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

February 12, 2014 updated by: Children's Oncology Group

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

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.

Study Overview

Status

Completed

Conditions

Graft Versus Host Disease

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Actual)

Phase

Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Australia
- New South Wales
  - Westmead, New South Wales, Australia, 2145
    - Children's Hospital at Westmead
- Queensland
  - Brisbane, Queensland, Australia, 4029
    - Royal Children's Hospital
- South Australia
  - North Adelaide, South Australia, Australia, 5006
    - Women's and Children's Hospital
- Victoria
  - Parkville, Victoria, Australia, 3052
    - Royal Children's Hospital
- Western Australia
  - Perth, Western Australia, Australia, 6001
    - Princess Margaret Hospital for Children
Canada
- Alberta
  - Calgary, Alberta, Canada, T2T 5C7
    - Alberta Children's Hospital
- British Columbia
  - Vancouver, British Columbia, Canada, V6H 3V4
    - British Columbia Children's Hospital
- Manitoba
  - Winnipeg, Manitoba, Canada, R3E 0V9
    - CancerCare Manitoba
- Ontario
  - Toronto, Ontario, Canada, M5G 1X8
    - Hospital for Sick Children
- Quebec
  - Montreal, Quebec, Canada, H3T 1C5
    - Hôpital Sainte Justine
  - Montreal, Quebec, Canada, H3H 1P3
    - McGill Cancer Centre at McGill University
New Zealand
- - Auckland, New Zealand
    - Starship Children's Health
Puerto Rico
- - Santurce, Puerto Rico, 00912
    - San Jorge Children's Hospital
Switzerland
- - Bern, Switzerland, CH 3010
    - Swiss Pediatric Oncology Group Bern
  - Lausanne, Switzerland, CH 1011
    - Swiss Pediatric Oncology Group Lausanne
United States
- Arizona
  - Tucson, Arizona, United States, 85724
    - Arizona Cancer Center at University of Arizona Health Sciences Center
- Arkansas
  - Little Rock, Arkansas, United States, 72205
    - Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
- California
  - Downey, California, United States, 90242
    - Southern California Permanente Medical Group
  - Duarte, California, United States, 91010-3000
    - City of Hope Comprehensive Cancer Center
  - Los Angeles, California, United States, 90095-1781
    - Jonsson Comprehensive Cancer Center at UCLA
  - Los Angeles, California, United States, 90027-0700
    - Children's Hospital Los Angeles
  - Los Angeles, California, United States, 90027
    - Kaiser Permanente Medical Center - Los Angeles
  - Los Angeles, California, United States, 90048
    - Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
  - Los Angeles, California, United States, 90027-0700
    - University Medical Center at Princeton
  - Oakland, California, United States, 94609
    - Children's Hospital and Research Center at Oakland
  - Orange, California, United States, 92868
    - Children's Hospital of Orange County
  - Palo Alto, California, United States, 94304-1812
    - Lucile Packard Children's Hospital at Stanford University Medical Center
  - San Diego, California, United States, 92123-4282
    - Children's Hospital and Health Center, San Diego
  - San Francisco, California, United States, 94143
    - UCSF Comprehensive Cancer Center
- Colorado
  - Colorado Springs, Colorado, United States, 80907
    - Presbyterian - St. Luke's Medical Center
  - Denver, Colorado, United States, 80218
    - Children's Hospital Cancer Center
- District of Columbia
  - Washington, District of Columbia, United States, 20007
    - Lombardi Cancer Center at Georgetown University Medical Center
  - Washington, District of Columbia, United States, 20010-2970
    - Children's National Medical Center
- Florida
  - Gainesville, Florida, United States, 32610-0296
    - University of Florida Shands Cancer Center
  - Jacksonville, Florida, United States, 32207-8482
    - Nemours Children's Clinic
  - Miami, Florida, United States, 33155-4069
    - Miami Children's Hospital
  - St. Petersburg, Florida, United States, 33701
    - All Children's Hospital
- Georgia
  - Atlanta, Georgia, United States, 30322
    - AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus
  - Augusta, Georgia, United States, 30912-4000
    - MBCCOP-Medical College of Georgia Cancer Center
- Hawaii
  - Honolulu, Hawaii, United States, 96813
    - Cancer Research Center of Hawaii
- Illinois
  - Chicago, Illinois, United States, 60614
    - Children's Memorial Hospital - Chicago
  - Chicago, Illinois, United States, 60601
    - University of Chicago Cancer Research Center
- Indiana
  - Indianapolis, Indiana, United States, 46202-5225
    - Riley Children Cancer Center at Riley Hospital for Children
- Iowa
  - Iowa City, Iowa, United States, 52242-1009
    - Holden Comprehensive Cancer Center at University of Iowa
- Kentucky
  - Lexington, Kentucky, United States, 40536-0084
    - Markey Cancer Center at University of Kentucky Chandler Medical Center
  - Louisville, Kentucky, United States, 40232
    - Kosair Children's Hospital
- Louisiana
  - New Orleans, Louisiana, United States, 70118
    - Children's Hospital of New Orleans
  - New Orleans, Louisiana, United States, 70112
    - MBCCOP - LSU Health Sciences Center
- Maine
  - Scarborough, Maine, United States, 04074-9308
    - Maine Children's Cancer Program
- Maryland
  - Baltimore, Maryland, United States, 21287
    - Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
- Massachusetts
  - Boston, Massachusetts, United States, 02115
    - Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  - Boston, Massachusetts, United States, 02111
    - Floating Hospital for Children
  - Boston, Massachusetts, United States, 02114-2696
    - Massachusetts General Hospital Cancer Center
- Michigan
  - Ann Arbor, Michigan, United States, 48109-0914
    - University Of Michigan Comprehensive Cancer Center
  - Detroit, Michigan, United States, 48201
    - Children's Hospital of Michigan
  - Grand Rapids, Michigan, United States, 49503
    - DeVos Children's Hospital
- Minnesota
  - Minneapolis, Minnesota, United States, 55455
    - University of Minnesota Cancer Center
  - Minneapolis, Minnesota, United States, 55404
    - Children's Hospitals and Clinics - Minneapolis/St. Paul
- Mississippi
  - Jackson, Mississippi, United States, 39216-4505
    - University of Mississippi Medical Center
- Missouri
  - Kansas City, Missouri, United States, 64108
    - Children's Mercy Hospital
  - Saint Louis, Missouri, United States, 63110
    - St. Louis Children's Hospital
  - Saint Louis, Missouri, United States, 63104
    - Cardinal Glennon Children's Hospital
  - Saint Louis, Missouri, United States, 63104
    - Methodist Cancer Center at Methodist Specialty and Transplant Hospital
- Nebraska
  - Omaha, Nebraska, United States, 68198-3330
    - UNMC Eppley Cancer Center at the University of Nebraska Medical Center
- New Jersey
  - Hackensack, New Jersey, United States, 07601
    - Cancer Center at Hackensack University Medical Center
- New York
  - New Hyde Park, New York, United States, 11042
    - Schneider Children's Hospital
  - New York, New York, United States, 10021
    - Memorial Sloan-Kettering Cancer Center
  - New York, New York, United States, 10016
    - NYU Cancer Institute at New York University Medical Center
  - New York, New York, United States, 10032
    - Herbert Irving Comprehensive Cancer Center at Columbia University
  - Rochester, New York, United States, 14642
    - James P. Wilmot Cancer Center at University of Rochester Medical Center
  - Syracuse, New York, United States, 13210
    - SUNY Upstate Medical University Hospital
  - Valhalla, New York, United States, 10595
    - New York Medical College
- North Carolina
  - Chapel Hill, North Carolina, United States, 27599-7070
    - Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
  - Durham, North Carolina, United States, 27710
    - Duke Comprehensive Cancer Center
- Ohio
  - Cincinnati, Ohio, United States, 45229-3039
    - Cincinnati Children's Hospital Medical Center
  - Cleveland, Ohio, United States, 44106-5065
    - Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
  - Columbus, Ohio, United States, 43205-2696
    - Columbus Children's Hospital
- Oklahoma
  - Oklahoma City, Oklahoma, United States, 73190
    - Oklahoma University Medical Center
- Oregon
  - Portland, Oregon, United States, 97225
