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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00702689
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arm: 1
• Actual Duration (Months): 134.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Sclerotic Graft Versus Host Disease; Imatinib Mesylate	Drug: Gleevec, STI571(Imatinib Mesylate)	Phase 2

Detailed Description

Background:

Chronic graft versus host disease (cGVHD) is a major complication of allogeneic stem cell transplant (alloHSCT). The sclerotic skin manifestations of chronic cutaneous GVHD (ScGVHD) can lead to significant functional impairment and no satisfactory therapy exists to adequately treat this form of cGVHD.

Imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor with potent activity against platelet derived growth factor receptor (PDGFR) signaling, a key cytokine pathway which has been implicated in fibrotic disease in general, and in extensive cGVHD in particular.

We hypothesize that treatment with imatinib mesylate will reduce the sclerotic manifestations of cGVHD as assessed by quantitative range of motion assessment of an affected joint.

Objectives:

Primary Objective:

To investigate whether imatinib mesylate results in clinical improvement in skin fibrosis in children and adults with ScGVHD using range of motion assessment of affected joints.

To determine if imatinib mesylate 200 mg daily is tolerated by patients with cGVHD.

Secondary Objectives:

To assess toxicity associated with imatinib mesylate in patients with cGVHD.

To establish outcome criteria for the evaluation of ScGVHD using multi-modality objective and subjective assessments, including magnetic resonance imaging, skin scoring, and patient self-reported measures.

To evaluate biomarkers of disease activity and correlative response measures to treatment with imatinib mesylate.

To assess quality of life and functional measures of disease activity and to evaluate changes through the course of therapy.

To evaluate the response of other organ manifestations affected by cGVHD to treatment with imatinib mesylate.

To evaluate steady-state pharmacokinetics of imatinib mesylate in the cGVHD patient population.

Eligibility:

Patients age 4 years of age or older with the diagnosis of ScGVHD.

Design:

This is an open-label, pilot study of imatinib mesylate.

Treatment cycles are 28-day cycles with no rest period between cycles.

A target of 10 evaluable patients will be enrolled on this trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Imatinib Mesylate in Children and Adults With Sclerotic Skin Changes of Chronic Graft-Versus-Host Disease
• Actual Study Start Date: Dec 15, 2008
• Actual Primary Completion Date: May 18, 2011
• Actual Study Completion Date: Feb 26, 2020

Arms and Interventions

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

1. Percent Change in Absolute Range of Motion (ROM) From Baseline to 6 Months [6 months]

   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. Percent improvement in ROM for 1-3 target joints. For patients with >1 target joint, the average ROM improvement was calculated. The average percentage change in ROM deficit from baseline to 6 months was obtained based on the number of degrees of ROM change (6 months)/total ROM deficit (baseline) at each joint.

2. Primary Range of Motion (ROM) Response [6 months]

   Progressive disease is defined as joint ROM: decrease of >25% in composite ROM score on 2 consecutive evaluations at least 2 weeks apart, but not greater than 4 weeks apart or steroid pulse: >1 steroid pulse per 3 month period if administered for sclerotic-type chronic graft versus host disease (ScGVHD). Response is joint ROM: increase of >25% in composite ROM score. Maximal response is a response with no further improvement over 2 sequential 3-month evaluations. Stable disease does not meet the criteria for progression, response, or maximal response.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [Date treatment consent signed to date off study, approximately, 41 months, 27 days]

   Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

2. Average Percentage Change in Range of Motion (ROM) Deficit [6 months]

   One or more joints were assessed for ROM deficit by a physiatrist with expertise in graft versus host disease and joint ROM.

3. Total Skin Score at Baseline and 6 Months [Baseline and 6 Months]

   Total skin score was graded by the National Institutes of Health Consensus Criteria. Skin score was calculated by dividing the total score by seven domains (skin, eye, oral, joint, gastrointestinal, hepatic, pulmonary) in men and 8 domains in women (previous domains noted plus gynecologic). Total skin score is a percentage of body surface area (BSA) involvement (range 0-100%). It was calculated from the sum of moveable body surface BSA and non-moveable BSA. Higher numbers = greater body surface area affected.

