Clinical Trial Details
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NCT01158651 : Study of RAD001 (Everolimus) for Children With NF1 and Chemotherapy-Refractory Radiographic Progressive Low Grade Gliomas
PhasePhase 2
AgesMin: 1 Year Max: 21 Years
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.

- 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:
delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, lopinavir

- Antifungals: itraconazole, ketoconazole, fluconazole (doses greater than 200 mg/day),

- Antidepressants: nefazodone, fluovoxamine Calcium channel blockers: verapamil,

- 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 (Felbtol)

- Phenobarbitol

- Phenytoin (Dilantin)

- Primidone (Mysoline)

- Oxcarbazepine (Trileptal)

- 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

- 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 RBC transfusions)

- Adequate Renal Function Defined As:

- A serum creatinine based on age as follows: Age (Years) Maximum Serum Creatinine

__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 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

- SGPT (ALT) __ 5 x upper limit of normal (ULN) for age, and

- Serum albumin __ 2 g/dL

- INR less than 1.3 (or less than 3 on anticoagulants)

- Serum creatinine less than or equal to 1.5x ULN

- Fasting 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

- 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

- 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
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

- Patients who have received prior treatment with an 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.
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