIH consortium studies in adult glioblastoma patients and in 
patients with multiple-recurrent anaplastic glioma, most patients (N=62) reported at least one adverse event.  The 
majority of adverse events were classified as either grade 1 (63%) or grade 2 toxicity (28%). The reported grade 3 
and grade 4 toxicities were 8% and 0.8% respectively. Only two grade 5 events were reported, which were not 
assessed to be related to the study drug.  The most frequently reported events (toxicities) were fatigue, pain, and 
myalgia. Very transient elevated liver enzymes, mainly grade 1 or 2, were also reported in fourteen patients. 
 
 
However, combining both trials, there were only eighteen toxicity grade 2 or higher adverse events that 
were definitely or probably ascribed to the study drug by the local study physician.  The seventeen grade 2 and 
one grade 3 events occurred in only nine patients and had a median duration of five days.  Two patients had six 
grade 2 hematologic reports with a median duration of five days.  Animal studies suggest that a major portion of 
this leucopenia does not reflect myelotoxicity, but is related to leukocyte trafficking, with transient migration of 
WBC to lymphoid organs, including spleen. 
 
 
3.0 
Patient Eligibility Criteria and Registration 
 
3.1 
Patient Registration  
 
This is a multi-institution study between UCSD/Rady Children’s Hospital and Emory University/Children’s 
Healthcare of Atlanta. UCSD/Rady Children’s Hospital will be the coordinating site for this investigator initiated 
trial. 
 
Eligible patients will be registered by contacting the Clinical Research Coordinator, Monday through Friday, 8:00 
am-5:00 pm Pacific Standard Time by phone except on holidays. Calls will be returned within one business day. 
The research coordinator will review preliminary eligibility by phone before forwarding a registration packet to the 

Poly-ICLC 10/22/2010 
 
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16
enrolling practitioner. The information requested in the registration packet must be completed. The signed 
informed consent statement along with the documentation confirming eligibility must be faxed. Upon receipt of the 
completed registration packet, the research coordinator will assign a unique patient registration number and study 
subject number. Patients must be registered prior to starting any protocol therapy.  
 
Contact Person:  
Mehrzad Milburn, RN, BSN, CCRC 
 
 
 
Oncology Research Center 
 
 
 
UCSD/Rady Children’s Hospital 
 
 
 
3020 Children’s Way MC 5128 
 
 
 
San Diego, CA 92123  
 
 
 
Phone: (858) 966-8155 
 
 
 
Fax: (858) 966-8966 
 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot be waived. Patients 
must begin treatment within two weeks of study registration. Registration will be completed only after pathologic 
diagnosis is confirmed by central review (please see below). 
 
Between the two sites, we anticipate enrolling up to 10-15 subjects per year, to achieve a total of 24 evaluable 
subjects. Thus we are confident that accrual can be completed within 2-3 years. The estimation is reflected by the 
number of patients with recurrent low grade glioma tumors that are treated annually at Rady Children’s Hospital 
and Children’s Healthcare of Atlanta.   
 
3.2 
Inclusion Criteria 
3.2.1  Age  
 
Subjects must be between 0 – 21 years of age when enrolled on this protocol. 
 
3.2.2    Diagnosis  
Subjects must have pathologically confirmed low grade glioma with histologic subtypes interpreted as WHO grade 
I and II including: 
-juvenile pilocytic astrocytoma (JPA)  
-pleomorphic JPA  
-diffuse astrocytoma (fibrillary, gemistocytic, giant cell, or pleomorphic xanthoastrocytoma) 
-subependymal giant cell astrocytoma (SEGA) 
-low grade oligoastrocytoma 
-low grade oligodendroglioma 
-pilomyxoid astrocytoma 
-low grade glioma NOS 
 
Tumors of all regions of the CNS, with appropriate histology are eligible for study. However patients with SEGA 
or tumors intrinsic to the optic nerve and involvement of the optic nerve that cannot be biopsied/resected are 
eligible without histological confirmation.  
 
Subjects with neurofibromatosis type 1(NF1) are also eligible (see appendix II for NF1 diagnostic criteria). 
 
All pathologic diagnoses of subjects from all enrolling sites will be confirmed with tissue block review of 
previously obtained specimens by Scott VandenBerg, M.D., Ph.D. This will be done in order to assure 

Poly-ICLC 10/22/2010 
 
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17
uniformity in the above subtypes for these sometimes difficult to diagnose tumors. Once consent is obtained, 
subjects’ tissue/slides and corresponding pathology report should be forwarded for central review at UCSD.  
These samples should be sent to: 
 
 
 
 
 
 
 
 
 
Scott R. VandenBerg, M.D., Ph.D. 
Professor of Pathology 
 Director of Neuropathology 
University of California, San Diego 
Pathology, MC 0612 
BSB Room 2008 
9500 Gilman Drive 
La Jolla, CA 92093-0612 
Phone: 858-822-2808  
 
3.2.3 Criteria 
Subjects must have demonstrated either tumor progression or recurrence by any of the radiographic criteria 
and/or clinical criteria as defined below: 
  
 
a.  
Subjects with progressive non-resectable disease regardless of location in the brain or spine are 
eligible for this study.  Patients with evidence of leptomeningeal dissemination are eligible for this 
study. Patients do not require biopsy/histologic confirmation at the time of progression or relapse. 
 
b. 
Radiographic progression is defined as >40% increase in the product of the three perpendicular  
diameters of current tumor relative to the baseline measurement (defined as either the initial 
scan or scan at start of a previous therapy): 
length (L) x width (W) x transverse (T) (current scan) > 1.4 x L x W x T (baseline scan), or the 
development of any new sites of disease independent of the response of the initial tumor.  
See section 7.1.2 for methodology for tumor measurement.  
 
 
c. 
Post radiation changes are often seen on post-treatment imaging studies, so that classification of a 
patient as having progressive disease may require several serial MRI’s if the child has received 
radiation within the preceding 12 months. 
 
 
d. 
Tumor volume includes the entire tumor volume seen on gadolinium enhanced T1 MR imaging  
 
plus non-enhancing abnormality seen on T2 or FLAIR.  Coronal and axial images will be evaluated. 
 
 
e. 
All tumor cysts will be included in the tumor volume 
 
f.  
Clinical progression without radiographic progression includes children with optic pathway gliomas 
who demonstrate sustained decrease in visual fields and/or acuity in three serial vision 
examinations.  Each of the vision examinations must be performed >2 weeks apart.   
 
 
g. 
Children with previously negative cerebrospinal fluid (CSF) cytology who show evidence of tumor 
cells in fluid obtained by lumbar puncture can be designated as having progressive disease in the 
absence of radiographic evidence of progression. 
 
 
 

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3.2.4  Performance Level and Life Expectancy 
 
Subjects must have a performance status of > 50% (Appendix I). Use Karnofsky for patients > 16 years of age 
and Lansky for patients ≤ 16 years of age. Subjects must have a life expectancy of ≥ 8 weeks. 
 
