A Phase 2, Multicenter, Randomized, Open-label Study of MEDI-551 in Adults With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

• ClinicalTrials.gov Identifier: NCT01453205
• Recruitment Status: Completed
• First Posted: October 17, 2011
• Results First Posted: March 12, 2018
• Last Update Posted: March 12, 2018
• Sponsor: MedImmune LLC
• Information provided by (Responsible Party): MedImmune LLC

Study Description

Brief Summary:

The overall purpose of the study is to determine if MEDI-551, when used in combination with salvage chemotherapy, Ifosfamide-carboplatin-etoposide (ICE) or Dexamethasone-cytarabine (DHAP) in patients with relapsed or refractory DLBCL who are eligible for Autologous Stem Cell Transplant (ASCT), has superior efficacy compared to rituximab in the same population.

Condition or disease	Intervention/treatment	Phase
Diffuse Large B-Cell Lymphoma	Drug: MEDI-551 2 mg/kg; Drug: Rituximab; Drug: ICE; Drug: DHAP; Procedure: Autologous Stem Cell Transplant (ASCT); Drug: MEDI-551 4 mg/kg	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 187 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Randomized Open-label Study of MEDI-551 in Adults With Relapsed or Refractory DLBCL
• Actual Study Start Date: February 27, 2012
• Actual Primary Completion Date: July 11, 2016
• Actual Study Completion Date: July 11, 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Rituximab+ ICE/DHAP; Participants will receive Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and will followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) will be administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.	Drug: Rituximab; Rituximab at 375 mg/m2 will be administered via IV infusion 2 days before the start of Cycle 1 and on Day 1 of each cycle. The infusion time for rituximab will be 50 400 mg/hr, depending on subject's tolerance. Subjects will receive 3 cycles of Rituximab with Ice (R ICE) or Rituximab with DHAP (R-DHAP) unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).; Other Name: Rituxan; MabThera; Drug: ICE; ICE will be administered via IV infusion as follows: ifosfamide 5 g/m2 continuously for 24 hours with mesna on Days 2 and 3; carboplatin AUC=5 mg/mL x min [800 mg maximum) on Day 2; etoposide 100 mg/m2 on Days 1, 2, and 3) in 21-day cycles.; Drug: DHAP; DHAP will be administered via IV infusion as follows: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m2 continuously for 24 hours on Day 1 of dosing cycle; cytarabine 2 g/m2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.; Procedure: Autologous Stem Cell Transplant (ASCT); Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.
Experimental: MEDI-551 2 mg/kg + ICE/DHAP; Participants will receive MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and will be followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) will be administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.	Drug: MEDI-551 2 mg/kg; MEDI-551 at the assigned dose will be administered via Intravenous (IV) infusion. Subjects will receive 3 cycles of M-ICE or M-DHAP unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).; Other Name: Inebilizumab; Drug: ICE; ICE will be administered via IV infusion as follows: ifosfamide 5 g/m2 continuously for 24 hours with mesna on Days 2 and 3; carboplatin AUC=5 mg/mL x min [800 mg maximum) on Day 2; etoposide 100 mg/m2 on Days 1, 2, and 3) in 21-day cycles.; Drug: DHAP; DHAP will be administered via IV infusion as follows: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m2 continuously for 24 hours on Day 1 of dosing cycle; cytarabine 2 g/m2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.; Procedure: Autologous Stem Cell Transplant (ASCT); Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.
Experimental: MEDI-551 4 mg/kg + ICE/DHAP; Participants will receive MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and will be followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) will be administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.	Drug: ICE; ICE will be administered via IV infusion as follows: ifosfamide 5 g/m2 continuously for 24 hours with mesna on Days 2 and 3; carboplatin AUC=5 mg/mL x min [800 mg maximum) on Day 2; etoposide 100 mg/m2 on Days 1, 2, and 3) in 21-day cycles.; Drug: DHAP; DHAP will be administered via IV infusion as follows: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m2 continuously for 24 hours on Day 1 of dosing cycle; cytarabine 2 g/m2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.; Procedure: Autologous Stem Cell Transplant (ASCT); Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.; Drug: MEDI-551 4 mg/kg; MEDI-551 at the assigned dose will be administered via Intravenous (IV) infusion. Subjects will receive 3 cycles of M-ICE or M-DHAP unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).; Other Name: Inebilizumab

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Objective Response Rate is defined as the proportion of participants with a best response of complete response (CR) or partial response (PR) according to the International Working Group criteria. CR is defined as disappearance of all evidence of disease. PR is defined as 50 percent (%) decrease in the sum of the product of the perpendicular diameters (SPD) of up to 6 largest dominant nodal masses and greater than or equal to (>=) 50% decrease in SPD of spleen/liver nodules.