4. Total Chronic Graft Versus Host Disease (cGVHD) Provider Global Rating Score at Baseline and 6 Months [Baseline and 6 months]

   The provider global rating is a physician impression of severity of cGVHD symptoms from a scale of zero (no symptoms) to 10 (most severe GVHD symptoms possible).

5. Lung Function Score at Baseline and 6 Months [Baseline and 6 Months]

   Lung function was graded by the National Institutes of Health Chronic Graft Versus Host Disease organ response criteria. The Lung function score = forced expiratory volume 1 (FEV1) score + carbon monoxide diffusing capacity (DLCO) score, with a possible range of 2 (better outcome)-12 (worst outcome). The percent predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% =1; 70-79% = 2; 60-69% = 3; 50-59% = 4; 40-49% = 5; <40% = 6.

6. Change in Immunosuppression [6 months]

   Change in immunosuppression was defined by an increase or decrease in steroid use form baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 4 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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

Locations

	Site	City	State	Country	Postal Code
1	National Cancer Institute (NCI), 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Edward W Cowen, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 20, 2015
• Informed Consent Form - Jan 19, 2012

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

None provided.

• Responsible Party: Edward Cowen, M.D., Principal Investigator, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• ClinicalTrials.gov Identifier: NCT00702689
• Other Study ID Numbers: 080148; 08-AR-0148
• First Posted: Jun 20, 2008
• Last Update Posted: Mar 30, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Edward Cowen, M.D., Principal Investigator, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS): Skin Sclerosis; Graft Versus Host Disease
• Additional relevant MeSH terms: Graft vs Host Disease; Sclerosis; Imatinib Mesylate

