A Phase 3 Open Label Randomized Study to Compare the Efficacy and Safety of Rituximab Plus Lenalidomide (CC-5013) Versus Rituximab Plus Chemotherapy Followed by Rituximab in Subjects With Previously Untreated Follicular Lymphoma (RELEVANCE)

A PHASE 3 OPEN-LABEL RANDOMIZED STUDY TO COMPARE THE EFFICACY AND SAFETY OF RITUXIMAB PLUS LENALIDOMIDE (CC-5013) VERSUS RITUXIMAB PLUS CHEMOTHERAPY FOLLOWED BY RITUXIMAB IN SUBJECTS WITH PREVIOUSLY UNTREATED FOLLICULAR LYMPHOMA The "RELEVANCE" Trial (Rituximab Lenalidomide Versus ANy ChEmotherapy)is Being Conducted as Two Companion Studies: RV-FOL-GELARC-0683 (N=750) and RV-FOL-GELARC-0683C (N=250); the Combined Total of 1000 Patients Enrolled in Both Studies Will be Analyzed.

The purpose of this study is to find out if lenalidomide when given along with rituximab can help to control the disease and also increase the length of your response (complete or partial response) compared to the standard of care rituximab chemotherapy treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Follicular Lymphoma
• Intervention / Treatment: Drug: Rituximab; Drug: Lenalidomide; Drug: Rituximab - CHOP; Drug: Rituximab - CVP; Drug: Rituximab - Bendamustine

Detailed Description

Follicular Lymphoma (FL) is a cancer of a B lymphocyte, a type of white blood cell. FL is typically a slowly progressing but incurable disease. Follicular lymphoma cells produce a specific defect in the patient's immune system impairing their ability to control their cancer. Lenalidomide has been shown to reverse the specific immune defect caused by FL in the patient. By including lenalidomide, the RELEVANCE study aims to eliminate the cancer while restoring the patient's immune competence.

• Study Type: Interventional
• Enrollment (Actual): 1030
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Concord, New South Wales, Australia
      • Concord Repatriation General Hospital
    • Penrith, New South Wales, Australia
      • Nepean Hospital
    • Wollongong, New South Wales, Australia
      • Wollongong Hospital
• Belgium
  • Yvoir, Belgium
    • CHU Mont-Godinne
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada
      • Cross Cancer Institute
  • British Columbia
    • Surrey, British Columbia, Canada
      • Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada
      • BCCA - Vancouver Cancer Centre
  • New Brunswick
    • Moncton, New Brunswick, Canada
      • Moncton Hospital
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Atlantic Health Sciences Corp - Saint John Regional Hospital
  • Ontario
    • Toronto, Ontario, Canada
      • Sunnybrook Health Sciences Centre
    • Toronto, Ontario, Canada
      • UHN-Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada
      • CHUM Hopital Notre-Dame
    • Montreal, Quebec, Canada
      • McGill University Department of Oncology
    • Quebec city, Quebec, Canada
      • Hôpital de l'Enfant-Jesus, CHU de Quebec
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada
      • Saskatoon Cancer Centre
• France
  • Lille, France
    • CHU Claude Huriez
• Germany
  • Munchen, Germany
    • LMU Munchën - Klinikum Grosshadern
  • Baden Wurtemberg
    • Tübingen, Baden Wurtemberg, Germany
      • Medizinische Klinik der Universität Tübingen
  • Nordrhein
    • Köln, Nordrhein, Germany
      • Uniklinik Koln
• Italy
  • Bologna, Italy
    • Policlinico Sant'Orsola-Malpighi
  • Lazio
    • Roma, Lazio, Italy
      • Sant'Andrea Hospital
• Portugal
  • Lisboa, Portugal
    • Instituto Português Oncologia
• Spain
  • Barcelona, Spain
    • Hospital de La Santa Creu i Sant Pau
  • Barcelona, Spain
    • Hospital Universitario Vall d´Hebrón
  • Barcelona, Spain
    • Hospital Clínico de Barcelona
  • Girona, Spain
    • Institut Català d'Oncologia de Girona (ICO Girona)
  • Madrid, Spain
    • Hospital Ramon y Cajal
  • Marbella, Spain
    • Hospital Costa del Sol
  • Salamanca, Spain
    • Hospital Universitario Salamanca
  • Valencia, Spain
    • Hospital Clínico Universitario de Valencia
  • Andaloucia
    • Sevilla, Andaloucia, Spain
      • Hospital Virgen del Rocío
  • Barcelona
    • Terrassa, Barcelona, Spain
      • Hospital Universitario Mutua de Terrassa
  • Canarias
    • Santa Cruz de Tenerife, Canarias, Spain
      • Hospital Universitario de Canarias
  • Mallorca
    • Palma, Mallorca, Spain
      • Hospital Son Llatzer

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically confirmed CD20+ follicular lymphoma grade 1, 2 or 3a
• Have no prior systemic treatment for lymphoma.
• Must be in need of treatment
• Bi-dimensionally measurable disease with at least one mass lesion > 2 cm that was not previously irradiated.
• Stage II, III or IV disease.
• Must be ≥ 18 years and sign an informed consent.
• Performance status ≤ 2 on the ECOG scale.
• Adequate hematological function (unless abnormalities are related to lymphoma infiltration of the bone marrow)
• Willing to follow pregnancy precautions

Exclusion Criteria:

• Clinical evidence of transformed lymphoma by investigator assessment or Grade 3b follicular lymphoma.
• Patients taking corticosteroids during the last 4 weeks, unless administered at a dose equivalent to < 10 mg/day prednisone (over these 4 weeks).
• Major surgery (excluding lymph node biopsy) within 28 days prior to signing informed consent.
• Known Seropositive for or active viral infection with hepatitis B virus (HBV), hepatitis C virus (HCV)or human immunodeficiency virus (HIV).
• Life expectancy < 6 months.
• Known sensitivity or allergy to murine products.
• Prior history of malignancies, other than follicular lymphoma, unless the patient has been free of the disease for ≥ 10 years.
• Prior use of lenalidomide.
• Neuropathy > Grade 1.
• Presence or history of CNS involvement by lymphoma.
• Patients who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis.
• serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) > 3x upper limit of normal (ULN), except in patients with documented liver or pancreatic involvement by lymphoma
• total bilirubin > 2.0 mg/dl (34 µmol/L) except in cases of Gilberts Syndrome and documented liver involvement by lymphoma
• creatinine clearance of < 30 mL/min
• Pregnant or lactating females.
• Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lenalidomide + Rituximab; Lenalidomide dose 20-mg on days 2-22 every 28 days x 6 cycles, if CR then 10-mg on days 2-22 every 28 days for 12 cycles. PR after 6 cycles, continue 20 mg for 3~6 cycles and then 10 mg on days 2-22 every 28-day cycles for upto 18 cycles; Rituximab, 375 mg/m2 on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.	Drug: Rituximab; • Rituximab, 375 mg/m2 on days 1, 8, 15 and 22 of cycle 1, day 1 of cycles 2 to 6; 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.; Other Names: rituxan; mabthera; Drug: Lenalidomide; • Lenalidomide dose 20-mg on days 2-22 every 28 days x 6 cycles, if CR then 10-mg on days 2-22 every 28 days for 12 cycles. PR after 6 cycles, continue 20 mg for 3~6 cycles and then 10 mg on days 2-22 every 28-day cycles for upto 18 cycles; Other Names: Revlimid
Active Comparator: Control; • ONE of the following: Rituximab - CHOP, Rituximab - CVP, Rituximab - Bendamustine. 7 to 8 weeks later responding patients will continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.	Drug: Rituximab - CHOP; six cycles of R-CHOP in 21 day cycles followed by two 21 day cycles of 375 mg/m2 rituximab; and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles; Drug: Rituximab - CVP; eight cycles of R-CVP in 21 day cycles; and 7 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles,; Drug: Rituximab - Bendamustine; six cycles of R-B in 28 day cycles and 8 weeks later responding patients continue with 375 mg/m2 rituximab every 8 weeks for 12 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
COMPLETE RESPONSE RATE	Complete response (CR/CRu) rate at 120 weeks Response evaluation was as defined by International Working Group (IWG) Response Criteria (Cheson 1999). Complete response (CR) is defined as the complete disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms if present before therapy.	Timeframe: CR/CRu rate at 120 weeks
Progression Free Survival (PFS)	PFS is defined as the time from the start of study drug therapy to the 1st observation of disease progression or death due to any cause.	up to 13 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Number of participants with adverse events	up to13 years
Time to Treatment Failure (TTF)	up to13 years
Event Free Survival (EFS)	up to13 years
Time to Next Anti-Lymphoma Treatment (TTNLT),	up to13 years
Time to Next Chemotherapy Treatment (TTNCT)	up to13 years
Overall Survival (OS)	up to13 years
Overall response rate at 120 weeks by International Working Group (IWG) 1999 criteria	up to13 years
Health related quality of life as measured by the EORTC QLQ-C30	up to13 years

Collaborators and Investigators

• Sponsor: The Lymphoma Academic Research Organisation
• Collaborators: Celgene Corporation
• Investigators: Study Chair: Franck Morschhauser, MD, PhD, The Lymphoma Study Association (LYSA)

Publications and helpful links

General Publications

• Morschhauser F, Nastoupil L, Feugier P, Schiano de Colella JM, Tilly H, Palomba ML, Bachy E, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Le Gouill S, Daguindau N, Guidez S, Pica GM, Garcia-Sancho AM, Lopez-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, Andre M, Kalung W, Sehn LH, Izutsu K, Cartron G, Gkasiamis A, Crowe R, Xerri L, Fowler NH, Salles G. Six-Year Results From RELEVANCE: Lenalidomide Plus Rituximab (R2) Versus Rituximab-Chemotherapy Followed by Rituximab Maintenance in Untreated Advanced Follicular Lymphoma. J Clin Oncol. 2022 Oct 1;40(28):3239-3245. doi: 10.1200/JCO.22.00843. Epub 2022 Aug 10.
• Delfau-Larue MH, Boulland ML, Beldi-Ferchiou A, Feugier P, Maisonneuve H, Casasnovas RO, Lemonnier F, Pica GM, Houot R, Ysebaert L, Tilly H, Eisenmann JC, Le Gouill S, Ribrag V, Godmer P, Glaisner S, Cartron G, Xerri L, Salles GA, Fest T, Morschhauser F. Lenalidomide/rituximab induces high molecular response in untreated follicular lymphoma: LYSA ancillary RELEVANCE study. Blood Adv. 2020 Aug 11;4(14):3217-3223. doi: 10.1182/bloodadvances.2020001955.
• Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, Fruchart C, Libby EN, Casasnovas RO, Flinn IW, Haioun C, Maisonneuve H, Ysebaert L, Bartlett NL, Bouabdallah K, Brice P, Ribrag V, Daguindau N, Le Gouill S, Pica GM, Martin Garcia-Sancho A, Lopez-Guillermo A, Larouche JF, Ando K, Gomes da Silva M, Andre M, Zachee P, Sehn LH, Tobinai K, Cartron G, Liu D, Wang J, Xerri L, Salles GA; RELEVANCE Trial Investigators. Rituximab plus Lenalidomide in Advanced Untreated Follicular Lymphoma. N Engl J Med. 2018 Sep 6;379(10):934-947. doi: 10.1056/NEJMoa1805104.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2012
• Primary Completion (Actual): May 31, 2017
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: July 24, 2012
• First Submitted That Met QC Criteria: July 24, 2012
• First Posted (Estimated): July 26, 2012

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: follicular lymphoma; rituximab treatment; rituximab and lenalidomide treatment; non-hodgkins follicular lymphoma; treatment for follicular lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, Follicular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: RV-FOL-GELARC-0683; 2011-002792-42 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No