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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



Baylor College of Medicine Houston, Texas  77030
Memorial Sloan-Kettering Cancer Center New York, New York  10021
University of Michigan Comprehensive Cancer Center Ann Arbor, Michigan  48109-0752
Children's Hospital of Philadelphia Philadelphia, Pennsylvania  19104
University of Chicago Cancer Research Center Chicago, Illinois  60637
University of Minnesota Cancer Center Minneapolis, Minnesota  55455
University of Mississippi Medical Center Jackson, Mississippi  39216-4505
Duke Comprehensive Cancer Center Durham, North Carolina  27710
Children's Hospital of Michigan Detroit, Michigan  48201
University of Texas Health Science Center at San Antonio San Antonio, Texas  78284-7811
Midwest Children's Cancer Center Milwaukee, Wisconsin  53226
Presbyterian - St. Luke's Medical Center Denver, Colorado  80218
Massachusetts General Hospital Cancer Center Boston, Massachusetts  02114
Kaiser Permanente Medical Center - Los Angeles Los Angeles, California  90027
New York Medical College Valhalla, New York  10595
Deaconess Medical Center Spokane, Washington  99210-0248
University of Wisconsin Comprehensive Cancer Center Madison, Wisconsin  53792
Holden Comprehensive Cancer Center at University of Iowa Iowa City, Iowa  52242-1002
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Chapel Hill, North Carolina  27599-7570
CCOP - Columbia River Oncology Program Portland, Oregon  97225
CCOP - Scott and White Hospital Temple, Texas  76508
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410
CCOP - St. Vincent Hospital Cancer Center, Green Bay Green Bay, Wisconsin  54301
Cancer Research Center of Hawaii Honolulu, Hawaii  96813
MBCCOP - LSU Health Sciences Center New Orleans, Louisiana  70112
Madigan Army Medical Center Tacoma, Washington  98431-5048
Children's Hospital Los Angeles Los Angeles, California  90027-0700
Children's Hospital of Orange County Orange, California  92668
Children's National Medical Center Washington, District of Columbia  20010-2970
Children's Mercy Hospital Kansas City, Missouri  64108
Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania  15213
Children's Hospital and Regional Medical Center - Seattle Seattle, Washington  98105
Nemours Children's Clinic Jacksonville, Florida  32207
Miami Children's Hospital Miami, Florida  33155-4069
All Children's Hospital St. Petersburg, Florida  33701
Children's Memorial Hospital - Chicago Chicago, Illinois  60614
Children's Hospital of New Orleans New Orleans, Louisiana  70118
Maine Children's Cancer Program Scarborough, Maine  04074-9308
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
Floating Hospital for Children Boston, Massachusetts  02111
Cardinal Glennon Children's Hospital Saint Louis, Missouri  63104
Schneider Children's Hospital New Hyde Park, New York  11042
St. Jude Children's Research Hospital Memphis, Tennessee  38105-2794
Cook Children's Medical Center - Fort Worth Fort Worth, Texas  76104
Inova Fairfax Hospital Falls Church, Virginia  22042-3300
City of Hope Comprehensive Cancer Center Duarte, California  91010
UCSF Comprehensive Cancer Center San Francisco, California  94115
Southern California Permanente Medical Group Downey, California  90242
Kosair Children's Hospital Louisville, Kentucky  40202-3830
St. Louis Children's Hospital Saint Louis, Missouri  63110
Arizona Cancer Center at University of Arizona Health Sciences Center Tucson, Arizona  85724
Arkansas Cancer Research Center at University of Arkansas for Medical Sciences Little Rock, Arkansas  72205
Markey Cancer Center at University of Kentucky Chandler Medical Center Lexington, Kentucky  40536-0084
Herbert Irving Comprehensive Cancer Center at Columbia University New York, New York  10032
Cancer Institute at Oregon Health and Science University Portland, Oregon  97201-3098
Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University Cleveland, Ohio  44106
Oklahoma University Medical Center Oklahoma City, Oklahoma  73104
M.D. Anderson Cancer Center at University of Texas Houston, Texas  77030
University of Florida Shands Cancer Center Gainesville, Florida  32610-0232
NYU Cancer Institute at New York University Medical Center New York, New York  10016
SUNY Upstate Medical University Hospital Syracuse, New York  13210
Cincinnati Children's Hospital Medical Center Cincinnati, Ohio  45229-3039
Hollings Cancer Center at Medical University of South Carolina Charleston, South Carolina  29425
CCOP - Marshfield Clinic Research Foundation Marshfield, Wisconsin  54449
James P. Wilmot Cancer Center at University of Rochester Medical Center Rochester, New York  14642
Lombardi Cancer Center at Georgetown University Medical Center Washington, District of Columbia  20007
UNMC Eppley Cancer Center at the University of Nebraska Medical Center Omaha, Nebraska  68198-7680
Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center Los Angeles, California  90048-1865
Jonsson Comprehensive Cancer Center at UCLA Los Angeles, California  90095-1781
Lucile Packard Children's Hospital at Stanford University Medical Center Palo Alto, California  95798
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus Atlanta, Georgia  30342
Children's Hospital and Research Center at Oakland Oakland, California  94609-1809
Children's Hospital and Health Center, San Diego San Diego, California  92123-4282
MBCCOP-Medical College of Georgia Cancer Center Augusta, Georgia  30912-4000
Riley Children Cancer Center at Riley Hospital for Children Indianapolis, Indiana  46202-5225
Cancer Center at Hackensack University Medical Center Hackensack, New Jersey  07601
Doernbecher Children's Hospital at Oregon Health & Science University Portland, Oregon  97239-3098
Vanderbilt Children's Hospital Nashville, Tennessee  37232-6310
Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas Dallas, Texas  75390-9063
MBCCOP - South Texas Pediatrics San Antonio, Texas  78229-3900
Children's Hospital Cancer Center Denver, Colorado  80218
DeVos Children's Hospital Grand Rapids, Michigan  49503
Children's Hospitals and Clinics - Minneapolis/St. Paul Minneapolis, Minnesota  55404
Columbus Children's Hospital Columbus, Ohio  43205-2696
Huntsman Cancer Institute at University of Utah Salt Lake City, Utah  84112
Children's Hospital at Milton S. Hershey Medical Center Hershey, Pennsylvania  17033
University Medical Center at Princeton Los Angeles, California  90027-0700
Methodist Cancer Center at Methodist Specialty and Transplant Hospital Saint Louis, Missouri  63104
Pediatric Hematology and Oncology Associates of South Texas, PLLC San Antonio, Texas  78229