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

Primary Purpose

Neurofibromatosis 1, Child, Neurofibroma, Plexiform

Status
Active
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Trametinib
Sponsored by
Region Skane
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neurofibromatosis 1

Eligibility Criteria

1 Year - 17 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Skåne University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

single arm study

Arm Description

children treated with trametinib

Outcomes

Primary Outcome Measures

Remission of tumor volume ≥20%
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.
Remission of tumor volume ≥20%
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

Reversal of NF1-related PN elicited - VAS scale pain
Evaluated with monthly VAS pain scale from 8 years at enrolment. Monthly. 0-10 point scale. Descriptive. Analysis of pooled data after month 30.
Reversal of NF1-related PN elicited pain - Faces Pain Scale
Evaluated with monthly Faces Pain Scale from under 8 years at enrolment. Monthly. 0-10 scale. Descriptive. Analysis of pooled data after month 30.

Full Information

First Posted
November 5, 2018
Last Updated
March 28, 2023
Sponsor
Region Skane
Collaborators
Novartis
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1. Study Identification

Unique Protocol Identification Number
NCT03741101
Brief Title
Treatment of NF1-related Plexiform Neurofibroma With Trametinib
Acronym
plexifpc
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 10, 2019 (Actual)
Primary Completion Date
July 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Region Skane
Collaborators
Novartis

4. Oversight

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
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neurofibromatosis 1, Child, Neurofibroma, Plexiform

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
single arm study
Arm Type
Experimental
Arm Description
children treated with trametinib
Intervention Type
Drug
Intervention Name(s)
Trametinib
Other Intervention Name(s)
mekinist
Intervention Description
treatment
Primary Outcome Measure Information:
Title
Remission of tumor volume ≥20%
Description
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.
Time Frame
0 - 30 months.
Title
Remission of tumor volume ≥20%
Description
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".
Time Frame
0 - 18 months
Secondary Outcome Measure Information:
Title
Reversal of NF1-related PN elicited - VAS scale pain
Description
Evaluated with monthly VAS pain scale from 8 years at enrolment. Monthly. 0-10 point scale. Descriptive. Analysis of pooled data after month 30.
Time Frame
0 - 30 months.
Title
Reversal of NF1-related PN elicited pain - Faces Pain Scale
Description
Evaluated with monthly Faces Pain Scale from under 8 years at enrolment. Monthly. 0-10 scale. Descriptive. Analysis of pooled data after month 30.
Time Frame
0 - 30 months.
Other Pre-specified Outcome Measures:
Title
Cognitive performance. Exploratory. WISC V.
Description
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.
Time Frame
0-18 months.
Title
Cognitive performance. Exploratory. NEPSYII.
Description
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.
Time Frame
0-18 months.
Title
Cognitive performance. Exploratory. CPT3.
Description
Change in attention, pooled data after 18 months versus before/at enrolment (CPT-3); with p-value <0.05.
Time Frame
0-18 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Björn Sigurdsson
Organizational Affiliation
Skane University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Skåne University Hospital
City
Lund
ZIP/Postal Code
22241
Country
Sweden

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-001846-32
Description
clinical trial register EU

Learn more about this trial

Treatment of NF1-related Plexiform Neurofibroma With Trametinib

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