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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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)

Conditions
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Lymphoproliferative Disorder

Intervention / Treatment
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* Biological: rituximab
* Drug: cyclophosphamide
* Drug: methylprednisolone
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide, prednisone, rituximab<br>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 | Biological: rituximab<br>* 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.<br>* Other names: NSC #687451;Drug: cyclophosphamide<br>* 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<br>* Other names: NSC #26271;Drug: methylprednisolone<br>* Methylprednisolone 0.8 mg/kg IV over 12 hours on days 1,2,3,4 and 5 of each cycle.<br>* Other names: NSC #010023;Drug: prednisone<br>* 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<br>* Other names: NSC #010023;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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post-transplant lymphoproliferative disorder