Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01419639
• Collaborator: Novartis Pharmaceuticals (Industry), The Children's Tumor Foundation (Other)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 26
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This trial studies whether Everolimus is efficacious in treating neurofibromatosis 2.

Condition or Disease	Intervention/Treatment	Phase
Neurofibromatosis Type II	Drug: Everolimus (RAD001) , Afinitor®	Phase 2

Detailed Description

Everolimus (RAD001) has been in clinical development since 1996 as an immunosuppressant in solid organ transplantation and has obtained marketing authorization (Certican®) for prophylaxis of rejection in renal and cardiac transplantation in a number of countries, including the majority of the European Union. Everolimus has been in development for patients with various malignancies since 2002. Everolimus 2.5mg, 5mg and 10mg tablets were approved under the trade name Afinitor® for patients with advanced renal cell carcinoma (RCC) after failure of treatment with Sutent® (sunitinib) or Nexavar® (sorafenib) in the US, EU and several other countries and is undergoing registration in other regions worldwide. Afinitor® was also recently approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapeutic intervention but are not candidates for curative surgical resection. Everolimus is being investigated as an anticancer agent based on its potential to act: 1. Directly on the tumor cells by inhibiting tumor cell growth and proliferation; and 2. Indirectly by inhibiting angiogenesis leading to reduced tumor vascularity.

For pediatric cancer patients, safety of RAD001 has been established in a phase 1 trial and the recommended phase II dose is 5 mg/m2 once daily. This existing pediatric data allows for inclusion of children in this phase 2 trial, which is an important consideration since some NF2 patients with the most aggressive clinical course present at school age.

RAD001 was recently approved by the Food and Drug Administration (FDA) for the treatment of children and adults with subependymal giant cell astrocytoma (SEGA), a benign brain tumor associated with tuberous sclerosis (TS). Although surgical resection is effective at tumor reduction, serious complications may follow a radical resection, such as permanent deafness and facial nerve damage. Most importantly, the tumors often recur after surgery. Radiation therapy (RT) has been proposed as an alternative. However, its safety and efficacy in the NF2 population has not been established. A medical therapy option is desperately needed. This study is a single-center, 2-stage, phase II open-label study. All subjects will get RAD001 taken continuously until disease progression or unacceptable toxicity. The primary objective of this study is to look at the objective response rate to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Participation will consist of screening/baseline visit(s), Day 1, Weeks 1, 2, and 4; and up to 12 cycles and will include standard of care procedures such as medical history, vital signs, physical examinations, ECGs, MRIs, audiograms, and laboratory tests. Novartis will provide the RAD001 free of charge to eligible study subjects. The primary efficacy response for study purposes will be a greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors will constitute a complete response (CR).

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Everolimus (RAD001) in Children and Adults With Neurofibromatosis Type 2
• Study Start Date: Oct 1, 2011
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: RAD001 RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age

Drug: Everolimus (RAD001) , Afinitor®; Everolimus will be provided by Novartis. Everolimus is formulated as tablets for oral administration of 2.5 mg, 5 mg, 10 mg strength. Everolimus will be self-administered (by the patients themselves) or administered by the patient's parent or guardian (for minors). The investigator will instruct the patient to take the study drug exactly as specified in the protocol. Depending the age-based dosing schedule, everolimus should be administered orally once (or twice) daily, preferably in the morning (and evening), at the same time every day with our without food. Everolimus tablets should be swallowed whole with a glass of water. The tablets must not be chewed or crushed. In cases where tablets can not be swallowed, the tablets should be disintegrated in water just prior to being taken. Everolimus will be administered orally as per the age-based dosing schedule continuously from study day 1 until progression of disease or unacceptable toxicity.; Other Names: Afinitor®

Outcome Measures

Primary Outcome Measures

1. Radiographic Response [1 Year]

   To estimate the objective response rates to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Radiographic response for study purposes = greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors = complete response. MRI of the brain and spine will be performed every 3 months. If an objective response (15% reduction in tumor volume compared to baseline) is observed in any target tumor or stable disease, drug will be continued.

