PNOC 001: Phase II Study of Everolimus for Recurrent or Progressive Low-grade Gliomas in Children

This is an open label study of everolimus in children with recurrent or progressive low-grade
glioma. All patients will receive everolimus at a dose of 5 mg/m2/dose daily. An adaptive
Simon two-stage design for phase 2 studies of targeted therapies will be used to assess the
efficacy primary objective. The proposed treatment with everolimus will be deemed not worthy
of further investigation in this patient population if the true PFS at 6-months (PFS6) is
less than 50%. If in the first stage, with a combined sample size of 25, there is preliminary
evidence to suggest efficacy of everolimus is restricted to patients with PI3K/AKT/mTOR
activation as measured by p-S6 positivity, a total of 45 patients will be enrolled and the
design will have 81% statistical power to detect a true disease stabilization rate ≥70%. If
in the first stage there is preliminary evidence to suggest efficacy of everolimus is
independent of PI3K/AKT/mTOR activation, a total of 65 patients will be enrolled and the
design will have >95% statistical power to detect a true disease stabilization rate ≥70%.

Inclusion Criteria:

--Patients must have radiographic progressive or recurrent confirmed WHO grade I or II
astrocytomas, that was confirmed histologically at initial diagnosis. Progressive or
recurrent disease should be based on MRI according to the definition below.

Eligible histologies:

- Pilocytic Astrocytoma - 90600112

- Astrocytoma, Low Grade (Fibrillary astrocytoma, WHO Grade 2) - 10065886

- Astrocytoma, Low Grade (Low-grade Astrocytoma, NOS, WHO Grade 2) - 10003571

- Tissue from the initial diagnosis or recurrence must be made available for
correlative testing.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least two dimensions on MRI.

- Patients may have had treatment (chemotherapy and/or radiotherapy) for any number
of relapses prior to this recurrence.

- Patients must have received their last dose of myelosuppressive anticancer
chemotherapy at least three (3) weeks prior to study registration or at least six
(6)weeks of nitrosourea.

- Patients must have received their last dose of other investigational or
biological agent > 7 days prior to study entry.

For agents that have known adverse events occurring beyond 7 days after administration,
this period should be extended beyond the time during which adverse events are known to
occur. This should be discussed with the study chair.

- If patients received prior monoclonal antibody treatment, at least three half-lives
must be elapsed by the time of treatment initiation. These patients should also be
discussed with the study chair.

- Patients must have received their last fraction of craniospinal or focal radiation to
primary tumor or other sites >12 weeks (3 months) prior to registration.

--Age ≥3 and ≤21 years.

- Because no dosing or adverse event data are currently available on the use of
everolimus in patients <3 years of age, these young children are excluded from this
study.

- Life expectancy of greater than 8 weeks.

- Patients must be able to swallow pills.

- Patient must have a Karnofsky (if ≥ 16 years of age) or Lansky Performance score
(if ≤ 16 years of age) of ≥50 by the time of registration.

- Patients must have adequate bone marrow function (ANC ≥ 1,000/mm3, platelet count
of ≥ 100,000/mm3, and hemoglobin ≥ 9 gm/dL) before starting therapy. Eligibility
level for hemoglobin may be reached by transfusion.

- INR ≤1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of
warfarin or on a stable dose of LMW heparin for >2 weeks at time of
randomization).

- Patients must have adequate liver function (SGPT/ALT ≤ 2.5 times ULN and
bilirubin ≤ 1.5 times ULN) before starting therapy.

- Patients must have adequate renal function (serum creatinine ≤ 1.5 times
institutional ULN for age or GFR ≥ 70 ml/min/1.73 m2) before starting therapy.

- Patients must have cholesterol level <350 mg/dL and triglycerides < 400 mg/dL
before starting therapy. In case one or both of these are exceeded, the patient
can only be included after initiation of appropriate lipid lowering medication
and documentation of cholesterol < 350mg/dL and triglycerides < 400mg/dl before
start of therapy.

- Patients must have normal pulmonary function testing for age based on pulse
oximetry.

- The effects of everolimus on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because everolimus are known to
be teratogenic, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation. Should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately.

- Female patients of child bearing potential must not be breastfeeding or pregnant
as evidenced by a negative pregnancy test.

Exclusion Criteria:

- Patients with primary spinal cord tumors

- Patients receiving concomitant medication that may interfere with study outcome. For
example, patients cannot be on enzyme inducing anticonvulsants like phenytoin.

- Patients should not receive immunization with attenuated live vaccines within one week
of study entry or during study period. Close contact with those who have received
attenuated live vaccines should be avoided during treatment with everolimus. Examples
of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio,
BCG, yellow fever, varicella and TY21a typhoid vaccines

- Hepatitis B/C blood test must be done at screening for all patients. Patients who test
positive for Hepatitis C antibodies and the Hepatitis B antigen are ineligible.

- A known history of HIV seropositivity. HIV-positive patients on combination
antiretroviral therapy are ineligible because of the potential for pharmacokinetic
interactions with everolimus. In addition, these patients are at increased risk of
lethal infections when treated with marrow-suppressive therapy.

- Patients receiving chronic, systemic treatment with corticosteroids or another
immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

- Patients may not have therapy for this recurrence (including radiation).

- Patients who do not have measurable disease on MRI.

- Patients who have been previously treated with an mTOR inhibitor.

- Patients with a known hypersensitivity to everolimus or other rapamycins (e.g.
sirolimus, temsirolimus).

- Patients receiving any other concurrent anticancer or investigational therapy.

- Patients with any clinically significant unrelated systemic illness that would
compromise the patient's ability to tolerate protocol therapy.

- Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter the absorption of everolimus (e.g., ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
resection.

- Patients with inability to return for follow-up visits to assess toxicity to therapy.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in situ of the cervix), unless in complete remission and off of all therapy
for that disease for a minimum of 3 years.

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done
at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening
for all patients with a positive medical history based on risk factors and/or confirmation
of prior HBV/HCV infection.