Study of Lenalidomide to Evaluate Safety and Effectiveness in Patients With Diffuse Large B-Cell Lymphoma (DLBCL)

A Phase 2/3, Multicenter, Randomized, Open-label Study to Compare the Efficacy and Safety of Lenalidomide (Revlimid ®) Versus Investigator's Choice in Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma

The purpose of this study is to compare lenalidomide to a control drug and see which one delays Diffuse Large B-Cell Lymphoma (DLBCL) disease progression longer.

Study Overview

• Status: Completed
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Drug: Lenalidomide; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Rituximab; Drug: Etoposide

Detailed Description

This research study is for patients who have been diagnosed with Diffuse Large B-cell Lymphoma (DLBCL) that did not respond to (refractory) or that has come back after chemotherapy treatment (relapsed). Lymphoma is a cancer of a type of blood cell called lymphocytes. DLBCL is just one type of lymphoma. Within DLBCL there are two different subtypes called Germinal Center B-cell (GCB) and non-GCB which can be determined by cell surface marker tests or by gene expression tests. Scientists can look at cells and genes in the laboratory and see that the two kinds are different, but they don't know yet what the difference means. To patients and doctors these two kinds seem the same. Right now doctors don't usually do tests to find out which kind a patient has because the treatment is the same for both.

This study will have two stages, 1 and 2. The main purpose of Stage 1 is to separate patients by subtype and then test whether patients taking lenalidomide or any one of four other drugs have a better response. It is possible that lenalidomide will work better than one of the other drugs in zero, one, or both subtypes. Stage 2 will further test only the subtype(s) from Stage 1 that showed a good response to lenalidomide. The main purpose of Stage 2 is to test how long patients are disease free on lenalidomide compared to one of the four other drugs.

On 29 January 2013 the enrolment goal for the Stage 1 portion of the study was met and enrollment was stopped. The final analysis for Stage 1 was performed as of the 04 Jul 2013 data cutoff date. According to the Stage 1 results as assessed by the independent response adjudication committee (IRAC), neither subtype met the pre specified requirement to be further studied in Stage 2. Additionally, a suitable assay for the selection of participants for the Stage 2 study was not available. Therefore, on 6 January 2014, Celgene decided to not open Stage 2.

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Royal Adelaide Hospital
  • Herston, Australia, 4029
    • Royal Brisbaine and Womens Hospital
  • Woolloongabba, Australia, 4102
    • Princess Alexandra Hospital
• Austria
  • Innsbruck, Austria, A6020
    • Innsbruck University Hospital
  • Salzburg, Austria, A-5020
    • Universitätsklinikum Salzburg
  • Vienna, Austria, A-1090
    • Medical University of Vienna
• Czechia
  • Hradec Kralove 5, Czechia, 5005
    • University hospital Hradec Králové
  • Praha, Czechia, 12808
    • Charles University
• France
  • Brest Cedex 2, France, 29609
    • ICH CHU Brest- C.H.U. MORAVAN
  • Grenoble, France, 38043
    • CHU de Grenoble-Hopital Albert Michallon
  • La Roche Sur Yon, France, 85205
    • Chd -Vendee
  • Lyon, France, 69495
    • Centre Hospitalier Lyon Sud
  • Marsielle, France, 13009
    • Institute Paoli-Calmette
  • Nantes Cedex 1, France, 44903
    • Hotel Dieu
  • Perpignan, France, 66046
    • Hopital Saint Jean
  • Pessac, France, 33604
    • CHRU-Hopital du Haut -Leveque
  • Rennes, France, 35033
    • CHU de Rennes Hopital de Pontchaillou
  • Toulouse, France, 31059
    • University Hospital OF Toulouse Purpan
  • Vandoeuvre-les Nancy cedex, France, 54511
    • Hôpital de Brabois Adultes
• Italy
  • Bologna, Italy, 40138
    • Istituto di Ematologica Istituto di Ematologica " L.e. A. Seragnoli' Azienda Ospedaliera Universitaria Policlinico
  • Firenze, Italy, 50141
    • Azienda Ospedaliera Universitaria Careggi
  • Genova, Italy, 16132
    • Clinica Ematologica, A.O.U. San Martino di Genova
  • Miano, Italy, 201401
    • IEO Istituto Europeo di Oncologia
  • Napoli, Italy, 80131
    • Universita Federico II di Napoli Nuovo Policlinico
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Rionero In Vulture (PZ), Italy, 85208
    • Irccs/Crob
  • Roma, Italy, 00133
    • Policlinico Tor Vergata (Universta Tor Vergata)
  • Terni, Italy, 6156
    • Azienda Ospedaliera di Perugai Ospedale S. Maria della Miseri
• Spain
  • Barcelona, Spain, 8035
    • Hospital Universitari Vll D' Hebron
  • Cordoba, Spain, 14004
    • Hospital Universitario Reina Sofía
  • Marbella, Spain, 29600
    • Hospital Costa del Sol
  • Ourense, Spain, 32005
    • CH de Orense
  • Pamplona, Spain, 31008
    • Complejo Hospitalario de Navarra
  • Salamanca, Spain, 37007
    • Hosptial Clinico Universitario de Salamanca
• Sweden
  • Umea, Sweden, 90185
    • Onkologiska Kliniken
  • Uppsala, Sweden, 75185
    • Akademiska sjukhuset
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth Hospital Haematology
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter Hospital Haematology Department
  • Leeds, United Kingdom, LS9 7TF
    • St. James Institute of Oncology
  • London, United Kingdom, SW3 6U
    • Royal Mardsen Hospital - Fulham (Satellite Site)
  • Manchester, United Kingdom, M20 4BX
    • The Christie Foundation Trust, I'st Floor, Haemotology Oncology Outpatients, Lymphoma Team
  • Plymouth, United Kingdom, PL6 8DH
    • Derrford Hospital
  • Southhampton, United Kingdom, SO16 6YD
    • Southhampton University Hospital NHS Trust
  • Sutton, United Kingdom, SM2 SPT
    • Royal Mardsen NHS Foundation Trust
• United States
  • California
    • Burbank, California, United States, 91505
      • Providence St Joseph Medical Center/Cancer Center
  • Florida
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center Orlando
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • Center for Cancer and Blood Disorders
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan, Comprehensive Cancer Center
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39402
      • Hattiesburg Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Siteman Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically proven Diffuse Large B-Cell Lymphoma (DLBCL).
• Relapsed or refractory to combination chemotherapy for DLBCL that contains rituximab and an anthracycline, and one additional combination chemotherapy or stem cell transplant.
• Measurable DLBCL disease by computed tomograph (CT) / magnetic resonance imagining (MRI).
• Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2.

