Combination Chemotherapy and Rituximab in Treating Patients With Newly Diagnosed AIDS-Related B-Cell Non-Hodgkin's Lymphoma

A Phase II Trial of Doxil, Rituximab, Cyclophosphamide, Vincristine, and Prednisone (DR-COP) in Patients With Newly Diagnosed AIDS-Associated B-Cell Non-Hodgkin's Lymphoma

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

PURPOSE: This phase II trial is studying how well giving combination chemotherapy together with rituximab works in treating patients with newly diagnosed AIDS-related B-cell non-Hodgkin's lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Biological: filgrastim; Biological: pegfilgrastim; Biological: rituximab; Biological: sargramostim; Drug: cyclophosphamide; Drug: pegylated liposomal doxorubicin hydrochloride; Drug: prednisone; Drug: vincristine sulfate; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis

Detailed Description

OBJECTIVES:

Primary

• Determine the complete response rate (complete response and complete response unconfirmed) in patients with newly diagnosed, AIDS-related B-cell non-Hodgkin's lymphoma treated with doxorubicin hydrochloride liposome, rituximab, cyclophosphamide, vincristine, and prednisone (DR-COP).
• Determine the duration of response (relapse-free survival) in patients treated with this regimen.
• Determine the median survival time of patients treated with this regimen.
• Determine rate of bacterial, fungal, and opportunistic infections in patients treated with this regimen.

Secondary

• Determine, preliminarily, the relationship between MDR-1 expression in tumor tissue and response to therapy in patients treated with this regimen.
• Determine, preliminarily, any relationship between response and survival and BCL-2 expression in tumor tissue in patients treated with this regimen.
• Determine any relationship between development of bacterial, fungal, and/or opportunistic infections and baseline CD4 lymphocyte count, HIV-1 RNA level, and quantitative immunoglobulin levels, or changes in quantitative immunoglobulin levels over time in patients treated with this regimen.
• Compare the results of positron emission tomography (PET) scanning with traditional CT scans in predicting response to therapy in these patients.
• Examine the relationship between chemotherapeutic drug levels and receipt of specific antiretroviral and/or anti-infective medications in these patients.
• Examine the mortality and the causes of death in patients treated with this regimen.
• Determine event-free survival at 1 year.

OUTLINE: This is a nonrandomized, multicenter study.

Patients receive doxorubicin hydrochloride liposome IV over 90 minutes, rituximab IV over 5-7 hours, cyclophosphamide IV over 1 hour, and vincristine IV over 1-2 minutes on day 1 and oral prednisone on days 1-5. Patients also receive filgrastim (G-CSF), sargramostim (GM-CSF), or pegfilgrastim beginning on day 3 and continuing until blood counts recover. Treatment repeats every 21-28 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

Patients undergo laboratory/biomarker studies at baseline and after every 2 courses of chemotherapy. Tissue is examined by immunohistochemistry for BCL-2, Ki67, and MDR-1, along with other markers.

After completion of study treatment, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 44 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 43
• 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
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Sylvester Comprehensive Cancer Center - Miami
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Cancer Institute at Ochsner Clinic Foundation
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research 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
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Joan Karnell Cancer Center at Pennsylvania Hospital
  • Washington
    • Seattle, Washington, United States, 98101
      • Virginia Mason Medical Center

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 or cytologically confirmed AIDS-related B-cell non-Hodgkin's lymphoma (NHL), including any of the following subtypes:

  • Grade III follicular large cell lymphoma
  • Diffuse large B-cell lymphoma
  • Immunoblastic lymphoma
  • Plasmablastic lymphoma
  • Primary effusion lymphoma
• Previously untreated disease
• Any stage disease
• CD20 positive disease

• Must have documented HIV infection

  • Documentation may be by serology (enzyme-linked immunosorbent assay, western blot), culture, or quantitative polymerase chain reaction or branched DNA assays
  • Prior documentation of HIV seropositivity allowed
• Measurable or nonmeasurable disease
• Currently receiving effective highly active anti-retroviral therapy
• No primary CNS lymphoma, including parenchymal brain or spinal cord lymphoma
• No presence of leptomeningeal disease (positive cerebrospinal fluid for lymphoma) or presence of metastatic disease to brain, in terms of any mass lesion

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-2 OR Karnofsky PS 50-100%
• Life expectancy ≥ 2 months
• Absolute granulocyte (neutrophil) count ≥ 1,000/mm³ (unless secondary to lymphomatous involvement of bone marrow)
• Platelet count ≥ 75,000/mm³ (unless secondary to lymphomatous involvement of bone marrow or due to HIV-related thrombocytopenia)
• Bilirubin ≤ 2.0 mg/dL (unless elevated secondary to lymphomatous involvement of liver or biliary system or due to other HIV medications [e.g., indinavir, tenofavir, or atazanavir])
• SGOT ≤ 5 times upper limit of normal
• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 60 mL/min (unless secondary to renal involvement by lymphoma)
• LVEF normal by MUGA or echocardiogram
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 6 months after completion of study treatment
• No other malignancy, except nonmelanoma skin cancer, carcinoma in situ of the cervix, or Kaposi's sarcoma that does not require systemic therapy
• No serious, ongoing, nonmalignant disease or infection that would preclude study compliance, in the opinion of the investigator
• No history of cutaneous or mucocutaneous reactions, or diseases in the past, due to any cause, severe enough to cause hospitalization or an inability to eat or drink for ≥ 2 days

