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

Graft Versus Host Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00031824
• Other study ID #: ASCT0031
• Secondary ID: COG-ASCT0031CCG-
• Status: Completed
• Phase: Phase 3
• First received: March 8, 2002
• Last updated: February 12, 2014
• Start date: April 2002
• Est. completion date: January 2011

Study information

• Verified date: February 2014
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 82
• Est. completion date: January 2011
• Est. primary completion date: May 2005
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 1 Year to 29 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Double-Blind, Primary Purpose: Supportive Care

Related Conditions & MeSH terms

• Graft Versus Host Disease
• Graft vs Host Disease

Intervention

Drug:
• cyclosporine

• hydroxychloroquine

• prednisone

• tacrolimus

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Brisbane	Queensland
Australia	Women's and Children's Hospital	North Adelaide	South Australia
Australia	Royal Children's Hospital	Parkville	Victoria
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	McGill Cancer Centre at McGill University	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Starship Children's Health	Auckland
Puerto Rico	San Jorge Children's Hospital	Santurce
Switzerland	Swiss Pediatric Oncology Group Bern	Bern
Switzerland	Swiss Pediatric Oncology Group Lausanne	Lausanne
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus	Atlanta	Georgia
United States	MBCCOP-Medical College of Georgia Cancer Center	Augusta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Floating Hospital for Children	Boston	Massachusetts
United States	Massachusetts General Hospital Cancer Center	Boston	Massachusetts
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	Hollings Cancer Center at Medical University of South Carolina	Charleston	South Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University	Cleveland	Ohio
United States	Presbyterian - St. Luke's Medical Center	Colorado Springs	Colorado
United States	Columbus Children's Hospital	Columbus	Ohio
United States	Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Children's Hospital Cancer Center	Denver	Colorado
United States	Children's Hospital of Michigan	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	City of Hope Comprehensive Cancer Center	Duarte	California
United States	Duke Comprehensive Cancer Center	Durham	North Carolina
United States	INOVA Fairfax Hospital	Falls Church	Virginia
United States	Cook Children's Medical Center - Fort Worth	Fort Worth	Texas
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	DeVos Children's Hospital	Grand Rapids	Michigan
United States	CCOP - St. Vincent Hospital Cancer Center, Green Bay	Green Bay	Wisconsin
United States	Cancer Center at Hackensack University Medical Center	Hackensack	New Jersey
United States	Children's Hospital at Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	Cancer Research Center of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	M.D. Anderson Cancer Center at University of Texas	Houston	Texas
United States	Riley Children Cancer Center at Riley Hospital for Children	Indianapolis	Indiana
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	Markey Cancer Center at University of Kentucky Chandler Medical Center	Lexington	Kentucky
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	Jonsson Comprehensive Cancer Center at UCLA	Los Angeles	California
United States	Kaiser Permanente Medical Center - Los Angeles	Los Angeles	California
United States	Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center	Los Angeles	California
United States	University Medical Center at Princeton	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin
United States	CCOP - Marshfield Clinic Research Foundation	Marshfield	Wisconsin
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Miami Children's Hospital	Miami	Florida
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics - Minneapolis/St. Paul	Minneapolis	Minnesota
United States	University of Minnesota Cancer Center	Minneapolis	Minnesota
United States	Vanderbilt Children's Hospital	Nashville	Tennessee
United States	Schneider Children's Hospital	New Hyde Park	New York
United States	Children's Hospital of New Orleans	New Orleans	Louisiana
United States	MBCCOP - LSU Health Sciences Center	New Orleans	Louisiana
United States	Herbert Irving Comprehensive Cancer Center at Columbia University	New York	New York
United States	Memorial Sloan-Kettering Cancer Center	New York	New York
United States	NYU Cancer Institute at New York University Medical Center	New York	New York
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Oklahoma University Medical Center	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Children's Hospital of Orange County	Orange	California
United States	Lucile Packard Children's Hospital at Stanford University Medical Center	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Cancer Institute at Oregon Health and Science University	Portland	Oregon
United States	CCOP - Columbia River Oncology Program	Portland	Oregon
United States	Doernbecher Children's Hospital at Oregon Health & Science University	Portland	Oregon
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Cardinal Glennon Children's Hospital	Saint Louis	Missouri
United States	Methodist Cancer Center at Methodist Specialty and Transplant Hospital	Saint Louis	Missouri
United States	St. Louis Children's Hospital	Saint Louis	Missouri
United States	Huntsman Cancer Institute at University of Utah	Salt Lake City	Utah
United States	MBCCOP - South Texas Pediatrics	San Antonio	Texas
United States	Pediatric Hematology and Oncology Associates of South Texas, PLLC	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Children's Hospital and Health Center, San Diego	San Diego	California
United States	UCSF Comprehensive Cancer Center	San Francisco	California
United States	Maine Children's Cancer Program	Scarborough	Maine
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Deaconess Medical Center	Spokane	Washington
United States	All Children's Hospital	St. Petersburg	Florida
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	Madigan Army Medical Center	Tacoma	Washington
United States	CCOP - Scott and White Hospital	Temple	Texas
United States	Arizona Cancer Center at University of Arizona Health Sciences Center	Tucson	Arizona
United States	New York Medical College	Valhalla	New York
United States	Children's National Medical Center	Washington	District of Columbia
United States	Lombardi Cancer Center at Georgetown University Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand,  Puerto Rico,  Switzerland, 

References & Publications (4)

Fujii H, Cuvelier G, She K, Aslanian S, Shimizu H, Kariminia A, Krailo M, Chen Z, McMaster R, Bergman A, Goldman F, Grupp SA, Wall DA, Gilman AL, Schultz KR. Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report fro — View Citation

Gilman AL, Schultz KR, Goldman FD, Sale GE, Krailo MD, Chen Z, Langholz B, Jacobsohn DA, Chan KW, Ryan RE, Kellick M, Neudorf SM, Godder K, Sandler ES, Sahdev I, Grupp SA, Sanders JE, Wall DA. Randomized trial of hydroxychloroquine for newly diagnosed chr — View Citation

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). 2010 Dec;3(12):1579-85. doi: 10.1158/1940-6207.CAPR-09-0218. — View Citation

Rozmus J, Schultz KR, Wynne K, Kariminia A, Satyanarayana P, Krailo M, Grupp SA, Gilman AL, Goldman FD. Early and late extensive chronic graft-versus-host disease in children is characterized by different Th1/Th2 cytokine profiles: findings of the Childre — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression Free Survival		Length of study	Yes
Secondary	Compare the efficacy of a two-drug regimen	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	Yes
Secondary	Compare conventional outcomes measures	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	Yes
Secondary	To determine if cytokine levels and T helper cell subtypes (Th1 and Th2) correlate with chronic GVHD activity and response		Length of study	No
Secondary	Determine if whole blood hydroxychloroquine levels correlate with response and toxicity.			No