Clinical trial NCT01880749: Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas
Official title: Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Neurofibromatosis Type 2
Vestibular Schwannomas
Meningiomas
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
First posted: 2013-06-19
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: The primary objective is to estimate the proportions of vestibular schwannomas (VS) and meningiomas after 10 days of exposure to the study drug RAD001 at a dose of 10 mg daily, as determined by immunohistochemistry. This is a "phase 0" PK (pharmacokinetic) and PD (pharmacodynamic) study of RAD001 in patients with Neurofibromatosis Type 2-related and sporadic VS and meningiomas. Enrolled patients will take RAD001 prior to a scheduled VS or meningioma surgery, and blood and tissue samples will be obtained for further analysis.


Eligibility criteria: Inclusion Criteria:

* Patients must satisfy all of the following eligibility criteria:
* Karnofsky performance status (KPS) ≥ 60%
* Absolute neutrophil count ≥ 1,000/mm³ (unsupported)
* Platelet count ≥ 100,000/mm³ (unsupported)
* Hemoglobin ≥ 8 g/dl (transfusion support allowed)
* Creatinine ≤ 1.5 times upper limit of normal (ULN\*) OR corrected glomerular filtration rate ≥ 70 ml/min
* Total bilirubin ≤ 1.5 times ULN\*
* ALT ≤ 2.5 times ULN\*
* Serum albumin ≥ 2 g/dl
* INR \< 1.3 (or \< 3 on anticoagulants)
* 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 ≤ 300 mg/dl OR ≤ 7.75 mmol/l AND fasting triglycerides ≤ 2.5 times ULN\*.
* Fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy
* Any neurologic deficits must be stable for ≥ 1 week
* Patients with the potential for pregnancy or impregnating their partner must agree to follow acceptable birth control methods to avoid conception. Women of childbearing potential must have a negative pregnancy test. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus.
* Able to provide written informed consent

Exclusion Criteria:

* Patients with any of the following are ineligible for this research study:
* Patients with VS or meningiomas deemed very high surgical risk for stroke and/or other complications by the attending surgeon, such as meningiomas with major vascular or dural sinus infiltration.
* Patients with serious concurrent infection or medical illness, which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety.
* Symptomatic congestive heart failure or unstable angina pectoris.
* Uncontrolled diabetes, as defined by fasting serum glucose \>1.5 times ULN\*.
* Current active hepatic or biliary disease such as cirrhosis, chronic active hepatitis, or chronic persistent hepatitis (with exception of patients with Gilbert's syndrome and asymptomatic gallstones).
* History of hepatitis B or C. Note: A detailed assessment of hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV serology, DNA and/or 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. If no positive medical history for risk factors, serology is not required.
* Seropositivity or DNA/RNA positivity for hepatitis B or C, with the exception of patients who have received prior Hepatitis B vaccination and are Anti-HBs positive only.
* Known HIV seropositivity
* Neurologic deficits that are rapidly progressing: all neurologic signs and symptoms must have been stable for a week prior to first dose
* Patients who are pregnant or breast-feeding. The anti-proliferative activity of this experimental drug may be harmful to the developing fetus or nursing infant.
* Anti-tumor therapy (i.e. chemotherapeutics or investigational agents or immunotherapy) within 4 weeks prior to enrollment
* Radiation therapy to a study target lesion within 6 months
* Prior therapy with mTOR inhibitors, including sirolimus, temsirolimus, deforolimus within 6 months prior to enrollment
* Known hypersensitivity to RAD001 or other rapamycins (sirolimus, temsirolimus, deforolimus)
* Patients with a concurrent malignancy
* Patients treatment with systemic steroids or another immunosuppressive agent. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary.
* Patients cannot receive CYP3A4 inhibiting drugs including antibiotics (clarithromycin, erythromycin, troleandomycin), anti-HIV agents (delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, saquinavir, lopinavir), antifungals (itraconazole, ketoconazole, fluconazole at doses \> 200 mg/day, voriconazole), antidepressants (nefazodone, fluovoxamine), calcium channel blockers (verapamil, diltiazem) oramiodarone
* Patients should avoid CYP3A4 inhibiting foods including grapefruit and Seville orange juice.
* Patients cannot receive CYP3A4 inducing anticonvulsants including carbamazepine, felbamate, phenobarbital, phenytoin, primidone and oxcarbazepine, or other CYP3A4 inducers such as St. John's Wort
* Patients who previously received CYP3A4 inducers or inhibitors must have discontinued these medications within at least 1 week prior to study entry and can re-start them 1 week post-operatively (or earlier if determined to be of clinical benefit, as determined by the treating physician).

  * of institutional norms

Primary outcomes:
measure: Proportions of VS and meningiomas after exposure to RAD001
timeFrame: 10 days
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: New York University School of Medicine
state: New York
Study officials:
affiliation: NYU Langone Health
name: Theodore Nicolaides, MD
role: STUDY_CHAIR
References: