Rituximab and Combination Chemotherapy in Treating Older Patients With Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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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 older patients with diffuse large B-cell lymphoma.

Detailed Description
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OBJECTIVES: Primary Determine the clinical response rate in older patients with previously untreated aggressive diffuse large B-cell stage II-IV lymphoma treated with rituximab, cyclophosphamide, pegylated doxorubicin hydrochloride liposome (HCl), vincristine, and prednisone. Determine the cardiotoxicity and myelosuppression of this regimen in these patients. Secondary Determine disease-free survival and overall survival of patients treated with this regimen. OUTLINE: This is a multicenter study. Patients receive rituximab intravenous (IV), cyclophosphamide IV over 1-1½ hours, pegylated doxorubicin HCl liposome IV over 1 hour, and vincristine IV on day 1, and oral prednisone on days 1-5. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 6 and continuing until blood counts recover OR pegfilgrastim SC once on day 6 (24 hours after the completion of chemotherapy). Treatment repeats every 21 days for up to 8 courses in the absence of unacceptable toxicity, disease progression, active hepatitis B virus infection, or hepatitis. Patients with no response OR who achieve less than a partial response after 4 courses are removed from the study. Patients are followed at 1 month, every 3 months for 1 year, every 4 months for 1 year, and then every 6 months thereafter. PROJECTED ACCRUAL: A maximum of 80 patients will be accrued for this study within 27 months.

Official Title
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A Phase II Study Of Rituximab-CHOP With Pegylated Liposomal Doxorubicin In Patients Older Than 60 Years Of Age With Untreated Aggressive B-Cell Non-Hodgkin's Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Biological: Filgrastim
* Biological: Pegfilgrastim
* Biological: Rituximab
* Drug: Cyclophosphamide
* Drug: Pegylated liposomal doxorubicin hydrochloride
* Drug: Prednisone
* Drug: Vincristine Sulfate


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed diffuse large B-cell lymphoma Stage II, III, or IV disease Previously untreated disease Measurable or evaluable disease No primary central nervous system (CNS) lymphoma or follicular B-cell lymphoma PATIENT CHARACTERISTICS: Age 61 and over Performance status Zubrod 0-2 Life expectancy Not specified Hematopoietic Absolute neutrophil count > 1,000/mm^3* Platelet count > 100,000/mm^3* NOTE: * Unless due to lymphoma-related hypersplenism or bone marrow infiltration Hepatic Bilirubin < 2 mg/dL Hepatitis B surface antigen negative Hepatitis B core antibody negative Hepatitis C Virus antibody negative Renal Creatinine < 2 mg/dL Cardiovascular left ventricular ejection fraction (LVEF) ≥ 50% by echocardiogram or ple gated acquisition (MUGA) scan No uncontrolled hypertension or cardiac symptoms Cardiologist consultation required for patients with stage A cardiac failure or any of the following known heart diseases: Diastolic dysfunction Prior coronary artery bypass graft Prior percutaneous transluminal coronary angioplasty Prior stent insertion Prior radiotherapy to the chest No myocardial infarction within the past 6 months No New York Heart Association class II-IV heart failure No uncontrolled angina No severe uncontrolled ventricular arrhythmias No clinically significant pericardial disease No acute ischemic or active conduction system abnormality by electrocardiogram (EKG) Other Not pregnant or nursing Fertile patients must use effective contraception No psychiatric illness that would preclude study compliance or giving informed consent No other major life-threatening illness that would preclude study treatment PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Not specified Endocrine therapy Not specified Radiotherapy See Cardiovascular Surgery See Cardiovascular

Ages Eligible for Study
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Minimum Age: 61 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: Rituximab - Combination Chemotherapy<br>Rituximab 375 mg/m^2 intravenous (IV), Cyclophosphamide IV over 1-1½ hours, Pegylated doxorubicin HCl liposome 40 mg/m^2 IV over 1 hour, Vincristine 2 mg IV, day 1, & oral Prednisone 40 mg/m^2 days 1 - 5; Filgrastim (G-CSF) 5 mcg/kg subcutaneously (SC) once daily beginning day 6 continuing until blood counts recover OR Pegfilgrastim 6 mg SC once on day 6 (24 hours after chemotherapy). Treatment repeats every 21 days for up to 8 courses. | Biological: Filgrastim<br>* 5 mcg/kg, SC daily, start 24 hours after chemotherapy<br>* Other names: Neupogen;Biological: Pegfilgrastim<br>* 6 mg SC one time (24 hours after chemotherapy)<br>* Other names: PEG-G-CSF;Biological: Rituximab<br>* 375 mg/m^2 intravenous piggy back (IVPB) on day 1, administered 1st<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* 750 mg/m^2 IVPB on day 1<br>* Other names: Neosar;Drug: Pegylated liposomal doxorubicin hydrochloride<br>* 40 mg/m^2 IV (maximum dose 90 mg) infusion over 1 hour on day 1<br>* Other names: liposomal doxorubicin hydrochloride;Drug: Prednisone<br>* 40 mg/m^2 oral days 1 - 5.<br>Drug: Vincristine Sulfate<br>* 2 mg IV, day 1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response (Complete, Complete Unconfirmed, and Partial Responses) After 4 Courses | Response was defined as participants with a complete response (CR), unconfirmed complete response (CRu) or partial response (PR), based on International Workshop Criteria (IWG) for Tumor Response Criteria assessed with CT & FDG-PET scans at 4 cycles (12 weeks). CR defined as disappearance of all target and non-target lesions in liver & spleen, & all lymph node masses regressed to normal size. PR defined as ≥50% reduction in sum of product of diameters (SPD) for measured lymph nodes, splenic & liver lesions separately compared to baseline SPD. CRu does not qualify for CR above, due to a residual nodal mass or an indeterminate bone marrow. | Evaluation after 12 weeks (4 cycles of 21 days) | 
| Number of Participants Experienced Grade 3 or Higher Cardiac Toxicity After Treatment: Cardiac Toxicity as Measured by Left Ventricular Ejection Fraction (LVEF) on Echocardiogram (ECHO) After 8 Courses | Ejection fraction ( EF) refers to the amount, or percentage, of blood that is pumped (or ejected) out of the ventricles with each contraction. Cardiology evaluation performed before second dose of pegylated liposomal doxorubicin or before entry onto trial, re-evaluation by cardiologist obtained in asymptomatic patients after chemotherapy cycle 4 and again after completion of therapy, and more often if symptomatic. Severe cardiac toxicity considered to be both Grade 3 and 4, and are graded according to NCI common toxicity criteria, CTCAE version 3.0. | Up to 24 weeks (8 cycles of 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival Rate | The percentage of participants still alive after treatment. Survival information obtained 1 month after completion of treatment, then every 3 months for 1 year, every 4 months for one year and every 6 months thereafter. | Up to 5 years | 
| Disease-free Survival | The percentage of participants with no disease progression for period of time after treatment. Survival assessed every 3 months for 1 year, every 4 months for 2 years, every 6 months for 3 years, and then yearly thereafter up to 5 years. | Up to 5 years or until disease progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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contiguous stage II adult diffuse large cell lymphoma, noncontiguous stage II adult diffuse large cell lymphoma, stage III adult diffuse large cell lymphoma, stage IV adult diffuse large cell lymphoma