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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

Phase 2
18 Years
Open (Enrolling)

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Trial Information

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



- 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.


- 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

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

Inclusion Criteria


- 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


- 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

- 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


- 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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Survival (OS) at 1 Year

Outcome Time Frame:

1 year post treatment

Safety Issue:


Principal Investigator

Ariela Noy, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center


United States: Federal Government

Study ID:




Start Date:

September 2006

Completion Date:

July 2013

Related Keywords:

  • Lymphoma
  • 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
  • Burkitt Lymphoma
  • Lymphoma



Memorial Sloan-Kettering Cancer Center New York, New York  10021
Beth Israel Deaconess Medical Center Boston, Massachusetts  02215
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland  21231-2410
USC/Norris Comprehensive Cancer Center and Hospital Los Angeles, California  90033-0804
Rebecca and John Moores UCSD Cancer Center La Jolla, California  92093-0658
Albert Einstein Cancer Center at Albert Einstein College of Medicine Bronx, New York  10461
Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis St. Louis, Missouri  63110
West Virginia University Health Sciences Center - Charleston Charleston, West Virginia  25302
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center Columbus, Ohio  43210-1240
UCLA Clinical AIDS Research and Education (CARE) Center Los Angeles, California  90024
Pennsylvania Oncology Hematology Associates, Incorporated - Philadelphia Philadelphia, Pennsylvania  19106
Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center Seattle, Washington  98111
UCSF Medical Center at Parnassus San Francisco, California  94143-0296