Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Objectives

Primary

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

Secondary

1. Compare the event-free and overall survival in patients treated with these regimens.
2. Compare the health-related quality of life, including longitudinal change in and magnitude of persistent disability, in patients treated with these regimens.
3. Correlate cytokine levels and T-helper cell subtypes with chronic GVHD activity and response in patients treated with these regimens.
4. Correlate whole blood hydroxychloroquine levels with response and toxicity in patients treated with these regimens.

Entry Criteria

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"]

Prior/Concurrent Therapy:

Biologic therapy:

• See Disease Characteristics
• No concurrent dacluzimab 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

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/mm³, 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

Expected Enrollment

A total of 232 patients (116 per treatment arm) will be accrued for this study within 3.6 years.

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.

Gilman AL, Schultz KR, Goldman FD, et al.: Randomized Trial of Hydroxychloroquine for Newly Diagnosed Chronic Graft-versus-Host Disease in Children: A Children's Oncology Group Study. Biol Blood Marrow Transplant 18 (1): 84-91, 2012.[PUBMED Abstract]

Rozmus J, Schultz KR, Wynne K, et al.: Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Children's Oncology Group Study ASCT0031. Biol Blood Marrow Transplant 17 (12): 1804-13, 2011.[PUBMED Abstract]

Hall MJ, Reid JE, Wenstrup RJ: Prevalence of BRCA1 and BRCA2 mutations in women with breast carcinoma In Situ and referred for genetic testing. Cancer Prev Res (Phila) 3 (12): 1579-85, 2010.[PUBMED Abstract]

Fujii H, Cuvelier G, She K, et al.: Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood 111 (6): 3276-85, 2008.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Andrew Gilman, MD, Protocol chair		Ph: 919-966-9631 Email: agilman@med.unc.edu

Registry Information
Official Title		Phase III Trial of Hydroxychloroquine + Standard Therapy for Chronic Graft-Versus-Host Disease
Trial Start Date		2002-04-01
Trial Completion Date		2005-05-27
Registered in ClinicalTrials.gov		NCT00031824
Date Submitted to PDQ		2002-01-16
Information Last Verified		2010-11-12
NCI Grant/Contract Number		CA98543

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