Everolimus for Children With NF1 Chemotherapy-Refractory Radiographic Progressive Low Grade Gliomas
Condition: Glioma
MeSH terms: Glioma
Intervention: RAD001 (Everolimus)
Intervention description: If you take part in this research study, you will be given a participant diary for each treatment course to help you keep track of when you take your RAD001. You will be required to bring the completed diary at each scheduled visit. A treatment "course" lasts 4 weeks and there will not be any breaks between courses. You may stay on study for a total of 12 courses (48 weeks).
You will take the study medication (tablets) by mouth, once a day during each course for as long as you are participating in this study. You will also be required to take an antibiotic during treatment to prevent infection.
Intervention MeSH terms: Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 23.0
Sex: All
Minimum age: 1 Year
Maximum age: 21 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: NF1; low-grade glioma; progressive; children; NF Type 1 - low grade glioma - not responded to treatments

Summary:

      The purpose of this research study is to learn if the study drug RAD001 can shrink or slow
      the growth of low-grade gliomas in children with Neurofibromatosis type 1 (NF1).
      Additionally, the safety of RAD001 will be studied.

      The study drug, RAD001, is a drug that may act directly on tumor cells by preventing tumor
      cell growth and development. RAD001 has been studied in participants with various types of
      cancer as a single agent (a drug that is used alone to treat the cancer) or in combination
      with a number of well known anticancer therapies. Information from these research studies
      suggests that RAD001 may help to shrink or slow the growth of low-grade gliomas.

      In this research study, the investigators are looking to see the response of RAD001 in
      children with low-grade gliomas and NF1 that have either not responded to treatment or have
      come back after treatment. We are also looking for the highest dose of RAD001 that can be
      given safely in this patient population.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis: All patients must have a radiographically progressive low-grade glioma and
             at least two of the following diagnostic criteria for NF1, and/or a pathogenic NF1
             gene mutation demonstrated in peripheral blood-derived DNA:

          -  Six or more café-au-lait spots (greater than or equal to 0.5 cm in prepubertal
             subjects or greater than or equal to 1.5 cm in postpubertal subjects)

          -  Freckling in the axilla and/or inguinal region

          -  Plexiform neurofibroma

          -  Two or more Lisch nodules

          -  A distinctive bony lesion (dysplasia of the sphenoid bone or dysplasia or thinning of
             long bone cortex)

          -  A first-degree relative with NF1

          -  An optic pathway glioma

          -  Disease Status: All patients must have radiographically progressive low-grade glioma
             (including NF1 related visual pathway gliomas) after failure of a
             carboplatin-containing regimen. Patients with recurrent/progressive disease do not
             require a biopsy to confirm the diagnosis.

          -  Evaluable or Measurable Disease: Patients must have at least one evaluable or
             measurable site of disease according to criteria described in Section 9. If the
             patient has had previous radiation to the marker lesion(s), there must be evidence of
             progression since the radiation.

          -  Age: Patients must be greater than 1 years and less than or equal to 21 years of age
             at the time of study entry.

          -  Performance Level: Karnofsky 50% for patients greater than 10 years of age and Lansky
             50% for patients 10 years of age (Appendix I). Note: 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.

          -  Prior Therapy

          -  Patients must have failed or not been able to tolerate a carboplatin-based regimen.

          -  Patients must have fully recovered from the acute toxic effects of all prior
             chemotherapy or radiotherapy prior to entering this study.

          -  Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto
             this study (6 weeks if prior nitrosourea).

          -  Hematopoietic growth factors: At least 7 days since the completion of therapy with a
             growth factor.

          -  Biologic (anti-neoplastic agent): At least 14 days since the completion of therapy
             with a biologic agent. For agents that have known adverse events occurring beyond 14
             days after administration, this period must be extended beyond the time during which
             adverse events are known to occur. These patients must be discussed with the Study
             Chair on a case-by-case basis.

          -  Investigational Drugs: Patients must not have received an investigational drug within
             14 days.

          -  Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or
             stress doses of steroids if necessary.

          -  Cytochrome P450 3A4 (CYP3A4) inhibitors: Patients may not be currently receiving
             strong inhibitors of CYP3A4, and may not have received these medications within 1 week
             prior to study entry. These include:

          -  Antibiotics: clarithromycin, erythromycin, troleandomycin Anti-HIV agents:
             delavirdine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, lopinavir

          -  Antifungals: itraconazole, ketoconazole, fluconazole (doses greater than 200 mg/day),
             voriconazole

          -  Antidepressants: nefazodone, fluvoxamine Calcium channel blockers: verapamil,
             diltiazem

          -  Miscellaneous: amiodarone,

          -  In addition, grapefruit juice should be avoided, as it inhibits CYP3A4.

          -  CYP3A4 inducers: Patients must also avoid St. John's Wort, an inducer of CYP3A4

          -  Enzyme inducing anticonvulsants: Patients may not be taking enzyme-inducing
             anticonvulsants, and may not have received these medications within 1 week prior to
             study entry, as these patients may experience different drug disposition. These
             medications include:

          -  Carbamazepine (Tegretol)

          -  Felbamate (Felbatol)

          -  Phenobarbitol

          -  Phenytoin (Dilantin)

          -  Primidone (Mysoline)

          -  Oxcarbazepine (Trileptal)

          -  Radiation therapy (XRT):

          -  6 months must have elapsed if the patient has received involved field XRT or gamma
             knife that includes all target lesions (i.e., there is no restriction if a new lesion
             arises outside the radiation field or a non-irradiated lesion progresses);

          -  6 months must have elapsed if the patient has received craniospinal XRT.

