Exploring the Activity of RAD001 in Vestibular Schwannomas and Meningiomas

• Status: Completed
• Trial end date: 2019-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Early Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: New York University School of Medicine; NYU Langone Health
• Treatments: Everolimus; Sirolimus

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