Cyclophosphamide, Rituximab, and Either Prednisone or Methylprednisolone in Treating Patients With Lymphoproliferative Disease After Solid Organ Transplantation

Lymphoproliferative Disorder Clinical Trial

Official title:

Phase II Study of Cyclophosphamide, Prednisone and Rituximab (CPR) in Children, Adolescents and Young Adults With B-lymphocyte Antigen CD20 (CD20) Positive Post-Transplant Lymphoproliferative Disease (PTLD) Following Solid Organ Transplantation (SOT)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00066469
• Other study ID #: ANHL0221
• Secondary ID: CDR0000316241COG
• Status: Completed
• Phase: Phase 2
• Start date: April 2004
• Est. completion date: December 31, 2013

Study information

• Verified date: September 2016
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy such as cyclophosphamide, prednisone, and methylprednisolone use different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies such as rituximab can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining cyclophosphamide and either prednisone or methylprednisolone with rituximab may be effective in treating lymphoproliferative disease following organ transplantation.

PURPOSE: Phase II trial to study the effectiveness of combining cyclophosphamide and either prednisone or methylprednisolone with rituximab in treating patients who have Epstein-Barr virus-positive lymphoproliferative disease following organ transplantation.

Description:

OBJECTIVES:

• Determine the safety and toxicity of cyclophosphamide, rituximab, and prednisone or methylprednisolone in patients with CD20-positive and Epstein-Barr virus-positive post-transplant lymphoproliferative disease (PTLD) after solid organ transplantation.

• Determine the 2-year event-free survival, defined as alive and in continuous complete remission with a functioning original allograft, of patients treated with this regimen.

• Determine the response rate in patients treated with this regimen.

• Determine the PTLD gene expression profile by microarray analysis and fluorescent in situ hybridization in patients treated with this regimen.

• Determine the accrual rate of patients to this study.

OUTLINE: This is a multicenter study.

Patients receive cyclophosphamide IV over 30-60 minutes on day 1 and oral prednisone or methylprednisolone IV twice daily on days 1-5. During courses 1 and 2 only, patients also receive rituximab IV over 2-5 hours on days 1, 8, and 15. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression, a new primary or secondary malignancy, or unrelated disease.

After finishing study treatment, patients are followed periodically for at least 5 years.

PROJECTED ACCRUAL: A total of 60 patients (50 with non-fulminant post-transplant lymphoproliferative disease [PTLD] and 10 fulminant PTLD) will be accrued for this study within 2.5-3 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: December 31, 2013
• Est. primary completion date: October 1, 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Years

Eligibility

DISEASE CHARACTERISTICS:

• Histologically confirmed post-transplant lymphoproliferative disease (PTLD)

• Presents with 1 of the following:

• Fulminant PTLD (F-PTLD)

• Fever greater than 38°C

• Hypotensive (for age)

• Evidence of multiple organ involvement/failure, including at least 2 of the following:

• Marrow (including pancytopenia without detectable B-cell proliferation)

• Liver (coagulopathy, transaminitis, and/or hyperbilirubinemia)

• Lungs (interstitial pneumonitis with or without pleural effusions)

• Gastrointestinal tract hemorrhage

• Non-fulminant PTLD (NF-PTLD)

• Does not meet the above F-PTLD criteria

• Considered medically refractory to reduced immune suppression (50% or more reduction of immunosuppression) for at least 1 week

• CD20 positive AND Epstein-Barr virus positive

• Must have received prior solid organ transplantation

• Must have residual disease after biopsy and/or surgery

• No PTLD central nervous system (CNS) disease, defined as positive cytology and/or radiographic evidence

PATIENT CHARACTERISTICS:

Age

• Under 31

Performance status

• Not specified

Life expectancy

• NF-PTLD patients:

• At least 8 weeks

Hematopoietic

• See Disease Characteristics

Hepatic

• See Disease Characteristics

Renal

• Not specified

Pulmonary

• See Disease Characteristics

Other

• Not pregnant or nursing

• Fertile patients must use effective contraception

• HIV negative

PRIOR CONCURRENT THERAPY:

Biologic therapy

• More than 1 month since prior rituximab

Chemotherapy

• More than 4 weeks since prior chemotherapy and recovered

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• See Disease Characteristics

Related Conditions & MeSH terms

• Lymphoproliferative Disorder
• Lymphoproliferative Disorders

Intervention

Biological:
• rituximab
Cycles 1 and 2 only: Given IV Incremental: First dosage: < 21 years of age: 0.5mg/kg/hr (maximum of 50 mg/hr) for the 1st hour = 21 years of age: 50 mg/hr for the 1st hour. Subsequent dosages: < 21 years of age: 1.0mg/kg/hr (maximum of 50 mg/hr) for the 1st hour = 21 years of age: 100 mg/hr for the 1st hour. Days 1, 8 and 15.

Drug:
• cyclophosphamide
Given IV over 30-60 minutes Dose 600 mg/m2 in 50-250 mL of normal saline (NS) or Dextrose-Water 5%(D5W) (at a maximum concentration of 20 mg/ml) over 30-60 minutes on day 1 of each cycle
• methylprednisolone
Methylprednisolone 0.8 mg/kg IV over 12 hours on days 1,2,3,4 and 5 of each cycle.
• prednisone
Dosage 1 mg/kg orally every 12 hours on days 1,2,3,4 and 5 of each cycle. Oral prednisone may be rounded up to the nearest 2.5 mg as necessary for tablet size

Locations

Country	Name	City	State
Australia	Royal Children's Hospital	Brisbane	Queensland
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Westmead Institute for Cancer Research at Westmead Hospital	Westmead	New South Wales
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Hopital Sainte Justine	Montreal	Quebec
Canada	Montreal Children's Hospital at McGill University Health Center	Montreal	Quebec
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	Children's & Women's Hospital of British Columbia	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Starship Children's Health	Auckland
New Zealand	Christchurch Hospital	Christchurch
United States	Akron Children's Hospital	Akron	Ohio
United States	Tulane Cancer Center Office of Clinical Research	Alexandria	Louisiana
United States	C.S. Mott Children's Hospital at University of Michigan Medical Center	Ann Arbor	Michigan
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Children's Hospital Center for Cancer and Blood Disorders	Aurora	Colorado
United States	Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham	Birmingham	Alabama
United States	Fletcher Allen Health Care - University Health Center Campus	Burlington	Vermont
United States	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina
United States	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia
United States	Blumenthal Cancer Center at Carolinas Medical Center	Charlotte	North Carolina
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	University of Chicago Cancer Research Center	Chicago	Illinois
United States	University of Illinois Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Ellis Fischel Cancer Center at University of Missouri - Columbia	Columbia	Missouri
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Inova Fairfax Hospital	Falls Church	Virginia
United States	Lee Cancer Care of Lee Memorial Health System	Fort Myers	Florida
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	Butterworth Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Hackensack University Medical Center Cancer Center	Hackensack	New Jersey
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	University of Mississippi Cancer Clinic	Jackson	Mississippi
United States	Nemours Children's Clinic	Jacksonville	Florida
United States	CCOP - Kalamazoo	Kalamazoo	Michigan
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Children's Hospital	Knoxville	Tennessee
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Arkansas Cancer Research Center at University of Arkansas for Medical Sciences	Little Rock	Arkansas
United States	Loma Linda University Cancer Institute at Loma Linda University Medical Center	Loma Linda	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin
United States	University of Miami Sylvester Comprehensive Cancer Center - Miami	Miami	Florida
United States	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	Children's Hospital of The King's Daughters	Norfolk	Virginia
United States	Oklahoma University Cancer Institute	Oklahoma City	Oklahoma
United States	UNMC Eppley Cancer Center at the University of Nebraska Medical Center	Omaha	Nebraska
United States	Sacred Heart Cancer Center at Sacred Heart Hospital	Pensacola	Florida
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Hospital and Health Center and Children's Hospital	Portland	Oregon
United States	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York
United States	Mayo Clinic Cancer Center	Rochester	Minnesota
United States	Kaiser Permanente Medical Center - Oakland	Sacramento	California
United States	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Methodist Children's Hospital of South Texas	San Antonio	Texas
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington
United States	Simmons Cooper Cancer Institute	Springfield	Illinois
United States	Stanford Cancer Center	Stanford	California
United States	SUNY Upstate Medical University Hospital	Syracuse	New York
United States	New York Medical College	Valhalla	New York
United States	Alfred I. duPont Hospital for Children	Wilmington	Delaware

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, 

References & Publications (1)

Gross TG, Orjuela MA, Perkins SL, Park JR, Lynch JC, Cairo MS, Smith LM, Hayashi RJ. Low-dose chemotherapy and rituximab for posttransplant lymphoproliferative disease (PTLD): a Children's Oncology Group Report. Am J Transplant. 2012 Nov;12(11):3069-75. d — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Event-free Survival	Alive in continuous complete remission with functioning original allograft. The Event Free Survival (EFS) will be estimated by the Kaplan-Meier method.	2 years