Trial record 1 of 10 for:    imatinib gvhd
Previous Study | Return to List | Next Study

Imatinib Mesylate to Treat Skin Changes in Patients With Chronic Graft-Versus-Host Disease

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Edward Cowen, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00702689
First received: June 19, 2008
Last updated: November 4, 2013
Last verified: November 2013
  Purpose

Background:

Chronic graft-versus-host disease (GVHD) is a common complication of stem cell transplant, resulting from the donor's immune cells attacking the cells of the body of the recipient. One effect of GVHD is fibrosis (scarring) of the skin that can lead to impaired function, decreased quality of life and increased risk of death. This is known as sclerotic skin changes of GVHD, or sclerodermatous graft versus host disease (ScGVHD).

Imatinib mesylate (Gleevec) is a drug that has been approved by the Food and Drug Administration to treat cancer in humans and fibrosing conditions in animals.

Objectives:

To see if imatinib mesylate can improve ScGVHD and evaluate its effect on other GVHD symptoms

To assess the side effects of imatinib mesylate in patients with GVHD

To evaluate blood, body fluids and tissue samples in patients to try to better understand the biology of ScGVHD

Eligibility:

Patients 4 years of age and older with ScGVHD

Design:

Initial treatment: Participants take imatinib mesylate tablets once a day for up to 6 months, as long as their GVHD does not get worse and they do not develop unacceptable side effects of the drug.

Evaluations: Participants are evaluated at 1, 3 and 6 months at the National Institutes of Health (NIH) Clinical Center with procedures that may include the following:

Medical history and physical examination

Blood and urine tests

Lung function test

Skin biopsy

Magnetic resonance imaging (MRI) scan

Specialty consultations (e.g., physical or rehabilitative therapy, dentist, eye doctor, dermatologist)

Electrocardiogram (EKG)

Echocardiogram (ultrasound test of the heart)

Muga scan (nuclear medicine test of the heart)

Quality-of-life questionnaires

Apheresis (procedure for collecting quantities of white blood cells)

Office visits with local physician once a week for 1 month, then once every 2 weeks for 5 months

Followup visits at National Institutes of Health (NIH) every 6 months for 1 year

Continuing treatment: Patients who improve continue to receive imatinib mesylate for up to 6 months after their best response and are followed for up to 2 years. Patients who continue to respond or who become worse after stopping treatment may receive additional treatment for up to 2 years.


Condition Intervention Phase
Sclerotic Graft Versus Host Disease
Imatinib Mesylate
Drug: Gleevec, STI571(Imatinib Mesylate)
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of Imatinib Mesylate in Children and Adults With Sclerotic Skin Changes of Chronic Graft-Versus-Host Disease

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Percent Change in Absolute Range of Motion (ROM) From Baseline to 6 Months [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    A change in ROM is 25% or greater from baseline. A partial response required improvement in 25% or more in ROM. Progression required 25% or greater loss of ROM.Patients with negative values in the Table are those who lost ROM.


Secondary Outcome Measures:
  • Number of Participants With Adverse Events [ Time Frame: 41 months, 27 days ] [ Designated as safety issue: Yes ]
    Here is the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.


Enrollment: 20
Study Start Date: May 2008
Study Completion Date: July 2013
Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Imatinib mesylate in patients with cGVHD

Cohort 1 - Pts 1-8:Adults: 400mg imatinib mesylate daily; Children: 260mg/m^2 daily (400mg maximum), followed by dose de-escalation for adverse events.

Cohort 2 - Pts 9-20:Adults - 100 mg oral dose daily (increase to 200 mg daily after 28 days if well tolerated). Children - 65 mg/m^2 oral dose daily (increase to 130 mg/m^2 daily after 28 days if well tolerated)

Drug: Gleevec, STI571(Imatinib Mesylate)

Cohort 1 - Pts 1-8:Adults: 400mg imatinib mesylate daily; Children: 260mg/m^2 daily (400mg maximum), followed by dose de-escalation for adverse events.

Cohort 2 - Pts 9-20:Adults - 100 mg oral dose daily (increase to 200 mg daily after 28 days if well tolerated). Children - 65 mg/m^2 oral dose daily (increase to 130 mg/m^2 daily after 28 days if well tolerated)

Other Names:
  • Gleevec
  • ST1571

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   4 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Sclerodermatous graft versus host disease (ScGVHD) manifesting after at least 100 days following allogeneic hematopoietic stem cell transplantation is considered diagnostic for chronic graft versus host disease (cGVHD) according to National Institutes of Health (NIH) cGVHD Consensus Statement diagnostic criteria.

This diagnosis can be made clinically or by histopathology. The diagnosis must be confirmed by the principal investigator (PI), or lead associate investigator (LAI).

Skin biopsies will be reviewed by the National Cancer Institute (NCI) Laboratory of Pathology to confirm the diagnosis of ScGVHD.

  • Patients must have measurable limitation in range of motion, defined as ScGVHD with or without fasciitis, restricting range of motion (ROM) of at least one joint with a minimum deficit of 25 percent.
  • Prior therapy: Patients must have cGVHD refractory to at least one treatment regimen for cGVHD.

One prior regimen must have included systemic corticosteroids at the equivalent prednisone dosing of 1mg/kg/day times 14 days.

Patients in whom calcineurin inhibitors or corticosteroids are medically contraindicated may also be eligible for enrollment.

