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

Sponsor

Children's Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00031824

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

104

Locations

105

Duration (Months)

0.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Graft Versus Host Disease	Drug: cyclosporine Drug: hydroxychloroquine Drug: prednisone Drug: tacrolimus	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

82 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Double

Primary Purpose:

Supportive Care

Official Title:

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

Study Start Date :

Apr 1, 2002

Actual Primary Completion Date :

May 1, 2005

Actual Study Completion Date :

Jan 1, 2011

Outcome Measures

Primary Outcome Measures

Progression Free Survival [Length of study]

Secondary Outcome Measures

Compare the efficacy of a two-drug regimen [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.
Compare conventional outcomes measures [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.
To determine if cytokine levels and T helper cell subtypes (Th1 and Th2) correlate with chronic GVHD activity and response [Length of study]
Determine if whole blood hydroxychloroquine levels correlate with response and toxicity. []

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Year to 29 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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