Study Results

Participant Flow

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Period Title: Overall Study
STARTED	20
COMPLETED	14
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Overall Participants	20
Age (Count of Participants)
<=18 years	2 10%
Between 18 and 65 years	18 90%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.59 (17.49)
Sex: Female, Male (Count of Participants)
Female	6 30%
Male	14 70%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 10%
Not Hispanic or Latino	18 90%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5%
White	17 85%
More than one race	0 0%
Unknown or Not Reported	2 10%
Region of Enrollment (Count of Participants)
United States	20 100%
Chronic Graft Versus Host Disease (cGVHD) category (percentage of participants) [Number]
Overlap	5 25%
Classic	95 475%
Late acute	0 0%
Chronic Graft Versus Host Disease presentation (Percentage of participants) [Number]
De novo	30 150%
Quiescent	20 100%
Progressive	50 250%
Global National Institutes of Health Graft Versus Host Disease (GVHD) score (Percentage of participants) [Number]
Mild (1)	0 0%
Moderate (2)	0 0%
Severe (3)	100 500%
Donor Source (Percentage of participants) [Number]
Bone marrow	10 50%
Peripheral blood	90 450%
Cord	0 0%
Donor Match (6/6) (Percentage of participants) [Number]
Number [Percentage of participants]	90 450%
Months from Chronic Graft Versus Host Disease (cGVHD) diagnosis (Months) [Median (Full Range) ]
Median (Full Range) [Months]	39.85
Months from transplant (Months) [Median (Full Range) ]
Median (Full Range) [Months]	55.4
Concomitant Immunosuppressive Medication (ISM) (Count of Participants)
Pred/tacro	2 10%
Pred	1 5%
MPred/MTX	1 5%
Pred/siro	2 10%
Pred/siro/tacro	1 5%
MPred/tacro/siro/MMF	1 5%
Pred/siro/MMF	2 10%
Tacro	1 5%
Pred/tacro/siro	1 5%
Tacro/MMF	3 15%
Pred/MMF	1 5%
Siro/MMF	1 5%
MPred/tacro/MMF	1 5%
Siro	1 5%
None	1 5%
Assessable Joints at Baseline (joints) [Number]
Patient 1	3
Patient 2	3
Patient 3	2
Patient 4	3
Patient 5	3
Patient 6	3
Patient 7	3
Patient 8	3
Patient 9	3
Patient 10	3
Patient 11	3
Patient 12	3
*Patient 13	3
Patient 14	3
Patient 15	3
Patient 16	1
Patient 17	3
Patient 18	3
Patient 19	3
Patient 20	3
Average National Institutes of Health Chronic Graft Versus Host Disease (cGVHD) Score at Baseline (scores on a scale) [Number]
Patient 1	1.28
Patient 2	1.14
Patient 3	.75
Patient 4	1.0
Patient 5	1.48
Patient 6	1.86
Patient 7	1.90
Patient 8	1.57
Patient 9	1.71
Patient 10	1.43
Patient 11	1.75
Patient 12	1.43
Patient 13	1.38
Patient 14	1.29
Patient 15	1.43
Patient 16	.86
Patient 17	1.13
Patient 18	1.57
Patient 19	1.14
Patient 20	2.00
Measure of Number of Organs with Graft Versus Host Disease (GVHD) (affected organs) [Number]
Patient 1	5
Patient 2	4
Patient 3	3
Patient 4	4
Patient 5	6
Patient 6	7
Patient 7	7
Patient 8	6
Patient 9	7
Patient 10	5
Patient 11	7
Patient 12	6
Patient 13	6
Patient 14	5
Patient 15	6
Patient 16	2
Patient 17	4
Patient 18	4
Patient 19	4
Patient 20	7
Percent Body Surface Area (BSA) Moveable Sclerosis at Baseline (Percent BSA moveable sclerosis) [Number]
Patient 1	57.15
Patient 2	2.7
Patient 3	6.3
Patient 4	0.18
Patient 5	8.1
Patient 6	59.4
Patient 7	29.7
Patient 8	15.3
Patient 9	3.33
Patient 10	0
Patient 11	82.08
Patient 12	12.6
Patient 13	1.8
Patient 14	5.4
Patient 15	49.77
Patient 16	0
Patient 17	84.24
Patient 18	15.84
Patient 19	9.45
Patient 20	0
Percent Body Surface Area (BSA) Nonmoveable Sclerosis at Baseline (Percent BSA nonmoveable sclerosis) [Number]
Patient 1	7.56
Patient 2	56.7
Patient 3	36.9
Patient 4	19.98
Patient 5	77.94
Patient 6	0
Patient 7	32.4
Patient 8	36.9
Patient 9	9
Patient 10	8.28
Patient 11	0
Patient 12	8.64
Patient 13	71.1
Patient 14	31.5
Patient 15	10.8
Patient 16	9.54
Patient 17	0
Patient 18	4.5
Patient 19	11.7
Patient 20	23.4
Baseline Range of Motion (ROM) Percent (of Predicted) (ROM Percent of Predicted) [Number]
Patient 1	37
Patient 2	56
Patient 3	73
Patient 4	7
Patient 5	34
Patient 6	47
Patient 7	61
Patient 8	35
Patient 9	42
Patient 10	-7
Patient 11	56
Patient 12	37
Patient 13	27
Patient 14	32
Patient 15	22
Patient 16	71
Patient 17	64
Patient 18	54
Patient 19	33
Patient 20	-5

Outcome Measures

1. Primary Outcome

Title	Percent Change in Absolute Range of Motion (ROM) From Baseline to 6 Months
Description	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. Percent improvement in ROM for 1-3 target joints. For patients with >1 target joint, the average ROM improvement was calculated. The average percentage change in ROM deficit from baseline to 6 months was obtained based on the number of degrees of ROM change (6 months)/total ROM deficit (baseline) at each joint.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
Pt 2 6mo response% change in deficit from baseline	94
Pt 7 6mo response% change in deficit from baseline	35
Pt 8 6mo response% change in deficit from baseline	16
Pt10 6mo response% change in deficit from baseline	21
Pt12 6mo response% change in deficit from baseline	16
Pt13 6mo response% change in deficit from baseline	61
Pt14 6mo response% change in deficit from baseline	27
Pt15 6mo response% change in deficit from baseline	22
Pt16 6mo response% change in deficit from baseline	3
Pt17 6mo response% change in deficit from baseline	-25
Pt18 6mo response% change in deficit from baseline	-2
Pt19 6mo response% change in deficit from baseline	31
Pt20 6mo response% change in deficit from baseline	15