3.2.5  Prior Therapy 
 
Subjects must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or 
radiotherapy prior to entering this study and meet time restrictions from end of prior therapy as stated below:  
 
a. Myelosuppressive chemotherapy: Subjects must have received the last dose of myelosuppresive 
therapy at least 3 weeks prior to study registration or at least 6 weeks if therapy included nitrosourea. 
b. Investigational / Biological agent: Subjects must have received the last dose of other investigational 
or biological agent >7 days prior to study registration. Subjects must not have received polyICLC in 
the past. 
c. XRT: Subjects must be ≥ 8 weeks since the completion of radiation therapy.  
d. Study specific limitations on prior therapy: There is no limit on the number of prior treatment 
regimens or received doses of radiation therapy.  
e. Growth factor(s): Subjects must not have received any hematopoietic growth factors within 7 days of 
study entry or 21 days for pegfilgastrim. 
f. 
Prior Surgery: Subjects must be ≥ 2 weeks from prior surgery. 
g. Steroids: Subjects must be on a stable steroid dose for 7 days prior to study entry if they are on 
steroid treatment. 
 
3.2.6 
Organ Function Requirements 
All subjects must have adequate organ function defined below when starting on protocol.  
 
3.2.6.1 Hematologic Function:  
 
 
a. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs) 
b. ANC: > 750/mm3,  Must be at least 7days after last dose of growth factor 
c. Platelet Count: > 50,000 (transfusion independent; ≥ 7 days from last transfusion) 
 
3.2.6.2. Renal Function defined as: 
 
 
 
Creatinine clearance/GFR > 70 cc/min/1.73 m2 or  
 
 
 
 

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            Serum creatinine based on age/gender as follows:        
 
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 
The threshold creatinine values in this Table were derived from the Schwartz formula for 
estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature 
data published by the CDC. 
  
 
3.2.6.3 Liver Function:  
 
a. 
Total bilirubin < 1.5 x ULN for age, AND 
b. 
SGPT (ALT) < 2.5x ULN 
c. 
SGOT (AST) < 2.5x ULN 
 
3.2.6.4 Pulmonary Function: 
            
No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry ≥ 94% if 
 
there is clinical indication for determination. 
 
3.2.6.5 Coagulation Function: 
 
            Normal PT and PTT at enrollment per institutional range 
 
3.2.6.6 Reproductive Function: 
 
            Due to potential teratogenic effects of (poly-ICLC), negative serum beta-HCG in females, and agreement 
            to the use of effective contraception in males and females of childbearing potential, IS REQUIRED.  
 
 
3.3   Exclusion Criteria 
 
3.3.1. Pregnant or lactating females.  Women of childbearing age will agree to use 
             contraception during the protocol. 
 
     3.3.2     Patients receiving other experimental immunotherapy. 
 
     3.3.3     Patients may not have fever (38.50C) within 7 days of enrollment. 

Poly-ICLC 10/22/2010 
 
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3.3.4     No concurrent XRT or chemotherapy is allowed. 
 
3.3.5    Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring             
requirements of the study.  
 
 
3.4   Regulatory 
 
      3.4.1 Informed Consent 
 
 
   All subjects and/or their parents or legal guardians must sign a written informed consent document.   
 
 
   Written assent will be obtained from patients per institutional guidelines. 
 
      3.4.2 Protocol Approval 
               All institutional, FDA, and NCI requirements for human studies must be met including institutional IRB 
               approval of the protocol. 
 
 
4.0 Study Treatment  
 
4.1 Treatment Schedule 
 
Children will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or Tuesday/Friday 
schedule if possible).  The first 2 doses will be administered in the clinic under supervision.  
 
Vital signs will be monitored every 30 minutes for 2 hours after the first dose. For all subsequent doses 
administered at home, a temperature log will be kept to document the temperature prior to study drug 
administration and at two separate time points after each of the 8 doses of study drug in cycle 1. One temperature 
reading will be assessed between hours 2-4 after study drug administration and one temperature reading will be 
assessed at 12 hours after study drug administration. After cycle 1, temperature will only be monitored on an as 
needed basis, such as if the subject is not feeling well. Subjects or their parents will be instructed to use a log to 
record the temperature monitored at home and any fever should be reported to the study team. In some cases, at 
the discretion of the research team, subject or parent will be allowed, after appropriate teaching, to administer the 
study drug at home. The study drug will be dispensed to the subject/parent by the research pharmacy. The study 
drug will be dispensed in vials along with labeled dose syringes in order to minimize errors in dosing.   
 
Total length of treatment will be two years. Each cycle will be 28 days in length. If subjects demonstrate a 
response to therapy (see section 7.0), treatment may be continued beyond two years at the discretion of the 
principal investigator and pending drug availability. For statistical analysis of toxicity, subjects will be divided into 
two separate cohorts (those with NF1 and those without NF1).  The subjects in each of these cohorts will be 
treated and monitored identically throughout treatment. 
 
Subjects who travel to the coordinating or enrolling sites for protocol therapy may return home to the care of their 
primary pediatric oncologist after completing cycle 1 of therapy for standard of care management at the discretion 
of the study physician/committee. Subjects will be seen and monitored by their primary treating oncologist at the 
start of each cycle. For those subjects, a 3 month supply of study drug will be dispensed to the subject/family from 
their enrolling site. The enrolling site will continue to see the subject every 3 months for evaluation and will remain 
responsible for continued data capture of all required information.    
 

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4.2:   Dose modifications based on Toxicity 
 
If  AST/ALT > 10x ULN while on study, Poly ICLC will be discontinued until the AST/ALT are < 5x ULN; the study 
drug will then be restarted at 20 mcg/kg/dose twice weekly (the initial dose).   
If AST/ALT > 10x ULN for a second time, hold study drug until values < 2.5x ULN; then restart drug at the reduced 
dose of 10 mcg/kg/dose twice weekly. 
Study drug will be stopped and subject will be off treatment for toxicity if AST/ALT do not decrease to < 5x ULN 
during the first episode and <2.5x ULN at second episode when drug is held for three weeks.  
 
For the NF 1 cohort, consider restarting drug again at 5 mcg/kg/dose twice weekly if toxicities recur at the prior 
reduced dose of 10mcg/kg/dose. 
 
For all other grade 3 or grade 4 toxicities the same dose modifications will be followed. The study drug will be held 
until resolution of these toxicities to ≤ grade 1. If the toxicity is not resolved within 3 weeks of the last dose of the 
study drug administration the subject will be taken off protocol therapy. 
 
 
4.3:  Concomitant Therapy 
 
Corticosteroids and anticonvulsants may be given as indicated clinically.  However, if the dose of steroids is 
increased while on therapy, MRI must be performed to rule out disease progression. Acetaminophen may be 
given as needed to control poly-ICLC side effects. A non-P450 inducing anticonvulsant will be used while on this 
study (see Appendix 3). 
 
Radiotherapy may not be given while on study to the lesions being utilized as measurable disease in order to 
assess response.  Patients may enter on study after completion of involved field radiation therapy, however at 
least 8 weeks should elapse after radiation, and scans should show residual disease prior to entry on study. 
Chemotherapy is not allowed.  
 
Antibiotics, blood products and general supportive care measures may be used as clinically indicated. 
Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general supportive care are to be 
used as necessary and as per institutional guidelines. 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 

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5.0 Required Observations 
All Pre-study Observations must be done within 14 days of study entry. 
 
