Rituximab and Combination Chemotherapy in Treating Patients With Newly Diagnosed, HIV-Associated Burkitt's Lymphoma

• Sponsor: AIDS Malignancy Consortium (Other)
• Overall Status: Completed
• CT.gov ID: NCT00392834
• Collaborator: National Cancer Institute (NCI) (NIH), The Emmes Company, LLC (Industry)
• Enrollment: 34
• Locations: 13
• Arms: 2
• Duration (Months): 82
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving rituximab together with combination chemotherapy may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving rituximab together with combination chemotherapy works in treating patients with newly diagnosed, HIV-associated Burkitt's lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma	Biological: filgrastim; Biological: pegfilgrastim; Biological: rituximab; Drug: cyclophosphamide; Drug: cytarabine; Drug: doxorubicin hydrochloride; Drug: etoposide; Drug: ifosfamide; Drug: leucovorin calcium; Drug: liposomal cytarabine; Drug: methotrexate; Drug: therapeutic hydrocortisone; Drug: vincristine sulfate	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the efficacy of rituximab, cyclophosphamide, vincristine, doxorubicin hydrochloride, and high-dose methotrexate (R-CODOX-M ) alone or alternating with rituximab and ifosfamide, etoposide phosphate, and high-dose cytarabine (IVAC) and intrathecal CNS prophylaxis in patients with newly diagnosed, previously untreated, HIV-associated Burkitt's lymphoma or atypical Burkitt's lymphoma.

• Determine the safety of this regimen in these patients.

Secondary

• Evaluate downstream effectors of apoptosis as mechanisms of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.

• Evaluate multi-drug resistance gene expression as a mechanism of chemotherapy resistance and prognosis and perform exploratory analysis of their relationship to treatment effect.

• Confirm the use of flow cytometry in the identification of occult leptomeningeal disease and determine whether abnormal flow cytometry is predictive when CNS cytology is negative for malignant cells.

• Determine the biologic and prognostic significance of Epstein-Barr virus (EBV)-positive Burkitt's lymphoma in the highly active antiretroviral therapy era and perform exploratory analysis of their relationship to treatment effect.

• Compare genotyping in patients with HIV-associated Burkitt's lymphoma with that of patients who are HIV-negative and determine whether they are uniform in their genetic profile or whether some cases are more like diffuse large B-cell lymphoma.

• Determine if EBV detection in cerebrospinal fluid at diagnosis is predictive of leptomeningeal disease.

OUTLINE: This is a prospective, multicenter study. Patients are stratified according to risk category (low-risk vs high-risk). Patients with low-risk disease receive 3 courses of R-CODOX-M chemotherapy as described below. Patients with high-risk disease receive 4 alternating courses of R-CODOX-M/IVAC chemotherapy as described below in an A/B/A/B sequence.* Courses repeat every 21-28 days in the absence of disease progression or unacceptable toxicity.

NOTE: *In patients presenting with anasarca, pleural effusion, or ascites, methotrexate can pool causing difficulties with clearance; in this case, treatment may be given in a reverse sequence: B/A/B/A.

• Regimen A (R-CODOX-M chemotherapy): Patients receive rituximab** IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim subcutaneously (SC) on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until the methotrexate level is less than 50 nmol/L. Patients receive CNS prophylaxis comprising methotrexate intrathecally (IT), cytarabine IT, and hydrocortisone IT on day

1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive filgrastim (G-CSF) SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.

• Regimen B (rituximab and IVAC chemotherapy): Patients receive rituximab** IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover.

Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.

NOTE: **Rituximab may be given up to 3 days before a chemotherapy course and anytime during the course for 3 (low-risk disease) or 4 (high-risk disease) total doses.

Patients undergo blood and cerebrospinal fluid collection and tumor biopsies periodically during study treatment for correlative studies of prognostic biomarkers predictive of survival (e.g., c-flip protein expression; p53 mutations [by immunohistochemistry (IHC)]; multidrug resistance gene expression [by IHC]; and Epstein-Barr virus in tumor DNA or cerebrospinal fluid [by polymerase chain reaction]); genotyping of Burkitt's lymphoma; and flow cytometry as a tool (by staining) for detecting occult positivity of leptomeningeal disease in Burkitt's lymphoma.