2. Change in Tumor Size From Baseline [1 Year]

Secondary Outcome Measures

1. Audiologic Response [1 Year]

   Defined as improvement in speech discrimination score (SDS), defined as an improvement in the score above the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Audiologic worsening: decrease in SDS score below the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Patients with vestibular schwannomas will receive baseline audiograms within 28 days before enrollments and subsequent audiograms at the time of each MRI.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 3 years and body surface area ≥ 0.5 m2

• Meets diagnostic criteria for NF2

• At least one volumetrically measurable and ≥ 0.5 cc NF2-related brain or spinal tumor (schwannoma, ependymoma, meningioma - histological confirmation not required) with radiographic evidence of progression (either as unequivocal progression on conventional MRI, or a >10% volume increase by 3D volumetrics) over the past ≤12 months, designated as the primary target tumor OR Volumetrically measurable and ≥ 0.5 cc VS with ipsilateral progressive hearing loss over the past ≤12 months, designated as the primary target tumor

• Progressive Hearing Loss Criteria for Enrollment: Audiogram showing drop in pure tone average (PTA) of 10dB HL at ≥ 2 nonconsecutive or consecutive frequencies or drop in speech discrimination score (SDS) below the 95% critical difference threshold, compared to previous audiogram ≤ 1 year prior.

• Karnofsky/Lansky performance status (PS) 50-100%. 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.

• Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb > 9 g/dL

• Adequate liver function as shown by:

1. serum bilirubin ≤ 1.5 x ULN

2. ALT and AST ≤ 2.5x ULN

• INR ≤ 1.5. (Anticoagulation is allowed if target INR ≤ 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of enrollment.)

• Adequate renal function: serum creatinine ≤ 1.5 x ULN

• Fasting serum cholesterol ≤300 mg/dL OR ≤ 7.75 mmol/L AND fasting triglycerides ≤ 2.5 x 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.

• Fully recovered from acute toxic effects of any prior chemotherapy, biological modifiers or radiotherapy

• Any neurologic deficits must be stable for ≥ 1 week

• Able to provide signed informed consent (or consent by parent/legal guardian for minors)

Exclusion Criteria:

• Patients currently receiving medical anticancer therapies or who have received medical anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, antibody based therapy, etc.)

• Radiation therapy to a study target tumor within 1 year prior to enrollment, or any radiation therapy within 4 weeks prior to enrollment.

• Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study

• Prior treatment with any investigational drug within the preceding 4 weeks

• Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.

• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period. Close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus. Examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines.

• Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases

• Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.

• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:

1. Symptomatic congestive heart failure of New York heart Association Class III or IV

2. 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

3. severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air

4. uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN (Note: Optimal glycemic control should be achieved before starting trial therapy.)

5. active (acute or chronic) or uncontrolled severe infections

6. liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C).

Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and 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.

• A known history of HIV seropositivity

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)

• Patients with an active, bleeding diathesis

• Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. Adequate contraception must be used throughout the trial and for 8 weeks after the last dose of study drug, by both sexes. (Females of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of everolimus)

• Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment

• Patients who have received prior treatment with an mTOR inhibitor (e.g., sirolimus, temsirolimus, everolimus).

• Patients with a known hypersensitivity to everolimus or other rapamycins (e.g., sirolimus, temsirolimus) or to its excipients

• History of noncompliance to medical regimens

• Patients unwilling to or unable to comply with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	New York University Medical Center	New York	New York	United States	10016

Sponsors and Collaborators

• NYU Langone Health
• Novartis Pharmaceuticals
• The Children's Tumor Foundation

Investigators

• Principal Investigator: Matthias A Karajannis, MD, MS, New York University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• New York University Medical Center

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT01419639
• Other Study ID Numbers: RAD001 NF2 (11-00587); 2010-10-011
• First Posted: Aug 18, 2011
• Last Update Posted: Jul 18, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by NYU Langone Health: Neurofibromatosis Type II; cranial nerve schwannomas; meningiomas; ependymomas
• Additional relevant MeSH terms: Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurofibromatosis 2; Everolimus

Study Results

Participant Flow

Recruitment Details	10 people enrolled; a total of 9 completed study

Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Period Title: Overall Study
STARTED	10
COMPLETED	9
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Overall Participants	10
Age (Count of Participants)
<=18 years	2 20%
Between 18 and 65 years	8 80%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	27
Sex: Female, Male (Count of Participants)
Female	3 30%
Male	7 70%
Region of Enrollment (participants) [Number]
United States	10 100%

