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Study of Imatinib Mesylate in Neurofibromatosis Type I Patients Aged 2 to 21 With Plexiform Neurofibromas

Primary Purpose

Plexiform Neurofibromas

Status
Terminated
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Imatinib Mesylate
Sponsored by
St. Justine's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Plexiform Neurofibromas

Eligibility Criteria

2 Years - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Age Greater than or equal to 2 years and up to 21 years of age at time of study enrolment
  2. Diagnosis Patients with NF1 and an inoperable plexiform NFs that has the potential to cause significant morbidity.
  3. Patients must have measurable disease by magnetic resonance imaging (MRI) and progressive plexiform neurofibroma(s) with or without clinical symptoms.

    • Patients must have a recent FDG-PET scan imaging study done in the last 3 months before being offered participation to the study
    • Surgery/Residual disease: Patients are only eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery. Evidence of recurrent or progressive disease is NOT necessary. Patients must be at least 21 days from surgery, if performed, prior to receiving their first dose of study drug
  4. Performance level Patients must have a Karnofsky of > 70% or Lansky of >50% and a life expectancy of > 6 months.
  5. Previous use of imatinib is permitted if there was no progressive disease during treatment.
  6. Prior therapy Patients must be at least 28 days without any treatment before enrolment in this study.
  7. Patient is free of another primary malignancy except if the other primary malignancy neither currently clinically significant nor requiring active intervention.
  8. Organ function requirement

    • Creatinine < 1.5 x upper limit of normal (ULN)
    • Total bilirubin < 1.5 x ULN and SGOT and SGPT < 2.5 x ULN
    • ANC > 1.5 x 109/L and Platelets > 100 x 109/L
  9. Reproductive potential Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

Exclusion Criteria:

  1. Patient has received any other investigational agents within 28 days of first day of study drug dosing.
  2. Patient with rapidly progressing disease may be enrolled before the 28 days period. In these cases, only the study chair can take this decision.
  3. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria.
  4. Female patients who are pregnant or breast-feeding.
  5. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection)
  6. Patient has a known brain metastasis. Non-specific central nervous system (CNS) changes on MRI/CT characteristic of NF1 are allowed, but not known CNS malignancies.
  7. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis).
  8. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
  9. Patient received chemotherapy within 4 weeks prior to study entry.
  10. Patient previously received radiotherapy to greater than or equal to 25% of the bone marrow within 24 months.
  11. Patient had a major surgery within 2 weeks prior to study entry.
  12. Patient with any significant history of non-compliance to medical regimens.
  13. Patients who have or anticipate receiving permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth, body piercings), which their physicians believe will interfere with the MRI.

Sites / Locations

  • CHU Sainte-Justine

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Imatinib Mesylate

Arm Description

Imatinib Mesylate at 110 mg/m2 up to 440mg/m2 PO per day for twelve months taken in one morning dose (if dose is less than 200 mg/day) or two doses (morning and evening)

Outcomes

Primary Outcome Measures

Demonstrate the clinical benefit of imatinib in a pediatric patient population with progressing and metabolically active plexiform NFs
Time to tumor progression as assessed by volumetric MRI and FDG-PETScan analysis at baseline, after 3, 6, 9, and 12 months on therapy.

Secondary Outcome Measures

Changes in NF1 biomarkers after treatment with imatinib
Patients on imatinib will have blood samples and urine taken at baseline and every 3 months until treatment completion or until disease progression. Mastocyte activation biomarkers will be monitored and evaluated as potential disease state indicators.

Full Information

First Posted
June 25, 2014
Last Updated
April 4, 2019
Sponsor
St. Justine's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02177825
Brief Title
Study of Imatinib Mesylate in Neurofibromatosis Type I Patients Aged 2 to 21 With Plexiform Neurofibromas
Official Title
Phase II Study of Imatinib Mesylate in Neurofibromatosis Type I Patients Aged 2 to 21 With Plexiform Neurofibromas
Study Type
Interventional