After completion of study treatment, patients are followed every 4 months for at least 2 years.

PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Phase II Study of a High Dose, Short Course Regimen (R-CODOX-M/IVAC) Including CNS Penetration and Intensive IT Prophylaxis in HIV-Associated Burkitt's and Atypical Burkitt's Lymphoma
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Jul 1, 2011
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regimen A (R-CODOX-M chemotherapy) Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.	Biological: filgrastim; given subcutaneously; Biological: pegfilgrastim; given subcutaneously; Biological: rituximab; given IV; Drug: cyclophosphamide; given IV; Drug: cytarabine; given intrathecally; Drug: doxorubicin hydrochloride; given IV; Drug: leucovorin calcium; given IV; Drug: liposomal cytarabine; given intrathecally; Drug: methotrexate; given intrathecally; Drug: therapeutic hydrocortisone; given intrathecally; Drug: vincristine sulfate; given IV
Experimental: Regimen B (rituximab and IVAC chemotherapy) Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.	Biological: filgrastim; given subcutaneously; Biological: pegfilgrastim; given subcutaneously; Biological: rituximab; given IV; Drug: cytarabine; given intrathecally; Drug: etoposide; given IV; Drug: ifosfamide; given IV; Drug: liposomal cytarabine; given intrathecally; Drug: methotrexate; given intrathecally; Drug: therapeutic hydrocortisone; given intrathecally

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) at 1 Year [1 year post treatment]

Secondary Outcome Measures

1. Complete Response Rate [6-8 weeks post treatment, every 4 months post-treatment for 2 years]

2. Failure-free Survival (FFS) [6-8 weeks post treatment, every 4 months post-treatment for 2 years]

3. Event-free Survival (EFS) [6-8 weeks post treatment, every 4 months post-treatment for 2 years]

4. Toxicity [baseline through 2 years post-treatment]

5. Incidence of Infection-related Deaths [baseline through 2 years post-treatment]

6. Correlation of C-flip Expression, p53 Mutations, and Multidrug Resistance Expression With OS, FFS, and EFS [baseline through 2 years post-treatment]

7. Utility of Flow Cytometry in Detecting Leptomeningeal Disease [baseline and 6-8 weeks post-treatment]

8. Degree of Disconcordance Between Flow Cytometry and CNS Cytology Results [baseline]

9. Biologic and Prognostic Significance of Epstein-Barr Virus (EBV) at Diagnosis and Correlation With OS, FFS, and EFS [baseline through 2 years post-treatment]

10. Correlation of EBV Load Measurements With OS, FFS, and EFS [baseline through 2 years post-treatment]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed Burkitt's lymphoma (BL) or new WHO 2009 criteria B-cell lymphoma unclassified (with features intermediated between difuse large B-cell lymphoma and BL)

• Any stage disease

• Newly diagnosed disease

• Meets 1 of the following criteria for disease risk:

• Low-risk disease, defined by 1 of the following:

• Stage I with a single focus of disease < 10 cm AND normal lactate dehydrogenase (LDH) level

• Totally resected intra-abdominal disease only AND normal LDH post surgery

• High-risk disease, defined as not meeting criteria for low-risk disease

• Measurable or nonmeasurable disease

• HIV-positive confirmed by enzyme-linked immunosorbent assay and Western blot OR by measurable HIV viral load

• No visceral Kaposi's sarcoma

PATIENT CHARACTERISTICS:

• Karnofsky performance status 40-100%

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• LVEF ≥ 50% by MUGA or echocardiogram

• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

• Absolute neutrophil count ≥ 1,000/mm³

• Platelet count ≥ 50,000/mm³ (unless related to lymphoma)*

• Direct bilirubin ≤ 2.0 mg/dL OR total bilirubin ≤ 3.5 mg/dL AND direct bilirubin normal (if elevated bilirubin secondary to antiretroviral therapy)

• AST and ALT ≤ 3 times upper limit of normal

• No other malignancy within the past 5 years except curatively treated cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, or cutaneous Kaposi's sarcoma

• No other medical illness unrelated to non-Hodgkin's lymphoma, including any of the following:

• Uncontrolled infection (including opportunistic infection)