Observation 
Pre-
Study 
 
Day 1 of 
Cycle 1 
Day 15 of 
Cycle 1 
Prior to 
subsequent 
cycles 2-12 
Prior to 
subsequent cycles 
13-24 
End of 
therapy/Off 
Study 
History, VS, Physical 
x 
x 
x 
x 
x 
x 
Performance Status1 
x 
x 
x 
x 
x 
x 
Toxicity Evaluation 
  
 
x 
x 
x 
x 
Neuro Evaluation 
x 
x 
x 
x 
x 
x 
Concomitant Meds 
x 
x 
x 
x 
x 
x 
CBCD, Platelets 
x 
x 
x 
x 
x 
x 
PT/PTT 
x 
x 
x 
x† 
x†  
 x† 
CMP w/Phos 
x 
x 
x 
x 
x 
x 
Urinalysis3 
x 
 
  
  
  
  
Serum Pregnancy3 
x 
 
  
  
  
  
MRI-Brain/Spine**  
x 
 
  
Every 3 cycles 
starting with 
end of Cycle 3↑ 
End of Cycle 18 and 
24 only↑ 
x 
LP/CSF cytology* 
x 
 
  
Every 3 cycles 
starting with 
end of Cycle 32 
End of Cycle 18 and 
24 only2 
x2 
Biology-red & purple 
top blood samples  
 
x 
x 
  
  
  
Data Collection 
Submission4 
x 
 
 
x 
x 
x 
 
 
1:Performance Status=Karnofsky if > 16 y/o or Lansky if ≤ 16 y/o 
 
 
2: repeat only if cytopathology showed tumor cells at study entry or disease progression 
 
 
3: Repeat as needed for good clinical care 
4: Data Collection should be submitted monthly 
†: Repeat PT/PTT only if abnormal after Day 15 
↑ Repeat MRI Spine only if not normal pre study 
 
 
 
 
* Lumbar Puncture/CSF cytology is not required if already done within 4 weeks of study entry.  
CSF will be obtained prior to initiation of therapy with Poly ICLC. If positive, CSF will be obtained at 3, 
6, 9, 12, 18, 24 months after study entry, as well as the time end of therapy/off study. 
 
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. 
MRI will be assessed at 3, 6, 9, 12, 18, 24 months after starting the therapy (at the end of those cycles), as 
well as at the time end of therapy/off study or if subject is going off study prematurely. 
**MRI spine does not have to be repeated during the study if it was normal pre-study. It should be repeated 
at the time end of therapy/off study or if subject is going off study prematurely. 
A copy of the MRI images on a CD should be sent to the coordinating site.  

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5.1:   Pretreatment Evaluation (must be performed within 14 days of study entry) 
 
      A. History, vital signs and physical examination, including neurologic evaluation and concomitant medication 
list 
      B.  CBC, differential, platelet count, PT/PTT 
      C.  AST, ALT, alkaline phosphatase, albumin, calcium, phosphorus, total bilirubin 
      D.  BUN, Cr, urinalysis 
      E. Disease evaluation with either MRI of brain/spine and CSF cytology. (LP is not required if already done 
within 4 weeks of study entry).    
      F.  Serum B-HCG in females of childbearing age 
G. Lansky Play Scale assessment for patients ≤ 16 years of age; Karnofsky score for patients >16 years old. 
(see Appendix I). 
H. Study entry form/eligibility check list to be filled out prior to starting treatment. 
 
5.2:  Evaluation during treatment 
 
      A. Disease evaluation (including MRI), if positive at study entry, every 3 cycles for the first 12 cycles (to be 
done at the end of the cycle), then every 6 cycles for as long as the subject remains on study. MRI spine 
does not have to be repeated if it was normal pre-study. Disease status and events form is to be filled 
every 3 months for the first 12 months and then every 6 months while subject is on study.  
      B.  History, vital signs, physical examination and concomitant medication list at day 1 and day 15 of cycle 1, 
and then prior to each cycle (monthly for as long as the patient remains on study). 
      C. Labs are to be obtained at day 1 and day 15 of cycle 1, and then prior to each cycle (monthly for as long 
as the subject remains on study). 
 
- CBC/differential, platelets 
 
- Chemistry panel including: AST, ALT, alkaline phosphatase, albumin, calcium, phosphorus, total bilirubin,  
 
 
BUN, Cr   
 
- PT/PTT at Cycle 1 Day 1 and 15, repeat further only if abnormal 
      D.  Neurologic assessment at each visit with scoring of overall exam compared to previous exam as follows: No    
change from previous exam; worsening from previous exam; improvement from previous exam.  
      E. Record at each visit if steroids are being given and if dose is same, lower, higher than at previous visit.  
MRI required if steroid dose increased.  
 
      F.   Toxicity monitoring form and Lansky Play Scale assessment for subjects ≤ 16 years of age; Karnofsky 
score for subjects >16 years old. (see Appendix I) at week 2 and then prior to each cycle. 

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5.3:   Evaluation at the end of therapy or relapsed disease 
 
    A. 
Disease evaluation (including MRI brain and spine) and lumbar puncture for CSF cytology (required only at 
time of disease progression) with all studies that were initially positive at study entry   
    B. 
History, vital signs, physical examination, and concomitant medication list 
    C. 
Labs:  
 
- CBC/differential, platelets 
 
- Chemistry panel including AST, ALT, alkaline phosphatase, albumin, calcium, phosphorus, total bilirubin,     
 
 
BUN, Cr 
 
-PT/PTT, if still abnormal 
    D.  Neurologic assessment with scoring of overall exam compared to previous exam as follows: No change from    
 
previous exam; worsening from previous exam; improvement from previous exam.  
   E.    Record if steroids are being given and if dose is same, lower, or higher than at previous visit. 
    F.   Toxicity monitoring form and Lansky Play Scale assessment for patients ≤ 16 years of age; Karnofsky score 
for patients >16 years old. (see Appendix I). 
   G.    If patient death occurs, fill out death report form. 
 
5.4:  Special laboratory specimens  
 
A. Biologic correlates 
 
1.  Blood Specimens 
 
Obtain 5ml of peripheral blood in a red top tube at study entry and at day 15 prior to the scheduled dose of 
the study drug. Separate serum and freeze at -70C in four equal aliquots. Label each specimen with subject’s 
research identifier and date drawn. These specimens will be sent to the lab identified on the next page.  
 
Obtain 10ml of peripheral blood in purple top tube, at study entry and at day 15 prior to the scheduled dose of 
the study drug. Label each specimen with subject’s research identifier and date drawn. These specimens will 
be sent to Dr. Donald L. Durden’s laboratory for isolation of peripheral blood mononuclear cells (PBMC).  
Samples will be shipped to the address listed below.  
 
 
 
 
Serum OAS and interferon , ,  levels will be measured by standard ELISA assays. Peripheral blood 
mononuclear cells (PBMC) will be isolated by ficoll-hypaque density gradient separation and stored as pellets 
at –80 degrees C. Levels of PKR kinase, phosphorylation state of eIF2, and the induction of p21waf-1 will be 
determined in cell lysates by standard in vitro kinase and Western blot methods using phospho-specific 
antibodies as described by Williams (1999). This evaluation will provide a surrogate marker for sensitivity of 
patient’s cells to known capacity of poly-ICLC to activate this serine/threonine kinase and to activate the p53 
tumor suppressor gene activity. 
 

