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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Lymphoma

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DR-COP<br>Single arm interventional study: all subjects receive DR-COP regimen. | Biological: filgrastim<br>* 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.<br>Biological: pegfilgrastim<br>* 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.<br>Biological: rituximab<br>* 375 mg/m2 IV Day 1 of each cycle<br>Biological: sargramostim<br>* 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.<br>Drug: cyclophosphamide<br>* 750 mg/m2 IV Day 1 of each cycle<br>Drug: pegylated liposomal doxorubicin hydrochloride<br>* 40 mg/m2 IV Day 1 of each cycle<br>Drug: prednisone<br>* 100 mg PO Days 1-5 of each cycle<br>Drug: vincristine sulfate<br>* 1.4 mg/m2 IV Day 1 (2.0 mg maximum) of each cycle<br>Other: immunohistochemistry staining method<br>* tissue specimen collected at baseline<br>Other: laboratory biomarker analysis<br>* tissue specimen collected at baseline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stage III adult immunoblastic large cell lymphoma, stage IV adult immunoblastic large cell lymphoma, AIDS-related peripheral/systemic lymphoma, contiguous stage II grade 3 follicular lymphoma, noncontiguous stage II grade 3 follicular lymphoma, stage I grade 3 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 3 follicular lymphoma, AIDS-related diffuse large cell lymphoma, contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, stage I adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma, AIDS-related immunoblastic large cell lymphoma, contiguous stage II adult immunoblastic large cell lymphoma, noncontiguous stage II adult immunoblastic large cell lymphoma, stage I adult immunoblastic large cell lymphoma