A Trial of Poly-ICLC in the Management of Recurrent Pediatric Low Grade Gliomas
A Trial of Poly-ICLC in the Management of Recurrent Pediatric Low Grade Gliomas
This study is for patients up to 21 years of age who have a tumor called a low grade glioma
 of the central nervous system (brain and spinal cord). The tumor has grown despite attempts
 to control it with chemotherapy or radiation. Low grade gliomas are a group of tumors that
 tend to grow slowly and could be cured if every bit of the tumor were surgically removed.
 These tumors are called Grade I or II astrocytomas.

 These tumors often grow in parts of the brain that prevent total removal without devastating
 neurologic complications or death. Although some low grade gliomas never grow, most will and
 are treated with either chemotherapy or radiation. There is good data showing that the growth
 of most low grade gliomas can be controlled with chemotherapy or radiation. However, some low
 grade gliomas in children and young adults grow despite these treatments. Poly-ICLC is a new
 drug that has been used safely in children and adults with different types of brain tumors.
 Earlier studies showed that this drug worked better for children and young adults with low
 grade gliomas than for children with more aggressive brain tumors. The main purpose of this
 study is to use Poly-ICLC treatment in a larger number of patients to see how well it works
 and how many side effects occur.

 As Poly-ICLC is not FDA approved, this study is authorized to use it under IND# 43984, held
 by Oncovir.

 Subjects will get injections of Poly-ICLC into muscle two times weekly. The first treatments
 will be given in the clinic so allergic or other severe reactions, if any, can be monitored.
 If subjects tolerate the injections and don't have a severe reaction, then the rest of the
 injections will be given at home. Subjects/caregivers will be trained to give injections.

 Treatment will last for about 2 years. Subjects may stay on treatment for longer than 2 years
 if their tumor shrinks in response to the injections, if study doctors think it is safe, if
 subjects want to remain on treatment, and if Poly-ICLC is available.

 Risks: Poly-ICLC has been used safely in children and adults at the dose used in this study,
 and at higher doses. Frequently seen side effects include irritation of the skin at the
 injection site and mild flu-like symptoms. These are usually relieved or avoided by use of
 over-the-counter medicines like acetaminophen (Tylenol).

 Funding Source: FDA OOPD
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 xanthoastrocytomas 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, and desmoplastic
 astrocytomas. Although children with low-grade astrocytomas often survive many years after
 conventional treatment with surgery and sometimes radiotherapy, some children will not fare
 as well. 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

 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. 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 show that such information reveals activity of different enzymes that
 correlate with 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. 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, 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 in high grade and low grade tumors is
 likely to help identify biological markers specific for tumor progression, or for tumor
 pathology.
Inclusion Criteria:

 -  Age:Patients must be between 0 - 21 years of age when registered on this protocol.

 -  Diagnosis:Patients 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)

 -  low grade oligoastrocytoma

 -  low grade oligodendroglioma

 -  low grade glioma NOS Tumors of all regions of the CNS, with appropriate histology are
 eligible for study. However patients with tumors intrinsic to the optic nerve and
 involvement of the optic nerve cannot be biopsied/resected are eligible without
 histological confirmation.

 Patients with neurofibromatosis type 1(NF1) are also eligible.

 Patients must have demonstrated either tumor progression or recurrence by radiographic
 criteria and/or clinical criteria as defined below:

 1. Patients 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.

 2. Radiographic progression is defined as >40% increase in the product of the three
 perpendicular diameters of initial tumor relative to the initial baseline measurement
 - length (L)x width (W) x transverse (T) (current scan) > 1.4 x L x W x T (initial
 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.

 3. 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.

 4. Tumor volume includes the entire tumor volume seen on gadolinium enhanced T1 MR
 imaging plus non-enhancing abnormality seen on T2 or FLAIR.

 5. All tumor cysts will be included in the tumor volume

 6. 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.

 7. 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.

 Measurable disease: Patients must have measurable disease documented by radiographic
 criteria prior to enrollment.

 Performance Level and Life Expectancy:Patients 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. Patients must have a life expectancy of ≥ 8 weeks.

 Prior Therapy:Patients 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:

 1. Myelosuppressive chemotherapy patients must have received the last dose of
 myelosuppressive therapy at least 3 weeks prior to study registration or at least 6
 weeks if nitrosourea.

 2. Investigational / Biological agent: Patient must have received the last dose of other
 investigational or biological agent >7 days prior to study registration

 3. XRT: Patients must be ≥ 8 weeks since the completion of radiation therapy.

 4. Study specific limitations on prior therapy: There is no limit on the number of prior
 treatment regimens or received doses of radiation therapy.

 5. Growth factor(s): Must not have received any hematopoetic growth factors within 7 days
 of study entry or 21 days for neulasta.

 6. Prior Surgery: Must be ≥ 2 weeks from prior surgery.

 7. Steroids: Must be on a stable steroid dose for 7 days prior to study entry.

 Organ Function Requirements:All patients must have adequate organ function defined as:

 Hematologic Function:

 1. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs)

 2. ANC: > 750/mm3 Must be at least 7days after last dose of growth factor

 3. Platelet Count: > 50,000 (transfusion independent; ≥ 7 days from last transfusion)

 Renal Function:

 Serum creatinine ≤ 2 x normal for age (see below) or Creatinine clearance/GFR > 60
 cc/min/1.73 m2 [Urine Creatinine (mg/dL)][Volume collected (ml)]/[Serum Creatinine
 9mg/dL)][Hours x 60]

 Age (years) Maximum Serum Creatinine (mg/dL)

 ≤ 5 0.8 > 5 & ≤ 10 1.0 > 10 & ≤ 15 1.2 > 15 1.5

 Liver Function:

 1. Total bilirubin < 1.5 x ULN for age, AND

 2. SGPT (ALT) < 2.5x ULN

 3. SGOT (AST) < 2.5x ULN

 Pulmonary Function:

 No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry ≥ 94% if
 there is clinical indication for determination.

 Coagulation Function:

 Normal PT and PTT at enrollment per institutional range

 Reproductive Function:Due to potential teratogenic effects of (poly-ICLC), negative serum
 beta-HCG in females, and use of effective contraception in males and females of
 childbearing potential, IS REQUIRED.

 Exclusion Criteria:

 -  Pregnant or lactating females. Women of childbearing age will agree to use
 contraception during the protocol.

 -  Patients receiving other experimental immunotherapy.

 -  Patients may not have fever (38.50C) within 7 days of enrollment.

 -  No concurrent XRT or chemotherapy is allowed.

 -  Patients who, in the opinion of the investigator, may not be able to comply with the
 safety monitoring requirements of the study.