2. Primary Outcome

Title	Primary Range of Motion (ROM) Response
Description	Progressive disease is defined as joint ROM: decrease of >25% in composite ROM score on 2 consecutive evaluations at least 2 weeks apart, but not greater than 4 weeks apart or steroid pulse: >1 steroid pulse per 3 month period if administered for sclerotic-type chronic graft versus host disease (ScGVHD). Response is joint ROM: increase of >25% in composite ROM score. Maximal response is a response with no further improvement over 2 sequential 3-month evaluations. Stable disease does not meet the criteria for progression, response, or maximal response.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
Partial Response	5 25%
Stable Disease	7 35%
Progressive Disease	2 10%

3. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	Date treatment consent signed to date off study, approximately, 41 months, 27 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	20
Number [Participants]	20 100%

4. Secondary Outcome

Title	Average Percentage Change in Range of Motion (ROM) Deficit
Description	One or more joints were assessed for ROM deficit by a physiatrist with expertise in graft versus host disease and joint ROM.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

This outcome is the average percentage change in ROM deficit among 13 evaluable patients based on each patients baseline range of motion deficit compared to his/her ROM deficit at 6 months.

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	13
Mean (Inter-Quartile Range) [Percent change]	24.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib Mesylate in Patients With cGVHD
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.011
	Comments
	Method	Paired t-test
	Comments

5. Secondary Outcome

Title	Total Skin Score at Baseline and 6 Months
Description	Total skin score was graded by the National Institutes of Health Consensus Criteria. Skin score was calculated by dividing the total score by seven domains (skin, eye, oral, joint, gastrointestinal, hepatic, pulmonary) in men and 8 domains in women (previous domains noted plus gynecologic). Total skin score is a percentage of body surface area (BSA) involvement (range 0-100%). It was calculated from the sum of moveable body surface BSA and non-moveable BSA. Higher numbers = greater body surface area affected.
Time Frame	Baseline and 6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
Patient # 2 - Baseline	66.6
Patient # 2 - 6 months	54
Patient # 3 - Baseline	43.38
Patient # 3 - 6 months	NA
Patient # 7 - Baseline	66.24
Patient # 7 - 6 months	55.53
Patient # 8 - Baseline	53.1
Patient # 8 - 6 months	55.26
Patient # 10 - Baseline	10.8
Patient # 10 - 6 months	6.12
Patient # 12 - Baseline	21.24
Patient # 12 - 6 months	30.06
Patient # 13 - Baseline	79.2
Patient # 13 - 6 months	62.28
Patient # 14 - Baseline	39.96
Patient # 14 - 6 months	40.5
Patient # 15 - Baseline	71.46
Patient # 15 - 6 months	61.83
Patient # 16 - Baseline	9.54
Patient # 16 - 6 months	8.1
Patient # 17 - Baseline	84.96
Patient # 17 - 6 months	85.11
Patient # 18 - Baseline	26.64
Patient # 18 - 6 months	24.3
Patient # 19 - Baseline	21.15
Patient # 19 - 6 months	37.8
Patient # 20 - Baseline	23.4
Patient # 20 - 6 months	25.2

6. Secondary Outcome

Title	Total Chronic Graft Versus Host Disease (cGVHD) Provider Global Rating Score at Baseline and 6 Months
Description	The provider global rating is a physician impression of severity of cGVHD symptoms from a scale of zero (no symptoms) to 10 (most severe GVHD symptoms possible).
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
Patient #2 at Baseline	5
Patient #2 at 6 Months	4
Patient #3 at Baseline	3
Patient #3 at 6 Months	NA
Patient #7 at Baseline	6
Patient #7 at 6 Months	8
Patient #8 at Baseline	6
Patient #8 at 6 Months	7
Patient #10 at Baseline	5
Patient #10 at 6 Months	4
Patient #12 at Baseline	6
Patient #12 at 6 Months	7
Patient #13 at Baseline	6
Patient #13 at 6 Months	4
Patient #14 at Baseline	7
Patient #14 at 6 Months	6
Patient # 15 at Baseline	7
Patient #15 at 6 Months	6
Patient #16 at Baseline	5
Patient #16 at 6 Months	4
Patient #17 at Baseline	6
Patient #17 at 6 months	8
Patient #18 at Baseline	8
Patient #18 at 6 Months	8
Patient #19 at Baseline	8
Patient #19 at 6 Months	5
Patient #20 at Baseline	8
Patient #20 at 6 Months	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib Mesylate in Patients With cGVHD
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.47
	Comments
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Lung Function Score at Baseline and 6 Months
Description	Lung function was graded by the National Institutes of Health Chronic Graft Versus Host Disease organ response criteria. The Lung function score = forced expiratory volume 1 (FEV1) score + carbon monoxide diffusing capacity (DLCO) score, with a possible range of 2 (better outcome)-12 (worst outcome). The percent predicted FEV1 and DLCO (adjusted for hematocrit but not alveolar volume) should be converted to a numeric score as follows: >80% =1; 70-79% = 2; 60-69% = 3; 50-59% = 4; 40-49% = 5; <40% = 6.
Time Frame	Baseline and 6 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
Patient #2 at Baseline	2
Patient #2 at 6 Months	2
Patient #3 at Baseline	9
Patient #3 at 6 Months	NA
Patient #7 at Baseline	3
Patient #7 at 6 Months	8
Patient #8 at Baseline	5
Patient #8 at 6 Months	6
Patient #10 at Baseline	3
Patient #10 at 6 Months	3
Patient #12 at Baseline	4
Patient #12 at 6 Months	5
Patient #13 at Baseline	4
Patient #13 at 6 Months	4
Patient #14 at Baseline	5
Patient #14 at 6 Months	5
Patient # 15 at Baseline	7
Patient #15 at 6 Months	6
Patient #16 at Baseline	3
Patient #16 at 6 Months	2
Patient #17 at Baseline	5
Patient #17 at 6 months	6
Patient #18 at Baseline	8
Patient #18 at 6 Months	8
Patient #19 at Baseline	9
Patient #19 at 6 Months	9
Patient #20 at Baseline	2
Patient #20 at 6 Months	2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Imatinib Mesylate in Patients With cGVHD
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.29
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Change in Immunosuppression
Description	Change in immunosuppression was defined by an increase or decrease in steroid use form baseline.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Pred:prednisone; tacro:tacrolimus; MPred:methylprednisolone; siro:sirolimus; and MMF:mycophenolate mofetil

Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
Measure Participants	14
↓ Pred 20 mg everyday (qd )to 5 mg every other day	1 5%
↓ MPred 16 mg every other day(qod) to 4 mg qod	1 5%
↓ Pred:24mg every day(qd) to 20mg qd	1 5%
No change	5 25%
↓ Tacro 2mg every am 1.5mg every pm to .5mg bid	1 5%
Pred↓ 25mg qd to 15mg qd;Tacro↓ 2mg bid to 1mg bid	1 5%
Pred↓ 2.5mg qd to 2.5mg every other day	1 5%
↓ Siro:2mg qd to 1 mg qd	1 5%
Pred wean then ↑ 10 12.5mg bid;Tacro↑1.0 to 1.5bid	1 5%
MMF↓ 1g/bid to discontinued	1 5%

Adverse Events

Time Frame	Date treatment consent signed to date off study, approximately, 41 months, 27 days.
Arm/Group Title	Imatinib Mesylate in Patients With cGVHD
Arm/Group Description	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)
All Cause Mortality
	Imatinib Mesylate in Patients With cGVHD
	Affected / at Risk (%)	# Events
Total	0/20 (0%)
Serious Adverse Events
	Imatinib Mesylate in Patients With cGVHD
	Affected / at Risk (%)	# Events
Total	5/20 (25%)
Gastrointestinal disorders
Nausea	1/20 (5%)	1
Vomiting	1/20 (5%)	1
General disorders
Edema::head and neck	1/20 (5%)	1
Edema: limb	1/20 (5%)	1
Edema:: trunk/genital	1/20 (5%)	1
Infections and infestations
Infection with unknown ANC::Lung (pneumonia)	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	1/20 (5%)	1
Nervous system disorders
Pain::Head/headache	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	2/20 (10%)	3
Hypoxia	1/20 (5%)	1
Pleural effusion (non-malignant)	1/20 (5%)	1
Pulmonary/Upper Respiratory - Other (Specify, Pulmonary edema)	2/20 (10%)	3
Vascular disorders
Hypertension	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Imatinib Mesylate in Patients With cGVHD
	Affected / at Risk (%)	# Events
Total	20/20 (100%)
Ear and labyrinth disorders
Pain::External ear	1/20 (5%)	1
Tinnitus	4/20 (20%)	6
Gastrointestinal disorders
Constipation	1/20 (5%)	1
Diarrhea	6/20 (30%)	19
Heartburn/dyspepsia	1/20 (5%)	2
Nausea	10/20 (50%)	30
Vomiting	4/20 (20%)	5
General disorders
Constitutional Symptoms-Other (Specify, cold intolerance; sleep walking)	2/20 (10%)	2
Edema::head and neck	3/20 (15%)	6
Edema: limb	3/20 (15%)	11
Fatigue (asthenia, lethargy, malaise)	9/20 (45%)	22
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/20 (10%)	2
Flu-like symptoms	2/20 (10%)	2
Immune system disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	3/20 (15%)	3
Infections and infestations
Infection with normal ANC or Grade 1 or 2 neutrophils::otitis externa	1/20 (5%)	1
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/20 (5%)	1
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase)	4/20 (20%)	8
AST, SGOT(serum glutamic oxaloacetic transaminase)	5/20 (25%)	10
Alkaline phosphatase	1/20 (5%)	1
CPK (creatine phosphokinase)	5/20 (25%)	11
Creatinine	2/20 (10%)	8
Hemoglobin	6/20 (30%)	13
Leukocytes (total WBC)	1/20 (5%)	2
Neutrophils/granulocytes (ANC/AGC)	1/20 (5%)	1
Platelets	1/20 (5%)	2
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	4/20 (20%)	6
Anorexia	1/20 (5%)	4
Calcium, serum-high (hypercalcemia)	3/20 (15%)	5
Glucose, serum-low (hyperglycemia)	1/20 (5%)	1
Magnesium, serum-high (hypermagnesemia)	1/20 (5%)	1
Magnesium, serum-low (hypomagnesemia)	1/20 (5%)	3
Phosphate, serum-low (hypophosphatemia)	11/20 (55%)	26
Potassium, serum-high (hyperkalemia)	3/20 (15%)	3
Potassium, serum-low (hypokalemia)	1/20 (5%)	2
Sodium, serum-low (hyponatremia)	2/20 (10%)	4
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy)::Whole body/generalized	1/20 (5%)	1
Musculoskeletal/Soft tissue - Other (Specify, hand & jaw cramps; hand & jaw cramps, intermittent	1/20 (5%)	2
Pain::Bone	1/20 (5%)	2
Pain::Joint	1/20 (5%)	3
Pain::Muscle	6/20 (30%)	14
Nervous system disorders
Dizziness	2/20 (10%)	2
leukoencephalopathy (radiographic findings)	1/20 (5%)	1
Pain::Head/headache	5/20 (25%)	11
Psychiatric disorders
Insomnia	1/20 (5%)	1
Mood alteration::Depression	1/20 (5%)	1
Reproductive system and breast disorders
Pain::Breast	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/20 (5%)	1
Cough	4/20 (20%)	5
Dyspnea	2/20 (10%)	3
Nasal cavity/paranasal sinus reactions	1/20 (5%)	1
Skin and subcutaneous tissue disorders
Dermatology/Skin-Other (Specify, intermt. bilateral hands & L. hip)	1/20 (5%)	1
Dry skin	1/20 (5%)	1
Pain::Skin	1/20 (5%)	1
Rash/desquamation	3/20 (15%)	5
Vascular disorders
Flushing	1/20 (5%)	2
Hypertension	1/20 (5%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.