• Chronic renal insufficiency

• Myocardial infarction within the past 6 months

• Unstable angina

• Cardiac arrhythmias other than chronic atrial fibrillation

• Patients with active hepatitis B infection are eligible provided they receive concurrent dual antiviral therapy NOTE: *Patients with bone marrow involvement are eligible irrespective of blood count

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No prior therapy for this disease except for 1 of the following :

• Seven consecutive days of steroids alone or in combination with a non-CHOP regimen necessary for patient stabilization (e.g., cyclophosphamide and steroids steroids for normalization of disease-related hyperbilirubinemia)

• One course of CHOP or fractionated CHOP (e.g. CODOX) with or without rituximab

• No epoetin alfa or filgrastim (G-CSF) within 24 hours of study chemotherapy

• No concurrent zidovudine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Rebecca and John Moores UCSD Cancer Center	La Jolla	California	United States	92093-0658
2	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
3	UCLA Clinical AIDS Research and Education (CARE) Center	Los Angeles	California	United States	90095-1793
4	UCSF Medical Center at Parnassus	San Francisco	California	United States	94143-0296
5	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
8	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York	United States	10461
9	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065
10	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240
11	Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia	Philadelphia	Pennsylvania	United States	19106
12	Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center	Seattle	Washington	United States	98101
13	West Virginia University Health Sciences Center - Charleston	Charleston	West Virginia	United States	25304

Sponsors and Collaborators

• AIDS Malignancy Consortium
• National Cancer Institute (NCI)
• The Emmes Company, LLC

Investigators

• Study Chair: Ariela Noy, MD, Memorial Sloan Kettering Cancer Center
• Study Chair: David M. Aboulafia, MD, Floyd & Delores Jones Cancer Institute at Virginia Mason Medical Center
• Study Chair: Lawrence D. Kaplan, MD, University of California, San Francisco

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jan 21, 2011

More Information

Publications

None provided.

• Responsible Party: AIDS Malignancy Consortium
• ClinicalTrials.gov Identifier: NCT00392834
• Other Study ID Numbers: AMC-048; U01CA070019; CDR0000510918
• First Posted: Oct 26, 2006
• Last Update Posted: Jun 6, 2018
• Last Verified: May 1, 2018

• Keywords provided by AIDS Malignancy Consortium: stage I adult Burkitt lymphoma; stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; contiguous stage II adult Burkitt lymphoma; noncontiguous stage II adult Burkitt lymphoma; AIDS-related peripheral/systemic lymphoma
• Additional relevant MeSH terms: Burkitt Lymphoma; Lymphoma; Leucovorin; Cytarabine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Cyclophosphamide; Ifosfamide; Rituximab; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Vincristine; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Regimen A (R-CODOX-M Chemotherapy)	Regimen B (Rituximab and IVAC Chemotherapy)
Arm/Group Description	Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.	Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
Period Title: Overall Study
STARTED	2	32
COMPLETED	2	32
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Regimen A (R-CODOX-M Chemotherapy)	Regimen B (Rituximab and IVAC Chemotherapy)	Total
Arm/Group Description	Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.	Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.	Total of all reporting groups
Overall Participants	2	32	34
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	2 100%	32 100%	34 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (8.5)	41.4 (9.4)	41.4 (9.2)
Sex: Female, Male (Count of Participants)
Female	0 0%	4 12.5%	4 11.8%
Male	2 100%	28 87.5%	30 88.2%
Region of Enrollment (participants) [Number]
United States	2 100%	32 100%	34 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS) at 1 Year
Time Frame	1 year post treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Regimen A (R-CODOX-M Chemotherapy)	Regimen B (Rituximab and IVAC Chemotherapy)
Arm/Group Description	Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.	Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
Measure Participants	2	32
Number (95% Confidence Interval) [Cumulative proportion surviving at 1 yr]	1.0	0.82

2. Secondary Outcome

Title	Complete Response Rate
Time Frame	6-8 weeks post treatment, every 4 months post-treatment for 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	Failure-free Survival (FFS)
Time Frame	6-8 weeks post treatment, every 4 months post-treatment for 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Secondary Outcome