Exclusion Criteria:

• Diagnosis of lymphoma histologies other than DLBCL.
• History of malignancies, other than DLBCL, unless the patient has been disease free for 3 years or more.
• Eligible for autologous stem cell transplant.
• Known seropositive for, or history of, active human immunodeficiency virus (HIV) hepatitis B virus (HBV), hepatitis C virus (HCV)
• Neuropathy grade 4.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Lenalidomide; Lenalidomide 25 mg capsules by mouth on days 1-21 of each 28 day cycle. For patients with Creatinine Clearance ≥ 30 mL/min but < 60 mL/min, lenalidomide 10 mg (max escalation is 15 mg).	Drug: Lenalidomide; Lenalidomide 25 mg orally for 21/28 days until Diffuse Large B-Cell Lymphoma (DLBCL) progressive disease. For patients with Creatinine Clearance ≥ 30 mL/min but < 60 mL/min, lenalidomide 10 mg (max escalation is 15 mg).
ACTIVE_COMPARATOR: Investigators Choice; One of the following: Gemcitabine, Oxaliplatin, Rituximab, or Etoposide	Drug: Gemcitabine; Suggested starting doses and regimens for Gemcitabine is 1,250 mg/m^2 intravenous (IV) administration on days 1, 8, 15 every 28 days for 6 Cycles or 1,000 mg/m^2 IV days 1 and 15 every 28 days for 6 Cycles; Drug: Oxaliplatin; Suggested starting dose and regimen for Oxaliplatin is 100 mg/m^2 IV day 1 for 21 days for 6 Cycles; Drug: Rituximab; Suggested starting dose for Rituximab is 375 mg/m^2 IV days 1, 8, 15, 22 during Cycle 1, and if stable disease at Week 12, also on Day 1 of Cycles 4, 6, 8, and 10 (CD20+ patients only); Drug: Etoposide; Suggested starting doses for Etoposide are: 100 mg/m^2 IV days 1-5 every 28 days for 6 Cycles, or 100 mg/m^2 IV days 1-3 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-21 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-14 every 28 days for 6 Cycles, or 50 mg/m^2 oral days 1-10 every 28 days for 6 Cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Percentage of Participants With an Overall Response According to the International Working Group (IWG) Response Criteria for Non Hodgkin's Lymphoma (NHL), Cheson 1999 and Evaluated by the Independent Response Adjudication Committee (IRAC)	An overall response is a complete response (CR), unconfirmed complete response (CRu) or partial response (PR) and was evaluated by the IRAC. A CR = complete disappearance of disease and related symptoms. Lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on exam, normal size by imaging, and absence of nodules related to lymphoma. If bone marrow was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or for single nodules, in the greatest transverse diameter;no new disease.	From the date of randomization to the data cut-off of 4 July 2013; when all patients reached the scheduled 16-week assessment or had progressed/died before the scheduled 16-week assessment); the median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Percentage of Participants With an Overall Response According to the IWG Response Criteria Based on the Investigators Assessment at the Final Data Cut During the Core Treatment Phase	Response was defined as having a CR, CRu or PR, based on IWG 1999 Response Criteria for NHL as evaluated by the investigators. CR = complete disappearance of disease and disease related symptoms. All lymph nodes and nodal masses regressed on computed tomography to normal size (≤ 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm prior to therapy and ≤ 1.0 cm in their short axis for nodes 1.1-1.5 cm in their long axis and > 1.0 cm in their short axis prior to therapy). Spleen and/or liver not palpable on physical exam, normal size by imaging, and absence of nodules related to lymphoma. If BM was involved prior to therapy, infiltrate must have cleared on repeat biopsy. PR = ≥ 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses. No increase in the other nodes, liver, or spleen. Splenic and hepatic nodules regressed by ≥ 50% in their SPD or, for single nodules, in the greatest transverse diameter. No new disease.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Events (TEAEs) in the Overall Treatment Phase by Initial Treatment Assignment	A TEAE was defined as an AE that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: Death;; Life-threatening event;; Any inpatient hospitalization or prolongation of existing hospitalization;; Persistent or significant disability or incapacity;; Congenital anomaly or birth defect;; Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event.The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.03) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death	From first dose of study drug to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 2: Overall Response Rate (ORR)	ORR is defined as: Complete Response + Complete Response unconfirmed + Partial Response based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999).	Approximately 3.5 years
Stage 2: Duration of Response (DoR)	Length of time of overall response (Complete Response + Complete Response unconfirmed + Partial Response) based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999).	Approximately 3.5 years