    - CCOP - Columbia River Oncology Program
  - Portland, Oregon, United States, 97239-3098
    - Doernbecher Children's Hospital at Oregon Health & Science University
  - Portland, Oregon, United States, 97239-3098
    - Cancer Institute at Oregon Health and Science University
- Pennsylvania
  - Hershey, Pennsylvania, United States, 17033-0850
    - Children's Hospital at Milton S. Hershey Medical Center
  - Philadelphia, Pennsylvania, United States, 19104
    - Children's Hospital of Philadelphia
  - Pittsburgh, Pennsylvania, United States, 15213
    - Children's Hospital of Pittsburgh
- South Carolina
  - Charleston, South Carolina, United States, 29425
    - Hollings Cancer Center at Medical University of South Carolina
- Tennessee
  - Memphis, Tennessee, United States, 38105
    - St. Jude Children's Research Hospital
  - Nashville, Tennessee, United States, 37232-6310
    - Vanderbilt Children's Hospital
- Texas
  - Dallas, Texas, United States, 75390-9063
    - Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas
  - Fort Worth, Texas, United States, 76104
    - Cook Children's Medical Center - Fort Worth
  - Houston, Texas, United States, 77030-4009
    - M.D. Anderson Cancer Center at University of Texas
  - Houston, Texas, United States, 77030-2399
    - Baylor College of Medicine
  - San Antonio, Texas, United States, 78207
    - University of Texas Health Science Center at San Antonio
  - San Antonio, Texas, United States, 78229-3900
    - MBCCOP - South Texas Pediatrics
  - San Antonio, Texas, United States, 78229
    - Pediatric Hematology and Oncology Associates of South Texas, PLLC
  - Temple, Texas, United States, 76508
    - CCOP - Scott and White Hospital
- Utah
  - Salt Lake City, Utah, United States, 84112
    - Huntsman Cancer Institute at University of Utah
- Virginia
  - Falls Church, Virginia, United States, 22042-3300
    - INOVA Fairfax Hospital
- Washington
  - Seattle, Washington, United States, 98105
    - Children's Hospital and Regional Medical Center - Seattle
  - Spokane, Washington, United States, 99210-0248
    - Deaconess Medical Center
  - Tacoma, Washington, United States, 98431-0001
    - Madigan Army Medical Center
- Wisconsin
  - Green Bay, Wisconsin, United States, 54301
    - CCOP - St. Vincent Hospital Cancer Center, Green Bay
  - Madison, Wisconsin, United States, 53792-4108
    - University of Wisconsin Comprehensive Cancer Center
  - Marshfield, Wisconsin, United States, 54449
    - CCOP - Marshfield Clinic Research Foundation
  - Milwaukee, Wisconsin, United States, 53226
    - Midwest Children's Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 29 years (Child, Adult)

Accepts Healthy Volunteers

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Interventional Model: Single Group Assignment
Masking: Double

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression Free Survival Time Frame: Length of study	Length of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Length of study
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.	Length of study
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		Length of study
Determine if whole blood hydroxychloroquine levels correlate with response and toxicity.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Children's Oncology Group

Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair: Andrew L. Gilman, MD, UNC Lineberger Comprehensive Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2002

Primary Completion (Actual)

May 1, 2005

Study Completion (Actual)

January 1, 2011

Study Registration Dates

First Submitted

March 8, 2002

First Submitted That Met QC Criteria

January 26, 2003

First Posted (Estimate)

January 27, 2003

Study Record Updates

Last Update Posted (Estimate)

February 14, 2014

Last Update Submitted That Met QC Criteria

February 12, 2014

Last Verified

February 1, 2014

More Information

Terms related to this study

Keywords

graft versus host disease

Additional Relevant MeSH Terms

Other Study ID Numbers

ASCT0031
COG-ASCT0031 (Other Identifier: Children's Oncology Group)
CCG-S9701 (Other Identifier: Children's Cancer Group)
NCI-P02-0213

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.