• No acute, intercurrent infection that would preclude study treatment

  • Patients with Mycobacterium avium are eligible

• No cardiovascular problems, including any of the following:

  • Myocardial infarction within the past 6 months
  • New York Heart Association class II-IV heart failure
  • Uncontrolled angina
  • Severe uncontrolled ventricular arrhythmias
  • Clinically significant pericardial disease
  • ECG evidence of acute ischemic or active conduction system abnormalities.
• No shortness of breath at rest
• Arterial PO_2 ≥ 70 or pulse oximeter-derived O_2 saturation ≥ 94% on room air (unless due to lymphomatous involvement of the lungs)
• Able to comply with study and provide adequate informed consent

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• At least 4 weeks since prior major surgery (except diagnostic surgery)
• At least 12 months since prior rituximab unless it was only given for indications other than the treatment of aggressive lymphoma

• No prior cytotoxic chemotherapy or radiotherapy for this lymphoma

  • Concurrent radiotherapy, with or without steroids, for emergency conditions secondary to lymphoma (i.e., CNS tumor or cord compression) allowed
• No zidovudine or zidovudine-containing regimen (including Combivir® or Trizivir®) during and for 2 months after completion of chemotherapy

• Concurrent erythropoietin or filgrastim (G-CSF) allowed

  • Growth factor therapy must be discontinued ≥ 24 hours prior to study entry

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: DR-COP; Single arm interventional study: all subjects receive DR-COP regimen.

Biological: filgrastim; Supportive therapy: GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Biological: pegfilgrastim; GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Biological: rituximab; 375 mg/m2 IV Day 1 of each cycle; Biological: sargramostim; GF therapy with G-CSF, GM-CSF, or pegfilgrastim will be used in all patients, beginning on Day 3 of each cycle, until post nadir of blood counts from each chemotherapy cycle.; Drug: cyclophosphamide; 750 mg/m2 IV Day 1 of each cycle; Drug: pegylated liposomal doxorubicin hydrochloride; 40 mg/m2 IV Day 1 of each cycle; Drug: prednisone; 100 mg PO Days 1-5 of each cycle; Drug: vincristine sulfate; 1.4 mg/m2 IV Day 1 (2.0 mg maximum) of each cycle; Other: immunohistochemistry staining method; tissue specimen collected at baseline; Other: laboratory biomarker analysis; tissue specimen collected at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete Response Rate (Complete Response and Complete Response Unconfirmed) Defined as Disappearance of All Evidence of Disease Based on Radiographic Findings on CT or MRI .	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation
Duration of Response	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation
Median Survival Time	After cycles 2, 4, 6, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation
Rate of Bacterial, Fungal, and Opportunistic Infections	After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Time Frame
Relationship Between MDR-1 Expression and Response to Treatment	Baseline
Relationship Between Response and Survival and BCL-2 Expression in Tumor Tissue	Baseline, after cycles 4 and 6, 1 month after treatment discontinuation
Relationship Between Development of Bacterial, Fungal, and/or Opportunistic Infections and Baseline CD4 Lymphocyte Count, HIV-1 RNA Level, and Quantitative Immunoglobin Level, or Changes in Quantitative Immunoglobin Levels Over Time	After every cycle of treatment, 1 month after treatment discontinuation, every 2 months for 1 year after treatment discontinuation, every 6 months during the second and third years after treatment discontinuation
Mortality and Cause of Death	At any time through the third year after treatment discontinuation
Event-free Survival at 1 Year	1 year post-treatment

Collaborators and Investigators

• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC
• Investigators: Study Chair: Alexandra M. Levine, MD, City of Hope Comprehensive Cancer Center

Publications and helpful links

General Publications

• Levine AM, Noy A, Lee JY, Tam W, Ramos JC, Henry DH, Parekh S, Reid EG, Mitsuyasu R, Cooley T, Dezube BJ, Ratner L, Cesarman E, Tulpule A. Pegylated liposomal doxorubicin, rituximab, cyclophosphamide, vincristine, and prednisone in AIDS-related lymphoma: AIDS Malignancy Consortium Study 047. J Clin Oncol. 2013 Jan 1;31(1):58-64. doi: 10.1200/JCO.2012.42.4648. Epub 2012 Nov 19.

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: October 18, 2006
• First Submitted That Met QC Criteria: October 18, 2006
• First Posted (Estimate): October 19, 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 diffuse large cell lymphoma; stage III adult immunoblastic large cell lymphoma; stage IV grade 3 follicular lymphoma; stage IV adult diffuse large cell lymphoma; stage IV adult immunoblastic large cell lymphoma; AIDS-related peripheral/systemic lymphoma; AIDS-related diffuse large cell lymphoma; AIDS-related immunoblastic large cell lymphoma; stage III grade 3 follicular lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; noncontiguous stage II grade 3 follicular lymphoma; noncontiguous stage II adult immunoblastic large cell lymphoma; contiguous stage II adult immunoblastic large cell lymphoma; stage I adult immunoblastic large cell lymphoma; contiguous stage II grade 3 follicular lymphoma; stage I grade 3 follicular lymphoma; contiguous stage II adult diffuse large cell lymphoma; stage I adult diffuse large cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Prednisone; Doxorubicin; Liposomal doxorubicin; Vincristine; Sargramostim
• Other Study ID Numbers: AMC-047; U01CA070019 (U.S. NIH Grant/Contract); CDR0000507634 (Other Identifier: NCI)