Secondary Outcome Measures :

1. Progression-Free Survival (PFS) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Progression-free survival (PFS) is defined as the time from randomization until the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first according to the International Working Group criteria. PD is defined as appearance of any new lesions or >= 50% increase in SPD of more than one node or >= 50% increase in longest diameter of a previously identified node or >50% increase from nadir in the SPD of any previous lesions. PFS (months) = (Date of PD/death or censoring - Date of randomization + 1) / (365.25/12).
2. Event-Free Survival (EFS) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Event-Free Survival (EFS) is defined as the time from randomization until the first documentation of EFS events which include PD, initiation of alternative antitumor treatment or death due to any cause, whichever occurs first according to the International Working Group criteria. PD is defined as appearance of any new lesions or >= 50% increase in SPD of more than one node or >= 50% increase in longest diameter of a previously identified node or >50% increase from nadir in the SPD of any previous lesions. EFS (months) = (Date of EFS or censoring - Date of randomization + 1) / (365.25/12).
3. Overall Survival (OS) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Overall survival is defined as the time from randomization until death due to any cause according to the International Working Group criteria. OS (months) = (Date of death or censoring - Date of randomization + 1) / (365.25/12).
4. Time to Progression (TTP) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Time to Progression (TTP) is defined as the time from randomization until the first documentation of PD according to the International Working Group criteria. PD is defined as appearance of any new lesions or >= 50% increase in SPD of more than one node or >= 50% increase in longest diameter of a previously identified node or >50% increase from nadir in the SPD of any previous lesions. TTP (months) = (Date of PD or censoring - Date of randomization + 1) / (365.25/12).
5. Time to Response (TTR) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Time to response (TTR) is defined as the time from randomization until the first documentation of disease response according to the International Working Group criteria. Only participants who have achieved objective response (confirmed CR or confirmed PR) assessed by investigator were evaluated for TTR. CR is defined as disappearance of all evidence of disease. PR is defined as 50% decrease in the SPD of up to 6 largest dominant nodal masses and >= 50% decrease in SPD of spleen/liver nodules. TTR (months) = (Date of first disease response - Date of randomization + 1) / (365.25/12).
6. Duration of Response (DR) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   Duration of Response (DR) is defined as time from start of first documented objective response (confirmed CR or confirmed PR) to first documented PD according to the International Working Group criteria. CR is defined as disappearance of all evidence of disease. PR is defined as 50% decrease in the SPD of up to 6 largest dominant nodal masses and >= 50% decrease in SPD of spleen/liver nodules. PD: appearance of any new lesions or >= 50% increase in SPD of more than one node or >= 50% increase in longest diameter of a previously identified node or > 50% increase from nadir in the SPD of any previous lesions. Only participants who have achieved objective response assessed by investigator were evaluated. DR calculated as (months) = (Date of PD or censoring - Date of first disease response + 1)/ (365.25/12).
7. Number of Participants With Best Overall Response Assessed by Blinded Independent Central Review (BICR) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number of participants for the following categories: CR, PR, stable disease (SD), PD, and unknown. Responses were assessed according to the International Working Group criteria. CR: disappearance of all evidence of disease; PR: 50% decrease in the SPD of up to 6 largest dominant nodal masses and >= 50% decrease in SPD of spleen/liver nodules; PD: appearance of any new lesions or >= 50% increase in SPD of more than one node or >= 50% increase in longest diameter of a previously identified node or >50% increase from nadir in the SPD of any previous lesions; SD: failure to attain CR/PR or PD.
8. Acceptable Dose of MEDI-551 [ Time Frame: After the administration of the first dose of MEDI-551 (7 days before the Cycle 1) to last dose of MEDI-551 (Cycle 3 Day 1) (each cycle of 21 days) ]
   Acceptable dose for MEDI-551 was evaluated based on the benefit-risk analysis.
9. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
   An Adverse Event (AE) is any unfavourable and unintended signs, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. Serious adverse event (SAE) is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 90 days after the end of treatment (EOT).
10. Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Hematology/Coagulation Laboratory Results [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
    An abnormal laboratory finding that was judged by the investigator to be clinically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment (EOT).
11. Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Chemistry Laboratory Results (Include Urinalysis) [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
    An abnormal laboratory findings that was judged by the investigator to be clinically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment.
12. Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and ECG Abnormalities [ Time Frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant) ]
    Vital signs included parameters such as heart rate, blood pressure, temperature, and respiratory rate. An abnormal vital signs and ECG findings that was judged by the investigator to be clinically significant was reported an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment.
13. Number of Participants Who Developed Detectable MEDI-551 Anti-drug Antibodies (ADA) [ Time Frame: 7 days before the start of Cycle 1, Day 1 of each subsequent Cycle, EOT, and post EOT on Days 30, 60, 90 and 270 (up to 36 months from the randomization of last participant) ]
    A participant was considered ADA-positive across the study if they had a positive reading (titer of 50 or higher) at any time point during the study.
14. Mean Serum Concentration of MEDI-551 [ Time Frame: Cycle 1 Day -7 Post dose, pre-dose and postdose on Day 1, post-dose on Days 4, 8, 15 of Cycle 1, pre-dose and postdose on Day 1 of Cycle 2 and Cycle 3 ]
    The mean serum concentration of MEDI-551 were observed.
15. Half-life (T1/2) of MEDI-551 [ Time Frame: Cycle 1 and EOT (Day 21 of Cycle 3 [each cycle of 21 days] or earlier cycles if treatment stopped before Cycle 3) ]
    Terminal elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 99 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Histologically confirmed aggressive B-cell DLBCL, including FL transforming to DLBCL & Grade III FL
• Relapsed from or refractory to at least one treatment containing rituximab or another anti-CD20 based immunotherapy combined with anthracycline- or anthracenedione-based chemotherapy
• Eligible for ASCT
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Life expectancy of ≥ 12 weeks
• Adequate hematological function