          -  6 weeks must have elapsed if patient has received radiation to areas outside optic
             glioma.

          -  Surgery: At least 2 weeks must have elapsed since undergoing major surgery.

          -  Organ Function Requirements:

          -  Adequate Bone Marrow Function Defined as:

               -  Peripheral absolute neutrophil count (ANC) __1000/__L

               -  Platelet count __ 100,000/__ L (transfusion independent)

               -  Hemoglobin __ 9.0 gm/dL (may receive red blood cell (RBC) transfusions)

          -  Adequate Renal Function Defined As:

             - A serum creatinine based on age as follows: Age (Years) Maximum Serum Creatinine
             (mg/dL)

             __5 / 5 less than age __ 10 / 10 less than age __ 15/ greater than 15 0.8 1.0 1.2 1.5
             OR a creatinine clearance or radioisotope glomerular filtration rate (GFR) __
             70ml/min/1.73 m2

          -  Adequate Liver Function Defined As:

               -  Bilirubin (sum of conjugated + unconjugated) __ 1.5 x upper limit of normal (ULN)
                  for age, and

               -  Serum glutamic pyruvic transaminase (SGPT) (alanine transaminase (ALT)) __ 5 x
                  upper limit of normal (ULN) for age, and

               -  Serum albumin __ 2 g/dL

               -  International normalised ratio (INR) less than 1.3 (or less than 3 on
                  anticoagulants)

               -  Serum creatinine less than or equal to 1.5x ULN

          -  Fasting Low-density lipoprotein cholesterol (LDL) Cholesterol:

               -  Patients must have a fasting LDL cholesterol within the normal range per
                  institutional guidelines

               -  Patients taking a cholesterol lowering agent must be on a single medication and
                  on a stable dose for at least 4 weeks

          -  Fasting Serum Cholesterol:

             - less than or equal to 300 mg/dL OR less than or equal to 7.75 mmol/L AND fasting
             triglycerides less than or equal to 2.5x ULN. NOTE: In case one or both of these
             thresholds are exceeded, the patient can only be included after initiation of
             appropriate lipid lowering medication.

          -  Signed informed consent/assent

        Exclusion Criteria:

          -  Chronic treatment with systemic steroids or another immunosuppressive agent. Patients
             with endocrine deficiencies are allowed to receive physiologic or stress doses of
             steroids if necessary.

          -  Evidence of an active lesion including: plexiform neurofibroma, malignant peripheral
             nerve sheath tumor, or other cancer requiring concurrent treatment with chemotherapy
             or radiation therapy. Patients not requiring treatment for these lesions are eligible
             for this protocol.

          -  Patients who:

               -  have had a major surgery or significant traumatic injury within 2 weeks of start
                  of study drug;

               -  have not recovered from the side effects of any major surgery (defined as
                  requiring general anesthesia but excluding a procedure for insertion of central
                  venous access), or

               -  may require major surgery during the course of the study.

          -  Other malignancies within the past 3 years except for adequately treated carcinoma of
             the cervix or basal or squamous cell carcinomas of the skin.

          -  Uncontrolled brain or leptomeningeal metastases, including patients who continue to
             require glucocorticoids for brain or leptomeningeal metastases.

          -  Patients with an active, bleeding diathesis or on oral anti-vitamin K medication
             (except low dose coumarin).

          -  Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as:

               -  symptomatic congestive heart failure of New York heart Association Class III or
                  IV.

               -  unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within 6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia or any other clinically significant cardiac disease.

               -  severely impaired lung function.

               -  uncontrolled diabetes as defined by fasting serum glucose greater than 1.5x ULN.

               -  active (acute or chronic) or uncontrolled severe infections.

               -  liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis.

          -  Other concurrent severe and/or uncontrolled medical disease which could compromise
             participation in the study (i.e., uncontrolled diabetes, uncontrolled hypertension,
             severe infection, severe malnutrition, chronic liver or renal disease, active upper
             gastrointestinal (GI) tract ulceration).

          -  A known history of HIV seropositivity or known immunodeficiency.

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled
             nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A
             nasogastric tube (NG tube) is allowed.

          -  Women who are pregnant or breast feeding.

          -  Males or females of reproductive potential may not participate unless they have agreed
             to use an effective contraceptive method during the time they are receiving the study
             drug and for 3 months thereafter. Abstinence is an acceptable method of birth control.
             Oral, implantable, or injectable contraceptives may be affected by cytochrome P450
             interactions, and are therefore not considered effective for this study. Women of
             childbearing potential will be given a pregnancy test within 7 days prior to
             administration of RAD001 and must have a negative urine or serum pregnancy test.

          -  Patients who have received prior treatment with a mammalian target of rapamycin (mTOR)
             inhibitor.

          -  Dental braces or prosthesis that interferes with tumor imaging.

          -  History of noncompliance to medical regimens.

          -  Patients unwilling to or unable to comply with the protocol or who, in the opinion of
             the investigator, may not be able to comply with the safety monitoring requirements of
             the study.