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

Phase 3
1 Year
29 Years
Not Enrolling
Graft Versus Host Disease

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Trial Information

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



- 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

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.

Inclusion Criteria


- 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

- 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

- 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

- 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

- 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 dacluzimab 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Supportive Care

Principal Investigator

Andrew L. Gilman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center


United States: Federal Government

Study ID:




Start Date:

April 2002

Completion Date:

Related Keywords:

  • Graft Versus Host Disease
  • graft versus host disease
  • Graft vs Host Disease



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