Exclusion Criteria:

• Any chemotherapy, radiotherapy, immunotherapy, biologic, investigational or hormonal therapy for treatment of lymphoma within 28 days prior to treatment
• Previous cancer therapy for DLBCL other than anthracycline- or anthracenedione based chemoimmunotherapy, monotherapy rituximab prior to first line therapy and/or as a maintenance therapy, or limited field radiotherapy
• Prior autologous or allogeneic SCT
• New York Heart Association ≥ Class II congestive heart failure; Clinically significant abnormality on ECG
• History of other invasive malignancy within 5 years except for localized/in situ, carcinomas such as cervical carcinoma in situ.
• Evidence of active infection
• Documented current central nervous system involvement by leukemia or lymphoma

Contacts and Locations

Locations

United States, Alabama

Research Site

Birmingham, Alabama, United States, 35061

United States, California

Research Site

Burbank, California, United States, 91501

Research Site

Palm Springs, California, United States, 92262

Research Site

Sylmar, California, United States, 91342

United States, Georgia

Research Site

Atlanta, Georgia, United States, 30342

United States, Kansas

Research Site

Westwood, Kansas, United States, 66205

United States, Kentucky

Research Site

Hazard, Kentucky, United States, 41701

United States, Louisiana

Research Site

Lafayette, Louisiana, United States, 70503

Research Site

Shreveport, Louisiana, United States, 71103

United States, Maryland

Research Site

Baltimore, Maryland, United States, 21215

United States, Minnesota

Research Site

Minneapolis, Minnesota, United States, 55455

Research Site

Rochester, Minnesota, United States, 55905

United States, Missouri

Research Site

Kansas City, Missouri, United States, 64111

Research Site

Kansas City, Missouri, United States, 66160

Research Site

Saint Louis, Missouri, United States, 63110

United States, New York

Research Site

Bronx, New York, United States, 10466

United States, North Dakota

Research Site

Fargo, North Dakota, United States, 58102

United States, Ohio

Research Site

Dayton, Ohio, United States, 45403

Research Site

Newark, Ohio, United States, 43055

Research Site

Sylvania, Ohio, United States, 43560

United States, Pennsylvania

Research Site

Hershey, Pennsylvania, United States, 17033

Research Site

Philadelphia, Pennsylvania, United States, 19104

United States, South Carolina

Research Site

Charleston, South Carolina, United States, 29425

United States, Tennessee

Research Site

Knoxville, Tennessee, United States, 37909

United States, Texas

Research Site

Dallas, Texas, United States, 75246

Research Site

Houston, Texas, United States, 77030

Research Site

Lubbock, Texas, United States, 79410

United States, West Virginia

Research Site

Morgantown, West Virginia, United States, 26505

United States, Wisconsin

Research Site

Milwaukee, Wisconsin, United States, 53266

Canada, New Brunswick

Research Site

St. John, New Brunswick, Canada, E2E5A2

Canada, Nova Scotia

Research Site

Halifax, Nova Scotia, Canada, B3H 1V7

Canada, Quebec

Research Site

Greenfield Park, Quebec, Canada, J4V 2H1

