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Treatment of NF1-related Plexiform Neurofibroma With Trametinib (plexifpc)

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ClinicalTrials.gov Identifier: NCT03741101
Recruitment Status : Recruiting
First Posted : November 14, 2018
Last Update Posted : December 24, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
Region Skane

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.


Condition or disease Intervention/treatment Phase
Neurofibromatosis 1 Child Neurofibroma, Plexiform Drug: Trametinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : January 2019
Estimated Primary Completion Date : July 2022
Estimated Study Completion Date : July 2022


Arm Intervention/treatment
Experimental: single arm study
children treated with trametinib
Drug: Trametinib
treatment
Other Name: mekinist




Primary Outcome Measures :
  1. Remission of tumor volume ≥20% [ Time Frame: 0 - 30 months. ]
    Final and primary analysis of primary outcome measure - of pooled data at 30 months (end of study) with volumetric mri of tumor volume versus volume at enrolment.

  2. Remission of tumor volume ≥20% [ Time Frame: 0 - 18 months ]
    Interim analysis of pooled data at 18 months with volumetric mri of tumor volume versus volume at enrolment. This is an interim analysis of primary outcome and not primary analysis of primary outcome".


Secondary Outcome Measures :
  1. Reversal of NF1-related PN elicited - VAS scale pain [ Time Frame: 0 - 30 months. ]
    Evaluated with monthly VAS pain scale from 8 years at enrolment. Monthly. 0-10 point scale. Descriptive. Analysis of pooled data after month 30.

  2. Reversal of NF1-related PN elicited pain - Faces Pain Scale [ Time Frame: 0 - 30 months. ]
    Evaluated with monthly Faces Pain Scale from under 8 years at enrolment. Monthly. 0-10 scale. Descriptive. Analysis of pooled data after month 30.


Other Outcome Measures:
  1. Cognitive performance. Exploratory. WISC V. [ Time Frame: 0-18 months. ]
    Change of full scale IQ or primary indexes of WISC V. Pooled data after 18 months versus before/at enrolment; with p-value <0.05.

  2. Cognitive performance. Exploratory. NEPSYII. [ Time Frame: 0-18 months. ]
    Change of Learning and Memory functions and visuospatial functions, pooled data after 18 months versus before/at enrolment (selected test from NEPSYII,; with p-value <0.05.

  3. Cognitive performance. Exploratory. CPT3. [ Time Frame: 0-18 months. ]
    Change in attention, pooled data after 18 months versus before/at enrolment (CPT-3); with p-value <0.05.



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Ages Eligible for Study:   1 Year to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03741101


Contacts
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Contact: Björn Sigurdsson, MD, PI 0046708253552 bjorn.sigurdsson@skane.se
Contact: Erik A Eklund, MD, PhD 0046730785917 erik.eklund@skane.se

Locations
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Sweden
Skåne University Hospital Recruiting
Lund, Sweden, 22241
Contact: Björn Sigurdsson, MD    0046708253552    bjorn.sigurdsson@skane.se   
Contact: Erik A Eklund, MD, PhD    0046730785917    erik.eklund@skane.se   
Sponsors and Collaborators
Region Skane
Novartis
Investigators
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Principal Investigator: Björn Sigurdsson Skane University Hospital

Additional Information:
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Responsible Party: Region Skane
ClinicalTrials.gov Identifier: NCT03741101     History of Changes
Other Study ID Numbers: BUS2018-1
2018-001846-32 ( EudraCT Number )
First Posted: November 14, 2018    Key Record Dates
Last Update Posted: December 24, 2018
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Neurofibromatoses
Neurofibromatosis 1
Neurofibroma
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 Diseases
Neuromuscular Diseases
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Trametinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action