Title	Event-free Survival (EFS)
Time Frame	6-8 weeks post treatment, every 4 months post-treatment for 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	Toxicity
Time Frame	baseline through 2 years post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	Incidence of Infection-related Deaths
Time Frame	baseline through 2 years post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Correlation of C-flip Expression, p53 Mutations, and Multidrug Resistance Expression With OS, FFS, and EFS
Time Frame	baseline through 2 years post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Utility of Flow Cytometry in Detecting Leptomeningeal Disease
Time Frame	baseline and 6-8 weeks post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Degree of Disconcordance Between Flow Cytometry and CNS Cytology Results
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Biologic and Prognostic Significance of Epstein-Barr Virus (EBV) at Diagnosis and Correlation With OS, FFS, and EFS
Time Frame	baseline through 2 years post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

11. Secondary Outcome

Title	Correlation of EBV Load Measurements With OS, FFS, and EFS
Time Frame	baseline through 2 years post-treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Regimen A (R-CODOX-M Chemotherapy)		Regimen B (Rituximab and IVAC Chemotherapy)
Arm/Group Description	Patients receive rituximab IV and doxorubicin hydrochloride IV over 15 minutes on day 1, cyclophosphamide IV over 30-60 minutes on days 1 and 2, pegfilgrastim SC on day 3, vincristine IV on days 1 and 8, high-dose methotrexate IV over 2-4 hours on day 15, and leucovorin calcium IV beginning 24 hours after the start of methotrexate and continuing every 6 hours until level is adequate. Patients receive CNS prophylaxis of methotrexate IT, cytarabine IT, and hydrocortisone IT on day 1. Patients with high-risk disease receive an additional dose of cytarabine IT on day 3. Patients also receive G-CSF SC once daily on days 3-9. Once the methotrexate levels drops below 50 nmol/L, patients resume G-CSF SC once daily beginning on approximately day 18 and continuing until blood counts recover.		Patients receive rituximab IV on day 1, ifosfamide IV continuously and etoposide IV continuously over 24 hours on days 1-5, and high-dose cytarabine IV over 1-3 hours twice daily on days 1-2. Patients receive CNS prophylaxis comprising methotrexate IT and hydrocortisone IT on day 5. Patients also receive pegfilgrastim SC once 24-48 hours after completion of chemotherapy OR G-CSF SC beginning on day 6 and continuing until blood counts recover. Patients with CNS involvement (leptomeningeal and/or intraparenchymal) at diagnosis do not receive CNS prophylaxis as above. Instead, these patients receive a combination of sequential liposomal cytarabine and methotrexate IT or via an Ommaya reservoir on day 1 and then every 14 days as tolerated until completion of systemic chemotherapy.
All Cause Mortality
	Regimen A (R-CODOX-M Chemotherapy)		Regimen B (Rituximab and IVAC Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Regimen A (R-CODOX-M Chemotherapy)		Regimen B (Rituximab and IVAC Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		23/32 (71.9%)
Blood and lymphatic system disorders
Anemia	0/2 (0%)	0	4/32 (12.5%)	7
Febrile neutropenia	0/2 (0%)	0	6/32 (18.8%)	8
Cardiac disorders
Acute coronary syndrome	0/2 (0%)	0	1/32 (3.1%)	1
Left ventricular systolic dysfunction	0/2 (0%)	0	1/32 (3.1%)	1
