Hydroxychloroquine in Treating Patients With Newly Diagnosed Chronic Graft-Versus-Host Disease

Study Overview
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Brief Summary
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RATIONALE: Hydroxychloroquine may decrease the immune response and be effective in treating chronic graft-versus-host disease. It is not yet known if standard therapy for graft-versus-host disease is more effective with or without hydroxychloroquine. PURPOSE: Randomized phase III trial to compare the effectiveness of standard therapy alone with that of standard therapy plus hydroxychloroquine in treating patients who have newly diagnosed chronic graft-versus-host disease.

Detailed Description
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OBJECTIVES: Primary Compare the efficacy of prednisone and cyclosporine with vs without hydroxychloroquine in patients with newly diagnosed extensive chronic graft-versus-host disease (GVHD). Secondary Compare the event-free and overall survival in patients treated with these regimens. Compare the health-related quality of life, including longitudinal change in and magnitude of persistent disability, in patients treated with these regimens. Correlate cytokine levels and T-helper cell subtypes with chronic GVHD activity and response in patients treated with these regimens. Correlate whole blood hydroxychloroquine levels with response and toxicity in patients treated with these regimens. OUTLINE: This is a randomized, placebo-controlled, double-blind, multicenter study. Patients are randomized to one of two treatment arms. Patients may receive standard therapy comprising prednisone orally or IV 2-3 times daily or every other day and cyclosporine orally or IV twice daily or tacrolimus orally twice daily or IV by continuous infusion before randomization. Patients not receiving cyclosporine or tacrolimus prior to randomization may receive cyclosporine or tacrolimus after randomization according to institutional preference. Arm I: Within 10-14 days of beginning therapy with prednisone and cyclosporine or tacrolimus, patients receive oral hydroxychloroquine twice daily. Arm II: Patients receive standard therapy with prednisone and cyclosporine or tacrolimus as in arm I and oral placebo twice daily. In both arms, treatment continues for 9 months in the absence of disease progression or unacceptable toxicity. Patients with no response after 2 months of therapy are taken off study. Quality of life is assessed at baseline, 1 month, 9 months, and 1 year. Patients are followed every month for 3 months and at 9 months. PROJECTED ACCRUAL: A total of 232 patients (116 per treatment arm) will be accrued for this study within 3.6 years.

Official Title
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Phase III Trial of Hydroxychloroquine + Standard Therapy for Chronic Graft-Versus-Host Disease

Conditions
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Graft Versus Host Disease

Intervention / Treatment
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* Drug: cyclosporine
* Drug: hydroxychloroquine
* Drug: prednisone
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed* newly diagnosed extensive chronic graft-versus-host disease (GVHD) of ≥ 1 organ system (e.g., lip, skin, or liver) documented by all of the following: Clinicopathologic features of GVHD, including involvement of any of the following organ systems: Skin changes Oral changes Hepatic involvement Gastrointestinal involvement Sicca syndrome Pulmonary involvement Myofascial Skeletal Other inflammatory conditions (e.g., myositis, arthritis, polyserositis, or unexplained pericardial, pleural, or peritoneal effusions) Autoantibodies Extent of disease, defined according to the following classification: Limited chronic GVHD, defined by 1 of the following: Localized skin involvement and/or liver dysfunction Involvement of only 1 target organ Extensive chronic GVHD, defined by 1 of the following: Generalized skin involvement of ≥ 50% of body surface area Localized skin involvement and/or liver dysfunction AND ≥ 1 of the following: Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis Eye involvement (Schirmer's test with < 5 mm wetting) Involvement of minor salivary glands or oral mucosa on lip biopsy Involvement of any other target organs Involvement of ≥ 2 target organs Timing of onset, including onset of any of the following types: Progressive onset defined as, evolving directly from acute GVHD, commonly with the development of typical manifestations such as oral or skin lichenoid changes or sclerodermatous skin changes Quiescent onset, defined as developing after the resolution of acute GVHD De novo onset, defined as developing with no prior history of acute GVHD Must have ≥ 1 typical clinical manifestation of chronic GVHD that differs from that of acute GVHD (e.g., rash, anorexia, nausea, emesis, diarrhea, abdominal pain, or cholestasis) Symptoms of acute GVHD allowed at the time of diagnosis of chronic GVHD Prior allogeneic bone marrow, peripheral blood stem cell, or cord blood transplantation from a family member or unrelated donor for malignancy required NOTE: *Histologic confirmation may be consistent with GVHD PATIENT CHARACTERISTICS: Age: 1 to 29 Performance status: Lansky 50-100% OR Karnofsky 50-100% Life expectancy: At least 2 months Hematopoietic: Absolute neutrophil count ≥ 1,000/mm^3, unless due to chronic GVHD (i.e., autoimmune neutropenia or bone marrow suppression) Hepatic: See Disease Characteristics Renal: Creatinine < 1.5 times upper limit of normal OR Creatinine clearance ≥ 60 mL/min Other: Not pregnant Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation No lysosomal storage disorder No uncontrolled infection (e.g., persistent bacterial, fungal, or viral infection despite appropriate antimicrobial therapy) No G6PD deficiency No history of psoriasis or porphyria No hypersensitivity to 4-aminoquinolines No prior retinal or visual field changes due to 4-aminoquinolines PRIOR CONCURRENT THERAPY: Biologic therapy: See Disease Characteristics No concurrent daclizumab or infliximab No concurrent thalidomide Chemotherapy: Not specified Endocrine therapy: Prior topical steroids for treatment of extensive chronic GVHD allowed Prior adjustment to prednisone dose allowed if done as a reversal of a taper Prior steroids (prednisone ≤ 1 mg/kg/day (or equivalent) for symptom management for up to 1 week before study entry allowed Concurrent steroids for treatment and/or prophylaxis of acute GVHD allowed if prednisone dose is ≤ 2 mg/kg/day (or equivalent) Concurrent topical steroids allowed Radiotherapy: Not specified Surgery: Not specified Other: No prior treatment for extensive chronic GVHD except the following: Topical treatment (e.g., tacrolimus ointment or pimecrolimus cream) Adjustments of cyclosporine or tacrolimus doses for GVHD prophylaxis or treatment of acute GVHD Concurrent cyclosporine or tacrolimus allowed Cyclosporine must have been started before study entry No other concurrent systemic or topical immunosuppressants, including any of the following: Azathioprine Mycophenolate mofetil Psoralen-ultraviolet light therapy Photopheresis No administration of any of the following for 1 hour before until 2 hours after study drug administration: Antacids Sucralfate Cholestyramine Bicarbonate

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 29 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: Supportive Care
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: cyclosporine|nan|
|Drug: hydroxychloroquine|nan|
|Drug: prednisone|nan|
|Drug: tacrolimus|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | Length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Compare the efficacy of a two-drug regimen | Compare the efficacy of a two-drug regimen including prednisone and cyclosporine versus that of a three-drug regimen including hydroxychloroquine, prednisone, and cyclosporine in patients treated for newly-diagnosed extensive chronic GVHD. | Length of study | 
| Compare conventional outcomes measures | Compare conventional outcomes measures (event-free survival, overall survival) and health-related quality-of-life (HRQL), including longitudinal change in and magnitude of persistent disability, for the two-drug versus the three-drug regimen. | Length of study | 
| To determine if cytokine levels and T helper cell subtypes (Th1 and Th2) correlate with chronic GVHD activity and response |  | Length of study | 
| Determine if whole blood hydroxychloroquine levels correlate with response and toxicity. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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graft versus host disease