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Total RNA for RNA sequencing or microarray analysis of PBMCs before and after treatment with poly-ICLC 
will be collected to determine differences in gene expression induced by poly-ICLC as index of somatic 
response to this agent. This will be compared to patient’s clinical response to poly-ICLC.  
Peripheral mononuclear cells will also be studied by Fluorescence Activated Cell Sorting to establish an 
immunophenotypic profile for each sample pre and post treatment with poly-ICLC. Regulatory T cells 
(Tregs), dendritic cells, mononuclear cells, macrophages, B/T cell subtypes, and pro-anti-inflammatory 
cytokines can also be analyzed. This will also be tested to determine if these markers can serve as 
feasible additional biomarkers of disease and response.  
2. CSF Specimens (optional) 
 
CSF will be obtained prior to initiation of therapy with Poly ICLC. CSF will be obtained via lumbar puncture 
as part of clinical staging prior to study enrollment, if not already done within 4 weeks of study entry. CSF 
cytology will be evaluated for presence of tumor cells by an institutional pathologist using standard methods. 
Approximately 3 ml of CSF will be requested for proteomic analysis. The CSF will be spun at 400-500 g for 
10 minutes to remove cellular contaminants. The first 2 ml of CSF supernatant will be aliquoted into four 
.500 ml units and frozen at -20 to -80 degrees Celsius to be used for proteomic analysis. Each tube must be 
labeled with the subject’s research identifier, the sample type and the time it was drawn. 
 
 
 
The remaining 1 ml of CSF will be aliquoted in 0.2 ml units and frozen at -20 to -80 degrees Celsius to be 
evaluated for cytokines. Each tube must be labeled with the subject’s research identifier, the sample type, 
site from where the sample was obtained, and the time it was drawn. 
 
All blood and CSF biologic samples should be sent on dry ice, along with a completed biologic specimen 
transmittal form to Dr. Donald Durden’s laboratory located at the Moores Cancer Center at UCSD. Enrolling 
practitioners should contact Donald Durden at 858-534-3355 to notify him of specimens ready for shipment 
or pickup and delivery: 
 
 
Donald L. Durden, MD PhD 
Moores UCSD Cancer Center RM 3312 
3855 Health Sciences Drive #0819 
University of California, San Diego 
La Jolla, CA 92093-0819 
ddurden@ucsd.edu 
858-534-3355 
 
 
Samples will only be received Monday through Thursday. 
 
 
 
 
 
 
 

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B. Laboratory analysis 
 
1. Proteomic Biomarker Evaluation 
 
Criteria for a successful proteomic methodology for identification of a usable biomarker include high throughput, 
reproducibility and toleration of real world collection and shipping conditions. In addition, such methods must be 
able to identify differentially expressed proteins in an unsupervised manner as well as provide information about 
specific proteins of interest. Currently, there is not a single mature technology available to meet all these criteria. 
Therefore, a combined approach will be employed in this exploratory study to attempt to fit all of these 
characteristics and improve the body of knowledge about the utility of these strategies.  
 
All these approaches will require concentration of the samples using Centricon 3kD filtration and partial depletion 
of IgG and albumin (Proteoprep Blue Albumin Depletion kit). Proteins can be precipitated using 15% trichloracetic 
acid, re-suspended in denaturing buffer and stored at -20 to -80 degrees Celsius until the time of analysis. 
 
The first component of the proteomic approach will employ 2-D gel electrophoresis to separated proteins in two 
dimensions according to their size and charge. The gels are then scanned and relative positions and intensities 
are quantitated by pixel reading software. Individual spots are normalized to total signal and proteins that are 
found to be differentially expressed can be identified by in-gel digestion and MALDI-TOF-TOF mass spectrometry 
[Clin Chem 2005; 51:2031-2042]. 
 
The second approach to employ is LC-MS/MS in combination with stable isotope labeling. The entire sample is 
subjected to mass spectrometry after trypsin digestion. Individual proteins can be quantitated and identified from 
the peptides present in the digestion reaction. The protein complements contained in CSF from different disease 
states can then be compared. 
 
The third component is low mass fingerprinting. Peptides are isolated from the CSF by ultra-filtration. These 
peptides are interrogated by MALDI-TOF-TOF mass spectrometry and profiles of peaks are generated. Peptide 
profiles are analyzed by bioinformatics software after signal normalization and informative peaks that distinguish 
between known disease states are identified. Combinations of informative peaks are compiled and tested against 
“unknowns” to validate their predictive power. 
 
2. ELISA for confirmation/correlation of target proteins 
 
CSF samples will be evaluated for expression of specific secreted proteins implicated in tumor progression, 
migration and response to therapy. These target proteins, described above, have well-characterized, 
commercially available antibodies including VEGF, dFGF, attractin, SPARC and EGF. 
 
3. Interrogation of spinal fluid samples will be performed after investigators have obtained extramural funding to 
pay for the studies.  If compelling evidence for biomarkers other than those described about becomes available 
as proteomics studies are completed in CSF of children with malignant tumors, inspection for these markers will 
be performed.   
 
 
5.5:  Pathology specimens (optional) 
If the subject has available fixed, frozen and/or cryopreserved tumor tissue from a prior tumor resection upon 
study entry it will be evaluated for genomics and other biomarkers by study pathologist Scott VandenBerg. 
Samples should be shipped or picked up and delivered Monday-Friday to: 

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Scott R. VandenBerg, M.D., Ph.D. 
Professor of Pathology, Director of Neuropathology 
University of California, San Diego 
9500 Gilman Drive, MC 0612 
La Jolla, CA 92093-0612 
Phone: 858-822-2808  
 
Additional Consideration 
If a patient relapses or second look surgery and/or lumbar puncture is required while the subject is on study, the 
tissue and/or CSF may be obtained for additional analysis post treatment with Poly ICLC. 
 
 
6.0  
DRUG INFORMATION 
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 done under IND #43984, held by Oncovir.  The drug to be used in this study is prepared 
and packaged in the GMP facility of Bioserv, Inc, San Diego, under the direction and under contract to Oncovir.  It 
is then tested for identity (RNAase resistance and thermal denaturation) bioactivity in primates, sterility and 
pyrogenicity before release for clinical experimental use.   
 
FORMULATION: Supplied in 1 ml vials of 2 mg/ml opalescent solution  
 
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. 
 
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. 
 
MAXIMAL TOLERATED DOSE: As reported in cancer trials, 250-300 micrograms/kg. 
 
The drug will be obtained from Oncovir.  
 
To obtain drug, call:                                                                            
 
 
   
 
 
 
 
 Andres M Salazar, MD 
Oncovir, Inc 
3203 Cleveland Ave, NW 
Washington, DC, 20008 
Tel: 202-342-1726 
Fax: 202-248-2324 
Email: asalazar@oncovir.com; asalazar@starpower.net 

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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. A copy of these records will be kept in the study binder at the coordinating site. 
 
 
7.0 RESPONSE CRITERIA 
 
MRI Response Criteria:  Comparison of objective assessments are based on major changes in tumor size 
compared to the baseline scan. Determination of progressive disease is based on tumor measurements described 
below.  
 
Interpretation of anatomic (MRI) response rates in gliomas can be difficult.  Tumors may be non-enhancing, and 
certain area of enhancement may represent post-operative or radiation change. Shrinkage of enhancing lesions 
can also be seen for months after radiation alone. These factors may confound the MRI interpretation of tumor 
response to poly-ICLC. Also in the Principal investigator’s previous experience, tumor regression or stabilization 
on MRI was seen at 12 and 52 months in some patients on poly ICLC.  Hence in the absence of clearly 
progressive disease (worsening neurological status, significant increase in tumor size on MRI), poly-ICLC should 
be continued for possible late benefits. 
 
7.1 EVALUATION CRITERIA 
 
7.1.1 Methodology to Determine Tumor Measurement 
 
All measureable tumors will be measured at each evaluation and will be used in the response assessment. 
Measurable Disease: Bi-dimensionally measurable lesions with clearly defined margins by MRI or CT scan. 
Evaluable Disease: Uni-dimensionally measurable lesions, masses with margins not clearly defined.  
Non-Evaluable Disease: Not Applicable for response evaluation 
 
For all measurable tumors, the 3 dimensional measurements: width (W), transverse (T), and length (L) 
measurements need to be recorded (if length L can be measured), using either T1 or T2 MR weighted images 
(which ever gives the best estimate of tumor size). The following section describes the methodology.  
 
 
1. Longest diameter of the tumor should be selected in the axial plane or the plane in which the tumor is best 
seen or measured, provided the same plane is used in follow ups. 
2. The longest measurement of the tumor (or width, W) should be determined. 
3. The 2 perpendicular measurements should be determined (transverse (T) measurement-perpendicular to 
the width in the selected plane, and the length (L) – tumor extent in the plane perpendicular to the selected 
plane). 

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The primary tumor response rate endpoint will be based on the 2 dimensional measurements (TxW) as in 
modified MacDonald criteria (section 7.1.2), which, in addition to radiographic scans, comprise elements of the 
steroid use. The response rate based on the 3 dimensional measurements (TxWxL) will be a secondary 
endpoint (section 7.1.3). 
 
All lesions are to be measured at each evaluation; however, if there are too many measurable lesions to 
measure at each evaluation (i.e. more than 10), choose the largest two to be followed before a subject is 
entered on study.  The remaining lesions will be considered evaluable for the purpose of objective status 
determination.   
 
7.1.2 Tumor Response Criteria on 2 Dimensional Measurements (per Modified MacDonald Criteria) 
 
a. Complete Response (CR): Complete disappearance of all measurable and evaluable disease. There are no 
new lesions and no evidence of non-evaluable disease.  All measurable, evaluable and non-evaluable lesions 
and sites must be assessed using the same techniques as baseline.  Patients must not be on any steroids. 
 
b. Partial Response (PR): ≥ 50% decrease over baseline in the sum of products of perpendicular diameters of 
all measurable lesions. There is no progression of evaluable disease and no new lesions.  All measurable and 
evaluable lesions and sites must be assessed using the same techniques as baseline. The steroid dose at the 
time of the scan should be no greater than the maximum dose during the first 8 weeks since initiation of 
therapy. 
 
c. Stable Disease (SD): Does not qualify for CR, PR, or progression. All measurable and evaluable sites must 
be assessed using the same techniques as baseline. The steroid dose at the time of the scan should be no 
greater than the maximum dose used during the first 8 weeks since initiation of therapy. 
 
d. Progressive Disease (PD): ≥ 25% increase in the sum of products of all measurable lesions over baseline 
using the same techniques as baseline, or clear worsening of any evaluable disease, or appearance of any 
new lesion/site, or clear clinical worsening or failure to return for evaluation due to death or deteriorating 
condition (unless clearly unrelated to this cancer). 
 
 
7.1.3 Tumor Response Criteria Based on 3 Dimensional Measurements 
 
 
a. Complete Response (CR): Disappearance of all measurable and evaluable tumors. There are no new 
lesions and no evidence of non-evaluable disease. 
 
b. Partial Response (PR): > 65% decrease in the sum of the products of the three perpendicular diameters of 
the measurable tumors relative to the sum of products of initial baseline measurements - LxWxT (current scan) 
< 0.65 * LxWxT (initial scan). There is no progression of evaluable disease and no new lesions. 
 
c. Stable disease (SD): Neither sufficient decrease in the product of the three perpendicular diameters to 
qualify for partial response nor sufficient increase to qualify for progressive disease. 
 
d. Progressive Disease (PD): >25% increase in the sum of products of the three perpendicular diameters of the 
measurable tumors relative to the initial baseline measurement - LxWxT (current scan) > 1.25* LxWxT (initial 

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30
scan) or the development of any new sites of disease. As post-radiation changes are often seen on post-
treatment imaging studies, classification of a patient as having progressive disease may require several serial 
MRIs. 
 
 
7.1.4   Response Assessment 
 
Tumor response will be assessed at 3, 6, 9, 12, 18, 24 months after starting the therapy, as well as at the time of 
going off study if prematurely. The overall response rate (ORR), defined as the percent of evaluable subjects who 
experience a complete response or partial response or stable disease, will be determined. The primary endpoint 
will be progression free survival rate (per MacDonald Criteria) at 6 months after starting therapy. Secondary 
endpoints also include tumor ORR at 6 months and 2 years after starting therapy and also the duration of the 
‘good’ response. The traditional overall response rate (CR's and PR's only) will also be summarized. 
 
Each subject will be classified according to their “best response” for the purposes of analysis of treatment 
effect. Best response is determined from the sequence of the objective statuses described above.  
 
Any subject removed from study protocol because of unacceptable progression (see Section 8.1) will be 
counted as progressive disease in the efficacy analysis. 
 
 
 
8.0  
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY CRITERIA  
 
8.1 
Criteria for Removal from Protocol Therapy 
  
a. Progressive disease 
 
 
Note: Transient enlargement of enhancing disease with subsequent shrinkage has been reported during 
poly-ICLC treatment. Because of this, if the patient has progressive disease by the conventional definition 
above but does not have unacceptable progression by the definitions below, the treating physician and 
patient have the options of continuing poly-ICLC treatment on this protocol or of discontinuing treatment. 
 
 b. Criteria for unacceptable progression:  See definitions of tumor progression outlined in section 7.1.3 
 
1. >50% increase in the product of the three perpendicular diameters of initial tumor relative to the initial 
baseline measurement – LxWxT (current can)> 1.5 x LxWxT (initial scan), or the development of any new sites 
of disease independent of the response of the initial tumor.  Post radiation changes are often seen on post-
treatment imaging studies, so that classification of a patient as having progressive disease may require several 
serial MRI’s if the child has received radiation within the preceding 12 months.  
 
2. Unacceptable worsening of neurological symptoms that cannot be controlled with corticosteroids. 
 
      3. Any other radiological or clinical evidence of worsening to the extent that the treating physician feels it is 
      not in the patient's best interest to continue poly-ICLC. 
 
 c.   Physician determines it is in patient’s best interest. 
 

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 d.   Patient and/or parent/guardian refusal to continue or inability to comply with protocol 
 
 e. Grade 3 or 4 toxicity that does not resolve to Grade 1 within three weeks after interruption of therapy, or 
recurrent grade 3 or 4 toxicity at a reduced dose level (see section 4.2). 
 
