Clinical trial NCT00031824: Hydroxychloroquine in Treating Patients With Newly Diagnosed Chronic Graft-Versus-Host Disease
Official title: Phase III Trial of Hydroxychloroquine + Standard Therapy for Chronic Graft-Versus-Host Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Graft Versus Host Disease
Keywords: graft versus host disease
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 82
Sex: ALL
Minimum age (years): 1
Maximum age (years): 29
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief 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.

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.

Eligibility 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"

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

Primary outcomes:
measure: Progression Free Survival
timeFrame: Length of study
Secondary outcomes:
measure: Compare the efficacy of a two-drug regimen
timeFrame: Length of study
measure: Compare conventional outcomes measures
timeFrame: Length of study
measure: To determine if cytokine levels and T helper cell subtypes (Th1 and Th2) correlate with chronic GVHD activity and response
timeFrame: Length of study
measure: Determine if whole blood hydroxychloroquine levels correlate with response and toxicity.
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Cancer Center at University of Arizona Health Sciences Center
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
state: Arkansas
city: Downey
country: United States
facility: Southern California Permanente Medical Group
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Los Angeles
country: United States
facility: University Medical Center at Princeton
state: California
city: Los Angeles
country: United States
facility: Kaiser Permanente Medical Center - Los Angeles
state: California
city: Los Angeles
country: United States
facility: Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: Jonsson Comprehensive Cancer Center at UCLA
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital at Stanford University Medical Center
state: California
city: San Diego
country: United States
facility: Children's Hospital and Health Center, San Diego
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
city: Colorado Springs
country: United States
facility: Presbyterian - St. Luke's Medical Center
state: Colorado
city: Denver
country: United States
facility: Children's Hospital Cancer Center
state: Colorado
city: Washington
country: United States
facility: Lombardi Cancer Center at Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Gainesville
country: United States
facility: University of Florida Shands Cancer Center
state: Florida
city: Jacksonville
country: United States
facility: Nemours Children's Clinic
state: Florida
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: St. Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus
state: Georgia
city: Augusta
country: United States
facility: MBCCOP-Medical College of Georgia Cancer Center
state: Georgia
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Chicago
country: United States
facility: University of Chicago Cancer Research Center
state: Illinois
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Children Cancer Center at Riley Hospital for Children
state: Indiana
city: Iowa City
country: United States
facility: Holden Comprehensive Cancer Center at University of Iowa
state: Iowa
city: Lexington
country: United States
facility: Markey Cancer Center at University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: MBCCOP - LSU Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Children's Hospital of New Orleans
state: Louisiana
city: Scarborough
country: United States
facility: Maine Children's Cancer Program
state: Maine
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Floating Hospital for Children
state: Massachusetts
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Comprehensive Cancer Center
state: Michigan
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Grand Rapids
country: United States
facility: DeVos Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics - Minneapolis/St. Paul
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Cardinal Glennon Children's Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Methodist Cancer Center at Methodist Specialty and Transplant Hospital
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Omaha
country: United States
facility: UNMC Eppley Cancer Center at the University of Nebraska Medical Center
state: Nebraska
city: Hackensack
country: United States
facility: Cancer Center at Hackensack University Medical Center
state: New Jersey
city: New Hyde Park
country: United States
facility: Schneider Children's Hospital
state: New York
city: New York
country: United States
facility: NYU Cancer Institute at New York University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University
state: New York
city: Rochester
country: United States
facility: James P. Wilmot Cancer Center at University of Rochester Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
state: North Carolina
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Ireland Cancer Center at University Hospitals of Cleveland and Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Columbus Children's Hospital
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Medical Center
state: Oklahoma
city: Portland
country: United States
facility: CCOP - Columbia River Oncology Program
state: Oregon
city: Portland
country: United States
facility: Cancer Institute at Oregon Health and Science University
state: Oregon
city: Portland
country: United States
facility: Doernbecher Children's Hospital at Oregon Health & Science University
state: Oregon
city: Hershey
country: United States
facility: Children's Hospital at Milton S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Charleston
country: United States
facility: Hollings Cancer Center at Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Children's Hospital
state: Tennessee
city: Dallas
country: United States
facility: Simmons Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center - Fort Worth
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: M.D. Anderson Cancer Center at University of Texas
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: San Antonio
country: United States
facility: MBCCOP - South Texas Pediatrics
state: Texas
city: San Antonio
country: United States
facility: Pediatric Hematology and Oncology Associates of South Texas, PLLC
state: Texas
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute at University of Utah
state: Utah
city: Falls Church
country: United States
facility: INOVA Fairfax Hospital
state: Virginia
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Spokane
country: United States
facility: Deaconess Medical Center
state: Washington
city: Tacoma
country: United States
facility: Madigan Army Medical Center
state: Washington
city: Green Bay
country: United States
facility: CCOP - St. Vincent Hospital Cancer Center, Green Bay
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin Comprehensive Cancer Center
state: Wisconsin
city: Marshfield
country: United States
facility: CCOP - Marshfield Clinic Research Foundation
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Westmead
country: Australia
facility: Children's Hospital at Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Children's Hospital
state: Queensland
city: North Adelaide
country: Australia
facility: Women's and Children's Hospital
state: South Australia
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Calgary
country: Canada
facility: Alberta Children's Hospital
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: McGill Cancer Centre at McGill University
state: Quebec
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
city: Auckland
country: New Zealand
facility: Starship Children's Health
city: Santurce
country: Puerto Rico
facility: San Jorge Children's Hospital
city: Bern
country: Switzerland
facility: Swiss Pediatric Oncology Group Bern
city: Lausanne
country: Switzerland
facility: Swiss Pediatric Oncology Group Lausanne
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Andrew L. Gilman, MD
role: STUDY_CHAIR
References:
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 chronic graft-versus-host disease in children: a Children's Oncology Group study. Biol Blood Marrow Transplant. 2012 Jan;18(1):84-91. doi: 10.1016/j.bbmt.2011.05.016. Epub 2011 May 30.
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 Children's Oncology Group Study ASCT0031. Biol Blood Marrow Transplant. 2011 Dec;17(12):1804-13. doi: 10.1016/j.bbmt.2011.05.011. Epub 2011 May 25.
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.
citation: 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 from the Children's Oncology Group. Blood. 2008 Mar 15;111(6):3276-85. doi: 10.1182/blood-2007-08-106286. Epub 2007 Oct 9.