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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Drug: ifosfamide; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: therapeutic hydrocortisone; Biological: filgrastim; Biological: pegfilgrastim; Biological: rituximab; Drug: cytarabine; Drug: leucovorin calcium; Drug: liposomal cytarabine; Drug: methotrexate; Drug: vincristine sulfate; Drug: etoposide

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 Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 2

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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.	Drug: cyclophosphamide; given IV; Drug: doxorubicin hydrochloride; given IV; Drug: therapeutic hydrocortisone; given intrathecally; Biological: filgrastim; given subcutaneously; Biological: pegfilgrastim; given subcutaneously; Biological: rituximab; given IV; Drug: cytarabine; given intrathecally; Drug: leucovorin calcium; given IV; Drug: liposomal cytarabine; given intrathecally; Drug: methotrexate; 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.	Drug: ifosfamide; given IV; Drug: therapeutic hydrocortisone; given intrathecally; Biological: filgrastim; given subcutaneously; Biological: pegfilgrastim; given subcutaneously; Biological: rituximab; given IV; Drug: cytarabine; given intrathecally; Drug: liposomal cytarabine; given intrathecally; Drug: methotrexate; given intrathecally; Drug: etoposide; given IV

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Complete Response Rate	6-8 weeks post treatment, every 4 months post-treatment for 2 years
Failure-free Survival (FFS)	6-8 weeks post treatment, every 4 months post-treatment for 2 years
Event-free Survival (EFS)	6-8 weeks post treatment, every 4 months post-treatment for 2 years
Toxicity	baseline through 2 years post-treatment
Incidence of Infection-related Deaths	baseline through 2 years post-treatment
Correlation of C-flip Expression, p53 Mutations, and Multidrug Resistance Expression With OS, FFS, and EFS	baseline through 2 years post-treatment
Utility of Flow Cytometry in Detecting Leptomeningeal Disease	baseline and 6-8 weeks post-treatment
Degree of Disconcordance Between Flow Cytometry and CNS Cytology Results	baseline
Biologic and Prognostic Significance of Epstein-Barr Virus (EBV) at Diagnosis and Correlation With OS, FFS, and EFS	baseline through 2 years post-treatment
Correlation of EBV Load Measurements With OS, FFS, and EFS	baseline through 2 years post-treatment

Collaborators and Investigators

• Sponsor: AIDS Malignancy Consortium
• Collaborators: 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

Publications and helpful links

General Publications

• Noy A, Lee JY, Cesarman E, Ambinder R, Baiocchi R, Reid E, Ratner L, Wagner-Johnston N, Kaplan L; AIDS Malignancy Consortium. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood. 2015 Jul 9;126(2):160-6. doi: 10.1182/blood-2015-01-623900. Epub 2015 May 8.

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: October 25, 2006
• First Submitted That Met QC Criteria: October 25, 2006
• First Posted (Estimate): October 26, 2006

Study Record Updates

• Last Update Posted (Actual): June 6, 2018
• Last Update Submitted That Met QC Criteria: May 3, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: stage III adult Burkitt lymphoma; stage IV adult Burkitt lymphoma; AIDS-related peripheral/systemic lymphoma; noncontiguous stage II adult Burkitt lymphoma; stage I adult Burkitt lymphoma; contiguous stage II adult Burkitt lymphoma
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; DNA Virus Infections; Tumor Virus Infections; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma, B-Cell; Lymphoma; Burkitt Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Dermatologic Agents; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Cyclophosphamide; Etoposide; Ifosfamide; Rituximab; Leucovorin; Levoleucovorin; Doxorubicin; Liposomal doxorubicin; Cytarabine; Methotrexate; Vincristine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate
• Other Study ID Numbers: AMC-048; U01CA070019 (U.S. NIH Grant/Contract); CDR0000510918 (Other Identifier: NCI)