Note: If final analysis confirms a beneficial effect of poly-ICLC, and/or if tumor recurs after withdrawal from 
poly-ICLC at the end of the 2-year prescribed treatment period, participating subjects may be offered 
continued treatment with poly-ICLC (subject to drug availability at that time). 
 
 f.   Completion of planned therapy. 
 
Subjects who are off protocol therapy are to be followed until they meet the criteria for Off Study (see below). 
Follow-up data will be required, unless consent is withdrawn, every 3 months for the first year, every 4 months 
for the second year, every 6 months for the third year, and then yearly thereafter  
 
8.2  
Off Study Criteria 
 
 a.  
Death. 
 b.  
Lost to follow-up. 
 c.  
Entry into another therapeutic study. 
 d.  
Withdrawal of consent for any further data submission. 
 
 
9.0    
STATISTICAL CONSIDERATIONS 
 
a. The primary goal of this trial is to obtain preliminary estimates of the ability of poly-ICLC to prevent or delay   
disease progression in subjects with recurrent or newly diagnosed low-grade gliomas. The primary endpoint will 
be progression free survival rate at 6 months (PFS6) after starting therapy. Progression free survival is defined as 
the time from starting study therapy to tumor progression, tumor recurrence, death from any cause, or occurrence 
of a second malignant neoplasm. Tumor assessment for the primary endpoint will be based on modified 
McDonald’s criteria (section 7.1.2). Tumor assessment results obtained based on the 3D measurements will be 
considered secondary.  The overall response rate (ORR) at 6 months will be a secondary endpoint. The ORR will 
include complete response, partial response, and stable disease (see Section 7.1.4). Time to progression will be 
documented for all patients who progress.  
 
b. The second goal is to further define the side effects and toxicity of this regimen in these subjects. Secondary 
endpoints also include tumor ORR at 2 years after starting therapy and also the duration of the good response. 
Tumor response will be assessed at 3, 6, 9, 12, 18, 24 months after starting the therapy, as well as at the time of 
going off study if prematurely. Other secondary endpoints also include tumor response rates based on 3 
dimension measurements as in section 7.1.3 at 3, 6, 9, 12, 18, 24 months after starting the therapy, progression 
free survival and overall survival over the course of the study. 
 
c. The third goal will be to examine a series of biochemical determinations (e.g. serum OAS and interferon levels, 
PKR, phosphorylation state of eIF2a, p21waf-1) as surrogate markers for sensitivity of patients to poly-ICLC. These 
will be compared to clinical response data. A subset of the proteins involved in apoptosis and signaling pathways 
will be looked into specifically to assess the effect of the study treatment on these signaling pathway changes. The 
specific endpoints are:  

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• 
Association of baseline levels of proteins (such as OAS, interferon, PKR, phosphorylation state of 
eIF2a, p21waf-1 ) in serum, PBMC and/or cerebrospinal fluid with tumor response status at 6 months 
after treatment with Poly-ICLC.  
• 
Association of baseline levels of proteins (such as OAS, interferon, PKR, phosphorylation state of 
eIF2a, p21waf-1 ) in serum, PBMC and/or cerebrospinal fluid with progression free survival.  
• 
Association of changes in levels of proteins (such as OAS, interferon, PKR, phosphorylation state 
of eIF2a, p21waf-1 ) serum, PBMC and/or cerebrospinal fluid from baseline with tumor response 
status at 6 months after treatment with Poly-ICLC.  
• 
Association of changes in levels of proteins (such as OAS, interferon, PKR, phosphorylation state 
of eIF2a, p21waf-1 ) in serum, PBMC and/or cerebrospinal fluid from baseline with progression free 
survival.  
9.1:    Study Design and Justification of Sample size 
 
9.1.1 This is a single arm study, to determine the radiographic progression free survival (PFS) rate to poly-ICLC 
in the treatment of children with recurrent or progressive low grade gliomas. The primary endpoint is the 
progression free survival status  at 6 months (PFS6) after starting therapy. The tumor response categories will 
include complete response, partial response, stable disease or progressive disease, as assessed according to 
section 7.1.2. 
 
Simon’s optimal two-stage design will be used for this study (Simon, 1989). Suppose 50% is the 
uninteresting level, i.e., if the PFS6 rate is ≤ 50%, we will consider the new regimen as not promising. This 
50% baseline response rate in the absence of treatment is from historical experience (this rate was also used 
by the Everolimus study which is a phase II study for recurrent or progressive LLG in children), also taking into 
account that this study patient population are more refractory. We will test the null hypothesis H0: p≤50% 
against the alternative hypothesis H1: p>75%, where p is the PFS6 rate. The two stage design proposed below 
will have 80% power to reject the null and conclude that the true response rate is above 50%, if the true 
response rate is ≥75%, at 5% significance level.  
 
The study design can be described in detail as follows: 
 
Stage 1: Fourteen subjects will be accrued; accrual will be held up until the PFS6 results for all the 14 subjects 
are known. The trial will be terminated at Stage 1 if ≤7 subjects have a PFS6 response; otherwise it continues 
to Stage 2. Note that any subject who goes off study early due to toxicity, will be counted as a non-response 
(an intent to treat analysis).  
 
Stage 2: Nine more patients will be accrued. We will reject the therapy if among all the 23 (14+9) subjects, the 
number of patients who have a defined response is ≤15.  
 
Early stopping probability: Under this design, if the null hypothesis is true, the probability of stopping the trial 
early will be 61%.  
 
9.1.2 Interim analysis and early stopping for efficacy:  
The interim analysis will be conducted as soon as the first 14 patients have accrued and are evaluable for the 
primary outcome.  If ≤7 subjects had a defined response, the trial will be stopped early for lack of efficacy.  
 
9.1.3 Early stopping for safety and feasibility 

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The study will also be stopped any time for safety. If 3 or more subjects have a grade 4 or 1 subject has grade 
5 toxicity probably or definitely treatment related toxicity while on therapy or within 3 months off the therapy, 
the trial will be stopped early for lack of safety.   
 
Interim Monitoring for Feasibility  
Primary early monitoring for feasibility will be based on the short-term feasibility endpoint that at least 60% of 
doses are administered to the subject, as assessed at 16 weeks. Less than 60% of doses administered for any 
reason constitutes an unacceptable level of dosing. An acceptable feasible outcome would be the successful 
administration of the study therapy to 80% or more of subjects at 16 weeks. Treatment compliance will be 
assessed in each cohort (children with or without NF1) when 4 patients have been accrued and completed the 
first 16 weeks of treatment. Failure to administer > 60% of doses in this interval in three out of the four patients 
will result in suspension of accrual to that cohort. 
 
9.1.4 Final analysis for the primary endpoint  
If the study continues, after all 23 subjects are evaluable for efficacy and safety the study data set will be 
locked.  Out of the total of 23 subjects, if the number of subjects with PFS6 is 16 or more, the conclusion will 
be that the trial has demonstrated a statistically significant improvement above a 50% PFS6 rate.  The final 
estimated PFS6 rate will also be presented, along with a lower 90% confidence interval.  
 