2. Study Status

Record Verification Date
April 2019
Overall Recruitment Status
Terminated
Why Stopped
Slow accrual 5 patients out of 25 expected. Primary objectives could not be met without recruiting more patients.
Study Start Date
June 2014 (undefined)
Primary Completion Date
March 1, 2019 (Actual)
Study Completion Date
March 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
St. Justine's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase II trial will test the hypothesis that inhibition of c-kit signalling pathways in pediatric patients with Neurofibromatosis Type I(NF-1) and progressing plexiform neurofibroma will result in objective reduction and/or inhibition of plexiform neurofibromas progression. This will be a Phase II study of imatinib mesylate given orally. Patients with stable or responding disease may receive the drug for a period not exceeding one year.
Detailed Description
Clinical objectives Demonstrate the clinical benefit of imatinib in a pediatric patient population with progressing and metabolically active plexiform neurofibromas (NF) Demonstrate the need or not to pursue treatment for more than a year in responders to imatinib Biological studies objectives Identify biological markers of plexiform neurofibroma progression and response to treatment Identify biological markers of mast cell responses to imatinib, given that mast cells are required for tumorigenesis and are a target for imatinib Imaging studies objectives Using 18-Fluorodeoxyglucose-positron Emission Tomography (FDG PET/CT): Identify imaging characteristics of progressing plexiform neurofibromas Assess the role of F18-FDG PET/CT in comparison with CT/MRI to evaluate response to imatinib ¸ Pharmacological study Evaluate trough plasma levels of imatinib and its active metabolite (NDMIL N-desmethyl imatinib) achieved in this pediatric population Identify potential correlation between imatinib (and NDMI) trough levels achieved and clinical response

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Plexiform Neurofibromas

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Imatinib Mesylate
Arm Type
Experimental
Arm Description
Imatinib Mesylate at 110 mg/m2 up to 440mg/m2 PO per day for twelve months taken in one morning dose (if dose is less than 200 mg/day) or two doses (morning and evening)
Intervention Type
Drug
Intervention Name(s)
Imatinib Mesylate
Other Intervention Name(s)
Imatinib
Intervention Description
oral administration
Primary Outcome Measure Information:
Title
Demonstrate the clinical benefit of imatinib in a pediatric patient population with progressing and metabolically active plexiform NFs
Description
Time to tumor progression as assessed by volumetric MRI and FDG-PETScan analysis at baseline, after 3, 6, 9, and 12 months on therapy.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Changes in NF1 biomarkers after treatment with imatinib
Description
Patients on imatinib will have blood samples and urine taken at baseline and every 3 months until treatment completion or until disease progression. Mastocyte activation biomarkers will be monitored and evaluated as potential disease state indicators.
Time Frame
12 months
Other Pre-specified Outcome Measures:
Title
Evaluate trough plasma levels of imatinib and its active metabolite (NDMIL N-desmethyl imatinib) achieved in this pediatric population
Description
We will evaluate trough plasma levels of imatinib achieved in this patient population at 3, 6, 9 and 12 month and correlate it with response to treatment
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age Greater than or equal to 2 years and up to 21 years of age at time of study enrolment Diagnosis Patients with NF1 and an inoperable plexiform NFs that has the potential to cause significant morbidity. Patients must have measurable disease by magnetic resonance imaging (MRI) and progressive plexiform neurofibroma(s) with or without clinical symptoms. Patients must have a recent FDG-PET scan imaging study done in the last 3 months before being offered participation to the study Surgery/Residual disease: Patients are only eligible if complete tumor resection is not feasible, or if a patient with a surgical option refuses surgery. Evidence of recurrent or progressive disease is NOT necessary. Patients must be at least 21 days from surgery, if performed, prior to receiving their first dose of study drug Performance level Patients must have a Karnofsky of > 70% or Lansky of >50% and a life expectancy of > 6 months. Previous use of imatinib is permitted if there was no progressive disease during treatment. Prior therapy Patients must be at least 28 days without any treatment before enrolment in this study. Patient is free of another primary malignancy except if the other primary malignancy neither currently clinically significant nor requiring active intervention. Organ function requirement Creatinine < 1.5 x upper limit of normal (ULN) Total bilirubin < 1.5 x ULN and SGOT and SGPT < 2.5 x ULN ANC > 1.5 x 109/L and Platelets > 100 x 109/L Reproductive potential Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing. Male and female patients of reproductive potential must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug. Exclusion Criteria: Patient has received any other investigational agents within 28 days of first day of study drug dosing. Patient with rapidly progressing disease may be enrolled before the 28 days period. In these cases, only the study chair can take this decision. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. Female patients who are pregnant or breast-feeding. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection) Patient has a known brain metastasis. Non-specific central nervous system (CNS) changes on MRI/CT characteristic of NF1 are allowed, but not known CNS malignancies. Patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). Patient has a known diagnosis of human immunodeficiency virus (HIV) infection. Patient received chemotherapy within 4 weeks prior to study entry. Patient previously received radiotherapy to greater than or equal to 25% of the bone marrow within 24 months. Patient had a major surgery within 2 weeks prior to study entry. Patient with any significant history of non-compliance to medical regimens. Patients who have or anticipate receiving permanent (or semi-permanent) metallic structures attached to their body. (e.g., braces on teeth, body piercings), which their physicians believe will interfere with the MRI.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sébastien Perreault, MD/FRCPC
Organizational Affiliation
St. Justine's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
CHU Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada

12. IPD Sharing Statement

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Study of Imatinib Mesylate in Neurofibromatosis Type I Patients Aged 2 to 21 With Plexiform Neurofibromas

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