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Use of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas (NFitor)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01412892
First Posted: August 9, 2011
Last Update Posted: November 14, 2014
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Novartis
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
  Purpose

Background:

Patients with the genetic disorder neurofibromatosis Type 1 (NF1) are at increased risk of developing tumors of the central and peripheral nervous system. These include plexiform neurofibromas. The conventional treatment of these internal plexiform neurofibromas is surgery. This surgery can be possible on a single and limited tumor. On the other hand these tumors are often surgically intractable due to their multiplicity and their infiltrating characteristics Increased activity of mammalian target of rapamycin(mTOR) protein is seen in neurofibromas. mTOR inhibitor rapamycin , or its derivatives such as everolimus may slow or stop tumor growth in patients with NF1.

Objectives:

Primary objectives To determine whether everolimus has an effect on the volume of surgically intractable and life-threatening internal plexiform neurofibromas in patients with neurofibromatosis 1.

Secondary objectives To determine whether everolimus has an effect on the number and the volume of cutaneous neurofibromas; to determine whether everolimus modify the signaling pathways in cutaneous neurofibromas.

Eligibility:

- Adults with neurofibromatosis type 1 with at least one internal plexiform neurofibroma, life-threatening or causing significant morbidity through compression of organs. This or these internal plexiform neurofibroma(s) should be intractable by surgery.

Design:

An open-label, single arm, non-randomized, single stage phase IIa study. Baseline phase: Baseline evaluations will be performed within 2 weeks, and up to a maximum of 4 weeks for specific exams, before the first dose of study drug.

Treatment phase/duration of treatment: All patients will be treated with RAD001 10 mg p.o daily dose for one year except in case of unacceptable toxicity, death, or discontinuation from the study for any other reason.

Follow-up phase: All patients will have two follow-up visits scheduled at 18 and 24 months after the first dose of the study drug to follow for adverse events (AEs) and serious adverse events (SAEs) that may have occurred after discontinuation from the study and for internal plexiform neurofibromas assessment.

Radiological review: All Magnetic Resonance Imaging (MRIs) obtained at baseline, during the treatment period and the follow-up period will be reviewed by the Neuroradiologist of the study.


Condition Intervention Phase
Neurofibromatosis Type 1 Plexiform Neurofibroma Neurofibromatoses Drug: RAD001: Everolimus Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Single Arm, Multicenter Phase II a Trial of RAD001 as Monotherapy in the Treatment of Neurofibromatosis 1 Related Internal Plexiform Neurofibromas That Cannot be Removed by Surgery

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • Radiographic response assessed by MRI analysis [ Time Frame: after 1 year of treatment ]

Secondary Outcome Measures:
  • Radiographic response assessed by MRI analysis [ Time Frame: At 2 years ]
  • Overall survival [ Time Frame: At 2 years ]
  • Pain [ Time Frame: At 2 years ]
  • Deficiency [ Time Frame: At 2 years ]
  • Quality of life [ Time Frame: At 2 years ]
  • adverse events [ Time Frame: At 2 years ]
  • laboratory evaluations [ Time Frame: At 2 years ]
  • measurement of vital signs [ Time Frame: At 2 years ]
  • performance of physical examinations [ Time Frame: At 2 years ]
  • all concomitant medications and therapies [ Time Frame: At 2 years ]

Enrollment: 30
Study Start Date: April 2011
Study Completion Date: October 2014
Primary Completion Date: October 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Everolimus
RAD001: Everolimus
Drug: RAD001: Everolimus
10 mg of RAD001 will be self-administered orally once daily continuously for one year or until unacceptable toxicity or discontinuation from the study from any other reason.

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Clinical diagnosis of NF1, according to NIH criteria, with internal plexiform neurofibroma (PN) and at least 1 of criteria for NF1:

    6 or more café-au-lait spots Freckling in the axilla or groin Optic glioma 2 or more Lisch nodules Distinctive bony lesion

    1-degree relative with NF1

  • At least 1 inoperable PN(s) that has/have the potential to cause significant morbidity: Paravertebral lesions that could compromise the spinal cord Head and neck lesions that could compromise the airway or great vessels Brachial or lumbar plexus lesions that could cause nerve compression and loss of function Lesions that could result in major deformity (e.g., orbital lesions) or significant cosmetic problems Lesions of the extremity that cause limb hypertrophy or loss of function Painful lesions
  • Complete resection of a PN with acceptable morbidity is not feasible OR patient refuses surgery OR the number of PNs leads to not feasible surgery according to the steering committee's site
  • Measurable PN amenable to volumetric MRI analysis using fusion of images
  • Measurable lesion (at least 3 cm in one dimension)
  • Karnofsky >70%
  • 18≤ Age ≤60
  • absolute neutrophil count (ANC) ≥1.5x109/L, Platelets ≥100x109/L, Hb >9g/dL
  • bilirubin: ≤1.5xULN, ALT and AST ≤2.5xULN unless evident Gilbert disease (amendment n°2). For patients with known liver metastases: AST and ALT ≤ 5xULN
  • Creatinine ≤ 1.5xULN
  • Life expectancy ≥ 2 years
  • Cholesterol ≤300 mg/dL or ≤7.75 mmol/L and triglycerides ≤ 2.5x ULN
  • Women of childbearing potential must have had a negative serum pregnancy test within 7 days and a negative urine pregnancy test within 72 hours prior to the administration of RAD001 start and must use an effective birth control method.
  • Men should use condoms and their partner(s) use an effective birth control method
  • A written informed consent obtained

Exclusion Criteria:

Patients who/with:

  • have previously received mTOR inhibitors
  • a known hypersensitivity to RAD001 or other rapamycin or to its excipients
  • receiving chronic systemic treatment with corticosteroids or another immunosuppressive agent. (Dose equivalent to 10 mg/day of methylprednisone), topical steroids or organotherapy for bilateral adrenalectomy are acceptable
  • a known history of HIV seropositivity
  • acute viral hepatitis
  • autoimmune hepatitis
  • with an active, bleeding diathesis. Patients may use coumadin or heparin preparations
  • have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation
  • have a history of another primary malignancy ≤3 years, with the exception of non-melanoma skin cancer and carcinoma in situ of the uterine cervix
  • Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Oral contraceptives are not acceptable alone
  • a contraindication to MRI
  • are using other investigational agents or who had received investigational drugs ≤ 4 weeks prior to study treatment start
  • unwilling or unable to comply with the protocol
  • not affiliated to health system
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01412892


Locations
France
Henri Mondor Hospital
Creteil, France, 94010
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Novartis
Investigators
Principal Investigator: Pierre Wolkenstein, MD, PhD Assistance Publique - Hôpitaux de Paris
  More Information

Publications:
Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01412892     History of Changes
Other Study ID Numbers: P090502
2010-023137-34 ( EudraCT Number )
First Submitted: August 8, 2011
First Posted: August 9, 2011
Last Update Posted: November 14, 2014
Last Verified: November 2014

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Neurofibromatosis type 1
Everolimus
Plexiform neurofibromas
Rapamycin

Additional relevant MeSH terms:
Neurofibromatoses
Neurofibroma
Neurofibromatosis 1
Neurofibroma, Plexiform
Nerve Sheath Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplastic Syndromes, Hereditary
Neurocutaneous Syndromes
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Peripheral Nervous System Diseases
Neuromuscular Diseases
Everolimus
Sirolimus
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents