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

NCT01412892 | Completed Phase 2 DMC

• 2 other identifiers: P0905022010-023137-34
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Neurofibromatosis Type 1; Plexiform Neurofibroma; Neurofibromatoses

Keywords

Neurofibromatosis type 1; Everolimus; Plexiform neurofibromas; Rapamycin

Outcome Measures

Primary Outcomes (1)

• Radiographic response assessed by MRI analysis

  after 1 year of treatment

Secondary Outcomes (10)

• Radiographic response assessed by MRI analysis

  At 2 years

• Overall survival

  At 2 years

• Pain

  At 2 years

• Deficiency

  At 2 years

• Quality of life

  At 2 years

Study Arms (1)

Everolimus

EXPERIMENTAL

RAD001: Everolimus

Drug: RAD001: Everolimus

Interventions

RAD001: Everolimus DRUG

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.

Everolimus

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Clinical diagnosis of NF1, according to NIH criteria, with internal plexiform neurofibroma (PN) and at least 1 of criteria for NF1:
• or more café-au-lait spots Freckling in the axilla or groin Optic glioma 2 or more Lisch nodules Distinctive bony lesion
• 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%
• ≤ 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Novartis: collaborator

Study Sites (1)

Henri Mondor Hospital

Créteil, 94010, France

Location

Related Publications (2)

• Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008 Jan 10;358(2):140-51. doi: 10.1056/NEJMoa063564.

  PMID: 18184959 BACKGROUND

• Zehou O, Ferkal S, Brugieres P, Barbarot S, Bastuji-Garin S, Combemale P, Valeyrie-Allanore L, Sbidian E, Wolkenstein P. Absence of Efficacy of Everolimus in Neurofibromatosis 1-Related Plexiform Neurofibromas: Results from a Phase 2a Trial. J Invest Dermatol. 2019 Mar;139(3):718-720. doi: 10.1016/j.jid.2018.09.016. Epub 2018 Oct 16. No abstract available.

  PMID: 30339775 DERIVED

MeSH Terms

Conditions

Neurofibromatosis 1; Neurofibroma, Plexiform; Neurofibromatoses

Condition Hierarchy (Ancestors)

Neurofibroma; 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; Peripheral Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Peripheral Nervous System Neoplasms; Nervous System Neoplasms

Study Officials

• Pierre Wolkenstein, MD, PhD

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 8, 2011
• First Posted: August 9, 2011
• Study Start: April 1, 2011
• Primary Completion: October 1, 2013
• Study Completion: October 1, 2014
• Last Updated: November 14, 2014

Record last verified: 2014-11

Locations

FR (1)