supraventricular tachycardia	0/2 (0%)	0	1/32 (3.1%)	1
Ear and labyrinth disorders
Extraocular muscle paresis	0/2 (0%)	0	1/32 (3.1%)	1
Gastrointestinal disorders
Nausea	0/2 (0%)	0	1/32 (3.1%)	1
Vomiting	0/2 (0%)	0	1/32 (3.1%)	1
General disorders
Death NOS	0/2 (0%)	0	2/32 (6.3%)	2
Fever	0/2 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Catheter related infection	0/2 (0%)	0	1/32 (3.1%)	1
Infections and infestations, other	0/2 (0%)	0	4/32 (12.5%)	5
Lung infection	0/2 (0%)	0	3/32 (9.4%)	4
Sepsis	0/2 (0%)	0	2/32 (6.3%)	2
Skin infection	0/2 (0%)	0	1/32 (3.1%)	1
Urinary tract infection	0/2 (0%)	0	1/32 (3.1%)	1
Injury, poisoning and procedural complications
Vascular access complication	0/2 (0%)	0	1/32 (3.1%)	1
Investigations
Cardiac tropinin I increased	0/2 (0%)	0	1/32 (3.1%)	1
Creatinine increased	0/2 (0%)	0	1/32 (3.1%)	1
Lymphocyte count decreased	0/2 (0%)	0	1/32 (3.1%)	2
Neutrophil count decreased	0/2 (0%)	0	6/32 (18.8%)	11
Platelet count decreased	0/2 (0%)	0	9/32 (28.1%)	13
White blood cell decreased	0/2 (0%)	0	8/32 (25%)	17
Metabolism and nutrition disorders
Hyperglycemia	0/2 (0%)	0	1/32 (3.1%)	2
Tumor lysis syndrome	0/2 (0%)	0	1/32 (3.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplastic syndrome	0/2 (0%)	0	1/32 (3.1%)	1
Nervous system disorders
Encephalopathy	0/2 (0%)	0	1/32 (3.1%)	2
Ischemia cerebrovascular	0/2 (0%)	0	1/32 (3.1%)	1
Transient ischemia attach	0/2 (0%)	0	1/32 (3.1%)	1
Nystagmus	0/2 (0%)	0	1/32 (3.1%)	1
Oculomotor nerve disorder	0/2 (0%)	0	1/32 (3.1%)	1
Peripheral sensory neuropathy	0/2 (0%)	0	1/32 (3.1%)	1
Renal and urinary disorders
Acute kidney injury	0/2 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/2 (0%)	0	1/32 (3.1%)	2
Pneumonitis	0/2 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Hypotension	0/2 (0%)	0	1/32 (3.1%)	2
Thromboembolic event	0/2 (0%)	0	2/32 (6.3%)	2
Other (Not Including Serious) Adverse Events
	Regimen A (R-CODOX-M Chemotherapy)		Regimen B (Rituximab and IVAC Chemotherapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		22/32 (68.8%)
Blood and lymphatic system disorders
Anemia	0/2 (0%)	0	15/32 (46.9%)	34
Febrile neutropenia	0/2 (0%)	0	3/32 (9.4%)	4
Gastrointestinal disorders
Diarrhea	0/2 (0%)	0	2/32 (6.3%)	3
Oral mucositis	0/2 (0%)	0	2/32 (6.3%)	2
Nausea	0/2 (0%)	0	4/32 (12.5%)	4
Vomiting	0/2 (0%)	0	5/32 (15.6%)	7
General disorders
Pain	0/2 (0%)	0	3/32 (9.4%)	3
Infections and infestations
Urinary tract infection	0/2 (0%)	0	2/32 (6.3%)	2
Investigations
Activated partial thromboplastin time prolonged	0/2 (0%)	0	2/32 (6.3%)	2
Alanine aminotransferase increased	0/2 (0%)	0	4/32 (12.5%)	9
Aspartate aminotransferase increased	0/2 (0%)	0	6/32 (18.8%)	14
Blood bilirubin increased	0/2 (0%)	0	3/32 (9.4%)	6
Lymphocyte count decreased	0/2 (0%)	0	2/32 (6.3%)	5
Neutrophil count decreased	0/2 (0%)	0	14/32 (43.8%)	26
Platelet count decreased	0/2 (0%)	0	16/32 (50%)	39
Weight loss	0/2 (0%)	0	2/32 (6.3%)	2
White blood cell count decreased	0/2 (0%)	0	9/32 (28.1%)	41
Metabolism and nutrition disorders
Hypercalcemia	0/2 (0%)	0	2/32 (6.3%)	2
Hyperglycemia	0/2 (0%)	0	7/32 (21.9%)	11
Hypocalcemia	0/2 (0%)	0	4/32 (12.5%)	8
Hypoglycemia	0/2 (0%)	0	2/32 (6.3%)	2
Hypokalemia	0/2 (0%)	0	8/32 (25%)	15
Hyponatremia	0/2 (0%)	0	4/32 (12.5%)	9
Hypophosphatemia	0/2 (0%)	0	5/32 (15.6%)	10
Nervous system disorders
Headache	0/2 (0%)	0	4/32 (12.5%)	5
Psychiatric disorders
Confusion	0/2 (0%)	0	2/32 (6.3%)	2
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/2 (0%)	0	3/32 (9.4%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.