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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00031824
Recruitment Status : Completed
First Posted : January 27, 2003
Last Update Posted : February 14, 2014
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Brief Summary:

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.

Condition or disease Intervention/treatment Phase
Graft Versus Host Disease Drug: cyclosporine Drug: hydroxychloroquine Drug: prednisone Drug: tacrolimus Phase 3

Detailed Description:



  • Compare the efficacy of prednisone and cyclosporine with vs without hydroxychloroquine in patients with newly diagnosed extensive chronic graft-versus-host disease (GVHD).


  • 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 82 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double
Primary Purpose: Supportive Care
Official Title: Phase III Trial of Hydroxychloroquine + Standard Therapy for Chronic Graft-Versus-Host Disease
Study Start Date : April 2002
Actual Primary Completion Date : May 2005
Actual Study Completion Date : January 2011

Primary Outcome Measures :
  1. Progression Free Survival [ Time Frame: Length of study ]

Secondary Outcome Measures :
  1. Compare the efficacy of a two-drug regimen [ Time Frame: Length of study ]
    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.

  2. Compare conventional outcomes measures [ Time Frame: Length of study ]
    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.

  3. To determine if cytokine levels and T helper cell subtypes (Th1 and Th2) correlate with chronic GVHD activity and response [ Time Frame: Length of study ]
  4. Determine if whole blood hydroxychloroquine levels correlate with response and toxicity.

Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 29 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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"



  • 1 to 29

Performance status:

  • Lansky 50-100% OR
  • Karnofsky 50-100%

Life expectancy:

  • At least 2 months


  • Absolute neutrophil count ≥ 1,000/mm^3, unless due to chronic GVHD (i.e., autoimmune neutropenia or bone marrow suppression)


  • See Disease Characteristics


  • Creatinine < 1.5 times upper limit of normal OR
  • Creatinine clearance ≥ 60 mL/min


  • 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


Biologic therapy:

  • See Disease Characteristics
  • No concurrent daclizumab or infliximab
  • No concurrent thalidomide


  • 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


  • Not specified


  • Not specified


  • 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

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 identifier (NCT number): NCT00031824

Show Show 104 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
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Study Chair: Andrew L. Gilman, MD UNC Lineberger Comprehensive Cancer Center

Publications of Results:
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Responsible Party: Children's Oncology Group Identifier: NCT00031824    
Other Study ID Numbers: ASCT0031
COG-ASCT0031 ( Other Identifier: Children's Oncology Group )
CCG-S9701 ( Other Identifier: Children's Cancer Group )
First Posted: January 27, 2003    Key Record Dates
Last Update Posted: February 14, 2014
Last Verified: February 2014
Keywords provided by Children's Oncology Group:
graft versus host disease
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Anti-Inflammatory Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Dermatologic Agents
Antirheumatic Agents
Antiprotozoal Agents
Antiparasitic Agents