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Imatinib Mesylate and Mycophenolate Mofetil for Steroid-Refractory Sclerotic/Fibrotic cGVHD in Children

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ClinicalTrials.gov Identifier: NCT01898377
Recruitment Status : Active, not recruiting
First Posted : July 12, 2013
Last Update Posted : April 8, 2019
Sponsor:
Information provided by (Responsible Party):
Seoul National University Hospital

Brief Summary:
In this study we will combine mycophenolate mofetil and imatinib mesylate to treat steroid-refractory sclerotic/fibrotic type chronic graft-versus-host disease (GVHD) to see the response rate and to find the safety of combination.

Condition or disease Intervention/treatment Phase
Chronic Graft-versus-host Disease Drug: Imatinib mesylate, Mycophenolate mofetil Phase 2

Detailed Description:

Sclerotic/fibrotic type chronic GVHD is one of the most severe forms of the disease and is frequently refractory to standard treatment approaches. Imatinib mesylate, a tyrosine kinase inhibitor, has been shown to be effective in patients with sclerotic/fibrotic type chronic GVHD by strongly inhibiting both PDGF (Platelet-derived growth factor) and TGF-β (transforming growth factor-β) intracellular signaling, which is responsible for the expression of extracellular matrix genes.

Mycophenolate mofetil (MMF) is one of effective agent for the treatment of chronic graft-versus-host disease. MMF is rapidly absorbed after oral administration and hydrolyzed to the active metabolite, MPA (mycophenolic acid). MPA selectively inhibits inosine monophosphate dehydrogenase, blocking the pathway of purine synthesis in T and B lymphocytes. In this study we will combine MMF and imatinib mesylate to treat steroid-refractory sclerotic/fibrotic type chronic GVHD to see the response rate and to find the safety of combination.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-label, Multicenter Phase II Study of Combination Therapy of Imatinib Mesylate and Mycophenolate Mofetil in Children With Steroid-Refractory Sclerotic/Fibrotic Type Chronic Graft-versus-host Disease
Study Start Date : August 2013
Actual Primary Completion Date : July 2018
Estimated Study Completion Date : July 2019


Arm Intervention/treatment
Experimental: Imatinib mesylate, Mycophenolate mofetil

MMF 15-20mg/kg (Max 1 g) bid + Imatinib mesylate qd

  • Dose of imatinib : starting dose 260 mg/m2/d (Max. 400 mg)
  • Imatinib dose adjustment : Dose is adjusted according to the guidelines if there is serious adverse event, toxicity, or intolerance.
Drug: Imatinib mesylate, Mycophenolate mofetil
Other Name: Glivec, Cellcept




Primary Outcome Measures :
  1. Overall (complete and partial) response rate [ Time Frame: 1 year ]

    Response evaluation will be performed every 3 months during the treatment by comprehensive response criteria based on NIH criteria. The complete and partial response categories apply only to organs that have measurable and reversible GVHD-related abnormalities at baseline.

    • Complete response (CR): Resolution of all signs and symptoms of chronic GVHD
    • Partial response (PR) : Improvement (at least 1 clinical score reduction, see Appendix 2) in 1 or more organs of involvement and no evidence of worsening in any organ
    • Objective response (OR): Either CR or PR


Secondary Outcome Measures :
  1. Evaluate the safety profile of MMF plus imatinib mesylate [ Time Frame: 1 year ]

    All adverse events will be recorded on the "Adverse Events CRF" with the following information

    • Severity grade (NCI CTCAE ver. 4.0)
    • Relationship to the study drug
    • Duration (start and end dates or if continuing at final exam)
    • Whether it constitutes a serious adverse event (SAE)

  2. Evaluate the quality of life (QOL) [ Time Frame: 1 year ]
    The assessment of QOL will be performed at baseline and every 3 months till 1 year with Lee cGVHD Symptom Scale.

  3. Discontinuation of steroid [ Time Frame: 1 year ]
    • Based on the response during study period, investigators could modify the dosage of concomitant immunosuppressive agents in the same manner as corticosteroid.
    • The rate of discontinuation among patients and the dose change from baseline of each patient.

  4. Overall survival rate [ Time Frame: 1 year ]
    For survival outcome, Kaplan-Meier method will be used for estimation.



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Ages Eligible for Study:   up to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria

  • Patients must have a diagnosis of chronic GVHD with fibrotic/scleroderma-like features. This diagnosis can be made clinically or by histopathology.
  • Patients must have active disease with at least one of the following manifestations: skin sclerosis, symptomatic bronchiolitis obliterans, extensive lung fibrosis, pathologically demonstrated visceral fibrotic involvement of the gut.
  • Patients with corticosteroid refractory or dependant cGVHD are eligible. Steroid-refractory chronic GVHD is defined as chronic GVHD of sustained severity during the last full month during which the patients received the equivalent of prednisone 0.5 mg/kg or more per day or 1 mg/kg or more every other day.
  • Age under 21 years old

Exclusion criteria

  • Patients who have had chemotherapy, radiotherapy within 4 weeks prior to entering the study.
  • Patients who have not recovered from adverse events.
  • Prior treatment with imatinib mesylate or other tyrosine kinase inhibitor after the date of transplant.
  • Patients on pregnancy or lactating

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): NCT01898377


Locations
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Korea, Republic of
Seoul National University Children's Hospital
Seoul, Chongno-gu, Korea, Republic of
Sponsors and Collaborators
Seoul National University Hospital
Investigators
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Principal Investigator: Hyoung Jin Kang, MD, Ph.D Seoul National University Children's Hospital

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Responsible Party: Seoul National University Hospital
ClinicalTrials.gov Identifier: NCT01898377     History of Changes
Other Study ID Numbers: SNUCH-1301
First Posted: July 12, 2013    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Keywords provided by Seoul National University Hospital:
Children
Chronic graft-versus-host disease
Additional relevant MeSH terms:
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Mycophenolic Acid
Graft vs Host Disease
Immune System Diseases
Imatinib Mesylate
Antibiotics, Antineoplastic
Antineoplastic Agents
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors