Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Neurofibromatosis Type 2; Vestibular Schwannomas; Meningiomas	Drug: RAD001	Early Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	5 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Other
Official Title:	Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas
Study Start Date :	June 2013
Estimated Primary Completion Date :	December 2018
Estimated Study Completion Date :	December 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: RAD001; RAD001 taken by mouth 10mg daily for 10 days before surgery	Drug: RAD001; Other Name: Everolimus

Outcome Measures

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Primary Outcome Measures :

1. Proportions of VS and meningiomas after exposure to RAD001 [ Time Frame: 10 days ]
   1) To estimate the proportions of VS and meningiomas with complete inhibition of phospho-S6 after10 days of exposure to RAD001 at a dose of 10 mg daily, as determined by immunohistochemistry. This endpoint was chosen based on prior pharmacodynamic data from a published trial, showing complete inhibition of phospho-S6 in solid tumor tissue of patients treated with RAD001 and our own preliminary data confirming baseline phospho-S6 expression in VS and meningiomas.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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Locations

United States, New York
New York University School of Medicine
New York, New York, United States, 10016

Sponsors and Collaborators

New York University School of Medicine

Investigators

Study Chair:	Matthias A Karajannis, MD	New York University School of Medicine

More Information

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Responsible Party:	New York University School of Medicine
ClinicalTrials.gov Identifier:	NCT01880749 History of Changes
Other Study ID Numbers:	12-02808
First Posted:	June 19, 2013
Last Update Posted:	July 24, 2017
Last Verified:	July 2017

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No
Product Manufactured in and Exported from the U.S.:		No

Additional relevant MeSH terms:

Meningioma; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma, Acoustic; Neurofibromatosis 2; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site

Nervous System Diseases; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neuroma; Cranial Nerve Neoplasms