9.1.5 Definition of study population for analysis 
All subjects who undergo at least one dose of the study treatment will be included in the analysis population. If 
applicable, “Intention-to-treat” analyses will be performed for an endpoint. If the endpoints for a subject cannot 
be assessed (for example, a subject drops early prior to the 6 months assessments due to toxicity), it will be 
considered to be an event that does not favor the study therapy (e.g., disease progression for the primary 
outcome).   
 
9.1.6 Accrual and study duration 
All the 23 patients are expected to be accrued in 3 years and the total study duration will be about 5 to 5.5 years. 
 
 
9.2:   Analysis of Results 
 
9.2.1:   Analysis of anti-tumor activity 
The "best response" rate is defined as the percent of evaluable subjects who experience a CR or PR or SD (see 
Section 7.1.2).  The best response rates as well as overall response rates at 6 and 24 months will be estimated 
and exact lower one sided confidence intervals for the true response rates will be presented (Jung, 2004). The 
duration of response for each subject that has tumor response will be summarized in a table. The same analysis 
will be done for the tumor response rate based on 3 dimension measurements as in section 7.1.3. 
 
9.2.2:   Summary of toxicities and side effects 
All observed toxicities and side effects will be recorded on toxicity sheets and the data collection forms. Toxicity 
information including type, severity, time of onset and resolution, and probable association with the study drugs will 
be recorded. Toxicities will also be analyzed by NF1 status (NF1 vs. non NF1 subject cohorts). Tables will be 
constructed to summarize the observed incidence by type of toxicity and severity.  
 
9.2.3:   Analysis of Survival 
Overall survival and progression-free survival rates will be estimated using the Kaplan-Meier method (Kaplan, 
1958).  

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9.2.4:   Analysis of biochemical measures. 
Laboratory studies will be done on subject’s serum and peripheral blood drawn prior to and at two weeks after 
starting treatment with Poly ICLC. Levels and changes in the measurement of serum markers and proteins such 
as OAS, interferon , , , PKR kinase, eIF2a, and p21waf-1 will be determined via proteomic analysis. For each 
marker, a Fisher’s exact test or a Wilcoxon rank sum test will be used to assess the association of a baseline 
protein level or changes from baseline against tumor response status at 6 months. A log rank test will be used 
if the outcome is progression free survival.   
All the p-values will be adjusted using the Benjamini & Hochberg method to control the false discovery rate 
(FDR) due to the fact that there may be thousands of proteins produced by proteomics. A marker will be 
claimed significant at FDR≤ 0.05.  To assess the effect of the study treatment on signaling pathways such as 
the one controlling apoptosis, paired t-tests will be used to compare if there are significant changes from 
baseline for the proteins involved in these pathways. To assess differential effects on these pathways between 
the subjects who had a response and those who did not, gene set enrichment analysis (GSEA) can be 
performed to see if a pathway is significantly up- or down-regulated in the patients with a response. These 
analyses will help to understand how poly-ICLC limits tumor growth and ultimately to identify patients who will 
benefit most from this form of therapy if it is effective.  
  
 
10.0:  ADVERSE REACTION REPORTING AND TOXICITY CRITERIA 
 
The timely reporting of adverse drug reactions (including toxic deaths) is required by the Food and Drug 
Administration. Reactions definitely felt not to be treatment related should not be reported.  However, a report 
should be submitted if there is any suspicion of drug effect or in the case of Serious Adverse Events.  The 
reporting of adverse reactions is in addition to and does not supplant the reporting of toxicities as part of the data 
reporting for this study.    
Serious Adverse Events (SAEs) Timely reporting of all serious adverse events or drug reactions (including toxic 
deaths) is required by the Food and Drug Administration, regardless of attribution. The reporting of serious 
adverse reactions is in addition to and does not supplant the reporting of toxicities as part of the data reporting for 
this study. 
 
Adverse event is defined as any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical treatment or procedure 
regardless of whether it is considered related to the medical treatment or procedure (attribution of 
unrelated, unlikely, possible, probable or definite). 
A Serious Adverse event is any adverse event, occurring at any dose that is fatal or life-threatening, results 
in persistent or significant disability/incapacity, requires in-patient hospitalization or prolongation of existing 
hospitalization is a congenital anomaly/birth defect, or is an important medical event. 
 
Relationship/attribution:  The Investigator will be asked to document his/her opinion of the relationship of the event 
to study medication as follows: 
 
1) 
Unrelated:  The adverse event is clearly not related to the investigational agent(s). 
2) 
Unlikely:  The adverse event is doubtfully related to the investigational agent(s). 

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3) 
Possible:  The adverse event may be related to the investigational agent(s). 
4) 
Probable:  The adverse event is most likely related to the investigational agent(s). 
5) 
Definite:  The adverse event is clearly related to the investigational agent(s). 
 
10.1:  Reporting Adverse Drug Reactions Occurring with Investigational Agents 
 
Within 24 hours of recognition, contact the Principal Investigator or his designee by telephone to verify the 
identification process and the existence of an adverse drug reaction or toxic death. 
 
The following data must be reported to the study PI: 
 
• 
Subject identification number 
• 
Presenting diagnosis, Description of event 
• 
Laboratory data supporting event 
• 
Total and daily doses of suspected drug 
• 
Time of event 
• 
Type and grade of adverse event 
• 
Methods used to recognize and characterize the effect 
• 
Physician attribution/relationship of event to study drug (see above) 
 
The participating site must then submit a completed adverse event case report form to the coordinating site.   
 
Within 10 days of the adverse event, a completed NCI Adverse Reaction Form for Investigational Agents with the 
NCI protocol number should be submitted to the IRB for life threatening (Grade 4) and fatal known reactions 
(except Grade 4 myelosuppression) or any unexpected, unanticipated Grade 2 and 3 reactions that are possibly, 
probably, or definitely attributed to the study drug.   
 
A completed (NCI) Adverse Reaction Form for Investigational Agents should be sent electronically or by FAX to 
the FDA (see Appendix IV for the electronic links).  Oncovir will be notified as soon as an adverse event form has 
been submitted.  
 
10.2:   Toxicity Criteria. 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used and referenced.  
The site, measure, grade, relationship, action taken, and outcome for all toxicities (grades 3 and 4 as well as any 
unexpected, unanticipated Grade 2 reactions that are possibly, probably, or definitely attributed to the study 
drug) are to be reported on the appropriate toxicity monitoring and adverse event forms. 
 
10.3: Data Safety Monitoring 
 
10.3.1  Data and Safety Monitoring Board 
This study will be monitored in accordance with the UCSD/Rady Children’s Hospital plan for data and safety 
monitoring of Phase 1 and 2 studies. This study will use the UCSD Moores Cancer Center DSMB. In brief, the 
role of the Data and Safety Monitoring Board is to protect the interests of patients and the scientific integrity for 
all Phase 1 and 2 studies. The DSMB consists of 7 members including a chair, a statistician, and a pharmacist. 
The DSMB meets on a regular basis to review current study results, as well as data available to the DSMB 

Poly-ICLC 10/22/2010 
 
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36
from other related studies. The DSMB will provide recommendations for each study reviewed to change the 
study or to continue the study unchanged. Data and Safety Board reports for institutional review boards will be 
prepared.  
 
10.3.2: Study Monitoring  
The Principal Investigator will monitor the study regularly to validate subjects’ eligibility, evaluability, and any 
toxicities that are entered in the study database. In addition, the study committee comprised of the coordinating 
site members and at least 2 members of the participating site via phone conference will discuss and review 
once a month the enrolled subjects, toxicities, and integrity of data collection.  
 
Monitoring of Source Documents: 
The participating site will submit case report forms and copies of necessary supporting clinical source 
documents to the coordinating site for review of data accuracy prior to data submission. This will occur at a 
monthly interval from the time of subject’s enrollment into the study.  
 
Additionally a member of the DSMB at the coordinating site will monitor the data collection and the source 
documentation of all subjects enrolled at the enrolling sites. This monitoring will review protocol compliance, 
drug accountability, and adverse event reporting as well as regulatory compliance annually. 
 
10.4:   FDA Annual Reporting  
 
Oncovir, the IND holder of the study drug, will submit an annual report to the FDA. This report will include de-
indentified aggregate data from this study as well as compiled NCI adverse event reports.  

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11.0:   REFERENCES 
 
Black K, K. Chen, et al. (1992). Inflammatory leukocytes associated with increased immunosuppression by 
glioblastoma.  Journal of Neurosurgery 77:120-126. 
 
Blyth CR, Still HA (1983). Binomial confidence intervals. Journal of the American Statistical Association 78:108-
116. 
 
Brandsma D, Ulfman L, Reijneveld JC, Bracke M, Taphoorn MJB, Zwaginga JJ, Gebbink MFB, deBoer H, 
Loenderman L, Voest EE (2006) Constitutive integrin activation on tumor cells contricutes to progression of 
leptomeningeal metastases Neuro-Oncology 8:127-136 
 
Carter W, D Strayer, et al (1987). Clinical, immunological, and virological effects of ampligen, a mismatched 
double-stranded RNA, in patients with AIDS or AIDS related complex. Lancet (June 6): 1286-1292. 
 
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 
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APPENDIX I 
 
 
 
 
 
 PERFORMANCE STATUS SCALES/SCORES 
 
 
 
 
 
 
 
 
  
 
 
 
 
PERFORMANCE STATUS CRITERIA 
 
 
  
 
 
 
 
 Karnofsky and Lansky performance scores are intended to be multiples of 10 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
ECOG (Zubrod) 
 
 
 Karnofsky 
 
 
 
Lansky* 
 
 
Score Description 
 
 Score 
Description 
  Score 
Description 
 
 
 
 
 
 
 
 
  
 
 
 
 
0 Fully active, able to carry on all 
100 Normal, no complaints, no 
 
100 Fully active, normal. 
 
 pre-disease performance 
 
 evidence of disease 
 
 
 
 
 
 without restriction. 
 
90 Able to carry on normal 
 
90 Minor restrictions in physically 
 
 
 
 
 activity, minor signs or 
 
 strenuous activity. 
 
 
 
 
 
 symptoms of disease. 
 
 
 
 
 
1 Restricted in physically 
 
 
 
  
 
 
 
 
 strenuous activity but 
 
80 Normal activity with effort; 
 
80 Active, but tires more quickly 
 ambulatory and able to carry 
 some signs or symptoms of 
 
 
 
 
 
 out work of a light or sedentary 
 disease. 
  
 
 
 
 
 nature, e.g., light housework, 
70 Cares for self, unable to carry 
 
70 Both greater restriction of and 
 office work. 
 
 
 on normal activity or do active 
 
 less time spent in play activity. 
 
 
 
 
 work. 
  
 
 
 
 
2 Ambulatory and capable of all 
60 Required occasional 
 
60 Up and around, but minimal 
 self-care but unable to carry out 
 assistance, but is able to care 
 
 active play; keeps busy with 
 about more than 50% of waking 
hours 
 
 for most of his/her needs. 
 
 quieter activities. 
 
  
50 Requires considerable 
 
50 Gets dressed, but lies around 
  
 
 
 assistance and frequent 
 
 much of the day; no active play, 
 
 
 
 
 medical care. 
  
 able to participate in all quiet play and 
activities. 
 
 
 
 
 
 
  
  
 
3 Capable of only limited self-care, 
40 Disabled, requires special care 
 
40 Mostly in bed; participates in 
 confined to bed or chair 
 
 and assistance. 
 
 Quiet activities. 
 
 more than 50% of waking 
 
30 Severely disabled, 
 
30 In bed; needs assistance even for 
 hours. 
 
 
 hospitalization indicated. 
 
 Quiet play. 
 
 
 
 
 
 
 Death not imminent. 
 
 
 
 
 
4 Completely disabled. Cannot 
20 Very sick, hospitalization 
 
20 Often sleeping; play entirely 
 carry on any self-care. Totally 
 indicated. Death not 
 
 limited to very passive activities. 
 confined to bed or chair. 
 
 imminent. 
  
 
 
 
 
 
 
 
 
10 Moribund, fatal processes 
 
10 No play; does not get out of bed. 
 
 
 
 
 progressing rapidly. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 *The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only. 
 
 
 
 
 
 
 
 
 

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APPENDIX II: Criteria for Type 1 Neurofibromatosis:  
 
• 
Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of NF1. Many 
of these signs do not appear until later childhood or adolescence, and thus confirming the diagnosis 
often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows: 
o 
Six or more café-au-lait spots or hyperpigmented macules greater than or equal to 5 mm in 
diameter in children younger than 10 years and to 15 mm in adults 
o 
Axillary or inguinal freckles 
o 
Two or more typical neurofibromas or one plexiform neurofibroma 
o 
Optic nerve glioma 
o 
Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp 
examination by an ophthalmologist 
o 
Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis 
o 
First-degree relative (eg, mother, father, sister, brother) with NF1 
 
http://www.emedicine.com/neuro/topic248.htm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III: List of Anticonvulsants Based on CYP3A/4/5 Enzyme Induction 
 
 
Anticonvulsant drugs with little or no enzyme induction: 
ELIGIBLE for concomitant use in study. 
 
Generic Name  
 
Trade Name 
Gabapentin  
 
 
Neurontin 
 
Lacosamide 
 
 
Vimpat 
 
Lamotrigine   
 
Lamictal 
Levetiracetam  
 
Keppra 
Tigabine  
 
 
Gabitril 
Topiramate  
 
 
Topamax 
Valproic Acid  
 
Depakote, Depakene 
Zonisamide   
 
Zonegran 
 
 
 
Enzyme inducting anticonvulsant drugs (EIACD): 
NOT ELIGIBLE for concomitant use in study. 
 
Generic Name  
 
Trade Name 
Carbamazepine  
 
Tegretol 
Felbamate  
 
 
Felbatol 
Phenobarbital  
  
Phenobarbital 
Phenytoin  
 
 
Dilantin 
Primidone  
 
 
Mysoline 
Oxcarbazepine  
 
Trileptal 
Rufinamide 
 
 
Banzel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX IV: MED Watch Links 
 
 
Use the following links to download the MED Watch forms and instructions for adverse event reporting to the 
NCI. 
 
http://www.fda.gov/downloads/Safety/MedWatch/HowToReport/DownloadForms/ucm082728.pdf 
  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm   -