Treatment of NF1-related Plexiform Neurofibroma With Trametinib

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Brief Title

Treatment of NF1-related Plexiform Neurofibroma With Trametinib

Official Title

Treatment of NF1-related Plexiform Neurofibroma With Trametinib; a Single Arm, Open-label Trial With the Goals of Volumetric Partial Remission and Pain Relief

Brief Summary

      This trial, Treatment of NF1-related plexiform neurofibroma with trametinib; a single
      arm,open-label study with the goals of volumetric partial remission and pain relief (EudraCT
      2018-001846-32, Sponsor protocol number BUS2018-1, related Novartis reference number
      CTMT212ASE01T) is a pediatric clinical trial that investigates the potential use of the drug
      trametinib (Mekinist®) as treatment for symptomatic or likely to become symptomatic
      NF1-related plexiform neurofibromas (PN) in children between 1 year and 17 year and 11 months
      of age.

      Trametinib is orally administered qd at 0.025 mg/kg up to a maximum of 2 mg from six years of
      age and 0.032mg/kilo up to 5 years of age, provided either as tablets or as oral solution. It
      is manufactured and distributed by Novartis under the trade name Mekinist®.

      The primary endpoint is remission of tumor volume ≥20%, evaluated using volumetric MRI at 18
      and 30 months of treatment.

      The secondary endpoint is reversal of pain from NF1-related PN, evaluated monthly with
      agespecific pain scales; VAS scale (from 8 years) or Faces Pain Scale (from 3 to 8 years).

      As an exploratory measure, the potential effects of the treatment on the cognitive function
      will be assessed using well-established tests such as WISC-V (age range 6:0 - 16:11),
      NEPSY-II (age range 3:0-16:11), and CPT-3 (age range 8:0 - adult).

      Cognitive dysfunction is well described in patients with NF1, and the MAPK/ERK-pathway has
      been indicated to be involved in cognition.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Remission of tumor volume ≥20%

Secondary Outcome

 Reversal of NF1-related PN elicited - VAS scale pain

Condition

Neurofibromatosis 1

Intervention

Trametinib

Study Arms / Comparison Groups

 single arm study
Description:  children treated with trametinib

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

15

Start Date

June 10, 2019

Completion Date

July 2022

Primary Completion Date

July 2022

Eligibility Criteria

        Inclusion Criteria

          -  NF1-related PN with severe - or with high suspicion of becoming severe -
             manifestations

          -  Informed consent provided

          -  Age 1:0-17:11

        Exclusion Criteria

          -  NF1-related PN does not fulfill characteristics for acceptable volumetric MRI
             assessments as outlined under Criteria for volumetric assessment.

          -  Lactating or pregnant females. Sexually active females, who do not (agree to) use safe
             contraception or adhere to regular controls during study. Sexually active males who do
             not (agree to) use a condom during coitus.

          -  A history of other malignancies than classic NF1-related WHO grade 1 tumors (i.e. PN
             or optic pathway glioma).

          -  A history of NF-1 related cerebral vascular anomalies (such as Moyamoya).

          -  Active pharmaceutical therapy for optic pathway malignancy/ies.

          -  Any medication for treatment of left ventricular systolic dysfunction.

          -  Use of any investigational drug within 30 days of the first dose of this study
             treatment.

          -  Impaired renal function (GFR under 45 ml/min/1,73m2 - It is only required to analyze
             eGFR if creatine is above institutional reference value for corresponding age group).

          -  A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study drug or excipients that contraindicate their
             participation.

          -  Active liver or biliary disease or moderate or severe liver impairment. If there are
             signs of liver disease (such as an increased prothrombin time or elevated
             transaminases),grading of the liver impairment has to be done in consultation with a
             hepatologist, since there is no universal definition.

          -  A history of hepatic sinusoid obstructive syndrome (venoocclusive disease) within the
             last 3 months.

          -  A history of heparin-induced thrombocytopenia.

          -  A history of interstitial lung disease or pneumonitis.

          -  A history of retinal vein occlusion (RVO).

          -  A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects
             with a confirmed cleared HBV and HCV infection may be enrolled.

          -  Presence of a condition that will interfere significantly with the absorption of
             drugs.

          -  Evidence of cardiovascular risk, such as left ventricular ejection fraction (LVEF)
             below the lower limit of normal (LLN), a corrected QT-interval (Qtc) >480
             milliseconds, clinically significant uncontrolled arrhythmia, congestive heart
             failure, or acute coronary syndrome or history thereof.
      

Gender

All

Ages

1 Year - 17 Years

Accepts Healthy Volunteers

No

Contacts

Björn Sigurdsson, 0046708253552, [email protected]

Location Countries

Sweden

Location Countries

Sweden

Administrative Informations


NCT ID

NCT03741101

Organization ID

BUS2018-1

Secondary IDs

2018-001846-32

Responsible Party

Sponsor

Study Sponsor

Region Skane

Collaborators

 Novartis

Study Sponsor

Björn Sigurdsson, Principal Investigator, Skane University Hospital


Verification Date

March 2021