Patients who have had stabilization of disease on calcineurin inhibitors or steroids, but in whom these medications cannot be tapered without disease flare are also eligible.

Patient must be on stable or tapering immunosuppressive regimen for at least one month.

  • Age: 4 years of age or older at the time of enrollment. Lower age limit set by lower established age limit norms of ROM scores for measurement criteria.
  • Life expectancy of greater than 6 months.
  • Karnofsky greater than or equal to 60 percent.
  • Patients must be platelet transfusion and growth factor independent at the time of study entry.

Patients must have adequate organ and marrow function as defined below. Patients with Gilbert syndrome are excluded from the requirement of a normal bilirubin.

(Gilbert syndrome is found in 3-10 percent of the general population, and is characterized by mild, chronic unconjugated hyperbilirubinemia in the absence of liver disease or overt hemolysis).

  • absolute neutrophil count greater than or equal to 1,000/mcL
  • platelets greater than or equal to 50,000/mcL
  • total bilirubin less than 3 times upper limit of normal
  • aspartate aminotransferase (AST)serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)serum glutamic pyruvic transaminase (SGPT) less than 5 times upper limit of normal
  • creatinine age-adjusted within normal limits

OR

  • creatinine clearance greater than 20mL/min/1.73 m^2 for adults and pediatric patients with body surface area (BSA) greater than 0.97 m^2 with creatinine levels above institutional normals and greater than or equal to 40 mL/min 1.73 m^2 for pediatric patients with BSA less than 0.97 m^2.
  • Age less than 5 years old Maximum Serum Creatinine 0.8 mg/dL
  • Age 5 or less than 10 years old Maximum Serum Creatinine 1.0 mg/dL
  • Age 10 or less than 15 years old Maximum Serum Creatinine 1.2 mg/dL
  • Age 15 years old or greater Maximum Serum Creatinine 1.5 mg/dL
  • Normal cardiac function for age as determined by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) (normal left ventricular (LV) function as measured by ejection fraction or shortening fraction).
  • The effects of imatinib mesylate on the developing human fetus at the recommended therapeutic dose are unknown.

For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for six months following completion of therapy.

Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

  • Ability to understand and the willingness to sign a written informed consent document.

All patients or their legal guardian (for patients less than 18 years old) must sign an institutional review board (IRB) approved document of informed consent (chronic graft versus host disease (cGVHD) natural history or any National Cancer Institute (NCI) protocol allowing for screening procedures) prior to performing studies to determine patient eligibility.

After confirmation of patient eligibility all patients or their legal guardian must sign the protocol-specific informed consent.

Pediatric patients will be included in age appropriate discussions and age appropriate assent will be obtained in accordance with National Institutes of Health (NIH) guidelines.

  • Durable Power of Attorney (DPA): All patients 18 years of age at the time of enrollment will be offered the opportunity to assign DPA so that another person can make decisions about their medical care if they become incapacitated or cognitively impaired.

EXCLUSION CRITERIA:

  • Patients who have had chemotherapy, radiotherapy, or immunotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
  • Patients may not be receiving any other investigational agents, including extracorporeal photopheresis.

Patients may not have received monoclonal antibody therapy within 6 weeks.

  • Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to imatinib mesylate.
  • Patients receiving any of the following medications or substances that are inhibitors or inducers of P450 3A4 are ineligible.

Use of the following medications must be discontinued at least two weeks prior to starting therapy:

  • Alfuzosin
  • Aprepitant
  • Carbamazepine
  • Clarithromycin
  • Eletriptan
  • Erythromycin
  • Pimozide
  • St John's Wort
  • Warfarin
  • A list of medications and substances known or with the potential to interact with the P450 3A4 isoenzyme is provided in Section 8.

Imatinib mesylate is likely to increase the blood level of drugs that are substrates of CYP2C9, CYP2D6 and CYP3A4/5.

Close monitoring is warranted when using agents metabolized by these enzymes. Grapefruit juice should not be consumed while on therapy.

  • Prior treatment with imatinib mesylate or other tyrosine kinase inhibitor after the date of transplant.
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, pulmonary, hepatic, or other organ dysfunction, or psychiatric illness/social situations that would limit compliance with study requirements or compromise the patient's ability to tolerate protocol therapy.
  • Pregnant women are excluded from this study because imatinib mesylate is an agent with the potential for teratogenic or abortifacient effects.

Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with imatinib mesylate, breastfeeding should be discontinued if the mother is treated with imatinib mesylate.

  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with imatinib mesylate and the possibility of associated severe immunosuppression.
  • Patients with active hepatitis C or hepatitis B infection as defined by seropositivity for hepatitis C or hepatitis B (HepBSAg) and elevated transaminases, as GVHD manifestations involving the liver will be indistinguishable and drug-toxicity uninterpretable.
  • Persistent malignancy, requiring ongoing therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00702689

Locations
United States, Maryland
National Cancer Institute (NCI), 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Edward W Cowen, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
No publications provided

Responsible Party: Edward Cowen, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00702689     History of Changes
Other Study ID Numbers: 080148, 08-C-0148
Study First Received: June 19, 2008
Results First Received: September 5, 2012
Last Updated: November 4, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by National Institutes of Health Clinical Center (CC):
Skin Sclerosis
Graft Versus Host Disease

Additional relevant MeSH terms:
Graft vs Host Disease
Imatinib
Sclerosis
Immune System Diseases
Pathologic Processes
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 22, 2014