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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Biological: Filgrastim; Biological: Pegfilgrastim; Biological: Rituximab; Drug: Cyclophosphamide; Drug: Pegylated liposomal doxorubicin hydrochloride; Drug: Prednisone; Drug: Vincristine Sulfate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Fort Smith, Arkansas, United States, 72913
      • Hembree Mercy Cancer Center at St. Edward Mercy Medical Center
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • CCOP - Grand Rapids
    • Kalamazoo, Michigan, United States, 49007-3731
      • CCOP - Kalamazoo
  • Missouri
    • Springfield, Missouri, United States, 65804
      • Cancer Research for the Ozarks
  • New York
    • East Syracuse, New York, United States, 13057-4510
      • Hematology Oncology Associates of Central New York, PC - Northeast Center
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas M.D. Anderson CCOP Research Base

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 61 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Rituximab - Combination Chemotherapy; 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; 5 mcg/kg, SC daily, start 24 hours after chemotherapy; Other Names: G-CSF; Neupogen; Biological: Pegfilgrastim; 6 mg SC one time (24 hours after chemotherapy); Other Names: Neulasta; PEG-G-CSF; Biological: Rituximab; 375 mg/m^2 intravenous piggy back (IVPB) on day 1, administered 1st; Other Names: Rituxan; Drug: Cyclophosphamide; 750 mg/m^2 IVPB on day 1; Other Names: Cytoxan; Neosar; Drug: Pegylated liposomal doxorubicin hydrochloride; 40 mg/m^2 IV (maximum dose 90 mg) infusion over 1 hour on day 1; Other Names: Caelyx; Doxil; liposomal doxorubicin hydrochloride; doxorubicin hydrochloride; liposomal doxorubicin; Drug: Prednisone; 40 mg/m^2 oral days 1 - 5.; Drug: Vincristine Sulfate; 2 mg IV, day 1

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI); Ortho Biotech, Inc.
• Investigators: Study Chair: Maria A. Rodriguez, MD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: January 7, 2005
• First Submitted That Met QC Criteria: January 7, 2005
• First Posted (Estimate): January 10, 2005

Study Record Updates

• Last Update Posted (Actual): October 19, 2020
• Last Update Submitted That Met QC Criteria: September 22, 2020
• Last Verified: September 1, 2020

More Information

Terms related to this study

• Keywords: stage III adult diffuse large cell lymphoma; stage IV adult diffuse large cell lymphoma; noncontiguous stage II adult diffuse large cell lymphoma; contiguous stage II adult diffuse large cell lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; 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; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Cyclophosphamide; Rituximab; Lenograstim; Prednisone; Doxorubicin; Liposomal doxorubicin; Vincristine
• Other Study ID Numbers: CDR0000407533; MDA-CCOP-2004-0305; NCI-6485; 2004-0305 (Other Identifier: UT MD Anderson Cancer Center); NCI-2009-00064 (Registry Identifier: NCI CTRP); 2U10CA045809 (U.S. NIH Grant/Contract)