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

Trial Requirements and Treatment

Patients will receive everolimus once daily by mouth. One course is 28 days. Subsequent courses will immediately follow, with no break in the administration of drug. Clinical assessment will be required every 2 months for the first 12 months, then every 3 months for the next 12 months.

Rationale for Study

This trial is testing the drug everolimus in pediatric low-grade gliomas. Everolimus works by interrupting the PI3K/Akt/mTOR cell-signaling pathway that is overactive in these tumors. In normal cells, the molecules in this pathway deliver signals to one another that regulate important processes such as cell proliferation, natural cell death (also called apoptosis) and blood vessel development. Nearly half of grade I and II pediatric gliomas have abnormal activation of the PI3K/Akt/mTOR pathway. One possible cause of this is methylation of the promoter of the PTEN gene. Everolimus specifically inhibits mTOR, stopping the hyperactivation at that point in the pathway.

This study will examine whether mTOR inhibition by everolimus can slow or halt growth of pediatric low-grade gliomas, and whether patients with abnormal activation of the PI3K/Akt/mTOR pathway have better responses to this treatment.

Primary Objectives

The primary objective of this study is to estimate the rate of progression-free survival (PFS) at 6 months following everolimus therapy for symptomatic, progressive or recurrent pediatric low-grade glioma patients. This will help us determine whether everolimus warrants additional study only in patients with activated PI3K/Akt/mTOR pathways or in the entire population.

Secondary Objectives

  1. Estimate PFS and overall survival (OS) as well as objective response (CR + PR) rates associated with everolimus treatment in recurrent pediatric low-grade gliomas
  2. Explore associations between S6 phosphorylation and outcome at 6 months. S6 is a protein found along the PI3K/Akt/mTOR pathway and preliminary studies in adults show that lack of S6 phosphorylation may be a marker for improved survival.
  3. Collect tissue from enrolled patients to prospectively analyze key molecular features of their tumors, including activation of the PI3K, mTOR, and MAPK pathways; aberrations in the PTEN, IDH and IDH2 genes; and activating mutations in the BRAF gene (specifically KIAA-1549-BRAF fusion and BRAFV600E missense mutation).
  4. Explore MR quantitative measures of relative cerebral blood volume, permeability and apparent diffusion coefficient within the region of hyperintensity of T2-weighted images as markers of disease response and/or progression in comparison to institutional evaluation of disease response and/or progression and quantitative measures of tumor response as determined by central review. Tumor size will be based on both area and volume.

Inclusion Criteria

  1. Patients must have progressive or recurrent confirmed low grade glioma (WHO grade I or II), that was confirmed histologically.
  2. Tissue from the initial diagnosis or recurrence must be made available for correlative testing.
  3. Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least two dimensions on MRI.
  4. Patients may have had treatment (chemotherapy and/or radiotherapy) for any number of relapses prior to this recurrence.
    1.    - Patients must have received their last dose of myelosuppresive 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

  5. 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 chilren are exlucded from this study.
  6. 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 who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
  7. 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.
  8. Patients must have adequate liver function (SGPT/ALT ≤ 2.5 times ULN and bilirubin ≤ 1.5 times ULN) before starting therapy.
  9. Patients must have adequate renal function, defined as:
    • Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or
    • A serum creatinine based on age/gender as follows:
      Age Maximum Serum Creatinine (mg/dL)
        Male Female
      3 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 utilizing child length and stature data published by the CDC.

  10. 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 medicatoin and documentation of cholesterol <350mg/dL and triglycerides <400mg/dl before start of therapy.
  11. Patients must have normal pulmonary function testing for age based on pulse oximetry.
  12. 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.
  13. Female patients of child bearing potential must not be breastfeeding or pregnant as evidenced by a negative pregnancy test.

Exclusion Criteria

  1. Patients with primary spinal cord tumors.
  2. Patients receiving concomitant medication that may interfere with study outcome. For example, patients cannot be on enzyme inducing anticonvulsants like phenytoin.
  3. 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.
  4. A 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.
  5. 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.
  6. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Note: Patients that are currently using inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not necessarily excluded from the study but need to be discussed with the study chair.
  7. Patients may not have therapy for this recurrence (including radiation).
  8. Patients who do not have measurable disease on MRI.
  9. Patients who have been previously treated with an mTOR inhibitor.
  10. Patients with a known hypersensitivity to everolimus or other rapamycins (e.g. sirolimus, temsirolimus).
  11. Patients receiving any other concurrent anticancer or investigational therapy.
  12. Patients with any clinically significant unrelated systemic illness that would compromise the patient’s ability to tolerate protocol therapy.
  13. 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.
  14. Patients with inability to return for follow-up visits to assess toxicity to therapy.
  15. 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.
  16. 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.


Funding provided by A Kids' Brain Tumor Cure Foundation (aka the PLGA Foundation)