Stage 2: Overall Survival (OS)	Overall survival was defined as time from randomization until death of any cause.	Approximately 3.5 years
Stage 2: Duration of Complete Response	Length of time of complete response (Complete Response + Complete Response unconfirmed) based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999).	Approximately 3.5 years
Stage 2: Overall Response Rate for With a Duration of Response Lasting ≥ 16 Weeks	Complete Response + Complete Response unconfirmed + Partial Response for participants with a duration of response lasting ≥ 16 weeks based on the International Lymphoma Workshop Response Criteria [IWRC] (Cheson 1999).	Approximately 3.5 years
Stage 2: Time to Progression	Length of time until disease progression occurs	Approximately 3.5 years
Stage 2: Health Related Quality of Life Questionnaires	Quality of Life based on the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EQ-5D assessments	Approximately 3.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stage 1: Percentage of Participants With a Durable Overall Response (dORR) According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase	Durable overall response rate was defined as the percentage of participants who maintained a response for at least 16 weeks after initial response.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Percentage of Participants With a Complete Response According to the IWG Response Criteria as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase	A complete response was defined as participants with a complete response (CR), or unconfirmed complete response (CRu) based on IWG 1999 Response Criteria for NHL as assessed by the investigator. A CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow must be negative if positive at baseline. Normalization of markers. CR Unconfirmed (CRu) does not qualify for CR above, due to a residual nodal mass or an indeterminate BM.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Kaplan Meier Estimates of Duration of Overall Response (DoR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase	Duration of overall response was calculated as the time of initial response (CR+CRu+PR) until documented disease progression determinted by computerized scan CT scan or MRI or death due to lymphoma, whichever occurred earlier, for participants who responded.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Kaplan Meier Estimates of Duration of Complete Response (DoCR) as Assessed by the Investigators at the Final Data Cut During the Core Treatment Phase	Duration of complete response was defined as the time from the first documented complete response (CR + CRu) until the first disease progression or death for participants who had a CR.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Kaplan Meier Estimates of Progression-Free Survival As Assessed By The Investigators At The Final Data Cut During The Core Treatment Phase	Progression-free survival was defined as the time from randomization to the first documented disease progression or death due to any cause.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 1: Kaplan Meier Estimates of Overall Survival As Assessed by the Investigators at the Final Data Cut During The Core Treatment Phase	Overall survival was defined as time from randomization until death of any cause.	From the date of randomization to the final data cut-off date of 18 May 2018; median study duration was 27.0 and 19.7 weeks, respectively.
Stage 2: Progression-Free Survival	Number of participants who survive without progressing based on the International Working Group Response Criteria [IWG].	Approximately 3.5 years

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Adrian Kilcoyne, MD, Celgene Corporation

Publications and helpful links

General Publications

• Czuczman MS, Trneny M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A Phase 2/3 Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Lenalidomide Versus Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. doi: 10.1158/1078-0432.CCR-16-2818. Epub 2017 Apr 5.
• Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, Goy A, Witzig TE, Czuczman MS. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer. 2011 Nov 15;117(22):5058-66. doi: 10.1002/cncr.26135. Epub 2011 Apr 14.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 2, 2010
• Primary Completion (ACTUAL): July 4, 2013
• Study Completion (ACTUAL): April 5, 2018

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: September 8, 2010
• First Posted (ESTIMATE): September 9, 2010

Study Record Updates

• Last Update Posted (ACTUAL): November 25, 2019
• Last Update Submitted That Met QC Criteria: November 13, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: DLBCL; relapsed; refractory; Diffuse Large B Cell Lymphoma; Diffuse Large B-Cell Lymphoma; Non Hodgkin's Lymphoma; relapsed/refractory
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Gemcitabine; Etoposide; Lenalidomide; Oxaliplatin; Rituximab
• Other Study ID Numbers: CC-5013-DLC-001