Czechia

Research Site

Brno, Czechia, 12808

Research Site

Praha 2, Czechia, 12808

Research Site

Praha, Czechia, 12808

France

Research Site

Bordeaux, France, 33300

Research Site

Le Mans, France, 72000

Research Site

Libourne Cedex, France, 33205

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Marseille, France, 13005

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Marseille, France, 13273

Research Site

Pessac, France, 33604

Research Site

Rouen, France, 76100

Research Site

Tours, France, 37100

Germany

Research Site

Berlin, Germany, 10967

Research Site

Frankfurt, Germany, 65929

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Mainz, Germany, 55131

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Muenchen, Germany, 80804

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Tuebingen, Germany, 72076

Research Site

Wuerzburg, Germany, 97080

Hungary

Research Site

Budapest, Hungary, 01083

Research Site

Debrecen, Hungary, 04032

Research Site

Gyor, Hungary, 09200

Research Site

Kaposvar, Hungary, 07400

Israel

Research Site

Ashkelon, Israel, 78278

Research Site

Haifa, Israel, 31999

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Jerusalem, Israel

Research Site

Tel Aviv, Israel, 64239

Poland

Research Site

Gdynia, Poland, 81-519

Research Site

Lublin, Poland, 20081

Russian Federation

Research Site

Nizhny Novgorod, Russian Federation, 603126

Research Site

Saint Petersburg, Russian Federation, 197341

Research Site

St. Petersburg, Russian Federation, 191024

Research Site

St. Petersburg, Russian Federation, 197341

Spain

Research Site

Barcelona, Spain, 08041

Research Site

Cadiz, Spain, 11009

Research Site

Girona, Spain, 17007

Research Site

L'Hospitalet de Llobregat, Spain, 08907

Research Site

Madrid, Spain, 28025

Research Site

Majadahonda, Spain, 28222

Research Site

Malaga, Spain, 29010

Research Site

Pamplona, Spain, 31008

Research Site

Salamanca, Spain, 37007

Research Site

San Sebastian de los Reyes, Spain, 28702

Research Site

Sevilla, Spain, 41013

Research Site

Sevilla, Spain, 41014

Research Site

Valencia, Spain, 46015

Research Site

Valencia, Spain, 46017

Research Site

Valencia, Spain, 46026

Turkey

Research Site

Izmir, Turkey, 35100

Research Site

Izmir, Turkey, 35340

Research Site

Kurupelit, Turkey, 55139

Research Site

Malatya, Turkey, 44100

Research Site

Talas, Turkey, 38280

Sponsors and Collaborators

MedImmune LLC

Investigators

• Study Director: MedImmune LLC; MedImmune LLC

More Information

• Responsible Party: MedImmune LLC
• ClinicalTrials.gov Identifier: NCT01453205
• Other Study ID Numbers: CD-ON-MEDI-551-1088
• First Posted: October 17, 2011
• Results First Posted: March 12, 2018
• Last Update Posted: March 12, 2018
• Last Verified: February 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by MedImmune LLC:

Lymphoma, Non-Hodgkin's Lymphoma, Diffuse Large B-Cell Lymphoma, DLBCL, B-Cell Malignancy, anti-CD19, monoclonal antibody, second line, ASCT, Refractory

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin; Rituximab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents