This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®)
treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary
objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive
low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first
48 weeks (12 cycles) of therapy.
The secondary objectives are to:
1. Determine 12, 24 and 60 month progression free survival (PFS) in pediatric NF1 patients
with progressive LGG treated with poly-ICLC.
2. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as
measured by best objective tumor response rate (CR+PR) within 24 cycles of therapy.
3. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as
measured by clinical benefit response rate (CR+PR+MR+SD) after 12 and 24 cycles of
therapy.
4. Assess the toxicity associated with poly-ICLC treatment in pediatric NF1 patients with
LGG.
Exploratory objectives are to:
1. Evaluate the visual outcome measures in children with progressive optic pathway gliomas
treated with poly-ICLC. Visual response is defined as 0.2 logMAR or greater in acuity
improvement.
2. Evaluate patient reported outcomes and quality of life measures.
3. Evaluate biological correlates.
Inclusion Criteria:
1. Age: Patients must be less than 22 years at the time of enrollment; there is no lower
age limit.
2. All participants must have an identified pathogenetic constitutional NF1 mutation OR
the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
3. Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible.
Histologic confirmation of tumor is not necessary in the presence of consistent
clinical and radiographic findings. Biopsy for histologic diagnosis is required if
there is clinical suspicion for a high-grade tumor; special attention is recommended
in older adolescents or young adults to the potential for malignant transformation.
Patients with metastatic disease are eligible.
4. Patients must meet at least one of the following criteria for progression or
recurrence of a previously treated target tumor:
1. Progression or recurrence on MRI.
2. New or worsening neurologic symptoms attributable to the target tumor.
3. For patients with OPG: visual worsening, defined as worsening of visual acuity
(VA) or visual fields (VF) documented within the past year by examination or
history, attributable to tumor.
5. Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2.
6. Prior Therapy: Patients must have had at least one prior medical treatment for the
target LGG.
7. Performance Level: Patients must have a performance status of equal or > than 50 using
Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years
of age.
8. Patients must have recovered to grade ≤1 from any acute toxicities from all prior
treatments. to enroll on this study and meet time restrictions from end of prior
therapy as defined below:
1. Myelosuppressive chemotherapy: must have received the last dose of
myelosuppressive therapy at least 4 weeks prior to study registration, or at
least 6 weeks if nitrosourea.
2. Investigational/biological agent: Patient must have received the last dose of
other investigational, immunotherapy, or biological agent > 14 days prior to
study registration or at least 5 half-lives, whichever is greater. Bevacizumab
last dose > 36 days prior to enrollment.
3. Radiation therapy: Patients SHOULD NOT have received prior irradiation.
4. Study specific limitations on prior therapy: There is no limit on the number of
prior treatment regimens.
5. Growth factor(s): Must not have received any hematopoietic growth factors within
7 days of study entry or > 14 days if pegylated GCSF is used.
6. Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major
surgery such as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from
minor surgery and completely recovered. Port or central line placement is not
considered a major surgery.
9. Organ Function Requirements:
All patients must have adequate organ function defined as:
9.1 Hematologic Function:
1. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs)
2. ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14
days since last dose of pegylated GCSF
3. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last
transfusion)
9.2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per
the table below) or GFR > 70 ml/min/1.73m2
Renal Function Normal for Age
Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6
months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10
years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4
≥ 16 years 1.7 1.4
Liver Function:
1. Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert's Syndrome will
be allowed on the study regardless of their total and indirect bilirubin levels
as long as the direct bilirubin is less than 3.1 mg/dL.)
2. SGPT (ALT) ≤ 5 x ULN
3. SGOT (AST) ≤ 5 x ULN
Pulmonary Function:
No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%.
Reproductive Function:
Female patients of childbearing potential must have negative serum or urine pregnancy
test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant
or breast-feeding. Patients of childbearing or child-fathering potential must be
willing to use a medically acceptable form of birth control, including abstinence,
while being treated on this study and for 90 days following cessation of treatment.
10. Patient is able to start treatment within 7 days after enrollment.
11. Patients with neurological deficits must be stable for a minimum of 1 week prior to
enrollment.
12. Patients are only eligible if complete resection of the LGG with acceptable morbidity
is not feasible, or if a patient with a surgical option refuses surgery.
13. Parents/legal guardians must provide written informed consent and agree that they will
comply with the study.
Exclusion Criteria:
1. Prior radiation treatment for the low-grade glioma.
2. Prior exposure to poly-ICLC.
3. Patients currently receiving other anti-tumor therapy or experimental therapy
(targeted agents, chemotherapy radiation).
4. Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV).
5. Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other
malignancy requiring treatment in the last 48 months.
6. Patients may not have fever (≥38.50 C) within 3 days of enrollment.
7. Patients who, in the opinion of the investigator, may not be able to comply with the
safety monitoring requirements of the study.
8. Active auto-immune illness.
9. Pregnant or lactating females.
10. Sexually active patients of reproductive potential who have not agreed to use an
effective contraceptive method for the duration of their study participation and for
90 days after stopping study therapy are not eligible.
11. Severe unresolved infection that requires systemic IV antibiotics.
12. Patients with any significant medical illnesses that in the investigator's opinion
cannot be adequately controlled with appropriate therapy or would compromise the
patient's ability to tolerate this therapy.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, impaired gastrointestinal function, or psychiatric illness/social
situations that would limit compliance with study requirements.
14. Patients requiring high doses of steroids. Patients may not be on immunosuppressive
therapy, including corticosteroids (with the exception of physiologic replacement,
defined as ≤ 0.75 mg/m2/day dexamethasone or equivalent) at time of enrollment.
However, patients who require intermittent use of bronchodilators or local steroid
injections will not be excluded from the study.
