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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00066469
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 55
• Locations: 78
• Arm: 1
• Duration (Months): 117
• Patients Per Site: 0.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Lymphoproliferative Disorder	Biological: rituximab; Drug: cyclophosphamide; Drug: methylprednisolone; Drug: prednisone	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 55 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: Apr 1, 2004
• Actual Primary Completion Date: Oct 1, 2009
• Actual Study Completion Date: Dec 31, 2013

Arms and Interventions

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: Deltaone Meticorten Orasone Liquid Pred Pediapred Sterapred NSC #010023 ; 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: Deltaone Meticorten Orasone Liquid Pred Pediapred Sterapred NSC #010023

Outcome Measures

Primary Outcome Measures

1. Event-free Survival [2 years]

   Alive in continuous complete remission with functioning original allograft. The Event Free Survival (EFS) will be estimated by the Kaplan-Meier method.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 30 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Study Chair: Thomas G. Gross, MD, PhD, Nationwide Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00066469
• Other Study ID Numbers: ANHL0221; CDR0000316241; COG-ANHL0221; NCI-2012-02544; U10CA098543
• First Posted: Aug 7, 2003
• Last Update Posted: Aug 6, 2019
• Last Verified: Sep 1, 2016

• Keywords provided by Children's Oncology Group: post-transplant lymphoproliferative disorder
• Additional relevant MeSH terms: Lymphoproliferative Disorders; Prednisone; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Rituximab; Prednisolone hemisuccinate; Prednisolone phosphate

Study Results

Participant Flow

Arm/Group Title	Cyclophosphamide, Prednisone, Rituximab
Arm/Group Description	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.
Period Title: Overall Study
STARTED	55
COMPLETED	39
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Cyclophosphamide, Prednisone, Rituximab
Arm/Group Description	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.
Overall Participants	55
Age (Count of Participants)
<=18 years	54 98.2%
Between 18 and 65 years	1 1.8%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	22 40%
Male	33 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 12.7%
Not Hispanic or Latino	46 83.6%
Unknown or Not Reported	2 3.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.8%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	7 12.7%
White	38 69.1%
More than one race	0 0%
Unknown or Not Reported	9 16.4%
Region of Enrollment (participants) [Number]
United States	46 83.6%
Canada	7 12.7%
Australia	2 3.6%

Outcome Measures

1. Primary Outcome

Title	Event-free Survival
Description	Alive in continuous complete remission with functioning original allograft. The Event Free Survival (EFS) will be estimated by the Kaplan-Meier method.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

One patient out of the 55 patients enrolled was ineligible for study and therefore was excluded from analysis.

Arm/Group Title	Cyclophosphamide, Prednisone, Rituximab
Arm/Group Description	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.
Measure Participants	54
Number (95% Confidence Interval) [percentage of participants analyzed]	71 129.1%

Adverse Events

Adverse Event Reporting Description	One patient out of the 55 patients enrolled was not eligible for this study. Only eligible patients were included in the Adverse Event (AE) analysis for both Serious and Other AE events.
Arm/Group Title	Cyclophosphamide, Prednisone, Rituximab
Arm/Group Description	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.
All Cause Mortality
	Cyclophosphamide, Prednisone, Rituximab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Cyclophosphamide, Prednisone, Rituximab
	Affected / at Risk (%)	# Events
Total	2/54 (3.7%)
Cardiac disorders
Sinus bradycardia	1/54 (1.9%)	1
General disorders
Death NOS	1/54 (1.9%)	1
Other (Not Including Serious) Adverse Events
	Cyclophosphamide, Prednisone, Rituximab
	Affected / at Risk (%)	# Events
Total	38/54 (70.4%)
Blood and lymphatic system disorders
Anemia	3/54 (5.6%)	3
Blood and lymphatic system disorders - Other, specify	1/54 (1.9%)	1
Febrile neutropenia	12/54 (22.2%)	12
Cardiac disorders
Sinus tachycardia	1/54 (1.9%)	1
Gastrointestinal disorders
Abdominal distension	1/54 (1.9%)	1
Abdominal pain	2/54 (3.7%)	2
Gastrointestinal disorders - Other, specify	1/54 (1.9%)	1
Lower gastrointestinal hemorrhage	1/54 (1.9%)	1
Mucositis oral	1/54 (1.9%)	1
Nausea	1/54 (1.9%)	1
Vomiting	1/54 (1.9%)	1
General disorders
Chills	1/54 (1.9%)	1
Death NOS	1/54 (1.9%)	1
Fever	2/54 (3.7%)	2
Hepatobiliary disorders
Hepatic hemorrhage	1/54 (1.9%)	1
Hepatic necrosis	1/54 (1.9%)	1
Infections and infestations
Bronchial infection	1/54 (1.9%)	1
Catheter related infection	3/54 (5.6%)	3
Enterocolitis infectious	2/54 (3.7%)	2
Infections and infestations - Other, specify	17/54 (31.5%)	17
Kidney infection	1/54 (1.9%)	1
Lung infection	2/54 (3.7%)	2
Peritoneal infection	1/54 (1.9%)	1
Pharyngitis	1/54 (1.9%)	1
Skin infection	1/54 (1.9%)	1
Small intestine infection	1/54 (1.9%)	1
Injury, poisoning and procedural complications
Postoperative hemorrhage	1/54 (1.9%)	1
Investigations
Alanine aminotransferase increased	6/54 (11.1%)	6
Aspartate aminotransferase increased	4/54 (7.4%)	4
Blood bilirubin increased	3/54 (5.6%)	3
Cholesterol high	1/54 (1.9%)	1
Creatinine increased	4/54 (7.4%)	4
GGT increased	5/54 (9.3%)	5
Investigations - Other, specify	1/54 (1.9%)	1
Lipase increased	2/54 (3.7%)	2
Neutrophil count decreased	15/54 (27.8%)	15
Platelet count decreased	2/54 (3.7%)	2
Serum amylase increased	2/54 (3.7%)	2
White blood cell decreased	9/54 (16.7%)	9
Metabolism and nutrition disorders
Acidosis	1/54 (1.9%)	1
Anorexia	1/54 (1.9%)	1
Dehydration	4/54 (7.4%)	4
Hyperglycemia	6/54 (11.1%)	6
Hypernatremia	3/54 (5.6%)	3
Hypertriglyceridemia	1/54 (1.9%)	1
Hyperuricemia	2/54 (3.7%)	2
Hypoalbuminemia	2/54 (3.7%)	2
Hypocalcemia	2/54 (3.7%)	2
Hypoglycemia	1/54 (1.9%)	1
Hypokalemia	6/54 (11.1%)	6
Hypomagnesemia	1/54 (1.9%)	1
Hyponatremia	5/54 (9.3%)	5
Hypophosphatemia	2/54 (3.7%)	2
Tumor lysis syndrome	1/54 (1.9%)	1
Nervous system disorders
Dizziness	1/54 (1.9%)	1
Nervous system disorders - Other, specify	1/54 (1.9%)	1
Seizure	3/54 (5.6%)	3
Psychiatric disorders
Agitation	1/54 (1.9%)	1
Renal and urinary disorders
Renal hemorrhage	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/54 (1.9%)	1
Dyspnea	3/54 (5.6%)	3
Epistaxis	1/54 (1.9%)	1
Hypoxia	3/54 (5.6%)	3
Pneumonitis	1/54 (1.9%)	1
Respiratory, thoracic and mediastinal disorders - Other, specify	1/54 (1.9%)	1
Vascular disorders
Hypertension	1/54 (1.9%)	1
Hypotension	3/54 (5.6%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Must obtain prior Sponsor approval.