Outcome Measures

1. Primary Outcome

Title	Radiographic Response
Description	To estimate the objective response rates to RAD001 in patients with NF2-related tumors including cranial nerve schwannomas, meningiomas and ependymomas. Radiographic response for study purposes = greater than or equal to 15% reduction in tumor volume in any of the target tumors (partial response). Complete disappearance of any of the target tumors = complete response. MRI of the brain and spine will be performed every 3 months. If an objective response (15% reduction in tumor volume compared to baseline) is observed in any target tumor or stable disease, drug will be continued.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Measure Participants	9
Measure Tumors	12
Number [participants]	0 0%

2. Secondary Outcome

Title	Audiologic Response
Description	Defined as improvement in speech discrimination score (SDS), defined as an improvement in the score above the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Audiologic worsening: decrease in SDS score below the 95% critical difference threshold, compared to baseline audiogram at initiation of treatment. Patients with vestibular schwannomas will receive baseline audiograms within 28 days before enrollments and subsequent audiograms at the time of each MRI.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Measure Participants	9
Number [participants]	0 0%

3. Primary Outcome

Title	Change in Tumor Size From Baseline
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
Measure Participants	9
Measure Tumors	12
Median (Full Range) [% of change in tumor size from baseline]	5.72

Adverse Events

Time Frame	Continuously throughout 1 year of study
Arm/Group Title	RAD001
Arm/Group Description	RAD001 taken orally continuously until disease progression or unacceptable toxicity, dosed according to age
All Cause Mortality
	RAD001
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	RAD001
	Affected / at Risk (%)	# Events
Total	10/10 (100%)
Blood and lymphatic system disorders
anemia	5/10 (50%)
Gastrointestinal disorders
constipation	1/10 (10%)
diarrhea	4/10 (40%)
mucositis oral	10/10 (100%)
nausea	1/10 (10%)
toothache	1/10 (10%)
vomiting	1/10 (10%)
General disorders
chills	1/10 (10%)
fatigue	6/10 (60%)
fever	1/10 (10%)
non-cardiac chest pain	1/10 (10%)
Infections and infestations
skin infection	1/10 (10%)
Injury, poisoning and procedural complications
bruising	1/10 (10%)
Investigations
alkaline phosphatase increased	2/10 (20%)
AST increased	3/10 (30%)
cholesterol high	7/10 (70%)
lymphocyte count decreased	5/10 (50%)
neutrophil count decreased	3/10 (30%)
platelet count decreased	6/10 (60%)
white blood cell decreased	4/10 (40%)
Metabolism and nutrition disorders
hyperglycemia	5/10 (50%)
hypernatremia	5/10 (50%)
hypertriglyceridemia	4/10 (40%)
hypoglycemia	1/10 (10%)
hyponatremia	1/10 (10%)
hypophosphatemia	2/10 (20%)
Musculoskeletal and connective tissue disorders
arthralgia	1/10 (10%)
muscle weakness- right sided	1/10 (10%)
neck pain	1/10 (10%)
pain (to bone; right clavicula)	1/10 (10%)
pain (to extremity; left 4th finger)	1/10 (10%)
pain (to right flank)	1/10 (10%)
Nervous system disorders
dysgeusia	1/10 (10%)
headache	6/10 (60%)
Psychiatric disorders
anxiety	1/10 (10%)
depression	1/10 (10%)
Reproductive system and breast disorders
azoospermia	1/10 (10%)
irregular menstruation	1/10 (10%)
Respiratory, thoracic and mediastinal disorders
cough	1/10 (10%)
dyspnea	1/10 (10%)
epistaxis	1/10 (10%)
nasal congestion	1/10 (10%)
Skin and subcutaneous tissue disorders
dry skin	3/10 (30%)
pruritis	4/10 (40%)
rash	5/10 (50%)
rash acneiform	1/10 (10%)
rash maculo-papular	1/10 (10%)
scalp pain	1/10 (10%)
Vascular disorders
hypertension	2/10 (20%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.