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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01412892
First received: August 8, 2011
Last updated: February 19, 2013
Last verified: February 2013
  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: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Radiographic response assessed by MRI analysis [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Pain [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Deficiency [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • Quality of life [ Time Frame: At 2 years ] [ Designated as safety issue: No ]
  • adverse events [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
  • laboratory evaluations [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
  • measurement of vital signs [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
  • performance of physical examinations [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]
  • all concomitant medications and therapies [ Time Frame: At 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 32
Study Start Date: April 2011
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2014 (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.
Other Name: RAD001: Everolimus

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: 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
Study First Received: August 8, 2011
Last Updated: February 19, 2013
Health Authority: France: Ministry of Health

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

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

ClinicalTrials.gov processed this record on October 21, 2014