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

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)

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.

Study Overview

• Status: Completed
• Conditions: Lymphoproliferative Disorder
• Intervention / Treatment: Biological: rituximab; Drug: cyclophosphamide; Drug: methylprednisolone; Drug: prednisone

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • Westmead Institute for Cancer Research at Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4029
      • Royal Children's Hospital
  • Western Australia
    • Perth, Western Australia, Australia, 6001
      • Princess Margaret Hospital for Children
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • University of Alberta Hospital
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3V4
      • Children's & Women's Hospital of British Columbia
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 6R8
      • IWK Health Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada, H3H 1P3
      • Montreal Children's Hospital at McGill University Health Center
    • Montreal, Quebec, Canada, H3T 1C5
      • Hopital Sainte Justine
• New Zealand
  • Auckland, New Zealand, 1
    • Starship Children's Health
  • Christchurch, New Zealand
    • Christchurch Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Lurleen Wallace Comprehensive Cancer at University of Alabama - Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Arkansas Cancer Research Center at University of Arkansas for Medical Sciences
  • California
    • Downey, California, United States, 90242-2814
      • Southern California Permanente Medical Group
    • Loma Linda, California, United States, 92354
      • Loma Linda University Cancer Institute at Loma Linda University Medical Center
    • Sacramento, California, United States, 95825
      • Kaiser Permanente Medical Center - Oakland
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
    • Stanford, California, United States, 94305-5824
      • Stanford Cancer Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Center for Cancer and Blood Disorders
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Lee Cancer Care of Lee Memorial Health System
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
    • Pensacola, Florida, United States, 32504
      • Sacred Heart Cancer Center at Sacred Heart Hospital
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Chicago, Illinois, United States, 60637-1470
      • University of Chicago Cancer Research Center
    • Chicago, Illinois, United States, 60612-7243
      • University of Illinois Cancer Center
    • Chicago, Illinois, United States, 60614
      • Children's Memorial Hospital - Chicago
    • Springfield, Illinois, United States, 62794-9677
      • Simmons Cooper Cancer Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
  • Kentucky
    • Louisville, Kentucky, United States, 40232
      • Kosair Children's Hospital
  • Louisiana
    • Alexandria, Louisiana, United States, 71315-3198
      • Tulane Cancer Center Office of Clinical Research
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0286
      • C.S. Mott Children's Hospital at University of Michigan Medical Center
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49503-2560
      • Butterworth Hospital at Spectrum Health
    • Kalamazoo, Michigan, United States, 49007-5341
      • CCOP - Kalamazoo
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center at University of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Cancer Clinic
  • Missouri
    • Columbia, Missouri, United States, 65203
      • Ellis Fischel Cancer Center at University of Missouri - Columbia
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Hospital
    • Saint Louis, Missouri, United States, 63110
      • Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
  • Nebraska
    • Omaha, Nebraska, United States, 68198-6805
      • UNMC Eppley Cancer Center at the University of Nebraska Medical Center
  • Nevada
    • Las Vegas, Nevada, United States, 89109-2306
      • Sunrise Hospital and Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Cancer Center
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
    • Charlotte, North Carolina, United States, 28232-2861
      • Blumenthal Cancer Center at Carolinas Medical Center
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Cleveland, Ohio, United States, 44106-5000
      • Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205-2696
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma University Cancer Institute
  • Oregon
    • Portland, Oregon, United States, 97227
      • Legacy Emanuel Hospital and Health Center and Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-9786
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Tennessee
    • Knoxville, Tennessee, United States, 37901
      • East Tennessee Children's Hospital
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Dallas, Texas, United States, 75230
      • Medical City Dallas Hospital
    • San Antonio, Texas, United States, 78229-3993
      • Methodist Children's Hospital of South Texas
    • San Antonio, Texas, United States, 78207
      • University of Texas Health Science Center at San Antonio
  • Utah
    • Salt Lake City, Utah, United States, 84113-1100
      • Primary Children's Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • Fletcher Allen Health Care - University Health Center Campus
  • Virginia
    • Falls Church, Virginia, United States, 22042-3300
      • Inova Fairfax Hospital
    • Norfolk, Virginia, United States, 23507-1971
      • Children's Hospital of The King's Daughters
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center - Seattle
  • West Virginia
    • Charleston, West Virginia, United States, 25302
      • West Virginia University Health Sciences Center - Charleston
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic - Marshfield Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 30 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Cyclophosphamide, prednisone, rituximab; 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; 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.; Other Names: IDEC-C2B8; NSC #687451; 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; Other Names: Cytoxan; NSC #26271; Drug: methylprednisolone; Methylprednisolone 0.8 mg/kg IV over 12 hours on days 1,2,3,4 and 5 of each cycle.; Other Names: Orasone; Meticorten; Liquid Pred; Sterapred; Pediapred; NSC #010023; Deltaone; Drug: 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; Other Names: Orasone; Meticorten; Liquid Pred; Sterapred; Pediapred; NSC #010023; Deltaone

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Thomas G. Gross, MD, PhD, Nationwide Children's Hospital

Publications and helpful links

General Publications

• 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. doi: 10.1111/j.1600-6143.2012.04206.x. Epub 2012 Aug 6.

Study record dates

Study Major Dates

• Study Start: April 1, 2004
• Primary Completion (Actual): October 1, 2009
• Study Completion (Actual): December 31, 2013

Study Registration Dates

• First Submitted: August 6, 2003
• First Submitted That Met QC Criteria: August 6, 2003
• First Posted (Estimate): August 7, 2003

Study Record Updates

• Last Update Posted (Actual): August 6, 2019
• Last Update Submitted That Met QC Criteria: July 25, 2019
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: post-transplant lymphoproliferative disorder
• Additional Relevant MeSH Terms: Immune System Diseases; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoproliferative Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Cyclophosphamide; Rituximab; Prednisone
• Other Study ID Numbers: ANHL0221; U10CA098543 (U.S. NIH Grant/Contract); CDR0000316241 (Other Identifier: Clinical Trials.gov); COG-ANHL0221 (Other Identifier: Children's Oncology Group); NCI-2012-02544 (Other Identifier: NCI)