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

Diffuse Large B-cell Lymphoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01197560
• Other study ID #: CC-5013-DLC-001
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: September 2, 2010
• Est. completion date: April 5, 2018

Study information

• Verified date: November 2019
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 111
• Est. completion date: April 5, 2018
• Est. primary completion date: July 4, 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

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).
• 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
• Oxaliplatin
Suggested starting dose and regimen for Oxaliplatin is 100 mg/m^2 IV day 1 for 21 days for 6 Cycles
• 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)
• 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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide
Australia	Royal Brisbaine and Womens Hospital	Herston
Australia	Princess Alexandra Hospital	Woolloongabba
Austria	Innsbruck University Hospital	Innsbruck
Austria	Universitätsklinikum Salzburg	Salzburg
Austria	Medical University of Vienna	Vienna
Czechia	University Hospital Hradec Kralove	Hradec Kralove 5
Czechia	Charles University	Praha
France	ICH CHU Brest- C.H.U. MORAVAN	Brest Cedex 2
France	CHU de Grenoble-Hopital Albert Michallon	Grenoble
France	Chd -Vendee	La Roche Sur Yon
France	Centre Hospitalier Lyon Sud	Lyon
France	Institute Paoli-Calmette	Marsielle
France	Hotel Dieu	Nantes Cedex 1
France	Hôpital Saint Jean	Perpignan
France	CHRU-Hopital du Haut -Leveque	Pessac
France	CHU de Rennes Hopital de Pontchaillou	Rennes
France	University Hospital OF Toulouse Purpan	Toulouse
France	Hopital de Brabois Adultes	Vandoeuvre-les Nancy cedex
Italy	Istituto di Ematologica Istituto di Ematologica " L.e. A. Seragnoli' Azienda Ospedaliera Universitaria Policlinico	Bologna
Italy	Azienda Ospedaliera Universitaria Careggi	Firenze
Italy	Clinica Ematologica, A.O.U. San Martino di Genova	Genova
Italy	IEO istituto Europeo di Oncologia	Miano
Italy	Universita Federico II di Napoli Nuovo Policlinico	Napoli
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Italy	Irccs/Crob	Rionero In Vulture (PZ)
Italy	Policlinico Tor Vergata (Universta Tor Vergata)	Roma
Italy	Azienda Ospedaliera di Perugai Ospedale S. Maria della Miseri	Terni
Spain	Hospital Universitari Vll D' Hebron	Barcelona
Spain	Hospital Universitario Reina Sofia	Cordoba
Spain	Hospital Costa Del Sol	Marbella
Spain	CH de Orense	Ourense
Spain	Complejo Hospitalario de Navarra	Pamplona
Spain	Hosptial Clinico Universitario de Salamanca	Salamanca
Sweden	Onkologiska kliniken	Umea
Sweden	Akademiska Sjukhuset	Uppsala
United Kingdom	Royal Bournemouth Hospital Haematology	Bournemouth
United Kingdom	Royal Devon and Exeter Hospital Haematology Department	Exeter
United Kingdom	St. James Institute of Oncology	Leeds
United Kingdom	Royal Mardsen Hospital - Fulham (Satellite Site)	London
United Kingdom	The Christie Foundation Trust, I'st Floor, Haemotology Oncology Outpatients, Lymphoma Team	Manchester
United Kingdom	Derrford Hospital	Plymouth
United Kingdom	Southhampton University Hospital NHS Trust	Southhampton
United Kingdom	Royal Mardsen NHS Foundation Trust	Sutton
United States	University of Michigan, Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Center for Cancer and Blood Disorders	Bethesda	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Providence St Joseph Medical Center/Cancer Center	Burbank	California
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Hattiesburg Clinic	Hattiesburg	Mississippi
United States	MD Anderson Houston	Houston	Texas
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	MD Anderson Cancer Center Orlando	Orlando	Florida
United States	Washington University Siteman Cancer Center	Saint Louis	Missouri
United States	Avera Cancer Institute	Sioux Falls	South Dakota

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Czechia,  France,  Italy,  Spain,  Sweden,  United Kingdom, 

References & Publications (1)

Czuczman MS, Trnený 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, Hagn — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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.
Other	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
Primary	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.
Primary	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	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.
Secondary	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
Secondary	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
Secondary	Stage 2: Overall Survival (OS)	Overall survival was defined as time from randomization until death of any cause.	Approximately 3.5 years
Secondary	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
Secondary	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
Secondary	Stage 2: Time to Progression	Length of time until disease progression occurs	Approximately 3.5 years
Secondary	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