Bortezomib Plus Prednisone for Initial Therapy of Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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The purpose of this research study is to determine the effectiveness of bortezomib (Velcade) plus prednisone for treating chronic graft versus host disease (cGVHD) and the safety of this drug combination in this patient population. Chronic GVHD is a medical condition that may occur after allogeneic stem cell transplantation. The donor's immune system may recognize the participants body (the host) as foreign and attempt to reject it. Bortezomib has been used in other research studies, and information from those studies suggests that this drug may help to control the abnormal immune responses that underlie cGVHD.

Detailed Description
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Each treatment cycle lasts five weeks, during which time participants will come to the clinic to receive bortezomib intravenously once a week for the first 4 weeks. Prednisone will be taken orally on a daily basis and dose reduction may be initiated after 1 cycle of therapy. During all treatment cycles, participants will have the following: physical exam and blood work. At the end of cycle 3 (week 15) the participants cGVHD will be evaluated. These assessments may include an eye examination, a skin examination, a pulmonary function test and/or, a flexion assessment test. Participants will receive 3 cycles of bortezomib.

Official Title
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A Phase II Trial of Bortezomib (Velcade) Plus Prednisone for Initial Therapy of Chronic Graft Versus Host Disease

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: bortezomib
* Drug: Prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipients of allogeneic stem cell transplantation with myeloablative or non-myeloablative conditioning regimens 100 days or more past stem cell transplantation Recipients of matched or mismatched, related or unrelated adult donor stem cells Must have cGVHD requiring systemic therapy No addition or subtraction of other immunosuppressive medications. The dose of immunosuppressive medicines may be adjusted based on the therapeutic range of that drug. However, if cGVHD occurs during a taper of immune suppression, the medication(s) may not be increased back up to therapeutic level, but will continue a the taper dose for the 15 week study duration Adequate bone marrow, hepatic and renal function as outlined in the protocol Does not require hemodialysis 18 years of age or older ECOG Performance Status of 0-2 or Karnofsky performance score of 70% or greater Life expectancy of more than 3 months Exclusion Criteria: Systemic steroid therapy in the 4 weeks prior to enrollment Active malignant disease after transplantation. Complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy will not be considered in this category Active uncontrolled infection Peripheral neuropathy CTC Grade 1 (or greater) with pain in the 4 weeks before enrollment. Other neurological deficits must be reviewed with the study PI prior to study entry Myocardial infarction within 6 months prior to enrollment or has NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities Hypersensitivity to bortezomib, boron, or mannitol Female subject is pregnant or breast-feeding Serious medical or psychiatric illness likely to interfere with participation in this clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Velcade (bortezomib)<br> | Drug: bortezomib<br>* Given intravenously at a dose of 1.3 mg/m^2 once a week for the first four weeks of a five week cycle for a total of 3 cycles<br>* Other names: Velcade;Drug: Prednisone<br>* Taken orally once a day at a dose of 0.5-1 mg/kg. Dose reduction may be initiated after 1 cycle of therapy. A suggested taper is 10-25% every 1-2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants had their cGVHD evaluated per NIH consensus criteria: Complete response: resolution of all reversible manifestations of cGVHD. Partial response: a decrease ≥ 1 point on a 3-point organ-specific scale or 2 points or more on a 10-point global scale without progression in any organ sites. Stable disease: no evidence of cGVHD response without evidence of progressive cGVHD. Progressive cGVHD: increase of ≥ 1 point on an organ-specific 3-point scale, addition of a new immunosuppressive agent prior to the completion of 15 weeks of combination therapy, or requirement an increase in the total daily dose of corticosteroids above a participant's baseline corticosteroid dose during the 15-week combined treatment period. Mixed response: a response in primary sites of cGVHD involvement but interval progressive cGVHD in other organs or sites. Responses were not scored for oral or ocular cGVHD, since topical therapies were permitted during the study. | Patients had their cGVHD assessed at Baseline and at 15 weeks or end of therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Tolerating >50% Steroid Dose Reduction After a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | The participants' total daily steroid dose was recorded at baseline and after a 15 week course of treatment. Starting at a dose of 0.5-1 mg/kg, dose reduction of steroids was permitted after 1 cycle of therapy. The suggested taper was 10-25% every 1-2 weeks. . | After 15 weeks of bortezomib plus prednisone therapy | 
| The Toxicity of a 15 Week Course of Bortezomib Plus Prednisone in Patients With cGVHD | Participants' toxicities were graded based on the CTCAE version 3.0. The toxicities were then given an attribution to the velcade treatment: unrelated, unlikely, possible, probable, definite. | Toxicities were collected from the start of treatment through 15 weeks of therapy or end of study treatmetn | 
| Proportion of cGVHD Patients Requiring Prednisone by 1 Year After Therapy | Participants who were still being followed 1 year after the start of therapy had their prednisone dose recorded. | 1 year after the start of study treatment | 
| Overall and cGVHD Progression-free Survival by 1 Year After Therapy |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cGVHD, Velcade, bortezomib